* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Chemistry - An Asian Journal, 2016, vol. 11, # 23, p. 3355 - 3358
3
[ 6638-79-5 ]
[ 79-04-9 ]
[ 67442-07-3 ]
Yield
Reaction Conditions
Operation in experiment
92%
With potassium carbonate In tert-butyl methyl ether; water at -5 - 20℃; for 3.5 h;
Example 139 N-methoxy-N-methylchloroacetamide A solution of N,O-dimethylhydroxylamine hydrochloride (200 g, 2.05 mol) and tert-butyl methyl ether (2 L) was added to a cooled (0°C) solution of potassium carbonate (624 g, 4.1 mol) in water (2 L). The mixture was cooled to -5°C and chloroacetyl chloride added such that the temperature remained below 5°C. The vigorously stirred mixture was allowed to warm to room temperature and stirred for an additional 3.5 hours. The phases were separated and the aqueous phase was extracted with tert-butyl methyl ether (3 x 1 L). The combined organic phase was washed with saturated aqueous sodium chloride solution (2 x 1 L), dried (MgSO4), and concentrated. The residue was dried in vacuo to yield a white solid (257 g, 92percent). Mp 39-40.5°C; 1H NMR (CDCl3, 300 MHz) δ 4.24 (s, 2 H), 3.74 (s, 3 H), 3.22 (s, 3 H); MS (CI) 138 (MH+); Anal. calcd for C4H8ClNO2: C, 34.92; H, 5.86; N, 10.18. Found: C, 35.06; H, 5.88; N, 10.23.
92%
With potassium carbonate In tert-butyl methyl ether; water
EXAMPLE 139 STR92 N-methoxy-N-methylchloroacetamide A solution of N,O-dimethylhydroxylamine hydrochloride (200 g, 2.05 mol) and tert-butyl methyl ether (2 L) was added to a cooled (0° C.) solution of potassium carbonate (624 g, 4.1 mol) in water (2 L). The mixture was cooled to -5° C. and chloroacetyl chloride added such that the temperature remained below 5° C. The vigorously stirred mixture was allowed to warm to room temperature and stirred for an additional 3.5 hours. The phases were separated and the aqueous phase was extracted with tert-butyl methyl ether (3*1 L). The combined organic phase was washed with saturated aqueous sodium chloride solution (2*1 L), dried (MgSO4), and concentrated. The residue was dried in vacuo to yield a white solid (257 g, 92percent). Mp 39-40.5° C.; 1 H NMR (CDCl3, 300 MHz) δ 4.24 (s, 2 H), 3.74 (s, 3 H), 3.22 (s, 3 H); MS (CI) 138 (MH+); Anal. calcd for C4 H8 ClNO2: C, 34.92; H, 5.86; N, 10.18. Found: C, 35.06; H, 5.88; N, 10.23.
90%
With potassium carbonate In tert-butyl methyl ether; water at -5 - 0℃; for 2 h;
A 3 L four necked flask equipped with Teflon-blade stirrer, reflux condenser and thermo-pocket was charged with N-methoxymethanamine hydrochloride (345g), water (1 .6 litre) and the resulting reaction mixture was cooled to 0 to -5 °C. Then potassium carbonate (1466 g) was added in lots to the above reaction mixture followed by the addition of methyl tert-butyl ether (1 .4 litre). The chloroacetyl chloride (400 g) was dissolved in tert-butyl methyl ether (0.2 litre) and added dropwise in to the above kept reaction mixture at - 5°C to 0°C and the reaction mixture was stirred for 2 h at 0°C. The reaction mixture was allowed to come to ambient temperature and two phases were separated. The organic layer was dried over sodium sulfate, filtered and evaporated to provide 2-chloro-N-methoxy-N-methyl-acetamide as white solid (440 g, 90percent yield and 98.0percent area purity by HPLC).
Reference：
[1] Journal of the American Chemical Society, [2] Journal of the American Chemical Society, 2009, vol. 131, p. 1077 - 1091
[3] European Journal of Organic Chemistry, 2017, vol. 2017, # 27, p. 3917 - 3920
[4] RSC Advances, 2013, vol. 3, # 26, p. 10158 - 10162
[5] Patent: EP1054881, 2008, B1, . Location in patent: Page/Page column 57
[6] Patent: US6051586, 2000, A,
[7] Patent: WO2018/177970, 2018, A1, . Location in patent: Page/Page column 70; 73
[8] Journal of the American Chemical Society, 2010, vol. 132, # 49, p. 17511 - 17515
[9] Journal of the American Chemical Society, 1990, vol. 112, # 19, p. 7001 - 7031
[10] Tetrahedron Letters, 1989, vol. 30, # 29, p. 3779 - 3780
[11] Journal of the American Chemical Society, 2008, vol. 130, # 10, p. 2916 - 2917
[12] Journal of Molecular Structure, 2010, vol. 977, # 1-3, p. 106 - 116
[13] Journal of Organic Chemistry, 2014, vol. 79, # 18, p. 8917 - 8925
[14] Dalton Transactions, 2015, vol. 44, # 45, p. 19464 - 19468
[15] Patent: US2016/83391, 2016, A1, . Location in patent: Paragraph 0595
[16] Angewandte Chemie - International Edition, 2017, vol. 56, # 38, p. 11594 - 11598[17] Angew. Chem., 2017, vol. 129, # 38, p. 11752 - 11756,5
4
[ 1634-04-4 ]
[ 6638-79-5 ]
[ 79-04-9 ]
[ 67442-07-3 ]
Yield
Reaction Conditions
Operation in experiment
95%
With potassium carbonate In water
EXAMPLE 7 Preparation of N-methoxy-N-methylchloroacetamide (3b). To a cold (0°C), stirred solution of K2CO3 (62.4 g, 450 mmol) in H2O (250 mL) was added, successively, N,O-dimethylhydroxylamine hydrochloride (20 g, 205 mmol) and organic solvent (250 mL, toluene or MTBE). The resulting two phase mixture was cooled to -5°C and chloroacetyl chloride (19.6 ml, 246 mmol) was added over 5 min (solution temperature maintained below 0°C). The vigorously stirred mixture was allowed to warm to 15°C over 30 min, the layers were separated, and the aqueous layer was extracted with organic solvent (3x100 mL, toluene or MTBE). The combined organic extracts were concentrated (MTBE used as solvent) to give the amide 3b (26.8 g, 95percent) as a white solid. Alternatively, the combined organic extracts (toluene used as solvent) were concentrated to 250 mL to effect azeotropic drying (water content 100μg/mL) and the solution of 3b was used directly in reactions with organometallic reagents.
N-Methoxy-N-methyl-acetamide (105). Pyridine (10 mL, 124 mmol) was slowly added to a well stirred slurry of O,N-dimethylhydroxylamine hydrochloride (6 g, 62 mmol) and acetyl chloride (4.15 mL, 59 mmol) in CH2Cl2(85 mL) under argon at O°C. The mixture was warmed to room temperature, stirred for 3 hours and then partitioned between brine (55 mL) and diethyl ether (85 mL). Extraction with additional diethyl ether, drying of the combined organic layers over anhydrous Na2SO4, concentration, followed by distillation under reduce pressure gave Weinreb amide 105(4.54 g, 72 percent) as a colourless liquid. bp 42-44°C / 20 mmHg; IR (neat) 3497, 2971, 2941, 2824, 1663 cm-1; 1H NMR (CDCl3, 300 MHz) δ 3.62 (s, 3H), 3.11 (s, 3H), 2.05 (s, 3H); 13C NMR (CDCl3, 75.4 MHz) δ 171.8 (C), 61.0 (CH3), 31.9 (CH3), 19.6 (CH3). Spectral properties identical to samples already described in literature.
65%
With triethylamine In dichloromethane at 0 - 20℃; for 0.5 h; Cooling with ice
N,O-dimethyl-hydroxylamine HCl (100 g, 1025 mmol) was suspended under nitrogen in DCM (1000 mL) and cooled in ice. Triethylamine (300 mL, 2152 mmol) was added slowly, then acetyl chloride (76.5 mL, 1076 mmol) was added slowly, the temperature reached 20° despite ice cooling and slow addition. Stirring without cooling was continued for 30 min. Extraction: 1.x.DCM, 1.x.1N HCl, 2.x. saturated NaCl solution. Distillation at 42° C./20 mbar gave 69 g (65percent) of a colorless oil.
65%
With triethylamine In dichloromethane at 0 - 20℃; for 0.5 h;
N, O-dimethyl-hydroxylamine HC1 (100 g, 1025 mmol) was suspended under nitrogen in DCM (1000 mL) and cooled in ice. Triethylamine (300 mL, 2152 mmol) was added slowly, then acetyl chloride (76.5 mL, 1076 mmol) was added slowly, the temperature reached 20° despite ice cooling and slow addition. Stirring without cooling was continued for 30 min. Extraction: 1 x DCM, 1 x 1 N HC1, 2 x saturated NaCl solution. Distillation at 42 °C/20 mbar gave 69 g (65 percent) of a colorless oil.
61%
With triethylamine In dichloromethane at 0 - 20℃; for 4 h;
Compound 25-1 (0442) To a suspension of N,O-dimethylhydroamine hydrochloride (100 g, 1026 mmol) in DCM (1000 mL) was added triethylamine (300 mL, 2052 mmol) at 0° C. Acetyl chloride was added dropwise to the suspension for 2 h at 0° C. When the addition was complete, the mixture was allowed to warm to rt and stirred for 2 h. The mixture was washed with brine (1 L), 1 N HCl (500 mL), brine (200 mL) respectively and dried with magnesium sulfate, filtered and concentrated to afford brown oil, which was purified by distillation to afford 25-1 as a colourless liquid (65 g, 61percent).
56%
Stage #1: With triethylamine In dichloromethane for 0.333333 h; Inert atmosphere Stage #2: at 20℃; for 1 h;
To a stirred solution of N, O-dimethylhydroxylamine hydrochloride 3 (25 g, 256.4 mmol) in CH2C12 (400 mL) under inert atmosphere was added TEA (51.8 g, 512.8 mmol), and the reaction mixture was stirred for 20 mi Acetyl chloride (22.5 g, 282.0 mmol) was added to the reaction mixture at RT, and the reaction mixture stirred for 1 h. The reaction progress was monitored by TLC; after reaction completion, the reaction mixture quenched with saturated NaHCO3 solution (250 mL) and extracted with CH2C12 (2 x 250 mL). The combined organic extracts were washed with 1 N HC1 solution (100 mL), water (100 mL), brine solution (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude material. The crude material was distilled at 50°C to get 4(11.5 g, 56percent) as colorless liquid. 1HNMR (500 MHz, CDC13): ö 3.68 (s, 3H), 3.17 (s, 3H), 2.11 (s, 3H); LC-MS: 97.3percent; (M+H) Found=104.4; (column: X bridge C-18, 50 x 3.0 mm, 3.5 tm); RT 0.63 mm. 5 mM NH4OAc: ACN; 0.8 mL/min).
Reference：
[1] Organic Letters, 2012, vol. 14, # 9, p. 2250 - 2253
[2] European Journal of Organic Chemistry, 2017, vol. 2017, # 2, p. 278 - 286
[3] Patent: EP1300403, 2003, A1,
[4] Tetrahedron Letters, 1983, vol. 24, # 18, p. 1851 - 1854
[5] Tetrahedron Letters, 2007, vol. 48, # 3, p. 377 - 380
[6] Patent: US2005/197337, 2005, A1, . Location in patent: Page/Page column 10
[7] Patent: WO2005/94828, 2005, A1, . Location in patent: Page/Page column 19
[8] Patent: US9138427, 2015, B2, . Location in patent: Page/Page column 301
[9] Patent: WO2015/48301, 2015, A1, . Location in patent: Paragraph 00439
[10] Angewandte Chemie - International Edition, 2017, vol. 56, # 7, p. 1914 - 1918[11] Angew. Chem., 2017, vol. 129, p. 1941 - 1945,5
[12] Journal of Materials Chemistry C, 2014, vol. 2, # 24, p. 4879 - 4892
[13] Bulletin de la Societe Chimique de France, 1996, vol. 133, # 10, p. 1011 - 1021
[14] Synthesis, 2003, # 15, p. 2415 - 2426
[15] Collection of Czechoslovak Chemical Communications, 2004, vol. 69, # 7, p. 1472 - 1478
[16] Tetrahedron Letters, 2007, vol. 48, # 17, p. 3069 - 3072
[17] Patent: US2003/166628, 2003, A1,
[18] Synlett, 2008, # 19, p. 3036 - 3040
[19] Journal of the American Chemical Society, 2010, vol. 132, # 26, p. 8862 - 8863
[20] Patent: US2007/14733, 2007, A1, . Location in patent: Sheet 14
[21] European Journal of Organic Chemistry, 2011, # 1, p. 150 - 165
Reference：
[1] Journal of Medicinal Chemistry, 2006, vol. 49, # 22, p. 6549 - 6560
15
[ 75-24-1 ]
[ 6638-79-5 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2011, vol. 9, # 14, p. 5062 - 5078
16
[ 589-18-4 ]
[ 6638-79-5 ]
[ 122334-36-5 ]
Yield
Reaction Conditions
Operation in experiment
87%
With tert.-butylhydroperoxide; copper(II) acetate monohydrate; calcium carbonate In acetonitrile at 80℃; for 24 h;
General procedure: An oven-dried 15 mL glass vial with a magnetic stirrer bar was charged with Cu(OAc)2·H2O (12 mg, 6 molpercent), N,O-dimethylhydroxylamine hydrochloride (2; 117 mg, 1.2 mmol), the respective benzyl alcohol 1 (1 mmol), aq 70percent TBHP (0.17 mL, 1.2 mmol), CaCO3 (120 mg, 1.2 mmol) in MeCN (1 mL). The glass vial was flushed with N2 three times and the contents were stirred at r.t. for 1 h. Then the reaction mixture was stirred for 24 h at 80 °C. After completion of the reaction, the mixture was cooled to r.t. All volatiles were removed under vacuum. The product was extracted with EtOAc (20 mL) and the organic layer was washed with sat. aq NaHCO3 (20 mL), dried (Na2SO4), and the solvent removed under vacuum. The Weinreb amide product 3 was purified by column chromatography (silica gel, 100–200 mesh) using a gradient of petroleum ether (bp 60–80 °C) and EtOAc. All the amides were identified by GC-MS, 1H, and 13C NMR spectroscopic analysis.
Reference：
[1] Australian Journal of Chemistry, 2017, vol. 70, # 1, p. 44 - 51
22
[ 10347-11-2 ]
[ 6638-79-5 ]
[ 122334-36-5 ]
Reference：
[1] Journal of the American Chemical Society, 2009, vol. 131, # 43, p. 15608 - 15609
23
[ 6638-79-5 ]
[ 3282-30-2 ]
[ 64214-60-4 ]
Reference：
[1] RSC Advances, 2013, vol. 3, # 26, p. 10158 - 10162
[2] Organic Letters, 2012, vol. 14, # 9, p. 2250 - 2253
[3] Archiv der Pharmazie, 1986, vol. 319, # 11, p. 1037 - 1043
[4] Journal of Labelled Compounds and Radiopharmaceuticals, 2007, vol. 50, # 5-6, p. 513 - 514
[5] Journal of Organometallic Chemistry, 2011, vol. 696, # 23, p. 3643 - 3648
[6] Chemical Communications, 2012, vol. 48, # 71, p. 8976 - 8978
[7] European Journal of Organic Chemistry, 2018, vol. 2018, # 12, p. 1416 - 1425
24
[ 6638-79-5 ]
[ 75-98-9 ]
[ 64214-60-4 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2010, vol. 31, # 1, p. 171 - 173
[2] Synthetic Communications, 2001, vol. 31, # 13, p. 2011 - 2019
25
[ 6638-79-5 ]
[ 87694-53-9 ]
Yield
Reaction Conditions
Operation in experiment
94%
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 16 h; Inert atmosphere
To a solution of (S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid (25 g, 94.34mmol) in DMF (250 mL) were added N,O-dimethylhydroxylamine hydrochloride (13.72g,141.50 mmol), HATU (37.64 g, 99.05 mmol) and N,N-diisopropylethylamine (50.70 mL, 283.01 mmol) under nitrogen atmosphere at room temperature. The reaction mixture was stuffed at room temperature for 16 h then diluted with ethyl acetate (1000 mL) and washed with water (5 x 250 mL). The organic layer was dried and concentrated under reduced pressure. The crude residuewas purified by CombiFlash column chromatography using 20percent EtOAc in hexane to afford 27.5 g (94percent) of (S)-1-(methoxy-methyl-carbamoyl)-2-phenyl-ethyl]-carbamic acid tert-butyl ester as colorless oil. LC/MS: (M+H) = 309.0.
With isopropylmagnesium chloride In tetrahydrofuran at -40 - 0℃; for 3.25 h; Inert atmosphere
General procedure: According to V. Druais, M.J. Hall, C. Corsi, S.V. Wendeborn, Ch. Meyer, J. Cossy, A convergent approach toward phoslactomycins and leustroducsins, Tetrahedron 66 (2010) 6358-6375 N‑Boc‑L‑leucine methylester (1 g, 4.08 mmol) was dissolved in a secured three-neck round‑bottom flask in the suspension of O,N‑dimethylhydroxylamine hydrochloride (CH3ONHCH3HCl, 0.597 g, 6.12 mmol) in dry tetrahydrofurane (25 mL) under nitrogen atmosphere. The reaction mixture was cooled to -40 °C and i-PrMgCl (2M in dry THF, 6.12 mL, 12.24 mmol) was added dropwise via syringe pump over 15 minutes. The mixture was stirred and over the period of 3 hours slowly heated from -30 °C to 0 °C, the quenched saturated solution of NH4Cl in H2O (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phase was washed with H20 (2 x 10 mL) and dried over Na2SO4. The crude product was purified by column chromatography (silica gel 70 g, n‑hexane/ethyl acetate (3:1)) to afford Weinreb amides in yield 53 percent as colourless oil.
Reference：
[1] European Journal of Medicinal Chemistry, 2017, vol. 135, p. 142 - 158
27
[ 13734-34-4 ]
[ 6638-79-5 ]
[ 87694-53-9 ]
Yield
Reaction Conditions
Operation in experiment
100%
Stage #1: With 4-methyl-morpholine; isobutyl chloroformate In dichloromethane at 0℃; for 0.333333 h; Stage #2: With triethylamine In dichloromethane for 1.25 h;
To a solution of (S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid (24.85 g, 93.66 mmol) in dichloromethane (150 mL) was added N-methylmorpholine (10.3 mL, 93.66 mmol), followed by addition of isobutyl chloroformate (12.25 mL, 93.66 mmol) at 0° C. The reaction mixture was stirred for 20 min. then N,O-dimethylhydroxylamine hydrochloride (9.14 g, 93.66 mmol) in one portion was added. Subsequently, triethylamine (13 mL, 93.66 mmol) was added dropwise over 15 min. The reaction mixture was stirred for another hour, then it was quenched with 1N HCl (100 mL) and the organic phase was washed with saturated NaHCO3 and brine (500 mL). The organic layers were dried over (MgSO4), filtered, and concentrated in vacua to give the Weinreb amide of Formula VII(a), [(S)-1-(methoxy-methyl-carbamoyl)-2-phenyl-ethyl]-carbamic acid tert-butyl ester as a clear sticky oil (29.3 g, 100percent). 1H NMR (400 MHz, d6-DMSO): δ (ppm) 7.33-7.09 (m, 6H), 4.61-4.47 (m, 1H), 3.70 (s, 3H), 3.08 (s, 3H), 2.89-2.78 (m, 1H), 2.75-2.63 (m, 1H), 1.29 (s, 9H).
94%
Stage #1: With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; N-ethyl-N,N-diisopropylamine In DMF (N,N-dimethyl-formamide) at 20℃; for 0.5 h; Stage #2: for 18 h;
The substrate 27 (70 mg, 0.213 mmol), was dissolved in dry DMF (3 mL). HOBT, 1-hydroxybenzotriazole hydrate (31 mg, 0.22 mmol), EDC, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, (43 mg, 0.224 mmol), DIEA, diisopropyl-ethylamine, (122 μl, 0.703 mmol) were added and the mixture stirred for 30 minutes at room temperature. The commercially available N-methoxy-methyl amine hydrochloride salt (73 mg, 0.255 mmol; Aldrich) was added and the reaction stirred for 18 hours. The reaction mixture was diluted with ethyl acetate (20 mL) and added to saturated ammonium chloride (30 mL). The aqueous phase was extracted with ethyl acetate (3.x.10 mL). The combined organic phases were then washed with water (2.x.5 mL), 1 N HCl (eq.) (5 mL), saturated sodium bicarbonate solution (aq.) (50 mL), water (5 mL), brine (5 mL) and dried (MgSO4) before concentration in vacuo to give the crude product. Flash chromatography eluting with ethyl acetate/hexane, 1:1 to give the desired coupled product 28 as a colorless oil (94percent).
93%
With 4-methyl-morpholine; isobutyl chloroformate In dichloromethane at -15 - 20℃;
N-Methylmorpholine was added to Boc-AA-OH or Cbz-AA-OH in CH2Cl2 at -15° C. followed by isobutyl chloroformate. N-Methylmorpholine was added to a cooled solution (-15° C.) of HCl.H-AA-VS-Ph in CH2Cl2. This solution was added to the Boc-AA-OH or Cbz-AA-OH mixture, which had been stirring at -15° C. The mixture was continued to stir at -15° C. for 30 minutes, then warmed to room temperature and continued to stir over night. The amount of solvent was doubled, then washed with citric acid (10percent, 3.x.), saturated NaHCO3 (3.x.), and brine (3.x.), and finally dried (MgSO4). The solvent was evaporated. -(tert-Butoxycarbonylamino)-3-phenylpropionaldehyde (Boc-Phe-H). Boc-Phe-N(OCH3)CH3 was prepared from Boc-Phe-OH and N,O-dimethylhydroxylamine hydrochloride using standard mixed anhydride coupling procedure, yield 93percent. 1H-NMR (CDCl3) δ 1.4 (s, 9H, Boc), 2.8-2.9 (m, 1H, CH2-Phe), 3.0-3.1 (m, 11H, CH2-Phe), 3.2 (s, 3H, N-CH3), 3.6 (s, 3H, O-CH3), 4.9 (m, 1H, α-H), 5.2 (b, 1H, NH), 7.1-7.3 (m, 5H, Ph). MS (FAB+) m/z 309 (M+1, 30percent), 253 (M-tBu+1, 100percent). Reduction of Boc-Phe-N(OCH3)CH3 with lithium aluminum hydride according to a previous method described in J. A. Fehrentz et al., Synthesis (1983), 8, 676 gave Boc-Phe-H, yield 88percent. 1H-NMR (CDCl3) δ 1.4 (s, 9H, Boc), 3.1 (d, 2H, CH2-Phe), 4.4 (m, 1H, α-H), 5.0 (b, 1H, NH), 7.1-7.3 (m, 5H, Ph), 9.6 (s, 1H, CHO). MS (FAB+) m/z 250 (M+1, 15percent), 150 (M-Boc+1, 100percent). Example 2 2-(tert-Butoxycarbonylamino)-3-phenylpropionaldehyde (Boc-Phe-H). General Procedure for the Mixed Anhydride Coupling. N-Methylmorpholine was added to Boc-AA-OH or Cbz-AA-OH in CH2Cl2 at -15° C. followed by isobutyl chloroformate. N-Methylmorpholine was added to a cooled solution (-15° C.) of HCl.H-AA-VS-Ph or N,O dimethylhydroxylamine hydrochloride in CH2Cl2. This solution was added to the Boc-AA-OH or Cbz-AA-OH mixture, which had been stirring at -15° C. The mixture was continued to stir at -15° C. for 30 minutes, then warmed to room temperature and continued to stir over night. The amount of solvent was doubled, then washed with citric acid (10percent, 3.x.), saturated NaHCO3 (3.x.), and brine (3.x.), and finally dried (MgSO4). The solvent was evaporated. Boc-Phe-N(OCH3)CH3 was prepared from Boc-Phe-OH and N,O-dimethylhydroxylamine hydrochloride using standard mixed anhydride coupling procedure, yield 93percent. 1H-NMR (CDCl3) δ 1.4 (s, 9H, Boc), 2.8-2.9 (m, 1H, CH2-Phe), 3.0-3.1 (m, 1H, CH2-Phe), 3.2 (s, 3H, N-CH3), 3.6 (s, 3H, O-CH3), 4.9 (m, 1H, 1-H), 5.2 (b, 1H, NH), 7.1-7.3 (m, 5H, Ph). MS (FAB+) m/z 309 (M+1, 30percent), 253 (M-tBu+1, 100percent). Reduction of Boc-Phe-N(OCH3)CH3 with lithium aluminum hydride according to a previously described method gave Boc-Phe-H, yield 88percent. 1H-NMR (CDCl3) δ 1.4 (s, 9H, Boc), 3.1 (d, 2H, CH2-Phe), 4.4 (m, 1H, α-H), 5.0 (b, 1H, NH), 7.1-7.3 (m, 5H, Ph), 9.6 (s, 1H, CHO). MS (FAB+) m/z 250 (M+1, 15percent), 150 (M-Boc+1, 100percent).
90%
Stage #1: With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at -10℃; for 0.25 h; Green chemistry Stage #2: at 0℃; for 0.25 h; Green chemistry Stage #3: With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 0.416667 h; Green chemistry
General procedure: N-Boc-protected amino acid 1R1 (7.5 mmol) was dissolved indichloromethane (20 mL) and stirred at –10 °C. Then HOBt (7.5 mmol)and EDCI (11.3 mmol) were added. The reaction was carried out for15 min, then N, O-dimethylhydroxylamine hydrochloride (7.5 mmol) was added and after 15 min, DIPEA (18.9 mmol) was added. Thereaction temperature was allowed to rise to room temperature 25 minlater and the mixture was left overnight. The resulting mixture waswashed with 1 M HCl (20 mL), 5percent NaHCO3 (20 mL) and saturatedbrine (20 mL) respectively and dried over anhydrous Na2SO4. It wasfiltered, and the solvent was evaporated to provide crude product 2R1which was used without further purification in the next reaction.
81%
Stage #1: With triethylamine In dichloromethane at 0℃; for 0.166667 h; Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0℃; for 3 h;
Triethyl amine (40 g, 0.4 mol) was added to a suspension of Boc-L-phenylalanine (90 g,0.34 mol) and N,O-dimethylhydroxylamine hydrochloride (36.5 g, 0.37 mol) in DCM (500 mL)0 °C with stirring. The suspension was stirred for 10 mm and EDCI (HC1 salt, 72 g, 0.37 mol)was added. The suspension was stirred for further 3 hours at 0 °C. The mixture was quenched with saturated aqueous NaHCO3 (1 L). The layers were separated, and the aqueous phase was reextracted with DCM (500 mL x 3). The combined organic phases were washed with water (1 L x 3), 5percent KHSO4 aqueous (1 L x 3), saturated aqueous NaHCO3 (1 L x 3), and brine (1 L X 1), was dried (Na2SO4), and was concentrated to dryness. The crude material was further purified byflash chromatography (silica gel, EtOAc/Hexane= 1:1) and afforded (S)-tert-butyl 1- (methoxy(methyl)amino)-1-oxo-3-phenylpropan-2-ylcarbamate (85.1 g, 81 percent yield) as a white solid. ‘H NMR (300 MHz, CDC13): ö 7.157.26 (m, 5H), 5.25 (bs, 1H), 4.95 (m, 1H), 3.63 (s, 3H), 3.14 (s, 3H), 2.833.O7 (m, 2H), 1.37 (s, 9H).
66%
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane; acetonitrile at 20℃;
General procedure: To a solution of appropriate amino protected carboxylic acidderivative (1 eq.) dissolved in a mixture of CH2Cl2 and CH3CN (1:1, 3.7 mL/mmol of carboxylic acid), EDC (1.3 eq.), HOBt (1.3 eq.), NMM (6.5 eq.) and HN(Me)OMe*HCl (2.1 eq.) were added. The mixture was stirred at room temperature over 24-72 h and then evaporated.The resulting crude product was dissolved in CH2Cl2, washed three times with saturated NaHCO3 solution, three times with 1 M HCl and once with brine. Organic layer was dried over MgSO4,filtered and concentrated in vacuo. Purification via flash chromatography was performed. 4.2.3 tert-Butyl N-[(1S)-1-benzyl-2-[methoxy(methyl)amino]-2-oxo-ethyl]carbamate (7a) According to general method 1, 7a was obtained as a brown oil (0.94 g, 66percent). 1H NMR (CDCl3, 300 MHz), δ (ppm): 7.29-7.12 (m, 5H); 5.18 and 5.03-4.86 [X part of ABX system (d, J = 6.0 Hz, 0.5H) and (m, 0.5H)]; 3.65 (s, 3H); 3.16 (s, 3H); 2.95 [AB part of ABX system (dd, J = 12.0 and 6.0 Hz, 1H) and (dd, J = 15.0 and 9.0 Hz, 1H), Δν = 60 Hz]; 1.39 (s, 9H) [52] .
Reference：
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[2] Journal of the American Chemical Society, 2011, vol. 133, # 3, p. 462 - 477
[3] Patent: US9441012, 2016, B2, . Location in patent: Page/Page column 55-57
[4] Journal of Medicinal Chemistry, 2018, vol. 61, # 5, p. 1785 - 1799
[5] Journal of Medicinal Chemistry, 1994, vol. 37, # 18, p. 2918 - 2929
[6] Journal of Medicinal Chemistry, 1992, vol. 35, # 26, p. 4795 - 4808
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[8] Synthesis, 1983, # 8, p. 676 - 678
[9] Patent: US6900238, 2005, B1, . Location in patent: Page/Page column 37
[10] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 19, p. 5203 - 5211
[11] Patent: US2006/241057, 2006, A1, . Location in patent: Page/Page column 9; 13-14
[12] Bioorganic and Medicinal Chemistry Letters, 1996, vol. 6, # 3, p. 219 - 224
[13] ACS Medicinal Chemistry Letters, 2014, vol. 5, # 5, p. 462 - 467
[14] European Journal of Organic Chemistry, 2014, vol. 2014, # 8, p. 1672 - 1683
[15] European Journal of Organic Chemistry, 2014, vol. 2014, # 8, p. 1672 - 1683
[16] Journal of Chemical Research, 2016, vol. 40, # 2, p. 82 - 86
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[18] Patent: WO2015/157594, 2015, A1, . Location in patent: Page/Page column 45; 46
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[20] European Journal of Medicinal Chemistry, 2015, vol. 106, p. 15 - 25
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[30] Journal of Medicinal Chemistry, 2000, vol. 43, # 18, p. 3434 - 3442
[31] Patent: US6107329, 2000, A,
[32] Patent: EP1134213, 2001, A2,
[33] Patent: US2007/37753, 2007, A1, . Location in patent: Page/Page column 12-13
[34] Organic and Biomolecular Chemistry, 2010, vol. 8, # 21, p. 4855 - 4860
[35] Organic and Biomolecular Chemistry, 2011, vol. 9, # 19, p. 6566 - 6574
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[47] Patent: WO2017/211818, 2017, A1, . Location in patent: Page/Page column 29; 31
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[2] Chemical Communications, 1996, # 5, p. 641 - 642
32
[ 6638-79-5 ]
[ 79-03-8 ]
[ 104863-65-2 ]
Yield
Reaction Conditions
Operation in experiment
89%
With pyridine In dichloromethane at 0 - 20℃;
Pyridine (17 mL, 0.4 mol) at 0 0C was added dropwise to a solution of O,Λ/-dimethyl- hydroxylamine hydrochloride (10 g, 0.1 mol) and propionyl chloride (10 g, 0.1 mol) in anhydrous dichloromethane (250 mL). The solution was stirred at room temperature for 24 h, washed with 2x 50 ml of 5percent hydrochloric acid, 100 ml of saturated NaHCO3 and 100 ml brine, dried over MgSO4 and concentrated under reduced pressure to give colorless oil (10 g, 89 percent).
25.6%
With triethylamine In dichloromethane at 20℃;
I. N-Methoxy-N-methylpropanamide. To a solution of N,O-dimethylhydroxylamine hydrochloride (5.61 g, 57.5 mmol) and triethylamine (17.6 mL, 126.5 mmol) in methylene chloride (100 mL) was added propionyl chloride (5 mL, 57.5 mmol) dropwise. The reaction was stirred at room temperature overnight. The reaction was then washed with water (100 mL) and the organic layer was dried over magnesium sulfate. Solvent was removed under reduced pressure and the crude material was purified using column chromatography (SiO2, n-Hexanes to 8:2 n-Hexanes:ethyl acetate) to provide the title compound (1.72 g, 25.6percent). 1H NMR (300 MHz, CD3OD) δ 3.71 (s, 3H), 3.17 (s, 3H), 2.47 (broad m, 2H), 1.09 (t, J=7.42, 3H).
61%
With triethylamine In dichloromethane
Preparation 9 N-Methyl-N-methoxypropionamide A mixture of N,O-dimethyl hydroxylamine hydrochloride (4.43 g, 45.39 mmol) and triethylamine (6.93 mL, 49.71 mmol) in methylene chloride (150 mL) was chilled to 0° C. and propionyl chloride (3.76 mL, 43.23 mmol in 25 mL of methylene chloride with a 25 mL rinse) was added dropwise. The mixture was allowed to warm to ambient temperature and stir over the weekend. The reaction was extracted with water and brine, dried, and concentrated to afford 3.08 g (61percent) of N-methyl-N-methoxypropionamide as a yellow oil which had: NMR δ 3.66 (s, 3 H), 3.16 (s, 3 H), 2.42 (q, J=7.5 Hz, 2 H), 1.12 (t, J=7.5 Hz, 3 H). This material was suitable for use without further purification.
55%
With sodium bicarbonate; sodium chloride; triethylamine In dichloromethane
Reference Example 1 N-Methoxy-N-methylpropionamide (19) To a suspension of 11.8 g (120 mmol) of N,O-dimethylhydroxylamine hydrochloride in 294 ml of dichloromethane were added at 0°C 33.7 ml (242 mmol) of triethylamine and then a solution of 10.0 ml (115 mmol) of propionyl chloride in dichloromethane (6 ml) and the resulting mixture was stirred at room temperature for 21.5 hours. The reaction mixture was washed successively with water, dilute hydrochloric acid, an aqueous solution of sodium hydrogen carbonate, and an aqueous saturated solution of sodium chloride and was concentrated. The residue was distilled under reduced pressure to obtain 7.42 g (55percent) of the objective compound (19). Boiling point: 67°C (21 mmHg) 1H NMR (CDCl3) δ 1.14 (t, J = 7.4 Hz, 3H), 2.45 (q, J = 7.4 Hz, 2H), 3.18 (s, 3H), 3.69 (s, 3H).
61%
With triethylamine In dichloromethane
Preparation 9 N-Methyl-N-methoxypropionamide A mixture of N,O-dimethyl hydroxylamine hydrochloride (4.43 g, 45.39 mmol) and triethylamine (6.93 mL, 49.71 mmol) in methylene chloride (150 mL) was chilled to 0° C. and propionyl chloride (3.76 mL, 43.23 mmol in 25 mL of methylene chloride with a 25 mL rinse) was added dropwise. The mixture was allowed to warm to ambient temperature and stir over the weekend. The reaction was extracted with water and brine, dried, and concentrated to afford 3.08 g (61percent) of N-methyl-N-methoxypropionamide as a yellow oil which had: NMR δ3.66 (s, 3 H), 3.16 (s, 3 H), 2.42 (q, J=7.5 Hz, 2 H), 1.12 (t, J=7.5 Hz, 3 H). This material was suitable for use without further purification.
Reference：
[1] Journal of Medicinal Chemistry, 2017, vol. 60, # 12, p. 4840 - 4860
[2] Organic Letters, 2012, vol. 14, # 9, p. 2250 - 2253
[3] Chemistry - A European Journal, 2001, vol. 7, # 21, p. 4562 - 4571
[4] Patent: WO2010/104488, 2010, A1, . Location in patent: Page/Page column 65
[5] Journal of Organic Chemistry, 2007, vol. 72, # 15, p. 5828 - 5831
[6] Bulletin de la Societe Chimique de France, 1996, vol. 133, # 10, p. 1011 - 1021
[7] ACS Medicinal Chemistry Letters, 2014, vol. 5, # 1, p. 73 - 77
[8] Journal of Chemical Research, Miniprint, 1995, # 9, p. 2111 - 2122
[9] Patent: US2008/242694, 2008, A1, . Location in patent: Page/Page column 65
[10] Patent: US2003/166628, 2003, A1,
[11] Patent: US6046213, 2000, A,
[12] Patent: EP987250, 2000, A1,
[13] Patent: US6258827, 2001, B1,
[14] Patent: US2008/90861, 2008, A1, . Location in patent: Page/Page column 20
33
[ 6638-79-5 ]
[ 123-62-6 ]
[ 104863-65-2 ]
Reference：
[1] Angewandte Chemie, International Edition, 2009, vol. 48, p. 4543 - 4545[2] Angewandte Chemie, 2009, vol. 121, p. 4613 - 4615
[3] Patent: WO2015/24905, 2015, A1, . Location in patent: Paragraph 00293-00294
[4] Patent: US2015/80391, 2015, A1, . Location in patent: Paragraph 0570; 0571; 0572
34
[ 6638-79-5 ]
[ 802294-64-0 ]
[ 104863-65-2 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2016, vol. 358, # 15, p. 2469 - 2479
[2] European Journal of Organic Chemistry, 2017, vol. 2017, # 25, p. 3584 - 3593
35
[ 6638-79-5 ]
[ 407-25-0 ]
[ 104863-67-4 ]
Yield
Reaction Conditions
Operation in experiment
95%
With pyridine In dichloromethane at 0℃; for 1 h; Large scale
To a suspension of N,O-dimethyl-hydroxylamine hydrochloride (107.2 Kg, 1.1 kmol) in dichloromethane (400 L) were added trifluoroacetic anhydride (210 Kg, 1 kmol) and pyridine (174 Kg, 2.2 kmol) sequentially at0 °C. The mixture was stirred at 0°C for 1 h and then diluted with ice water (300 L) and washed with 2 M HCl (300 L). The aqueous solution was extracted twice with dichloromethane and dried under MgSO4. The crude Weinreb amide was obtained after concentration without further purification (90 percentpurity, 95 percent yield).
Reference：
[1] Asian Journal of Chemistry, 2015, vol. 27, # 7, p. 2406 - 2408
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[4] Patent: WO2003/101932, 2003, A2, . Location in patent: Page 64
[5] Patent: WO2003/82787, 2003, A1, . Location in patent: Page/Page column 108
[6] Patent: WO2003/104195, 2003, A1, . Location in patent: Page 64-65
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[10] RSC Advances, 2013, vol. 3, # 25, p. 9820 - 9828
Stage #1: With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 0.166667 h; Stage #2: With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0℃; for 0.166667 h; Stage #3: With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 25℃; for 17 h;
An oven dry 100 mL round bottom flask was charged with 3 (3.0 g, 15.8 mmol), dry CH2Cl2 (60 mL),and DIPEA (2.5 mL, 14.2 mmol) and the resulting solution was cooled to 0° C.After stirring for 10 min at 0 °C, EDC (3.7 g, 19.0 mmol) and HOBt (2.6 g, 19.0mmol) were added as solids. The mixture was stirred at 0 °C for 10 min, then N,O-dimethylhydroxylamine hydrochloride (1.9 g, 19.0 mmol) and DIPEA (3.3 mL, 19.0 mmol) were added. The mixture was allowed to stir at 0° C for an additional hour, then allowed towarm to 25 °C and kept at the same temperature for 16 h. The reaction mixture was diluted with CH2Cl2 (300 mL) and the organic layer was washed with 2 N HCl (3 x 180 mL), a satured solution of NaHCO3(2x180 mL), and brine (2x180 mL). The organic phase was dried (Na2SO4)and the solvent removed in vacuo.11 The resulting amide was obtained as a white solid without further purification (3.6 g, 99percent yield):mp (CHCl3) 138-140 °C; 1H NMR (300 MHz, DMSO) d1.11 (d, J= 6.9 Hz, 3H), 1.33 (s, 9H), 3.07 (s, 3H), 3.69 (s, 3H), 4.36 (t, J = 6.9 Hz, 1H), 7.03 (d, J = 6.9 Hz, 1H); ESI MS: m/z 255 (M+Na)+. The above compound(3.7 g, 15.8 mmol) was dissolved in dry THF (100 mL) and cooled to 0 °C. To this solution was added LiAlH4 (660 mg, 17.4 mmol) and the reaction was stirred for 20 min. After consumption of the starting material, as indicated by TLC, the reaction mixture was quenched with a 5percent solution of HCl.The organic layer was evaporated and the aqueous phase was extracted with EtOAc(3 x 30 mL). The organic phase was dried (Na2SO4) and the solvent was removed in vacuo. 12The title compound was obtained as a white solid without further purification (2.6g, 94percent yield); mp (CHCl3)82-84 °C; 1H NMR (300 MHz, DMSO) d1.09 (d, J= 7.5 Hz, 3H), 1.36 (s, 9H), 3.83 (t, J= 9.9 Hz, 1H), 7.33 (d, J = 5.7 Hz,1H), 9.39 (s, 1H); ESI MS: m/z 173(M+H)+, 196 (M+Na)+.
99%
Stage #1: With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 0.166667 h; Stage #2: With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0℃; for 0.166667 h; Stage #3: at 0 - 25℃; for 17 h;
An oven dry 100 mL round bottom flask was charged with 3 (3.0 g, 15.8 mmol), dry CH2Cl2 (60 mL), and DIPEA (2.5 mL, 14.2 mmol) and the resulting solution was cooled to 0° C. After stirring for 10 min at 0 °C, EDC (3.7 g, 19.0 mmol) and HOBt (2.6 g, 19.0 mmol) were added as solids. The mixture was stirred at 0 °C for 10 min, then N,O-dimethylhydroxylamine hydrochloride (1.9 g, 19.0 mmol) and DIPEA (3.3 mL, 19.0 mmol) were added. The mixture was allowed to stir at 0° C for an additional hour, then allowed to warm to 25 °C and kept at the same temperature for 16 h. The reaction mixture was diluted with CH2Cl2 (300 mL) and the organic layer was washed with 2 N HCl (3 x 180 mL), a satured solution of NaHCO3 (2x180 mL), and brine (2 x 180 mL). The organic phase was dried (Na2SO4) and the solvent removed in vacuo.11 The resulting amide was obtained as a white solid without further purification (3.6 g, 99percent yield): mp(CHCl3) 138-140 °C; 1H NMR (300 MHz, DMSO) δ 1.11 (d, J = 6.9 Hz, 3H), 1.33 (s, 9H), 3.07 (s,3H), 3.69 (s, 3H), 4.36 (t, J = 6.9 Hz, 1H), 7.03 (d, J = 6.9 Hz, 1H); ESI MS: m/z 255 (M+Na)+.
99%
Stage #1: With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 1 h; Stage #2: at 20℃; for 16 h;
(S) -tert-butoxycarbonylaminopropionic acid (15 g, 79.3 mmol) was dissolved in dichloromethane (200 mL) and carbonyldiimidazole (14.2 g, 87.3 mmol) was slowly added and the reaction was stirred at ambient temperature for 1 hour. N, O-dimethylhydroxylamine hydrochloride (8.5 g, 87.3 mmol) was then added and the reaction was stirred at room temperature for 16 hours. The mixture was extracted with ethyl acetate (100 mL × 3) and the combined organic phases were washed with 1 mol / L aqueous HCl (20 mL × 2), saturated aqueous NaHCO 3 (30 mL × 2) and saturated brine (40 mL × 2), respectively. The organic phase is dried over anhydrous sodium sulphate. The solvent was concentrated under reduced pressure to give 18.3 g of (S) -tert-butoxycarbonylamino-1-methyl (methoxy) amino-propionamide as a white solid in a yield of 99percent
95%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In ISOPROPYLAMIDE at 10℃; for 2.6 h;
Example 1Synthesis of (S)-3-(1-aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-oneExample 1A Compound 1 (6.00 kg) was treated with 1-hydroxybenzotriazole monohydrate (HOBt.bul.H2O), triethylamine, N,O-dimethylhydroxylamine hydrochloride, and EDCI in dimethylacetamide (DMA) at 10° C. The reaction was monitored by proton NMR and deemed complete after 2.6 hours, affording Compound 2 as a white solid in 95percent yield. The R-enantiomer was not detected by proton NMR using (R)-(-)-alpha-acetylmandelic acid as a chiral-shift reagent.
91%
Stage #1: With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 1 h; Inert atmosphere Stage #2: With N-ethyl-N,N-diisopropylamine In tetrahydrofuran; N,N-dimethyl-formamide at 20 - 30℃; for 18 h; Inert atmosphere
To a solution of Boc-Ala-OH 32 (10.5 mmol, 2 g) in anhydrous THF (17.5 mL), CDI (12.6 mmol, 2.1 g) was added portion wise so as to control foaming, under N2 flow. The mixture was stirred at room temperature for 1 h, after which a solution of N,O-dimethyl hydroxylamine hydrochloride 33 (11.6 mmol, 1.1 g) and DIEA (21 mmol, 2.7 g) in anhydrous DMF (7 mL) were added over 0.5 h (with cooling as necessary to maintain the reaction temperature < 30 °C) and under N2 flow. The reaction mixture was allowed to warm up to room temperature and stirred for 18 h. The solvent was evaporated under reduced pressure and the residue was partitioned between EtOAc (20 mL) and aq. solution 1.7 M NaHSO4 (10 mL). The two phases were separated in the funnel and the aqueous layer (pH ~ 1 2) was extracted with EtOAc (7 mL x 3). The combined organic layers were washed with water (3.5 mL), NaHCO3ss (7 mL) and water (3.5 mL), dried over MgSO4, filtered and the solvent removed under reduced pressure. The residue was dried over high vacuum, affording 2.23 g (91percent) of desired product 34 as white solid, which was used for the next step without further purification. 1H NMR (400 MHz, CDCl3), δ 5.25 (d, J = 8.6 Hz, 1H), 4.67–4.64 (m, 1H), 3.74 (s, 3H), 3.18 (s, 3H), 1.41 (s, 9H), 1.28 (d, J = 6.9 Hz, 3H). 13C NMR (100 MHz, CDCl3), δ 173.77, 155.29, 79.59, 61.71, 46.63, 32.24, 28.47, 18.78. C10H20N2O4, MS (ESI): m/z 233 [M+H]+.
89%
Stage #1: With 1,1'-carbonyldiimidazole In dichloromethane at 0℃; for 1 h; Stage #2: With triethylamine In dichloromethane at 2 - 25℃;
Boc-Ala-OH (20Og, 1057 mmol) in 3400 ml dichloromethane were cooled to 0°C. 1,1'- Carbonyldiimidazol (205,7g, 1268 mmol) was added in multiple portions over 30 min and stirring was continued for 30 minutes at 00C. Triethylamine (175,8 ml, 1268 mmol) was added over 20 min at 2°C followed by N,O-dimethyl hydroxylamine mono hydrochloride (123,7 g, 1268 mmol) in multiple portions and stirring was continued for 30 minutes at 00C. After stirring for 14 hours at room temperature the mixture was diluted with 4 L t-butyl methyl ether and washed with IM HCl solution (2 times 800 ml, 15 min stirring, then phase separation), saturated NaHCO3 solution (1,3 L) and brine (1,3L). After drying over Na2SO4 the solvent was removed i.vac, and the white crystalline product purified by recrystallization in 500 ml t- butyl methyl ether to yield 217,8 g (89percent)of /(7S)-2-(methoxymethylamino)-l-methyl-2- oxoethyl]-carbamic acid t-butyl ester.1H-NMR (300 MHz, CDCl3); δ = 5.25 (br, IH), 4.67 (dq, IH), 3.76 (s, 3H), 3.20 (s, 3H), 1.43 (s, 9H), 1.30 (d, 3H).
86%
With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at -10 - 20℃;
To a mixture of (S)-2-((tert-butoxycarbonyl)amino)propanoic acid (22.00 g, 116.27 mmol), N,O-dimethylhydroxyamine hydrochloride (12.35 g, 127.90 mmol) and HOAT (18.99 g, 139.53 mmol) in DCM (232 mL) was added NEt3 (64.8 mL, 465.09 mmol) at 0° C., and followed by addition of EDCI (26.75 g, 139.53 mmol) portionwise at −10° C., After addition, the resulted mixture was stirred at −10° C. for 1 hour, and then stirred at rt for 2 days, quenched with 200 mL of 1:120. The organic phase was washed with 200 mL of saturated NaHCO3 aq. and 200 mL of saturated brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=4/1) to give the title compound as a white solid (7.4 g, 86percent). [0539] MS (ESI, pos. ion) mz: 177.0 [M-C4H8+H]+, 133.0 [M-Boc+H]+; [0540] 1H NMR (600 MHz, CDCl3) δ (ppm): 5.24 (d, J=5.4 Hz, 1H), 4.68 (m, 1H), 3.76 (s, 3H), 3.20 (s, 3H), 1.43 (s, 9H), 1.31-1.30 (d, J=6.6 Hz, 3H).
81%
With benzotriazol-1-ol; triethylamine; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃;
[00318] (25^-2-r(tert-Butoxy)carbonylaminol-N-methoxy-N-methylpropanamide; [00319] To a solution of Boc-alanine (20 grams, 105.7 mmol) in dichloromethane(170 ml) was added HOBT (14.28 g, 105.7 mmol) and N, O-dimethylhydroxylamine hydrochloride (10.31 g, 105.7 mmol). The mixture was chilled with an ice water bath then triethylamine (30 ml, 211.4 mmol) and 1,3-dicyclohexylcarbodiimide (21.81g, 105.7 mmol) were added. The reaction was stirred in the ice water bath for 1 hour and then allowed to warm to room temperature overnight. The crude reaction was then chilled in an ice water bath and the precipitate filtered. The resulting organic solution was then washed twice with IN aqueous sodium hydroxide (50 mL), twice with 10 percent aqueous citric acid (50 mL), and once with brine. The solution was then dried over anhydrous sodium sulfate, filtered, and the solvent evaporated. The resulting residue was purified by chromatography on a normal phase silica gel column with 30-100percent ethyl acetate in hexanes. Fractions containing clean product were combined and the solvent evaporated to give the title compound (20 g, 81percent): ΕS-MS (m/z) 233.2 [M+l]+.
80%
With N-ethyl-N,N-diisopropylamine In dichloromethane for 1 h;
In 10 ml of DCM stirred on magnetic stirrer a 190 mg (1,0 mmole) of Boc-Ala-OH and 353 mg (1,1 mmole) N-methyl,N-methoxyamine hydrochloride was added followed by 205 µl (1,2 mmole) DIPEA. The reaction was monitored by TLC using hexane: ethyl acetate (1:1 v/v). The reaction occurs in 1 hour and after this time the mixture was diluted with 20 ml of DCM, transferred to a separatory funnel and washed trough three times with 30 ml portions of 3M aqueous HCl, saturated NaHCO3 and brine. The organic layer was dried over MgSO4 and concentrated on rotary evaporator obtaining 186 mg (0,8 mmole) of product with a yield of 80percent.
71%
With 4-methylmorpholine N-oxide; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at -20 - 0℃; for 4 h; Inert atmosphere
To a stirred solution of N-Boc-L-alanine (9.00 g, 47.55 mmol), N,O-dimethylhydroxylamine hydrochloride (5.1 g, 52.32 mmol) and N-methylmorpholine (10.5 mL, 95.13 mmol, until pH=8-9) in dry DCM (250 mL) at -20°C under an argon atmosphere, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (10 g, 52.32 mmol) was added portionwise over a period of 30 min. The resulting reaction mixture was allowed to stir for 4h at 0°C (as monitored by TLC analysis for almost complete reaction; Silica gel, EtOAc 100percent; Rf(adduct)= 0.1; Rf(product)=0.56; visualized with 1.3percent ninhydrine solution), and was then quenched with saturated NH4Cl solution (200 mL). The layers were separated and the aqueous layer was extracted several times with CH2Cl2 (4×100 mL). The organic layers were combined, washed with saturated NaHCO3 solution (150 mL), brine (150 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford compound 1 as a white solid. The product was used in the next step without any further purification. Yield: 8.65 g (71 percent). Rf: 0.42 (cyclohexane/ethylacetate 3:2, visualized with 1.3percent ninhydrine). 1H NMR (CDCl3, 500 MHz, ppm): δ 1.31 (d, J= 6.9 Hz, 3H), 1.44 (s, 9H), 3.21 (s, 3H), 3.77 (s, 3H), 4.62-4.74 (br. m, 1H), 5.27 (d, J= 6.9 Hz, 1H). 13C NMR (CDCl3, 126 MHz, ppm): δ 18.80, 28.50, 32.27, 46.66, 61.75, 79.65, 155.33, 173.80. ESI-HRMS: m/z calcd for C10H19N2O4 [M-H]- 231.1345; observed 231.1351.
69.2%
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 10 h;
To a solution of (S)-2-((tert-butoxycarbonyl)amino)propanoic acid (10.0 g, 52.9 mmol), Ν,Ο- dimethylhydroxylamine hydrochloride (7.7 g, 78.9 mmol) and TEA (22.0 g, 217.4 mmol) in DMF (100 mL) was added HATU (30.0 g, 78.9 mmol). The reaction mixture was then stirred at 20 °C for 10 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL), washed with sat. aq. Na2CO3 (150 mL) and brine (100 mL). The water phase was extracted with EtOAc (2 x 200 mL). The combined organic extracts were dried over Na2S04, filtered and concentrated under reduced pressure to give a crude product. The crude product was re crystallized form EtOAc to get the product (8.5 g, yield: 69.2percent). 1H NMR (400 MHz, DMSO-c/6): δ 7.06 (d, J = 7.6 Hz, 1 H), δ 4.43-4.38 (m, 1 H), 3.72 (s, 3 H), 3.10 (s, 3 H), 1 .37 (s, 9 H), 1 .14 (d, J = 7.2 Hz, 3 H)
64%
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane; acetonitrile at 20℃;
General procedure: To a solution of appropriate amino protected carboxylic acidderivative (1 eq.) dissolved in a mixture of CH2Cl2 and CH3CN (1:1, 3.7 mL/mmol of carboxylic acid), EDC (1.3 eq.), HOBt (1.3 eq.), NMM (6.5 eq.) and HN(Me)OMe*HCl (2.1 eq.) were added. The mixture was stirred at room temperature over 24-72 h and then evaporated.The resulting crude product was dissolved in CH2Cl2, washed three times with saturated NaHCO3 solution, three times with 1 M HCl and once with brine. Organic layer was dried over MgSO4,filtered and concentrated in vacuo. Purification via flash chromatography was performed. 4.2.7 tert-Butyl N-[(1S)-2-(methoxy(methyl)amino)-1-methyl-2-oxo-ethyl]carbamate (11a) According to general method 1, 11a was obtained as a yellow oil (0.566 g, 64percent). Analyses similar to literature description [53] .
606 kg
With 1,1'-carbonyldiimidazole In dichloromethane at 0 - 15℃; for 16 h; Industrial scale
(vii) Tert-butyl V-[(lS)-2-(3-methoxyphenyl)-l-methyl-2-oxo-ethyl]carbamate To a cooled (0-5 °C) solution of N-(tert-butyloxycarbonyl)-L-alanine (45.0 kg, 238 mol) in dichloromethane (596.5 kg) was added 1,1-carbonyldiimidazole (52.5 kg, 324 mol) over 3 hours and the resultant solution maintained at 0-5 °C for 30 minutes. Ν,Ο- Dimethylhydroxylamine hydrochloride (31.5 kg, 323 mol) was added over 1 hour 30 minutes and the resultant solution maintained at 0-5 °C for 30 minutes. After stirring for 14 hours at 15 °C, the reaction mixture was washed sequentially with two portions of 1M hydrochloric acid (164.5 kg, 163 mol and 166 kg, 164 mol), 10percent> aqueous sodium hydrogen carbonate (164.5 kg) and then 20percent> aqueous sodium chloride solution (199 kg) to give an organic phase solution of tert-butyl N-[(15)-2-(methoxy (methyl)amino)-l-methyl-2-oxo-ethyl] carbamate (606 kg). Half of the solution (303 kg) was solvent swapped by distillation into tetrahydrofuran (220 kg). The solution was cooled to below 10 °C and isopropylmagnesium chloride 1.91 M in tetrahydrofuran (54 kg, about 114 mol) added over 1 hour 20 minutes, maintaining the temperature between 10-15 °C, followed by a tetrahydrofuran rinse (3 kg). 3-Methoxy phenylmagnesium bromide 0.86 M in THF (203 kg, about 202 mol) was gradually added, maintaining the temperature between 10-15 °C, followed by a tetrahydrofuran rinse (3 kg). After warming to 20 °C, 20percent aqueous acetic acid (101 kg) was added, maintaining the temperature below 30 °C, followed by a water rinse (5 kg). After phase separation, the aqueous layer was back-extracted with ethyl acetate (91 kg). The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution (101 kg) and then saturated aqueous sodium chloride solution (100 kg). The organic layer was solvent swapped into heptane (80 kg) by distillation, then methyl tert-butyl ether (6.3 kg) was charged and the slurry stirred at 20 °C for 6 hours. The solids were then filtered off, washed with a mixture of heptane (15.75 kg) and methyl tert- butyl ether (4.25 kg), and dried in a 50 °C vacuum oven. Yield 26.2 kg (93.8 mol, 79percent> by moles). 1H NMR (300 MHz, CDC13) δ 7.55 (m, 2H), 7.38 (t, J=7.8Hz, 1H), 7.13 (m, 1H), 5.61 (m, 1H), 5.27 (m, 1H), 3.85 (s, 3H), 1.39-1.46 (m, 12H).
237.8 g
Stage #1: With 1,1'-carbonyldiimidazole In dichloromethane at 5℃; for 1 h; Stage #2: With triethylamine In dichloromethane at 15℃; for 1.5 h;
1st Step CDI (185.6 g) was added to a dichloromethane (2000 ml) solution containing N-(tert-butoxycarbonyl)-L-alanine (200 g) at 5° C. or less, followed by stirring for 1 hour. Subsequently, triethylamine (115.8 g) and N-methoxy-N-methylamine hydrochloride (111.7 g) were added to the solution, followed by stirring at 15° C. or less for 1.5 hours. Dichloromethane (230 ml) was added to the reaction solution. The organic layers were washed with a 20percent sodium hydroxide aqueous solution and the solvent was distilled away under reduced pressure. Heptane was added to the obtained residue for suspension and a solid was collected by filtration. A white solid of (S)-tert-butyl (1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate (237.8 g) was thus obtained.
36 g
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 16 h;
(S)-2-((tert-butoxycarbonyl)amino)propanoic acid (39 g, 206 mmol), Ν,Ο-dimethyl- hydroxylamine hydrochloride (24 g, 246 mmol), HATU (117 g, 308 mmol) and N,N-diisopropylethylamine (66.3 g, 513 mmol) were dissolved in DMF (500 mL) and stirred at room temperature for 16 hours. The reaction mixture was poured into water (500 mL) and the formed precipitate was filtered off. The filter cake was washed with water (1 L) and dried to give tert-butyl N-[(l S)-2-[methoxy(methyl)amino]-l-methyl-2-oxo-ethyl]carbamate (36 g) as a white powder, tert-butyl N- [( 1 S)-2- [methoxy(methyl)amino] - 1 -methyl-2-oxo-ethyl] carbamate (35 g, 151 mmol) was dissolved in THF (500 mL) and cooled to 0°C. Methylmagnesium bromide (3.0 M in diethyl ether, 140 mL) was added and the reaction mixture was stirred 16 hours at room temperature. The reaction mixture was poored into water (100 mL) and evaporated to dryness. The residue was dissolved in EtOAc, washed with water, dried over Na2S04, filtered and evaporated to dryness yielding tert-butyl N-[(lS)-l-methyl-2-oxo- propyl] carbamate (22 g) as a white powder. To a cooled (-78°C) solution of tert-butyl N-[(1 S)-1- methyl-2-oxo-propyl]carbamate (12 g, 64.1 mmol) in CH2C12 (200 mL) bis(2-methoxyethyl)- aminosulfur trifluoride (18.9 g, 117.5 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was poored into water and extracted with CH2C12. The organic layer was washed with water, dried over Na2S04, filtered and evaporated to dryness. The obtained residue was purified by silica gel chromatography yielding tert-butyl N-[(l S)-2,2-difluoro-l-methyl-propyl]carbamate (5.8 g) as a pale yellow solid. Tert-butyl N-[(lS)-2,2-difluoro-l-methyl-propyl]carbamate (5.8 g, 27.7 mmol) was dissolved in EtOAc (100 mL). HC1 (g) was bubbled through for 30 minutes and then the volatiles were removed under reduced pressure yielding (2S)-3,3-difluorobutan-2-amine hydrochloride (3.8 g) 1H NMR (400MHz, DMSO-d6) δ ppm 8.69 (br. s., 3H), 3.76 - 3.63 (m, 1H), 1.72 (t, J=19.7 Hz, 3H), 1.28 (d, J=6.8 Hz, 3H).
36 g
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 16 h;
(S)-2-((tert-butoxycarbonyl)amino)propanoic acid (39 g, 206 mmol), N,O-dimethylhydroxylamine hydrochloride (24 g, 246 mmol), HATU (117 g, 308 mmol) andN,N-diisopropylethylamine (66.3 g, 513 mmol) were dissolved in DMF (500 mL) and stirred at room temperature for 16 hours. The reaction mixture was poured into water (500 mL) and the formed precipitate was filtered off. The filter cake was washed with water (1 L) and dried to give tert-butyl N-[(1 S)-2-[methoxy(methyl)amino]- 1 -methyl-2-oxo-ethyl]carbamate (36 g) as a white powder.
36 g
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 16 h;
Synthesis of (2S)-3,3-difluorobutan-2-amine hydrochloride (S)-2-((tert-butoxycarbonyl)amino)propanoic acid (39 g, 206 mmol), Ν,Ο-dimethyl- hydroxylamine hydrochloride (24 g, 246 mmol), HATU (117 g, 308 mmol) and N,N-diisopropylethylamine (66.3 g, 513 mmol) were dissolved in DMF (500 mL) and stirred at room temperature for 16 hours. The reaction mixture was poured into water (500 mL) and the formed precipitate was filtered off. The filter cake was washed with water (1 L) and dried to give tert-butyl N-[(lS)-2-[methoxy(methyl)amino]-l-methyl-2-oxo- ethyl] carbamate (36 g) as a white powder, tert-butyl N-[(l S)-2-[methoxy(methyl)amino]-l- methyl-2-oxo-ethyl]carbamate (35 g, 151 mmol) was dissolved in THF (500 mL) and cooled to 0°C. Methylmagnesium bromide (3.0 M in diethyl ether, 140 mL) was added and the reaction mixture was stirred 16 hours at room temperature. The reaction mixture was poored into water (100 mL) and evaporated to dryness. The residue was dissolved in EtOAc, washed with water, dried over Na2S04, filtered and evaporated to dryness yielding tert-butyl N-[(lS)-l-methyl-2-oxo-propyl] carbamate (22 g) as a white powder. To a cooled (-78°C) solution of tert-butyl N-[(lS)-l-methyl-2-oxo-propyl]carbamate (12 g, 64.1 mmol) in CH2C12 (200 mL) bis(2-methoxyethyl)aminosulfur trifluoride (18.9 g, 117.5 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was poored into water and extracted with CH2C12. The organic layer was washed with water, dried over Na2S04, filtered and evaporated to dryness. The obtained residue was purified by silica gel chromatography yielding tert-butyl N-[(l S)-2,2-difluoro-l-methyl-propyl]carbamate (5.8 g) as a pale yellow solid. Tert-butyl N-[(l S)-2,2-difluoro-l-methyl-propyl]carbamate (5.8 g, 27.7 mmol) was dissolved in EtOAc (100 mL). HC1 (g) was bubbled through for 30 minutes and then the volatiles were removed under reduced pressure yielding (2S)-3,3-difluorobutan-2-amine hydrochloride (3.8 g) 1H NMR (400MHz, DMSO-d6) δ ppm 8.69 (br. s., 3H), 3.76 - 3.63 (m, 1H), 1.72 (t, J=19.7 Hz, 3H), 1.28 (d, J=6.8 Hz, 3H).
13.1 g
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 1.5 h;
To 20.0 g of N-(tert-butoxycarbonyl)-L-alanine in 352 ml of dichloromethane, 12.4 g of N,O-dimethylhydroxylamine hydrochloride, 15.7 g of 1-hydroxybenzotriazole monohydrate, 24.3 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 42.7 g of triethylamine were added, and the mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, the reaction mixture was washed with 500 ml of saturated aqueous sodium hydrogen carbonate, 500 ml of 1 N aqueous hydrochloric acid and 500 ml of water in this order, the resulting organic layer was dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was washed with 200 ml of hexane to obtain 13.1 g of the desired product as white crystals. m.p.: 144.0 to 145.0°C 1H NMR (CDCl3, Me4Si, 300MHz) δ5.22 (bs, 1 H), 4.68 (bs, 1 H), 3.77 (s, 3H), 3.21 (s, 3H), 1.44 (s, 9H), 1.31 (d, J=6.9Hz, 3H).
36 g
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 16 h;
(S)-2-((tert-butoxycarbonyl)amino)propanoic acid (39 g, 206 mmol), Ν,Ο-dimethyl- hydroxylamine hydrochloride (24 g, 246 mmol), HATU (117 g, 308 mmol) and (0383) N,N-diisopropylethylamine (66.3 g, 513 mmol) were dissolved in DMF (500 mL) and stirred at room temperature for 16 hours. The reaction mixture was poured into water (500 mL) and the formed precipitate was filtered off. The filter cake was washed with water (1 L) and dried to give tert-butyl N-[(l S)-2-[methoxy(methyl)amino]-l-methyl-2-oxo-ethyl]carbamate (36 g) as a white powder, tert-butyl N- [( 1 S)-2- [methoxy(methyl)amino] - 1 -methyl-2-oxo-ethyl] carbamate (35 g, 151 mmol) was dissolved in THF (500 mL) and cooled to 0°C. Methylmagnesium bromide (3.0 M in diethyl ether, 140 mL) was added and the reaction mixture was stirred 16 hours at room temperature. The reaction mixture was poored into water (100 mL) and evaporated to dryness. The residue was dissolved in EtOAc, washed with water, dried over Na2S04, filtered and evaporated to dryness yielding tert-butyl N-[(lS)-l-methyl-2-oxo- propyl] carbamate (22 g) as a white powder. To a cooled (-78°C) solution of tert-butyl N-[(1 S)-1- methyl-2-oxo-propyl]carbamate (12 g, 64.1 mmol) in CH2C12 (200 mL) bis(2-methoxyethyl)- aminosulfur trifluoride (18.9 g, 117.5 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was poored into water and extracted with CH2CI2. The organic layer was washed with water, dried over Na2S04, filtered and evaporated to dryness. The obtained residue was purified by silica gel (0384) chromatography yielding tert-butyl N-[(l S)-2,2-difluoro-l-methyl-propyl]carbamate (5.8 g) as a pale yellow solid. Tert-butyl N-[(lS)-2,2-dif uoro-l-methyl-propyl]carbamate (5.8 g, 27.7 mmol) was dissolved in EtOAc (100 mL). HC1 (g) was bubbled through for 30 minutes and then the volatiles were removed under reduced pressure yielding (2S)-3,3-difluorobutan-2-amine hydrochloride (3.8 g) 1H NMR (400MHz, DMSO-d6) d ppm 8.69 (br. s., 3H), 3.76 - 3.63 (m, 1H), 1.72 (t, J=19.7 Hz, 3H), 1.28 (d, J=6.8 Hz, 3H).
13.1 g
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 1.5 h;
To 20.0 g of N-(tert-butoxycarbonyl)-L-alanine in 352 ml of dichloromethane, 12.4 g of N,O-dimethylhydroxylamine hydrochloride, 15.7 g of 1-hydroxybenzotriazole monohydrate, 24.3 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 42.7 g of triethylamine were added, and the mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, the reaction mixture was washed with 500 ml of saturated aqueous sodium hydrogen carbonate, 500 ml of 1N aqueous hydrochloric acid and 500 ml of water in this order, the resulting organic layer was dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was washed with 200 ml of hexane to obtain 13.1 g of the desired product as white crystals.
4 g
With 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at -15℃; for 1 h; Inert atmosphere
A solution of (S)-2-((tert-butoxycarbonyl)amino)propanoic acid 216 (5.00 g, 26.4 mmol) in CH2Cl2 (50 mL) was cooled to -15 °C and was added Ν,Ο-dimemylhydroxylamine hydrochloride 217 (2.81 g, 28.8 nimol) followed by NMM (2.90 g, 28.6 mmol) under nitrogen atmosphere. Then EDCI.HCl (5.56 g, 29.0 mmol) was added to the reaction mixture in portions while maintaining the temperature at -15°C and the reaction mixture was stirred at the same temperature for 1 h. The reaction mixture was diluted with CH2Cl2 (50 mL) and washed with water(60 mL) and the organic layer was separated and washed with brine (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to provide (S)-tert-butyl(1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate 218 (4.0 g, crude). 1H NMR (400 MHz, DMSO-d6): 0 7.01 (d, ./ 7.6 Hz, i l l). 4.41-4.36 (m, 1H), 3.71 (s, 3H), 3 ,09 (s, 3H), 1.36 (s, 9H), 1.14 (d, J = 7,2 Hz, 3H).
1.1 g
Stage #1: With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; triethylamine In dichloromethane at 0 - 20℃; for 1 h; Stage #2: at 20℃; for 20 h;
While a mixture of N-(tert-butoxycarbonyl)-L-alanine (1 g, 5.3 mmol), triethylamine (2.9 mL, 21.1 mmol) and hydroxybenzotriazole (135 mg, 5.3 mmol) in anhydrous dichloromethane (20 mL) was stirred at 0, 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (384.3 mg, 10.9 mmol) was slowly added thereto over 30 minutes. The reaction mixture was stirred at room temperature for 30 minutes and then N,O-dimethylhydroxylamine hydrochloride (568.7 mg, 5.8 mmol) was added thereto. The reaction mixture was stirred at room temperature for 20 hours and then quenched by water (100 mL). The organic layer was washed with water (2 x 1L) and brine (500 mL), dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue was slurried in petroleum ether (200 mL), stirred at room temperature for 10 minutes, and then filtered. The resulting solid was dried in vacuo to give 1.1 g of the titled compound as a white solid
11.5 g
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In tetrahydrofuran at 0 - 20℃; for 15 h; Inert atmosphere
To a solution of (25)-2-(tert-butoxycarbonylamino)propanoic acid (compound I-20a, 10 g, 52.85 mmol) in THF (200 mL) was added HATU (30.1 g, 79 mmol), TEA (13.4 g, 132 mmol) and N-methoxymethanamine hydrochloride (7.7 g, 79 mmol) at 0 °C. The reaction mixture was stirred under nitrogen atmosphere at 20 °C for 15 hours, then extracted with EtOAc (200 mL) fortimes. The combined organic layer was washed with brine, dried over anhydrous Na2504, filtered and concentrated. The residue was purified by column chromatography to give compound I-20b (11.5 g) as a white solid. MS obsd. (ESIj [(M+H)’i: 233.
5.5 g
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃;
A round-bottom flask was charged with 104 N-Boc-L-Ala-OH (5.0g, 26mmol), 35 N,O-dimethylhydroxylamine hydrochloride (3.1g, 32mmol), 105 HOBT (4.3g, 32mmol), 102 DIPEA (17g, 0.13mol), EDCI (6.1g, 0.32mol) and 94 dichloromethane(100mL). The resulting suspension was cooled to 0°C and was stirred overnight. The reaction mixture was washed with 1N hydrochloric acid solution, saturated sodium carbonate solution, and extracted by ethyl acetate. The combined organic phase were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether: ethyl acetate=5:1 to 3: 1) to afford weinreb 17 amide 13 as a white solid (5.5g, 90percent). [α]D20=−21.5, (c=1.0, MeOH). m. p.139°C νmax (KBr):3293, 3049, 3008, 2975, 2823, 1660, 1540, 1456, 1423cm−1.1H NMR (400MHz, CDCl3) δ 5.25 (d, J=7.4Hz, 1H), 4.66 (t, J=7.6Hz, 1H), 3.75 (s, 3H), 3.19 (s, 3H), 1.42 (s, 9H), 1.29 (d, J=6.9Hz, 3H). 13C NMR (100MHz, CDCl3) δ 173.8, 155.3, 79.6, 61.7, 46.6, 32.2, 28.4, 18.8. HRMS-ESI (m/z): [M+Na]+ calcd. for C10H20N2O4Na+, 255.1315; found, 255.1314.
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[51] Patent: EP2873658, 2015, A1, . Location in patent: Paragraph 0460
[52] Patent: WO2015/118057, 2015, A1, . Location in patent: Page/Page column 55
[53] Patent: JP2016/11286, 2016, A, . Location in patent: Paragraph 0501
[54] Patent: WO2017/58503, 2017, A1, . Location in patent: Page/Page column 299; 300
[55] Patent: WO2017/188720, 2017, A2, . Location in patent: Paragraph 222
[56] Patent: WO2018/11163, 2018, A1, . Location in patent: Page/Page column 35
[57] European Journal of Medicinal Chemistry, 2018, vol. 156, p. 21 - 42
40
[ 6638-79-5 ]
[ 146553-06-2 ]
Yield
Reaction Conditions
Operation in experiment
81%
With isopropylmagnesium chloride In tetrahydrofuran at -20℃; for 1.5 h;
In an inert atmosphere of argon, the phosphonium supported N-BocAla (21) (500 mg, 0.68 mmol) and Me(MeO)NH-HCl (100 mg, 1.02 mmol) were suspended in THF (4 ml). The resulting mixture was cooled to - 20 C, and i- PrMgCl (2 M in THF, 1.5 ml, 2.73 mmol) was added drop-wise. At that point, the colorless solution turned to yellow. The reaction mixture was stirred at - 20 C for 1.5 h, quenched with a sat. aq. soln. of NH4Cl (10 ml), and extracted with CH2C12 (2x 30 ml). The combined organic phases were washed with H20 (2x 60 ml), brine (2x 60 ml), dried (Na2S04), and concentrated in vacuo to afford a white foam. This white foam was taken up with CH2C12 (just a few amount), and washed with Et20 (50 ml). This operation was done twice. The Et20 phase was concentrated, affording compound (25) as a white residue, which was sufficiently pure (>95percent) (130 mg, 81percent). The compound (25) has been characterized as follows: 1H-NMR (400 MHz, CDC13): # 5.27 (d, J = 8.76, NH, 1 H), 4.63 (br. t, CH-alipha. , 1 H), 3.68 (s, OCH3,3 H), 3.13 (s, CH3,3 H), 1.35 (s, CH3,9 H), 1.26 (d, J= 6.92, CH3, 3 H). 13C-NMR (50 MHz, CDC13): 174.02, 155.55, 79.82, 61.97, 46.88, 32.51, 28.72, 18.99.
Reference：
[1] Journal of Medicinal Chemistry, 1997, vol. 40, # 25, p. 4113 - 4135
[2] Journal of Organic Chemistry, 2011, vol. 76, # 15, p. 6209 - 6217
[3] Zeitschrift fur Naturforschung - Section B Journal of Chemical Sciences, 2014, vol. 69, # 5, p. 615 - 626
42
[ 6638-79-5 ]
[ 146553-06-2 ]
Reference：
[1] Synlett, 2004, # 10, p. 1826 - 1828
43
[ 4530-20-5 ]
[ 6638-79-5 ]
[ 121505-93-9 ]
Yield
Reaction Conditions
Operation in experiment
96%
With dmap; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; dicyclohexyl-carbodiimide In dichloromethane; N,N-dimethyl-formamide at 0℃; for 24 h;
N-Boc-Gly-OH (10.5 g, 60.0 mmol), N, O-dimethylhydroxylamine hydrochloride (11.1 g, 120 mmol) and DIEA (31.2 g, 240 mmol) were dissolved in 1:1 1 CH2C12/DMF (500 mL) and cooled to 0 °C. 1-Hydroxy-1H- benzotriazole (HOBt, 11.0 g, 72.0 mmol), DCC (14.9 g, 72.0 mmol) and DMAP (ca. 100 mg) were added and the reaction was stirred for 24 h. The reaction was filtered to remove dicyclohexylurea and concentrated. The resulting slurry was diluted with 500 mL ethyl acetate and washed with NH4C1 (2 x 100 mL), NaHC03 (2 x 100 mL) and brine (100 mL). The organic layer was dried on MgS04 and concentrated. Chromatography on silica with 20percent EtOAc in hexane gave 12.6 g (96percent) of 4 as a colorless plate-like crystal. m.p. 101-102 °C. 1H NMR 8 5.25 (br, s, 1H), 4.07 (d, J=3.7, 2H), 3.70 (s, 3H), 3.19 (s, 3H), 1.44 (s, 9H).
94%
Stage #1: With dmap; triethylamine In dichloromethane at 0℃; for 1.5 h; Large scale Stage #2: at 0 - 24℃; for 25 h; Large scale
To a solution of Boc-Gly-OH (4250g, 24.26 mol), Ν,Ο-dimethylhydroxylamine- HCl(2839g, 29.10 mol) and DMAP(297g, 2.43 mol) in dichloromethane(36 L), is added triethylamine (5.54 L) at 0 °C over a period of 90 min followed by the addition of EDC hydrochloride (5674g, 29.60 mol). The mixture is stirred at 0 °C for lh then warmed to room temp for 24 h. The reaction mixture is cooled to 0 °C and quenched with 1.0M HC1 to pH 3 to 4, stirred at room temp for 20 min, then allowed to stand and separate. The organic phase is washed successively with 1.0M HC1 (15L), water (15.0 L) and brine (8.0 L), dried over Na2SC>4 and filtered. The filtrate is concentrated under reduced pressure to provide the title compound (4985 g; 94percent yield) as a white solid
90%
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide at 20℃;
Boc-glycine was coupled with N,O-dimethyl hydroxylamine hydrochloride, 1 equivalent, in DMF/CH2Cl2 (1:5) using HBTU reagent (1 eq.) and DIEA (2 eq.) at room temperature. The CH2Cl2 was evaporated in vacuo and the residue partitioned between diethyl ether and aq. NaHCO3. The aqueous layer was separated and the ether layer washed in turn with 1M HCl (.x.2), aq. NaHCO3, brine, and then dried over MgSO4. Filtration and removal of the solvent in vacuo left the product amide 69 as a viscous oil that slowly crystallised to a waxy solid and was further purified by chromatography on silica gel. Yield was >90percent. 1H NMR (300 MHz, CDCl3): δ 5.3, 1H, bs, NH; 4.09, 2H, bd, aH2; 3.72, 3H, s, OCH3; 3.20, 3H, s, NCH3; 1.46, 9H, s, Boc. 13C NMR (75 MHz, CDCl3): δ 79.6; 61.4; 41.7; 32.4; 28.3.
90%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 0 - 20℃; for 72.5 h;
Step 1: To a suspension of /V-(ie f-butoxycarbonyl)glycine (4.0 g, 23 mmol), Ν,Ο- dimethylhydroxylamine hydrochloride (3.0 g, 31 mmol) and /V,/V-dimethylpyridin-4-amine (300 mg, 2.5 mmol) in dry CH2CI2 (100 ml.) was added /V-(3-dimethylaminopropyl)-/V'- ethylcarbodiimide hydrochloride (5.2 g, 27 mmol) followed by triethylamine (5.4 mL, 39 mmol) at 0 °C. The mixture was stirred at that temperature 30 minutes and then at room temperature over 3 days. The suspension was washed with aqueous HCI (1 M, 2 x 40 mL) followed by a saturated aqueous solution of NaHC03 (2 x 40 mL). The organic layer was dried (Na2S04), filtered and concentrated in vacuo to yield fe/f-butyl {2-[methoxy(methyl)amino]-2-oxoethyl}carbamate as a white solid (4.5 g, yield 90percent). 1H-NMR (400 MHz, CDCI3): δ 1.45 (s, 9H), 3.20 (s, 3H), 3.71 (s, 3H), 4.08 (br s, 2H), 5.26 (br s, 2H).
82%
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 15 h; Inert atmosphere
Preparation Example 15fe -Butyl 2-(methoxy(methyl)amino)-2-oxoethylcarbamate (45)To a mixture of N-Boc-glycine 44 (10.0 g, 57.1 mmol), Ν,Ο- dimethylhydroxylamine hydrochloride (6.68 g, 68.5 mmol), EDCI (13.1 g, 68.5 mmol), and HOBt (9.26 g, 68.5 mmol) in CH2C12 (200 mL) was added NMM (31.4 mL, 285 mmol). The resulting mixture was stirred at room temperature for 15 h. The reaction mixture was poured into 1.0 M HC1 solution, and extracted with EtOAc. The organic phase was washed with a saturated NaHC03 solution and brine, and then dried over anhydrous MgS04. After evaporation of solvent, the residue was triturated with hexanes (100 mL) to provide the Weinreb amide 45 (10.2 g, 82percent) as white solid.
80%
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 16 h;
Example 54 - Synthesis of Compound 49 tert-butyl 2-(methoxy(methyl)amino)-2- oxoethylcarbamate (Boc-Gly Weinreb amide)49 tert-butyl 2-(methoxy(methyl)amino)- 2-oxoethylcarbamateTo a stirred mixture of Boc-Gly-OH (20 g, 114.1 mmol), DIPEA (19.8 ml_, 1 14.1 mmol) and BOP (50.5 g, 1 14.1 mmol) in DCM (20 ml.) was added a pre-mixed solution of N,O- dimethylhydroxylamine hydrochloride (11.2 g, 1 14.1 mmol) and DIPEA (19.8 ml_, 114.1 mmol) in DCM (20 ml.) at room temperature. The resulting mixture was stirred for 16 h then washed with 1 N HCI (3 x 120 ml_), H2O (3 x 120 ml_), saturated NaHCO3 aqueous solution (3 x 120 ml_) and brine (40 ml_), dried over MgSO4, filtered and concentrated under reduced pressure to give 49 as a white solid (20 g, 80percent), which was used in the next step without further purification. MS(ESI) 219 (M+1 ); HPLC fR 4.12 min.
80%
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 16 h;
To a stirred mixture of Boc-Gly-OH (20 g, 114.1 mmol), DIPEA (19.8 mL, 1 14.1 mmol) and BOP (50.5 g, 1 14.1 mmol) in DCM (20 mL) was added a pre-mixed solution of N, O- dimethylhydroxylamine hydrochloride (11.2 g, 1 14.1 mmol) and DIPEA (19.8 mL, 114.1 mmol) in DCM (20 mL) at room temperature. The resulting mixture was stirred for 16 h then washed with 1 N HCI (3 x 120 mL), H2O (3 x 120 mL), saturated NaHCO3 aqueous solution (3 x 120 mL) and brine (40 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give 34 as a white solid (20 g, 80percent), which was used in the next step without further purification. MS(ESI) 219 (M+1 ); HPLC fR 4.12 min.
80%
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 16 h;
To a stirred mixture of Boc-Gly-OH (20 g, 114.1 mmol), DIPEA (19.8 mL, 114.1 mmol) and BOP (50.5 g, 114.1 mmol) in DCM (20 mL) was added a pre-mixed solution of N,O-dimethylhydroxylamine hydrochloride (11.2 g, 114.1 mmol) and DIPEA (19.8 mL, 114.1 mmol) in DCM (20 mL) at room temperature. The resulting mixture was stirred for 16 h then washed with 1N HCl (3*120 mL), H2O (3*120 mL), saturated NaHCO3 aqueous solution (3*120 mL) and brine (40 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give 49 as a white solid (20 g, 80percent), which was used in the next step without further purification. MS (ESI) 219 (M+1); HPLC tR 4.12 min.
80%
Stage #1: With 4-methyl-morpholine; isobutyl chloroformate In dichloromethane at -25℃; for 0.5 h; Stage #2: at -25℃; for 5 h;
N-Boc-Gly-OH (20 mmol) was dissolved in CH2Cl2(100 mL) and cooled to 25 °C. NMM (44 mmol) and isobutyl chloroformate(22 mmol) were added. After stirring for 30 min, N,O-dimethylhydroxylaminehydrochloride (22 mmol) was added at 25 °C. After 5 h, the reaction mixturewas washed with 10percent KHSO4 (2 100 mL), sat. NaHCO3 (2 100 mL) and H2O(1 100 mL), dried over Na2SO4 and evaporated. The obtained yellowish solidwas purified by column chromatography using CH2Cl2/EtOAc (1+1) to give 1 asa white solid (80percent). mp 102–104 C (lit. 102–103 C);36 1H NMR (500 MHz,DMSO-d6) d 1.37 (s, 9H), 3.08 (s, 3H), 3.66 (s, 3H), 3.81 (d, 3J = 6.0 Hz, 2H), 6.79(t, 3J = 6.0 Hz, 1H); 13C NMR (125 MHz, DMSO-d6) d 28.31, 32.23, 40.95, 61.21,78.05, 156.00, one carbon signal (CH2CO) is missing; LC-MS (ESI) (90percent H2O to100percent MeOH in 10 min, then 100percent MeOH for 10 min, DAD 200.0–400.0 nm): tr =8.16 min, 96percent purity, m/z= 219.2 ([M+H]+).
77%
Stage #1: With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 0.5 h; Stage #2: at 20℃; for 12 h;
Example 33 (Compound 46) Step 1; N-tert-Butoxycarboxylglycine (10.0 g, 57.1 mmol) was dissolved in THF (100 mL). To the solution was added CDI (14.3 g, 59.0 mmol) at room temperature, and the mixture was stirred for 30 minutes. To the reaction mixture was added N,O-dimethylhydroxylamine hydrochloride (6.2 g, 64.0 mmol), and the mixture was further stirred at room temperature for 12 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give [(methoxymethylcarbamoyl)methyl]carbamic acid tert-butyl ester (9.55 g, yield: 77percent). APCI-MS m/z: 218 [M+H]+.
72%
Stage #1: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide at 0℃; for 1 h; Inert atmosphere Stage #2: With dmap; benzotriazol-1-ol In dichloromethane; N,N-dimethyl-formamide at 20 - 27℃; for 16 h;
Intermediate 83, [(teit-butoxycarbonyl)amino]acetic acid (5.00 g, 28.5 mmol), DIPEA (14.75 g, 104 mmol) and Intermediate 84, N-methoxymethanamine hydrochloride (5.60 g, 57.0 mmol)were dissolved in DCM (100 mL) and DMF (100 mL) and Intermediate 85, EDC hydrochloride (6.56 g, 34.0 mmol) was added. The reaction mixture was stirred under nitrogen at 0 °C for 1 h, then Intermediate 86, HOBt (4.63 g, 34.0 mmol) and DMAP (100 mg) were added portionwise and the resulting mixture was stirred for 16 h at room temperature. The reaction mixture was partitioned between H20 (250 mL) and DCM (100 mL), and the aqueous layer was furtherextracted with EtOAc (2 x 100 mL). The combined organic layers were dried (Na2SO4), filteredand the solvent was removed in vacuo. The residue was purified by column chromatography(Normal-Phase Silica, 0 to 3 percent methanol in DCM) to give tert-butyl {2-[methoxy(methyl)amino]-2-oxoethyl}carbamate (4.50 g, 72 percent) as a solid.LCMS (Method F): mlz 219 (M+H) (ES), at 1 .77 mi UV active.
71%
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;
2-(tert-Butoxycarbonylamino)acetic acid (800 mg, 4.57 mmol), N,O-dimethylhydroxylamine hydrochloride (535 mg, 5.48 mmol), EDCI (1.05 g, 5.48 mmol) and HOBt (740 mg, 5.48 mmol) were dissolved in DCM (25 mL), to which NMM (2.77 g, 27.42 mmol) was added at room temperature. The reaction mixture was stirred overnight. After the reaction was completed, DCM was evaporated in vacuo. The residue was dissolved in MeOH, filtered through a syringe filter, and then purified by reverse-phase preparative HPLC to provide the desired product (705 mg, 71percent) as a white solid1H NMR (400 MHz, CDCl3) δ 5.27 (br, 1H), 4.09 (d, J=4.6 Hz, 2H), 3.72 (s, 3H), 3.21 (s, 3H) 1.46 (s, 9H).MH+219.
6 g
Stage #1: With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane for 0.25 h; Cooling with ice Stage #2: With triethylamine In dichloromethane at 20℃; for 2 h;
A mixture of Boc-glycine (8.75g, 50mmol, 1 equiv), EDCI (11.5g, 60mmol) and HOBt (7.43g, 55mmol) in DCM (100ml) was stirred in an ice bath for 15min to give a clear solution. Then N,O-Dimethylhydroxylamine hydrochloride (5.1g, 52.5mmol) and triethylamine (5.85ml, 55mmol) were added and the mixture was stirred for 2h at room temperature. Water (100ml) was added and the solution was stirred tempestuously. The precipitate so formed was filtered off and the filtrate was transferred into a separating funnel. The organic phase was separated and the aqueous phase was extracted with CH2Cl2 once again. The combined organic phase was washed with brine (X2), dried over MgSO4 and concentrated. The residue was recrystallized from PE-EA to give F1 (6.0g) as a crystal.
6.0 g
Stage #1: With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane for 0.25 h; Stage #2: With triethylamine In dichloromethane at 20℃; for 2 h;
A mixture of l3oc-glycine (8.75 g, 50 mmol, 1 equiv), EDCI (11.5 g, 60 mmol) and HOSt (7.43 g, 55 mmol) in DCM (100 ml) was stirred in an ice bath for 15 mm to give a clear solution. Then N,O-Dimethylhydroxylamine hydrochloride (5.1 g, 52.5 mmol) and triethylamine (5.85 ml, 55 mmol) were added and the mixture was stirred for 2 h at room temperature. Water (100 ml) was added and the solution was stirred tempestuously. The precipitate so formed was filtered off and the filtrate was transferred into a separating funnel. The organic phase was separated and the aqueous phase was extracted with CH2C12 once again. The combined organic phase was washed with brine (X2), dried over MgSO4 and concentrated. The residue was recrystallized from PE-EA to give Fl (6.0 g) as a crystal.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 1, p. 65 - 77
[2] Tetrahedron, 2002, vol. 58, # 9, p. 1719 - 1737
[3] Patent: WO2005/105138, 2005, A2, . Location in patent: Page/Page column 15-16
[4] Patent: WO2014/66151, 2014, A1, . Location in patent: Page/Page column 12
[5] Patent: US2011/40087, 2011, A1, . Location in patent: Page/Page column 15
[6] Patent: WO2011/94823, 2011, A1, . Location in patent: Page/Page column 126-127
[7] Organic Letters, 2004, vol. 6, # 25, p. 4699 - 4702
[8] Journal of the American Chemical Society, 2006, vol. 128, # 51, p. 16456 - 16457
[9] ACS Medicinal Chemistry Letters, 2011, vol. 2, # 4, p. 303 - 306
[10] Tetrahedron, 2009, vol. 65, # 20, p. 4025 - 4034
[11] Patent: WO2011/159067, 2011, A2, . Location in patent: Page/Page column 58
[12] Journal of Medicinal Chemistry, 2017, vol. 60, # 21, p. 8963 - 8981
[13] Patent: WO2010/96853, 2010, A1, . Location in patent: Page/Page column 96
[14] Patent: WO2010/96854, 2010, A1, . Location in patent: Page/Page column 102
[15] Patent: US2012/141392, 2012, A1, . Location in patent: Page/Page column 53
[16] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 11, p. 2008 - 2012
[17] Journal of Medicinal Chemistry, 1995, vol. 38, # 2, p. 223 - 233
[18] Patent: EP1671957, 2006, A1, . Location in patent: Page/Page column 36-37
[19] Patent: WO2017/21730, 2017, A1, . Location in patent: Page/Page column 54
[20] Patent: US2008/207704, 2008, A1, . Location in patent: Page/Page column 19
[21] Journal of Medicinal Chemistry, 1996, vol. 39, # 2, p. 446 - 457
[22] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 10, p. 1501 - 1510
[23] Tetrahedron Letters, 1998, vol. 39, # 39, p. 6993 - 6996
[24] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 16, p. 2359 - 2364
[25] Tetrahedron, 2006, vol. 62, # 8, p. 1787 - 1798
[26] Organic Letters, 2002, vol. 4, # 16, p. 2665 - 2668
[27] Journal of Organic Chemistry, 2009, vol. 74, # 5, p. 1932 - 1938
[28] Patent: US2009/221557, 2009, A1, . Location in patent: Page/Page column 116
[29] Journal of Organic Chemistry, 2009, vol. 74, # 15, p. 5614 - 5617
[30] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 22, p. 8119 - 8133
[31] Patent: US2013/289020, 2013, A1, . Location in patent: Paragraph 0195; 0196
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[33] Patent: EP2725024, 2014, A1, . Location in patent: Paragraph 0552
[34] Patent: US2014/171431, 2014, A1, . Location in patent: Paragraph 0915
[35] European Journal of Organic Chemistry, 2014, vol. 2014, # 15, p. 3067 - 3071
44
[ 13734-36-6 ]
[ 6638-79-5 ]
[ 121505-93-9 ]
Yield
Reaction Conditions
Operation in experiment
95%
Stage #1: With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 2 h; Inert atmosphere Stage #2: at 20℃;
To a solution of 2-((tert-butoxycarbonyl)(methyl)amino)acetic acid (25.0 g, 132.0 mmol) in 300 mL of anhydrous THF under N2 atmosphere was added CDI (1.2 eq; 25.7 g; 159.0 mmol) portionwise over 10 min. The reaction mixture was stirred at room temperature for 2 h and N,O-dimethylhydroxylamine hydrochloride (1.2 eq.; 15.5 g; 159 mmol) and Et3N (1.2 eq; 22.0 mL; 159.0 mmol) were added. The resolution was stirred overnight at room temperature. The precipitated salts were filtered off and the filtrate was concentrated. The residue was diluted with H2O (300 mL) and extracted with EtOAc (3×100 mL). Combined organic phases were washed with 10percent KHSO4 (3×50 mL), saturated NaHCO3 (50 mL), water and brine, then dried over MgSO4 and concentrated. This gave tert-Butyl (2-(methoxy(methyl)amino)-2-oxoethyl)(methyl)carbamate as a colorless oil (29 g, 95percent). 1H-NMR spectrum in DMSO-d6 indicates a mixture of rotamers (1:1). 1H NMR (DMSO-d6) δ: 4.08 (s, 1H), 4.07 (s, 1H), 3.68 (s, 1.5H), 3.66 (s, 1.5H), 3.10 (s, 1.5H), 3.09 (s, 1.5H), 2.82 (s, 1.5H), 2.78 (s, 1.5H), 1.39 (s, 4.5H), 1.33 (s, 4.5H). MS 132 (MH+).
Stage #1: With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane for 0.166667 h; Stage #2: for 0.333333 h;
To a well stirred solution of Boc-Gly (21.02 g, 0.12 mole) and BOP (53.10 g, 0.12 mole) in 300 ml of DCM, was added DIEA (20.88 mi, 0.12 mole). After 10 min, a solution of O,N-dimethylhydroxylamine hydrochloride (14.05 g, 0.144 mole) and DIEA (31.32 ml, 0.18 mole) in 100 ml of DCM was added to above stirred solution. The reaction was monitored by TLC (silica gel, hexane-EtOAc =2:1). After 20 min, 200 ml of DCM was added to the reaction solution. The DCM solution was washed successively with 1 N aqueous hydrochloric acid solution (500 ml.x.4), saturated aqueous sodium bicarbonate solution (500 ml.x.3), and saturated aqueous sodium chloride solution (500 ml). The organic solution was dried with 5 g of magnesium sulfate overnight, filtered, and concentrated under reduced pressure. The residue was dissolved in a minimal volume of DCM, followed by addition of hexane until the solution became cloudy. The solution was warmed until it became clear and then kept to stay at room temperature to give colorless needles of 19 (21 g). Yield: 80percent. TLC Rf=0.24 (hexane-EtOAc=2:1).1H-NMR (90 MHz, CDCl3) δ ppm: 5.21 (s, br, 1 H), 4.05 (d, 2 H, J=5.0 Hz), 3.70 (s, 3 H), 3.18 (s, 3 H), and 1.45 (s, 9 H).
Reference：
[1] European Journal of Medicinal Chemistry, 1991, vol. 26, # 9, p. 921 - 928
50
[ 6638-79-5 ]
[ 18185-77-8 ]
[ 121505-93-9 ]
Reference：
[1] Journal of Organic Chemistry, 2011, vol. 76, # 15, p. 6209 - 6217
51
[ 6638-79-5 ]
[ 4635-59-0 ]
[ 64214-66-0 ]
Yield
Reaction Conditions
Operation in experiment
96%
With triethylamine In dichloromethane at 0 - 20℃; for 3 h;
N,O-dimethylhydroxylamine hydrochloride (30.4 g, 0 . 31 µM) dissolved in dichloromethane (500 ml), cooled in a ice bath cooling, and triethylamine (65 g, 0.64 µM) added and stirred, then compound 1 (40 g, 0.28 µM) dropped, in controlled temperature 0 - 6 degree c. The completion of the dropping, the reaction is carried out at room temperature 3 hours, dilute hydrochloric acid for (1 M) quenching. Separating the organic layer, the organic layer sequentially saturated NaHCO3 (100 ml) and saturated salt water (100 ml) each washing again, using anhydrous Na2 SO4 Drying, the solvent is removed under reduced pressure, to obtain compound 2 (45 g, 96percent, light brown liquid).
95%
With pyridine In dichloromethane at 0 - 20℃; for 1 h;
Step 1. 4-chloro-N-methyl-N (methyloxy) butanamide To a solution of 4-chlorobutanoyl chloride (5.64 g, 40.0 mmol) and a N, O- dimethylhydroxylamine hydrochloride (3.91 g, 40.0 mmol) in CH2C12 (80 mL) at 0 °C, was added pyridine (7.2 ml, 88.0 mmol) in CHzClx (30 mL). This mixture was kept stirring at 0 °C for lh, then warmed to rt. The reaction mixture then diluted with Et20 (200 mL), washed with saturated IN HCl (2X), saturated NaHC03 solution and brine, dried over Na2S04, filtered and concentrated to afford the title compound as a colorless oil (6.28 g, 95percent).
95%
With pyridine In dichloromethane at 0 - 20℃; for 1 h;
Step 1. 4-chloro-N-methyl-N (methyloxy) butanamide To a solution of 4-chlorobutanoyl chloride (5.64 g, 40.0 mmol) and a N, O- dimethylhydroxylamine hydrochloride (3.91 g, 40.0 mmol) in CH2C12 (80 mL) at 0 °C, was added pyridine (7.2 ml, 88.0 mmol) in CHzClx (30 mL). This mixture was kept stirring at 0 °C for lh, then warmed to rt. The reaction mixture then diluted with Et20 (200 mL), washed with saturated IN HCl (2X), saturated NaHC03 solution and brine, dried over Na2S04, filtered and concentrated to afford the title compound as a colorless oil (6.28 g, 95percent).
94%
With triethylamine In dichloromethane at 0℃; for 3.5 h;
To a solution of 4-chlorobutanoyl chloride (50.0 g, 355 mmol) and N-MeO-N-Methyl amine HCl (34.6 g, 355 mmol) in DCM (709 mL) was slowly added TEA (109 mL, 780 mmol) at 0° C. over 30 minutes. The reaction mixture was stirred at 0° C. for 3 hours and then treated with water (250 mL). The separated organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford 4-chloro-N-methoxy-N-methylbutanamide (55.0 g, 94percent) as yellow oil, which was used for the next reaction without further purification. 1H-NMR (CDCl3, Varian, 400 MHz): δ 2.12 (2H, quint, J=6.4 Hz), 2.63 (2H, t, J=7.2 Hz), 3.19 (3H, s), 3.64 (2H, t, J=6.4 Hz), 3.71 (3H, s).
92%
With potassium carbonate In diethyl ether; water at 0 - 20℃; Inert atmosphere
General procedure: To an aqueous solution of K2CO3 (2.0 equiv.) was added Et2O andN,O-dimethylhydroxyamine hydrochloride (1.5 equiv.). The resultingmixture was cooled at 0 °C and after 2 min the correspondingacyl chloride (1.0 equiv.) was added dropwise. The reaction wasstirred overnight until the room temperature was reached. Thereaction mixture was extracted with Et2O (2 5 mL) and washedwith water (5 mL) and brine (10 mL). The organic phase was dried(anhydrous Na2SO4), filtered and, after removal of the solvent underreduced pressure, the pure compounds 2-3 were obtained.
79 g
Stage #1: With pyridine In dichloromethane at 0℃; for 0.25 h; Stage #2: at 0℃; for 2 h;
Pyridine (101.28 g, 106.6mL 1281.79 mmol) was added to a solution of N,0- dimethylhydroxylamine hydrochloride (50 g, 512.72 mmol) in DCM (800mL) at 0°C and stirring was continued for 15 min. Chlorobutyrylchloride (72.29 g, 512.72 mmol) was then added to this mixture and was stirred continuously at 0°C for 2 h. The reaction mixture was diluted with DCM and the organic layer was washed with water followed by brine. The organic layer was separated; dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 79 g of the title compound as a pale brown liquid. MS (ESI): m/z 166.1(M+H)
79 g
Stage #1: With pyridine In dichloromethane at 0℃; for 0.25 h; Stage #2: at 0℃; for 2 h;
Pyridine (101.28 g, 106.6 mL 1281.79 mmol) was added to a solution of N,O-dimethylhydroxylamine hydrochloride (50 g, 512.72 mmol) in DCM (800 mL) at 0° C. and stirring was continued for 15 min. Chlorobutyrylchloride (72.29 g, 512.72 mmol) was then added to this mixture and was stirred continuously at 0° C. for 2 h. The reaction mixture was diluted with DCM and the organic layer was washed with water followed by brine. The organic layer was separated; dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 79 g of the title compound as a pale brown liquid. MS (ESI): m/z 166.1 (M+H).
Reference：
[1] Patent: CN104672121, 2017, B, . Location in patent: Paragraph 0038-0040
[2] Patent: WO2005/37197, 2005, A2, . Location in patent: Page/Page column 104
[3] Patent: WO2005/37197, 2005, A2, . Location in patent: Page/Page column 104
[4] Patent: US2016/168156, 2016, A1, . Location in patent: Paragraph 0195; 0197; 0198
[5] European Journal of Medicinal Chemistry, 2018, vol. 158, p. 353 - 370
[6] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 14, p. 4141 - 4145
[7] Synthesis, 2001, # 15, p. 2239 - 2246
[8] Patent: US5981550, 1999, A,
[9] Patent: US5985901, 1999, A,
[10] Patent: US5985901, 1999, A,
[11] Patent: US6156767, 2000, A,
[12] Patent: US6156772, 2000, A,
[13] Patent: US6156767, 2000, A,
[14] Patent: US5756507, 1998, A,
[15] Patent: US5780437, 1998, A,
[16] Patent: US6197975, 2001, B1,
[17] Patent: US6200957, 2001, B1,
[18] Patent: WO2013/59437, 2013, A1, . Location in patent: Paragraph 0186-0187
[19] Patent: WO2013/88256, 2013, A1, . Location in patent: Page/Page column 57
[20] Journal of Organic Chemistry, 2013, vol. 78, # 18, p. 9181 - 9189
[21] Patent: US2014/371217, 2014, A1, . Location in patent: Paragraph 0551
[22] Tetrahedron Letters, 2017, vol. 58, # 27, p. 2640 - 2643
[23] Patent: CN108003161, 2018, A, . Location in patent: Paragraph 0324-0328
52
[ 6638-79-5 ]
[ 7623-11-2 ]
[ 64214-66-0 ]
Yield
Reaction Conditions
Operation in experiment
79 g
Stage #1: With pyridine In dichloromethane at 0℃; for 0.25 h; Stage #2: at 0℃; for 2 h;
Pyridine (101.28 g, 106.6 mL 1281.79 mmol) was added to a solution of N,O-dimethylhydroxylamine hydrochloride (50 g, 512.72 mmol) in DCM (800 mL) at 0° C. and stirring was continued for 15 min. Chlorobutyrylchloride (72.29 g, 512.72 mmol) was then added to this mixture and was stirred continuously at 0° C. for 2 h. The reaction mixture was diluted with DCM and the organic layer was washed with water followed by brine. The organic layer was separated; dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 79 g of the title compound as a pale brown liquid. MS (ESI): m/z 166.1 (M+H)
With triethylamine In dichloromethane at 0 - 25℃; for 16 h;
In a dry ice/acetone bath, a suspension of N,O-dimethylhydroxylamine hydrochloride (350.53 g, 3.59 mol) in methylene chloride was cooled to O0C and TEA (71 1.5 g, 7.03 mol) was added. Compound 113 was dissolved in methylene chloride (2.4 L) and added to the mixture at a rate such that the reaction mixture temperature did not exceed 150C. After the addition of 113 was complete, the reaction mixture was allowed to warm slowly to a temperature of about 250C over 16 h. Then the reaction mixture was poured into 2L of water, the layers were separated, and the aqueous portion was extracted twice with methylene chloride (500 mL for each extraction). The organic portions were combined, dried (MgSO4), and concentrated under reduced pressure to yield a brown solid. The solid was treated with I L of boiling hexanes and heated at reflux for about 10 minutes. The resulting pale orange solution was decanted from the dark yellow-brown tar and allowed to cool. This boiling hexanes treatment was repeated twice on the tar (500 mL for each treatment). The hexane mixtures were combined, allowed to cool to a temperature of about 250C, then cooled in an ice/water bath. The resulting yellow needles were collected by vacuum filtration and dried in air to provide 730 g of 5,6-dichloro-N-methoxy-N-methylnicotinamide 114 (99percent yield). 1H NMR (400 MHz, CDCl3) δ 8.68 (m, I H), 8.18 (m, I H), 3.59 (OCH3, 3H), 3.40, (NCH3, 3H).
I. N-Methoxy-2-methyl-N-methylpropanamide. To a solution of N,O-dimethyl hydroxylamine hydrochloride (5.61 g, 57.5 mmol) and triethylamine (17.6 mL, 126.5 mmol) in methylene chloride (100 mL) was added isobutyryl chloride (6.02 mL, 57.5 mmol) dropwise. The reaction was stirred at room temperature overnight. The reaction was washed with water (100 mL) and the organic layer was dried over magnesium sulfate. Solvent was removed under reduced pressure and crude purified using column chromatography (SiO2, n-Hexanes to 9:1 n-Hexanes:ethyl acetate) to provide the title compound (5.55 g, 74percent). 1H NMR (300 MHz, DMSO-d6) δ 3.72 (s, 3H), 3.31 (m, 1H), 3.18 (s, 3H), 1.09 (d, J=6.87, 6H).
Reference：
[1] Organic Letters, 2012, vol. 14, # 9, p. 2250 - 2253
[2] Journal of Medicinal Chemistry, 2015, vol. 58, # 7, p. 3117 - 3130
[3] Journal of Medicinal Chemistry, 2017, vol. 60, # 12, p. 4840 - 4860
[4] Chemistry - A European Journal, 2017, vol. 23, # 57, p. 14345 - 14357
[5] Organic and Biomolecular Chemistry, 2013, vol. 11, # 20, p. 3337 - 3340
[6] Patent: US2008/242694, 2008, A1, . Location in patent: Page/Page column 66
[7] Synlett, 2008, # 19, p. 3036 - 3040
[8] European Journal of Organic Chemistry, 2018, vol. 2018, # 12, p. 1416 - 1425
56
[ 6638-79-5 ]
[ 403-43-0 ]
[ 116332-54-8 ]
Yield
Reaction Conditions
Operation in experiment
97%
With pyridine In dichloromethane
Step 1. N-methoxy-N-methyl-4-fluorobenzamide. To a 0° C. solution of 4-fluorobenzoyl chloride (11.9 g, 75.0 mmol) in CH2 Cl2 (150 mL) was added N,O-dimethylhydroxylamine hydrochloride (8.00 g, 82.0 mmol) and a solution of pyridine (13.0 g, 164 mmol) in CH2 Cl2 (25 mL). The cold bath was removed and the reaction mixture was stirred for 2 hours at ambient temperature and then was washed with 0.5N aqueous HCl (3*100 mL), saturated aqueous NaHCO3, and brine. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to give N-methoxy-N-methyl-4-fluorobenzamide (13.3 g, 97percent) as an oil.
96%
With pyridine In chloroform at 0 - 22℃; for 1 h;
4-Fluorobenzoyl chloride (15g, 94.6 mmol) and N,O-dimethylhydroxylamine hydrochloride (10.1g, 104mmol) were dissolved in CHCl3 (200mL) and stirred at room temperature. The solution was cooled to 0°C and pyridine (17.3mL, 230mmol) was added. The mixture was warmed and stirred at room temperature for 1h and then poured into aq. sat. NaCl solution (300mL). The organic layer was separated and the aqueous layer extracted with CH2Cl2 (3×100mL). The combined organic layers were washed with water (3×50mL), dried (anhyd. Na2SO4) and then evaporated. The crude 4-fluoro-N-methoxy-N-methylbenzamide 7a was purified via distillation under vacuum to afford a colourless liquid (96percent), bp=120°C at 0.3 mmHg (lit. b.p. 70°C at 0.1mmHg [13]); νmax 583, 905, 918, 1262, 1375, 1508, 1582, 1630, 2972, 3274cm−1; δH 3.34 (3H, s, CH3), 3.52 (3H, s, OCH3), 7.08 (2H, m, Ar–H), 7.73 (2H, m, Ar–H).
88%
With triethylamine In dichloromethane at 5℃; for 0.5 h;
In A VOLUMETRIC flask N,O-dimethylhydroxylamine hydrochloride (25.54 g, 261.8 mmol) and CH2Cl2 (443 mL) were introduced under argon atmosphere at 0°C. 4- Fluorobenzoyl chloride (34. 59 G, 218. 2 MMOL) WAS ADDED FOLLOWED BY THE SLOW addition OF TRIETHYLAMINE (48. 13 G, 475. 6 MMOL). THE REACTION WAS STIRRED FOR 30 min at 5 C and allowed to reach room temperature. It was washed with 5percent aqueous citric acid (180 ML) and with 5percent aqueous NaHCO3 (180 ML). The aqueous phase was extracted with CH2Cl2. The organic phase was dried over NA2S04 and concentrated to dryness, to afford 20. 23 G OF THE DESIRED COMPOUND (YIELD : 88percent).
Reference：
[1] Bioorganic and Medicinal Chemistry, 1997, vol. 5, # 1, p. 49 - 64
[2] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 5, p. 1352 - 1357
[3] Organic and Biomolecular Chemistry, 2013, vol. 11, # 20, p. 3337 - 3340
[4] Journal of Organic Chemistry, 2007, vol. 72, # 15, p. 5828 - 5831
[5] Patent: US5616596, 1997, A,
[6] Dyes and Pigments, 2015, vol. 113, p. 239 - 250
[7] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 3, p. 333 - 336
[8] Patent: WO2006/21449, 2006, A1, . Location in patent: Page/Page column 8; 9
[9] Patent: WO2004/76450, 2004, A1, . Location in patent: Page 37
[10] Angewandte Chemie - International Edition, 2013, vol. 52, # 33, p. 8551 - 8556[11] Angew. Chem., 2013, vol. 125, # 33, p. 8713 - 8718,6
[12] Patent: WO2004/18458, 2004, A1, . Location in patent: Page/Page column 57-58
[13] Patent: US2014/107097, 2014, A1, . Location in patent: Paragraph 0420; 0421
[14] Molecular Pharmacology, 2016, vol. 89, # 6, p. 667 - 677
[15] Journal of Organic Chemistry, 2017, vol. 82, # 2, p. 1114 - 1126
[16] Patent: US2018/237419, 2018, A1, . Location in patent: Paragraph 0314
57
[ 456-22-4 ]
[ 6638-79-5 ]
[ 116332-54-8 ]
Yield
Reaction Conditions
Operation in experiment
96%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 3 h;
General procedure: To a solution of 3-cyanobenzoic acid 8a (3.0 g, 19.7 mmol) in DMF was added N,O-dimethylhydroxylamine hydrochloride (2.0 g, 20.7 mmol), Et3N (2.88 mL, d = 0.73, 20.7 mmol) and EDC*HCl (4.0 g, 20.7 mmol). After the mixture was stirred for 3 h at room temperature, the solvent was removed in vacuo and the residue was dissolved in EtOAc, washed with 10percent citric acid, 10percent NaHCO3 and saturated NaCl, and dried over Na2SO4. Then, the solvent was removed to give a colorless oil of compound 9a (3.0 g, 79percent).
92%
Stage #1: With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In tetrahydrofuran; ethyl acetate at 0 - 5℃; for 0.166667 h; Inert atmosphere Stage #2: at 0 - 25℃; for 1.33333 h; Inert atmosphere
General procedure: To a solution of acid 1 (1.0g, 8.9 mmol) in THF (15 mL) was added Et3N (3.1 mL, 22.2 mmol), and T3P (50percent solution in EtOAc, 10.6mL, 17.7 mmol) at 0-5 °C and the solution was stirred for about 10 min under a nitrogen atmosphere. Then N,O-dimethylhydroxylaminehydrochloride salt (1.1g, 13.3 mmol) was added to the reaction mixture at 0-5 °C and the heterogeneous mixture was allowed to stir at room temperature till the completion of the reactionas indicated by TLC (see Table S-1). The mixture was then diluted with water(20 mL) followed by ethyl acetate (20 mL) and stirred for about 10 min. The separated organic layer was collected, washed with 5percent citric acid (2 x10 mL),5percent Na2CO3 (2 x 10 mL), and then brine solution. The collected organic layer was dried over anhydrous Na2SO4, filtered and concentrated under low vacuum. The crude product obtainedwas purified by flash column chromatography over silicagel (100-200 mesh) using 12-15percent EtOAc / n-hexane as eluent to affordthe desired compound.
79%
at 20℃; for 2 h;
Step 4a: 4-Fluoro-N-methoxy-N-methyl-benzamide (4a)To a solution of 4-fluorobenzoic acid (6.8 g, 48.57 mmole) in 100 mL of DMF at room temperature, is added diisopropylethylamine (25.3 mL, 145.7 mmole). After stirring at room temperature for 20 minutes, HOBT (7.22 g, 53.43 mmole), HBTU (20.26 g, 53.43 mmole) and N,O-dimethyl hydroxylamine hydrochloride (5.69 g, 58.29 mmole) are added to the reaction solution. After stirring at room temperature for 2 hours, the reaction solution is diluted with 200 mL of EtOAc and washed with 4.x.50 mL of water. The combined organic layers is concentrated and purified by flash column chromatography (hexane 70percent, EtOAc 30percent) to yield 4-fluoro-N-methoxy-N-methyl-benzamide (4a) (7.0 g, yield 79percent).
77%
Stage #1: With chloroformic acid ethyl ester; triethylamine In dichloromethane at 10℃; for 0.833333 h; Stage #2: With triethylamine In dichloromethane at 10℃; for 1 h;
Method C: a solution of ethyl chloroformate (3.40mL, 35.68mmol) in anhydrous dichloromethane (6mL) was added dropwise at 10°C to a solution of 4-fluorobenzoic acid (5.00g, 35.68mmol) and triethylamine (5mL, 35.68mmol) in anhydrous dichloromethane (50mL). This reaction mixture was stirred at 10°C for 50min, and then N,O-dimethylhydroxylamine hydrochloride (3.48g, 35.68mmol) and triethylamine (5mL, 35.68mmol) were added. The resulting mixture was stirred for 1h at 10°C and the suspension was taken up in water (150mL) and extracted with CH2Cl2 (150mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was finally chromatographed on silica gel eluting with ethyl acetate:petroleum ether (gradient from 0/100 to 20/80 v/v) to give 77percent of 3a as clear oil. 1H NMR (300MHz, CDCl3) δ 7.69 (m, 2H, F-Ph-2,6), 7.02 (m, 2H, F-Ph-3,5), 3.47 (d, 3H, J=1.2Hz, OCH3), 3.29 (d, 3H, J=1.2Hz, NCH3). 13C NMR (75MHz, CDCl3) δ 168.7, 164.0 (J=249Hz), 130.8 (2×C, J=9Hz), 129.8 (J=3Hz), 115.0 (2×C, J=22Hz), 61.0, 33.6.
57%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃;
To a solution of 4-fluorobenzoic acid (200 g, 1.43 mol), N,O-dimethylhydroxylamine hydrochloride (207 g, 2.14 mol) and EDCI (407 g, 2.14 mol) in dichloromethane (2 L) was added diisopropylethylamine (553 g, 4.28 mol) at 0° C. and the mixture was stirred at RT overnight. The reaction mixture was then washed with aqueous HCl (1 N, 1 L*4), water (1 L) and brine (1 L) sequentially. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give the title compound (150 g, yield 57percent). MS (ES+) C9H10FNO2 requires: 183. found 184 [M+H]+; purity: 90percent (UV254).
53.9%
Stage #1: With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1 h; Stage #2: With triethylamine In dichloromethane at 20℃; for 2 h;
Reference：
[1] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 14, p. 4279 - 4289
[2] Tetrahedron Letters, 2016, vol. 57, # 35, p. 3924 - 3928
[3] Patent: US2011/65726, 2011, A1, . Location in patent: Page/Page column 14
[4] European Journal of Medicinal Chemistry, 2015, vol. 89, p. 386 - 400
[5] Patent: US2015/111887, 2015, A1, . Location in patent: Paragraph 0293; 0294; 0295
[6] Patent: WO2018/153279, 2018, A1, . Location in patent: Paragraph 87-88
58
[ 15226-74-1 ]
[ 6638-79-5 ]
[ 460-00-4 ]
[ 116332-54-8 ]
Yield
Reaction Conditions
Operation in experiment
80%
With palladium diacetate; triethylamine; [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane In 1,4-dioxane at 90℃; for 1 h; Sealed tube
General procedure: A mixture of arylhalide (I, Br) (1 mmol), Weinreb amine hydrochloride(1.5 mmol), Pd(OAc)2 (5 mol percent), xantphos (6 mol percent), triethylamine (3 mmol), and cobalt carbonyl (0.3 mmol) in 1,4-dioxane was heated at 90 °C for 1h in a septum-closed sealed tube. After cooling, the reaction mixture was concentrated in vacuum and the residue was extracted with ethylacetate and water. The ethylacetate layer was concentrated and the residue obtained was purified by flash column chromatography to get the desired product. Note: Carbon monoxide gas is highly toxic and should be handled by trained professionals in a well-ventilated fumehood with appropriate ventilation. In all the reactions, Co2(CO)8 was handled carefully in fumehoods using appropriate personal protective clothing and equipment.
With potassium carbonate In water; acetonitrile at 20℃; for 2 h;
The method of Faul et al. was used. To a suspension of N,O-dimethylhydroxyamine hydrochloride (7.07 g, 72.5 mmol) and K2C03 (10.0 g, 72.5 mmol) in ACN (100 mL) and water (50 mL) was added 4-cyanobenzoyl chloride (27) (8.00 g, 48.3 mmol), and the reaction was stirred for 2 h at room temperature. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo to give a crude solid that was purified by column chromatography (250 mL Si02, hexanesrethyl acetate 45:55 to 1 : 1) to give 28 (8.12 g, 88percent) as a white crystalline solid: ? NMR (400 MHz, CDC13) ? 7.76 (d, J= 8.4, 2H), 7.69 (d, J= 8.4, 2H), 3.50 (s, 3H), 3.36(s, 3H); 13C NMR (100.6 MHz, CDC13) ? 167.8, 138.2, 131.8, 128.7, 118.1, 114.0, 61.2, 33.0; GC-MS (M)+ calcd for C10H10N2O2 190.0742, found 190.0739.
Reference：
[1] Patent: WO2013/40227, 2013, A2, . Location in patent: Page/Page column 27; 28
[2] Journal of Medicinal Chemistry, 2013, vol. 56, # 21, p. 8432 - 8454
[3] Journal of Organic Chemistry, 2001, vol. 66, # 17, p. 5772 - 5782
[4] Journal of Medicinal Chemistry, 2008, vol. 51, # 19, p. 6138 - 6149
[5] Journal of Organic Chemistry, 2003, vol. 68, # 14, p. 5500 - 5511
[6] European Journal of Organic Chemistry, 2013, # 22, p. 4918 - 4932
63
[ 623-03-0 ]
[ 201230-82-2 ]
[ 6638-79-5 ]
[ 116332-64-0 ]
Reference：
[1] Organic Letters, 2006, vol. 8, # 21, p. 4843 - 4846
[2] Journal of Organic Chemistry, 2008, vol. 73, # 18, p. 7102 - 7107
64
[ 201230-82-2 ]
[ 3058-39-7 ]
[ 6638-79-5 ]
[ 116332-64-0 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2014, vol. 12, # 30, p. 5727 - 5732
Reference：
[1] Australian Journal of Chemistry, 2017, vol. 70, # 1, p. 44 - 51
69
[ 6638-79-5 ]
[ 4023-34-1 ]
[ 147356-78-3 ]
Yield
Reaction Conditions
Operation in experiment
72.9%
With triethylamine In dichloromethane at 0 - 20℃;
Example 96. Synthesis of 3-fluoro-2-(4-(3-(5-hydroxy-2-methylpiperidin-l-yl)- -pyrazol-l-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)benzonitrile, 1-96 Synthesis of compound 96.2. To a solution of Ν,Ο-dimethylhydroxylamine HCl (10.0g, 95.69 mmol, 1.0 eq) and Et3N (19.36 g, 191.6 mmol, 2.0 eq) in CH2C12 (60 mL) reaction mixture was stirred at 0 °C for 30 min. Compound 96.1 was added at 0 °C. Reaction mixture was stirred at room temperature for 15 h. Upon completion of the reaction, organic layer was washed with water, brine, sat NaHCC solution and 1.0 N HCl, dried over Na2S04 and concentrated under reduced pressure to pressure to obtain crude. Crude was purified by column chromatography to provide 96.2 (9.0 g, 72.9percent).
61%
With triethylamine In dichloromethane at 0℃; for 1 h; Cooling with ice
N,O-dimethyl-hydroxylamine HCl (40 g, 410 mmol) was suspended under nitrogen in DCM (400 mL) and cooled in ice. Triethylamine (63 mL, 451 mmol) was added slowly, then cyclopropanecarbonyl chloride (41 mL, 451 mmol) was added slowly. Stirring without cooling was continued for 1 h. Extraction: 2.x.DCM, 1.x.1N HCl, 1.x.NaCl. Distillation: 75° C./20 mbar. One obtained 32.5 g (61percent) of a colorless oil.
61%
With triethylamine In dichloromethane at 0℃; for 1 h;
Cyclopropanecarboxylic acid methoxy-methyl-amide N, O-dimethyl-hydroxylamine HC1 (40 g, 410 mmol) was suspended under nitrogen in DCM (400 mL) and cooled in ice. Triethylamine (63 mL, 451 mmol) was added slowly, then cyclopropanecarbonyl chloride (41 mL, 451 mmol) was added slowly. Stirring without cooling was continued for 1 h. Extraction: 2 x DCM, 1 x 1 N HC1, 1 x NaCl. Distillation: 75 °C/20 mbar. One obtained 32.5 g (61 percent) of a colorless oil.
Reference：
[1] Patent: KR2016/5361, 2016, A, . Location in patent: Paragraph 0805; 0808; 0809-0811
72
[ 76271-74-4 ]
[ 6638-79-5 ]
[ 154698-93-8 ]
Yield
Reaction Conditions
Operation in experiment
85%
With dicyclohexyl-carbodiimide In dichloromethaneReflux
Acid 9 (7.34 g, 23.3 mmol) and N,O-dimethylhydroxylamine hydrochloride (6.83 g, 69.9 mmol) were dissolved in CH2Cl2 (20 mL) at room temperature. To this mixture was added, slowly, DCC (14.4 g, 69.9 mmol) in CH2Cl2 (23 mL) and then refluxed until all the starting material had been consumed (TLC). After cooling to room temperature, H2O was added, the resulting mixture was extracted with ethyl acetate (3 .x. 30 mL), the extracts dried with anhydrous MgSO4, concentrated under vacuum and purified by flash chromatography (30:70 EtOAc/hexanes) to afford 10 as white crystals (7.10 g, 85percent yield). Mp = 53.4-54.8 °C. 1H NMR (400 MHz, CDCl3): δ 7.74-7.72 (m, 4H), 7.42-7.37 (m, 6H), 4.43 (s, 2H), 3.43 (s, 3H), 3.13 (s, 3H), 1.10 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 180.4, 135.5, 133.1, 129.8, 127.7, 62.0, 61.2, 32.5, 26.7, 19.4. FT-IR (KBr): 1691 (CO). M/z 300.4 (M+-tBu). Elemental Anal. Calcd: C, 67.19; H, 7.61; N, 3.92. Obtained: C, 67.30; H, 7.23; N, 4.30.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 3, p. 1236 - 1241
73
[ 6638-79-5 ]
[ 154698-92-7 ]
[ 154698-93-8 ]
Reference：
[1] Journal of Organic Chemistry, 1994, vol. 59, # 1, p. 74 - 79
[2] Synthetic Communications, 1998, vol. 28, # 20, p. 3727 - 3741
74
[ 6638-79-5 ]
[ 84358-13-4 ]
[ 139290-70-3 ]
Yield
Reaction Conditions
Operation in experiment
100%
Stage #1: With triethylamine In DMF (N,N-dimethyl-formamide) at 20℃; for 0.166667 h; Stage #2: With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In DMF (N,N-dimethyl-formamide) Stage #3: With hydrogenchloride In water
To a stirring suspension of t-Boc-isonipecotic acid (19) (2.34 g, 10.2 mmol) and the Weinreb amine (1.5 g, 15 mmol) in DMF (50 mL), was added triethylamine (2.8 mL, 20 mmol) at room temperature. After stirring for 10 min, HOBt (1.62 g, 12 mmol) was added, followed by EDCI (2.3 g, 12 mmol). The resulting solution was stirred overnight and concentrated. The residue was taken up in 1 N HCl (100 mL) and extracted with EtOAc (3.x.100 mL). The combined organic extracts were washed with sat NaHCO3 (50 mL), brine (50 mL), dried (MgSO4) and concentrated to obtain a colorless oil (20) (2.79 g, >100percent). 1H NMR (500 MHz, CDCL3) δ4.14 (m, 2H), 3.71 (s, 3H), 3.19 (s, 3H), 2.78 (m, 3H), 1.68 (m, 4H), 1.46 (s, 9H); MS (ESI+) m/z 217.72 (M+H+-isobutylene).
99%
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 48 h;
PREPARATION 557erf-butyl 4-acetylpiperidine-1 -carboxylatea) Tert-butyl 4-[methoxy(methyl)amino]carbonyl}piperidine-1 -carboxylateTo a solution of N.O-dimethylhydroxylamine hydrochloride (894 mg, 9.17 mmol), 2- benzotriazol-1-yl-N,N,N',N'-tetramethyluronio hexafluorphosphate (HBTU) (3.48 g, 9.17 mmol) and diisopropylethylamine (DIPEξA) in N,N-dimethylformamide (40 mL) was carefully added 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (2 g, 8.73 mmol) and the reaction mixture was stirred at room temperature for 2 days. The mixture was diluted with water (200 mL), extracted with ethyl acetate, washed with aqueous citric acid 5percent, aqueous sodium bicarbonate 4percent, water, and brine and dried over sodium sulphate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica flash, using ethyl acetate as eluent (isocratic), to yield the title compound (2.63 g, 99percent) as yellowish oil. <n="63"/>1H-NMR δ (CDCI3): 1.46 (s, 9H), 1.63-1.74 (m, 4H), 2.70-2.84 (m, 3H), 3.19 (s, 3H), 3.72 (s, 3H), 4.11-4.18 (m, 2H).
99%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;
To a solution of compound 25 (40 g, 175 mmol) in DMF (250 mL) at 4°C was added N.O - dimethyl-OHamine, hydrochloride (34 g), EDCI (44 g, 0.228 mol), HOBT (2.4 g), and DIPEA (120 mL). The reaction was warmed to room temperature and stirred overnight. The reaction was then concentrated to half volume in vacuo and poured onto 1:1 ethyl acetate: water. The organic layer was separated and the aqueous layer extracted with additional ethyl acetate. The combined organic layers were washed with saturated aqueous NH4Cl, saturated aqueous NaHCO3, water, and brine, and dried. Concentration gave 26 as a light yellow oil (46.7 g, 99percent)
95%
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 72 h;
Intermediate 1; 1,1-dimethylethyl4-[methyl(methyloxy)amino]carbonyl}-1-piperidine-carboxylate; QN,O-Dimethylhydroxylamine hydrochloride (4.26 g, 43.7 mmols), di-isopropylethylamine (33.88 g, 45.66 ml, 262.2 mmols) and HATU (19.94 g, 52.4 mmols) were added to a solution of N-Boc-piperidine-4-carboxylic acid (11.03 g, 48.1 mmols) in dry DMF (250 ml_). The reaction mixture was stirred at room temperature for 72 hrs. The DMF was removed in vacuo and the residue was partitioned between ethyl acetate (200 mL) and saturated aqueous sodium bicarbonate (200 mL). The organic phase was separated, washed with saturated aqueous sodium bicarbonate (200 mL) and brine (200 mL), and dried over MgSO4. Evaporation of the solvent afforded a dark oil (21.0 g) that was purified by flash chromatography (Silica, gradient elution with pentane/ethyl acetate 9:1 v/v to 3:2 v/v) to give the title compound 12.5 g (95percent) as a gum. LC/MS-M+H 273
95%
Stage #1: With 1,1'-carbonyldiimidazole In dichloromethane at 0 - 25℃; for 1 h; Inert atmosphere Stage #2: With triethylamine In dichloromethane at 25℃; for 0.5 h; Stage #3: at 25℃; for 15 h;
3. Synthesis of intermediate D-1: C-1 D-1 To a stirred solution of C-1 (80 g, 0.35 mol) in 1 L of anhydrous CH2CI2 was added CDI (62.24 g, 0.38 mol) under N2 at 0°C. After the addition, the mixture was stirred at 25°C for 1 hour, gas formation was observed. Et3N (42.37 g, 42 mol) was added, the mixture was stirred at 25°C for 30 min, then Ο,Ν-dimethylhydroxylamine hydrochloride (42.54 g, 0.44 mol) was added. After the addition, the mixture was stirred at 25 °C for 15 hrs. The mixture was washed with water, aq. NaHC03 and aq. citric acid monohydrate. The organic layer was separated, dried over anhydrous Na2S04 and concentrated to get intermediate D-1 (80 g, 95percent) as a white solid.
95%
Stage #1: With 1,1'-carbonyldiimidazole In dichloromethane at 0 - 25℃; for 1 h; Inert atmosphere Stage #2: With triethylamine In dichloromethane at 25℃; for 0.5 h; Stage #3: at 25℃; for 15 h;
To a stirred solution of C-1 (80 g, 0.35 mol) in 1 L of anhydrous CH2Cl2 was added CDI (62.24 g, 0.38 mol) under N2 at 0° C. After the addition, the mixture was stirred at 25° C. for 1 hour, gas formation was observed. Et3N (42.37 g, 42 mol) was added, the mixture was stirred at 25° C. for 30 min, then O,N-dimethylhydroxylamine hydrochloride (42.54 g, 0.44 mol) was added. After the addition, the mixture was stirred at 25° C. for 15 hrs. The mixture was washed with water, aq. NaHCO3 and aq. citric acid monohydrate. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated to get intermediate D-1 (80 g, 95percent) as a white solid.
95%
With 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide
Add N,O-dimethylhydroxylamine hydrochloride (2.52 g, 26 mmol), 1-hydroxybenzotriazole (HOBt) (2.8 g, 20.8 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI.HCl)(4 g, 20.8 mmol) and 4-methylmorpholine (5.28 g, 52 mmol) at 0° C. to the solution of N-Boc-piperidine-4-carboxylic acid (4 g, 17.4 mmol) in DMF (50 mL), stir the mixture overnight at room temperature. TLC (PE:EtOAc=1:1) shows the reaction is complete. Partition between ethyl acetate and water, collect the organic layer and wash with brine, dry over anhydrous sodium sulfate, filter and concentrate the filtrate under reduced pressure to give the crude product (4.5 g, 95percent) which is used in next step without further purification.
95%
Stage #1: With 1,1'-carbonyldiimidazole In dichloromethane at 0 - 25℃; Inert atmosphere Stage #2: With triethylamine In dichloromethane at 25℃; for 0.5 h; Stage #3: at 25℃; for 15 h;
To a stirred solution of C-1 (80 g, 0.35 mol) in 1 L of anhydrous CH2Cl2 was added CDI (62.24 g, 0.38 mol) under N2 at 0° C. After the addition, the mixture was stirred at 25° C. for 1 hour, gas formation was observed. Et3N (42.37 g, 42 mol) was added, the mixture was stirred at 25° C. for 30 min, then O,N-dimethylhydroxylamine hydrochloride (42.54 g, 0.44 mol) was added. After the addition, the mixture was stirred at 25° C. for 15 hrs. The mixture was washed with water, aq. NaHCO3 and aq. citric acid monohydrate. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated to get intermediate D-1 (80 g, 95percent) as a white solid.
95%
With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 18 h;
[0211] 1-(1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (6.51 g, 0.022 mol) was dissolved in dichloromethane (50 ml). To the resulting solution were added 1,1'-carbonyldiimidazole (CDI) (6.31 g, 0.033 mol) and N,O-dimethylhydroxylamine hydrochloride (9.62 g, 0.67 mol) and the solution was stirred at room temperature for 18 hrs. After completion of the reaction by addition of water, the solution was extracted with dichloromethane, washed with distilled water, and dried over magnesium sulfate (MgSO4) to concentrate. The resulting residue was isolated and purified by silica gel column chromatography (dichloromethane/methanol = 10/1) to give the white title compound (5.36 g, 95.0 percent). 1H NMR (400 MHz, CDCl3) δ 4.14 (m, 2H), 3.71 (s, 3H), 3.13 (s, 3H), 2.79 (m, 5H), 1.42 (s, 9H).
88%
Stage #1: With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide for 0.333333 h; Stage #2: With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide
INTERMEDIATE B4 tert-Butyl 4-[methoxy(methyl)amino]carbonyl}piperidine-l-carboxylate A suspension of l-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (5.0 g, 21.8 mmol), EDC (6.27 g, 32.7 mmol) and HOBT (2.95 g, 21.8 mmol) in DMF (10 mL) was stirred for20 min. To the mixture were then added 1 ,2-dimethylhydroxylamine hydrochloride (3.19 g, 32.7 mmol) and DIEA (13 mL, 76.3 mmol) and the stirring continued overnight. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was concentrated and the residue was purified by flash chromatography on silica using EtOAc as eluent. Yield 5.22 g (88percent). Analytical HPLC: purity 100percent (System A and B);LRESIMS (ESI+) m/z = 217 (M+H-φu)+.
80%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 19 h;
Synthesis of 4-(Methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid t-butyl ester Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.0 eq, 21.8 mmol) was dissolved under inert conditions in 35 ml dry N,N-dimethylformamide. O,N-dimethyl-hydroxylamine hydrochloride (1.03 eq, 22.5 mmol), benzotriazol-1-ol monohydrate (1.03 eq, 22.5 mmol) and triethylanine (1.5 eq, 32.7 mmol) were added. The reaction mixture was cooled to 0° C., N-(3-Dimethylaminopropyl)-N-ethylcarbodiimid hydrochloride (1.0 eq, 21.8 mmol) was added over a period of 1.0 minutes and the mixture was stirred vigorously at 0° C. for 1 h and at r.t. for 18 h. The solvent was removed under vaccum and the residue was suspended in 400 ml ethylacetate. The organic layer was extracted 3 times with 100 ml of 1 M citric acid, aqueous sodium carbonate and twice with 100 ml brine, dried over MgSO4 and filtered. The solvent was removed and the residue as purified by distillation resulting in a yield of 80percent.
80%
at 0 - 20℃; for 19.8333 h;
Synthesis of 4-(Methoxy-methyl-carbamoyl)-piperidine-l-carboxylic acid t-butyl esterPiperidine-l,4-dicarboxylic acid mono-tert-butyl ester (1.0 eq, 21.8 mmol) was dissolved under inert conditions in 35 ml dry N, N- dimethylformamide. O,N-dimethyl- hydroxylarnine hydrochloride (1.03 eq, 22.5 mmol), benzotriazol-1-ol monohydrate (1.03 eq, 22.5 mmol) and triethylamine (1.5 eq, 32.7 mmol) were added. The reaction mixture was cooled to O0C, N-(3-Dimethylaminopropyl)-N-ethylcarbodiimid hydrochloride (1.0 eq,21.8 mmol) was added over a period of 10 minutes and the mixture was stirred vigorously at O0C for 1 h and at r.t. for 18 h.The solvent was removed under vaccum and the residue was suspended in 400 ml ethylacetate. The organic layer was extracted 3 times with 100 ml of 1 M citric acid, aqueous sodium carbonate and twice with 100 ml brine, dried over MgSO4 and filtered. The solvent was removed and the residue was purified by distillation resulting in a yield of 80percent.
80%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 19.1667 h;
Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.0 eq, 21.8 mmol) was dissolved under inert conditions in 35 ml dry N, N- dimethylformamide. O,N-dimethylhydroxylamine hydrochloride (1.03 eq, 22.5 mmol), benzotriazol-1-ol monohydrate (1.03 eq, 22.5 mmol) and triethylamine (1.5 eq, 32.7 mmol) were added. The reaction mixture was cooled to 0°C, N-(3-Dimethylaminopropyl)-N-ethylcarbodiimid hydrochloride (1.0 eq, 21.8 mmol) was added over a period of 10 minutes and the mixture was stirred vigorously at 0°C for 1 h and at r.t. for 18 h. The solvent was removed under vaccum and the residue was suspended in 400 ml ethylacetate. The organic layer was extracted 3 times with 100 ml of 1 M citric acid, aqueous sodium carbonate and twice with 100 ml brine, dried over MgSO4 and filtered. The solvent was removed and the residue was purified by distillation resulting in a yield of 80percent.
80%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 19.1667 h;
Piperidine-l,4-dicarboxylic acid rnono-tert-butyl ester (1.0 eq, 21.8 mmol) was dissolved under inert conditions in 35 ml dry N, N- dimethylformamide. O,N-dimethyl- hydroxylamine hydrochloride (1.03 eq, 22.5 mmol), benzotriazol-1-ol monohydrate (1.03 eq, 22.5 mmol) and triethylamine (1.5 eq, 32.7 mmol) were added. The reaction mixture was cooled to 00C, N-(3 -Dimethyl aminopropyl)-N-ethylcarbodiimid hydrochloride (1.0 eq, 21.8 mmol) was added over a period of 10 minutes and the mixture was stirred vigorously at 0°C for 1 h and at r.t. for 18 h.The solvent was removed under vaccum and the residue was suspended in 400 ml ethylacetate. The organic layer was extracted 3 times with 100 ml of 1 M citric acid, aqueous sodium carbonate and twice with 100 ml brine, dried over MgSO4 and filtered. The solvent was removed and the residue was purified by distillation resulting in a yield of 80percent.
80%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 19.1667 h;
Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.0 eq, 21.8 mmol) was dissolved under inert conditions in 35 ml dry N,N-dimethylformamide. O,N-dimethyl-hydroxylamine hydrochloride (1.03 eq, 22.5 mmol), benzotriazol-1-ol monohydrate (1.03 eq, 22.5 mmol) and triethylamine (1.5 eq, 32.7 mmol) were added. The reaction mixture was cooled to 0° C., N-(3-Dimethylaminopropyl)-N-ethylcarbodiimid hydrochloride (1.0 eq, 21.8 mmol) was added over a period of 10 minutes and the mixture was stirred vigorously at 0° C. for 1 h and at r.t. for 18 h.The solvent was removed under vacuum and the residue was suspended in 400 ml ethylacetate. The organic layer was extracted 3 times with 100 ml of 1 M citric acid, aqueous sodium carbonate and twice with 100 ml brine, dried over MgSO4 and filtered. The solvent was removed and the residue was purified by distillation resulting in a yield of 80percent.
80%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 19 h;
Synthesis of 4-(Methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid t-butyl ester Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.0 eq, 21.8 mmol) was dissolved under inert conditions in 35 ml dry N, N- dimethylformamide, O,N-dimethyl-hydroxylamine hydrochloride (1.03 eq, 22.5 mmol), benzotriazol-1-ol monohydrate (1.03 eq, 22.5 mmol) and triethylamine (1.5 eq, 32.7 mmol) were added. The reaction mixture was cooled to 0°C, N-(3-Dimethylaminopropyl)-N-ethylcarbodiimid hydrochloride (1.0 eq, 21.8 mmol) was added over a period of 10 minutes and the mixture was stirred vigorously at 0°C for 1h and at r.t. for 18h. The solvent was removed under vaccum and the residue was suspended in 400 ml ethylacetate. The organic layer was extracted 3 times with 100 ml of 1 M citric acid, aqueous sodium carbonate and twice with 100 ml brine, dried over MgSO4 and filtered. The solvent was removed and the residue was purified by distillation resulting in a yield of 80percent.
77%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 16 h;
To the mixture of 10 (47.0 g, 205 mmol) and N,O-dimethylhydroxylamine hydrochloride (20.8 g, 213 mmol) in CH2Cl2 (1 L) was added EDC (44.6 g, 232 mmol) in one portion followed by Et3N (32.4 mL, 232 mmol) dropwise at rt. The resulting solution was stirred at rt for 16 h. The solution was washed with brine (800 mL x 4) and a saturated NaHCO3 solution (500 mL), and then dried over Na2SO4. After evaporating the solvent, the residue was purified on silica gel using 60percentEtOAc/hexane to give 11 (43.2 g, 77percent) as an oil.
71%
Stage #1: With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 0℃; for 0.166667 h; Stage #2: at 20℃; for 2 h;
To a stirred solution of l-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (5.0 g, 21.7 mmol) in DMF (20 mL) was added HATU (12.39 g, 32.60 mmol) and diisopropylethylamine (18.94 ml, 108.6 mmol). The solution was stirred for 10 min at 0 °C. After that Ν,Ο-dimethylhydroxylamine hydrochloride (2.12 g, 21.7 mmol) was added and stirred at RT for 2 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain a crude residue which was purified by column chromatography to afford tert-butyl 4- (methoxy(methyl)carbamoyl)piperidine-l-carboxylate (4.3 g, 71percent). LCMS: m/z = 173.05 (M-Boc)+.
61%
Stage #1: With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 2 h; Stage #2: at 20℃;
Example 5; Synthesis of 2-(4-(phenyl(4-(trifluoromethyl)phenyl)methyl)piperidin- 1 -yl)acetic acidStep lTo a solution of l-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (11 g, 48 mmol) in DCM (120 mL) was added CDI (11 g). After stirring at rt for 2 h, N,O-dimethylhydroxyl- amine hydrochloride was added in portions. The mixture was stirred for 3 h at rt and was then left to stand overnight. The solvent was removed under vacuum, the residue was extracted with DCM, washed with brine and water, dried over anhydrous sodium sulfate and concentrated to give crude tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-l-carboxylate (8 g, 61percent yield) as a white solid which was used directly in the next step.
42%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃;
Reagents and conditions: (a) B0C2O, 1,4-dioxane, H2O, NaOH, overnight, rt, (yield 94percent); (b) HOBt, EDCl, TEA,DMF, NHMeOMe-HCl, overnight, rt, (yield 42percent); (c) BuLi, 2-bromobiphenyl, TMEDA, THF, 3h, -78°C, (yield 35percent) ; (d) TFA, DCM , lh, rt, (yield quant); (e) toluene, 2h, (yield 24percent), (f) NaBH4, THF, MeOH, overnight, rt, (yield 25percent). Compounds 8-9 were synthesized from isonipecotic acid. The amine function was first protected with tert-butyl carbamate group followed by the formation of the Weinreb amide using HOBt and EDCl. Then, the lithium anion of 2-bromobiphenyl reacted on the Weinreb amide and Boc deprotection to give compounds 8. Addition reaction on iso(thio)cyanate with the piperidine in toluene afforded (thio)urea 9a-9b, followed by a reduction of the ketone group give the alcohol derivatives lOa-lOb.
%
Stage #1: With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; Stage #2: With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃;
N,Oτdimethylhydroxylamine hydrochloride (851 mg, 8.72 mmols) was, :,O suspended in dichloromethane (6 ml) and cooled to 0 C. N, N-diisopropylethylaminev (1.66 ml, 9.53 mmols) was added and the mixture was stirred at 0 C until a clear solution was obtained. The resulting solution was kept at 0 C for further use. Boc- isonipecotic acid (2 g, 8.72 mmol), 1-hydroxybenzotriazole (1.2 g, 8.88 mmols) and 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (1.83 g, 9.58 mmols) were dissolved in DMF (15 ml) and cooled to 0 C. The solution of N,O- dimethylhydroxylamine in dichloromethane was added with stirring, and the resulting reaction mixture was allowed to stir overnight at room temperature. DMF was removed under reduced pressure and residue was partitioned between ethyl acetate and 10percent citric acid. Organic layer was isolated, washed with water, saturated NaHCO3, water and brine and dried over MgSO4. Solvent was removed under reduced pressure and the residue was purified on silica gel eluting with ethyl acetate in hexanes (2:1 ) to provide the title compound (1.88 g, 79percent). LCMS m/e (295, M + Na).
Stage #1: With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.75 h; Stage #2: at 20℃; for 1.5 h;
tert-Butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate. tert-Butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (640 mg, 2.8 mmol) and o-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (1.0 g, 3.1 mmol) were combined and dissolved in N,N-dimethylformamide (12 mL). N,N-Diisopropylethylamine was added to the mixture. Reaction stirred at room temperature for 45 minutes. N,O-Dimethylhydroxylamine hydrochloride (450 mg, 4.6 mmol) was added to the mixture. Reaction stirred at room temperature for 1.5 hours. Mixture was diluted with diethyl ether and then washed 3.x. water, 1.x.1N hydrochloric acid. Organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo. Title compound was obtained as clear colorless oil in 70percent yield. MS m/e (M-C4H8+H)+=217.1.
70%
Stage #1: With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.75 h; Stage #2: at 20℃; for 1.5 h;
tert-Butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate; tert-Butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (640 mg, 2.8 mmol) and o-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (1.0 g, 3.1 mmol) were combined and dissolved in N,N-dimethylformamide (12 mL). N,N-Diisopropylethylamine was added to the mixture. Reaction stirred at room temperature for 45 minutes. N,O-Dimethylhydroxylamine hydrochloride (450 mg, 4.6 mmol) was added to the mixture. Reaction stirred at room temperature for 1.5 hours. Mixture was diluted with diethyl ether and then washed 3.x. water, 1.x. 1N hydrochloric acid. Organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo. Title compound was obtained as clear colorless oil in 70percent yield. MS m/e (M-C4H8+H)+=217.1.
With sodium hydrogencarbonate In n-heptane; dichloromethane; water; toluene
EXAMPLE 66 Scheme G, step b: 4-[(Methoxymethylamino)carbonyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (15) Into a 250-mL four-neck flask equipped with a mechanical stirrer, a nitrogen bubbler, a 125-mL addition funnel with a stopper, and a thermowell with a thermocouple was placed 1,1'-carbonyldiimidazole (7.2 g, 0.044 mol) and methylene chloride (20 g). The addition funnel was charged with a solution of 1,4-piperidinedicarboxylic acid, 1-(1,1-dimethylethyl)ester (14) (10.0 g, 0.043 mol) and methylene chloride (75 g). The solution was added to the reaction mixture over a 2 minute period, causing rapid CO2 evolution. The reaction mixture was allowed to stir at 28° C. for 2 hours. Into a 500-mL four-neck flask equipped with a mechanical stirrer, a nitrogen bubbler, a thermowell with a thermocouple, and a 125-mL addition funnel with a septum was placed N,O-dimethylhydroxylamine hydrochloride (4.9 g, 0.049 mol) and methylene chloride (38 g). The imidazole amide intermediate/methylene chloride solution was added to the slurry of N,O-dimethylhydroxylamine hydrochloride and methylene chloride over a 20 minute period. The resulting slurry was allowed to stir at 28° C. for 2 hours. To the reaction mixture was added sodium bicarbonate (4.3 g) and water (75 g). After stirring for 30 minutes at ambient temperature, the phases were allowed to stand and separate for 20 minutes. The phases were separated and to the organic phase was added toluene (100 g). The solution was concentrated and azeotropically dried by rotary evaporation (29 Hg, bath 60° C.) to afford the crude title compound as a thick oil. The oil and heptane (25 g) were placed into a 100-mL jacketed-bottom-drain resin pot fitted with a four-joint head equipped with a mechanical stirrer, a thermowell with a thermocouple, a nitrogen bubbler, and a stopper. The slurry was warmed to 60° C. before allowing it to slowly cool to 10° C. over a 2 hour period. The solution was maintained at 10° C. for 1 hour (nucleation temperature) before cooling to 3° C. and stirring overnight. The title compoundcompound was collected by suction filtration and washed with cold heptane (7 g, ~0° C.). The wet cake was allowed to air dry for 24 hours to afford the title compound (15) as a white crystalline material (10.5 g, 89percent); m.p. 69-71° C. 1H NMR (CDCl3) δ 4.08 (m, 2H, CHN's), 3.66 (s, 3H, -OCH3), 3.13 (s, 3H, -NCH3), 2.76 (m, 3H), 1.51 (m, 4H, CH2's), 1.40 (s, 9H, t-Bu); 13C NMR (CDCl3) δ 175.5, 154.7, 121.6, 79.5, 61.6, 43.3, 36.1, 28.5, 28.0; IR (KBr) 2973, 2935, 1694, 1663, 1421, 1367, 1289, 1133, 998, 870, 770 cm-1.
Reference：
[1] Patent: US2005/261341, 2005, A1,
77
[ 6638-79-5 ]
[ 530-62-1 ]
[ 139290-70-3 ]
Yield
Reaction Conditions
Operation in experiment
89%
With sodium chloride; sodium hydrogencarbonate In n-heptane; dichloromethane; water
EXAMPLE 67 Scheme G, step b: 4-[(Methoxymethylamino)carbonyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (15) A suitable reactor maintained under nitrogen was charged with 7.6 kg of 1,1'-carbonyldiimidazole and 15 L of methylene chloride. A solution of 1,4-piperidinedicarboxylic acid, 1-(1,1-dimethylethyl)ester (14) (10.5 kg, 45.8 mol) in 62 L of methylene chloride was added over 30 minutes while maintaining a reaction temperature of 20° C. After stirring the reaction mixture at ambient temperature for 2 hours, 0.1 kg of 1,1'-carbonyldiimidazole was added. A solution of 4.55 kg of N,O-dimethylhydroxylamine hydrochloride in 32 L of methylene chloride was added to the mixture with stirring. The reaction mixture was stirred at 28° C. for 24 hours, followed by the addition of 0.52 kg of N,O-dimethylhydroxylamine hydrochloride and 0.7 kg of 1,1'-carbonyldiimidazole. Stirring was continued at 28° C. for 48 hours. The stirred reaction mixture was diluted with a solution of sodium bicarbonate (4.5 kg, 53.6 mol) in 50 L of water. The organic phase was separated and washed with a solution of sodium chloride (7 kg) in 46 L of water. The organic phase was separated and dried with sodium sulfate (4 kg). Drying agent was filtered off and washed with 2*5 L of methylene chloride. Solvent was removed below 50° C. at 500 torr. The residue was diluted with 5 L of heptane and solvent was removed below 50° C. at 500 torr. A total of 40 L of heptane was added and the stirred solution was heated to 70° C. to obtain solution. The stirred solution was cooled to ambient temperature over 18 hours, then cooled to and maintained at 10C for 12 hours, then cooled to 0° C. Solid which crystallized was filtered off, then dried at ambient temperature to give 11.1 kg (89percent yield).
Reference：
[1] Patent: US2005/261341, 2005, A1,
78
[ 478408-77-4 ]
[ 6638-79-5 ]
[ 84358-13-4 ]
[ 530-62-1 ]
[ 139290-70-3 ]
Yield
Reaction Conditions
Operation in experiment
89%
With sodium hydrogencarbonate In n-heptane; dichloromethane; water; toluene
EXAMPLE 66 Scheme G, step b: 4-[(Methoxymethylamino)carbonyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (15) Into a 250-mL four-neck flask equipped with a mechanical stirrer, a nitrogen bubbler, a 125-mL addition funnel with a stopper, and a thermowell with a thermocouple was placed 1,1 '-carbonyldiimidazole (7.2 g, 0.044 mol) and methylene chloride (20 g). The addition funnel was charged with a solution of 1,4-piperidinedicarboxylic acid, 1-(1,1-dimethylethyl)ester (14) (10.0 g, 0.043 mol) and methylene chloride (75 g). The solution was added to the reaction mixture over a 2 minute period, causing rapid CO2 evolution. The reaction mixture was allowed to stir at 28° C. for 2 hours. Into a 500-mL four-neck flask equipped with a mechanical stirrer, a nitrogen bubbler, a thermowell with a thermocouple, and a 125-mL addition funnel with a septum was placed N,O-dimethylhydroxylamine hydrochloride (4.9 g, 0.049 mol) and methylene chloride (38 g). The imidazole amide intermediate/methylene chloride solution was added to the slurry of N,O-dimethylhydroxylamine hydrochloride and methylene chloride over a 20 minute period. The resulting slurry was allowed to stir at 28° C. for 2 hours. To the reaction mixture was added sodium bicarbonate (4.3 g) and water (75 g). After stirring for 30 minutes at ambient temperature, the phases were allowed to stand and separate for 20 minutes. The phases were separated and to the organic phase was added toluene (100 g). The solution was concentrated and azeotropically dried by rotary evaporation (29 Hg, bath 60° C.) to afford the crude title compound as a thick oil. The oil and heptane (25 g) were placed into a 100-mL jacketed-bottom-drain resin pot fitted with a four-joint head equipped with a mechanical stirrer, a thermowell with a thermocouple, a nitrogen bubbler, and a stopper. The slurry was warmed to 60° C. before allowing it to slowly cool to 10° C. over a 2 hour period. The solution was maintained at 10C for 1 hour (nucleation temperature) before cooling to 3° C. and stirring overnight. The title compoundcompound was collected by suction filtration and washed with cold heptane (7 g, 0° C.). The wet cake was allowed to air dry for 24 hours to afford the title compound (15) as a white crystalline material (10.5 g, 89percent); m.p. 69-71° C. 1H NMR (CDCl3) δ 4.08 (m, 2H, CHN's), 3.66 (s, 3H, -OCH3), 3.13 (s, 3H, -NCH3), 2.76 (m, 3H), 1.51 (m, 4H, CH2's), 1.40 (s, 9H, t-Bu); 13C NMR (CDCl3) δ 175.5, 154.7, 121.6, 79.5, 61.6, 43.3, 36.1, 28.5, 28.0; IR (KBr) 2973, 2935, 1694, 1663, 1421, 1367, 1289, 1133, 998, 870, 770 cm-1.
Reference：
[1] Organic Preparations and Procedures International, 2000, vol. 32, # 1, p. 96 - 99
87
[ 6638-79-5 ]
[ 142851-03-4 ]
[ 139290-70-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 8, p. 2989 - 3002
88
[ 873-63-2 ]
[ 6638-79-5 ]
[ 145959-21-3 ]
Yield
Reaction Conditions
Operation in experiment
90%
With tert.-butylhydroperoxide; copper(II) acetate monohydrate; calcium carbonate In acetonitrile at 80℃; for 24 h;
General procedure: An oven-dried 15 mL glass vial with a magnetic stirrer bar was charged with Cu(OAc)2·H2O (12 mg, 6 molpercent), N,O-dimethylhydroxylamine hydrochloride (2; 117 mg, 1.2 mmol), the respective benzyl alcohol 1 (1 mmol), aq 70percent TBHP (0.17 mL, 1.2 mmol), CaCO3 (120 mg, 1.2 mmol) in MeCN (1 mL). The glass vial was flushed with N2 three times and the contents were stirred at r.t. for 1 h. Then the reaction mixture was stirred for 24 h at 80 °C. After completion of the reaction, the mixture was cooled to r.t. All volatiles were removed under vacuum. The product was extracted with EtOAc (20 mL) and the organic layer was washed with sat. aq NaHCO3 (20 mL), dried (Na2SO4), and the solvent removed under vacuum. The Weinreb amide product 3 was purified by column chromatography (silica gel, 100–200 mesh) using a gradient of petroleum ether (bp 60–80 °C) and EtOAc. All the amides were identified by GC-MS, 1H, and 13C NMR spectroscopic analysis.
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 3 h;
General procedure: To a solution of 3-cyanobenzoic acid 8a (3.0 g, 19.7 mmol) in DMF was added N,O-dimethylhydroxylamine hydrochloride (2.0 g, 20.7 mmol), Et3N (2.88 mL, d = 0.73, 20.7 mmol) and EDC*HCl (4.0 g, 20.7 mmol). After the mixture was stirred for 3 h at room temperature, the solvent was removed in vacuo and the residue was dissolved in EtOAc, washed with 10percent citric acid, 10percent NaHCO3 and saturated NaCl, and dried over Na2SO4. Then, the solvent was removed to give a colorless oil of compound 9a (3.0 g, 79percent).
Reference：
[1] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 14, p. 4279 - 4289
[2] Patent: WO2017/214505, 2017, A1, . Location in patent: Paragraph 000678; 000679
90
[ 6638-79-5 ]
[ 618-46-2 ]
[ 145959-21-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 4, p. 1415 - 1419
[2] European Journal of Organic Chemistry, 2017, vol. 2017, # 46, p. 6840 - 6850
[3] Patent: EP579833, 1997, B1,
[4] Patent: WO2011/23677, 2011, A1, . Location in patent: Page/Page column 122
[5] Chemical Communications, 2012, vol. 48, # 71, p. 8976 - 8978
91
[ 201230-82-2 ]
[ 625-99-0 ]
[ 6638-79-5 ]
[ 145959-21-3 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2014, vol. 12, # 30, p. 5727 - 5732
92
[ 586-76-5 ]
[ 6638-79-5 ]
[ 192436-83-2 ]
Yield
Reaction Conditions
Operation in experiment
92%
With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 18 h;
To a solution of 4-bromobenzoic acid, 5 g (586-76-5, 24.87 minol) in N,N-dimethylformamide, 30 mL, was added triethylamine, 13.9 mL (99.49 minol), N,O-dimethylhydroxylamine hydrochloride, 3.64 g (37.31 minol), 1-hydroxy-7-azabenzotriazole, 5.08 g (37.31 minol) and 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 9.54 g (49.75 minol). The reaction was stirred at room temperature for 18 hours. The reaction mixture was diluted with saturatedsolution of sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layers were washed with a saturated solution of sodium hydrogen carbonate, brine dried over solid sodium sulfate, filtered and concentrated under vacuum to give Intermediate 84, 5.6 g (92percent) as a colourless solid.1H NMR (400 MHz, CDCI3): 6 [ppm] = 3.34 (s, 3H), 3.52 (s, 3H), 7.50-7.65 (m, 4H).U PLC-MS (Method 3): R = 0.71 min., 93percent. MS (ESIpos): mz = [M÷H] 244, 246.
81%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 12 h;
A solution of 4-bromobenzoic acid (1.0 mg, 5.0 mmol), N,O-dimethylhydroxylamine hydrochloride (536 mg, 5.5 mmol), EDC·HCl (1.05 g, 5.5 mmol), and NEt3 (556 mg, 5.5 mmol) in DCM (30 mL) was allowed to stir at rt for 12 h. The reaction mixture was diluted with EtOAc (100 mL), and the organic phase was washed with water and dried over anhydrous Na2SO4. After removal of the solvent, the residue was purified by flash column chromatography (0-30percent EtOAc/hexanes) to afford 11 as a colorless oil (1.0 g, 81percent). 1H NMR (CDCl3, 600 MHz) δ 7.59 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 3.54 (s, 3H), 3.36 (s, 3H). HRMS (ESI+) calcd for C9H11BrNO2 (M+H)+ 243.9968, found 243.9970.
68%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 3 h;
General procedure: To a solution of 3-cyanobenzoic acid 8a (3.0 g, 19.7 mmol) in DMF was added N,O-dimethylhydroxylamine hydrochloride (2.0 g, 20.7 mmol), Et3N (2.88 mL, d = 0.73, 20.7 mmol) and EDC*HCl (4.0 g, 20.7 mmol). After the mixture was stirred for 3 h at room temperature, the solvent was removed in vacuo and the residue was dissolved in EtOAc, washed with 10percent citric acid, 10percent NaHCO3 and saturated NaCl, and dried over Na2SO4. Then, the solvent was removed to give a colorless oil of compound 9a (3.0 g, 79percent).
Reference：
[1] Patent: WO2018/86703, 2018, A1, . Location in patent: Page/Page column 252
[2] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 4, p. 686 - 692
[3] Journal of Medicinal Chemistry, 2015, vol. 58, # 21, p. 8564 - 8572
[4] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 14, p. 4279 - 4289
[5] MedChemComm, 2013, vol. 4, # 2, p. 443 - 449
[6] Patent: US2013/158031, 2013, A1, . Location in patent: Paragraph 0303; 0304
[7] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 4, p. 1098 - 1103
[8] Patent: WO2016/22448, 2016, A1, . Location in patent: Page/Page column 90
[9] Patent: US2018/305346, 2018, A1, . Location in patent: Paragraph 0099; 0100; 0101
93
[ 6638-79-5 ]
[ 586-75-4 ]
[ 192436-83-2 ]
Yield
Reaction Conditions
Operation in experiment
84%
With triethylamine In dichloromethane at -78 - 20℃; for 1.5 h;
Example 8 5-{4-[hydroxy(thien-2-yl)methyl]phenyl}-1-methyl-1H-pyrrole-2-carbonitrile To a stirred solution of 4-bromobenzoyl chloride (20.0 g, 91.1 mmol) in dichloromethane (300 mL) at -78° C. was added triethylamine (28.0 mL, 200.0 mmol), and O,N-dimethylhydroxylamine hydrochloride (9.33 g, 95.6 mmol). The resulting solution was allowed to warm to room temperature, stirred for 1.5 hours, and then concentrated. The residue was triturated in acetone and the resulting solid was dissolved in ethyl acetate washed with water and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give 4-bromo-N-methoxy-N-methylbenzamide (18.6 g, 84percent).
84%
With triethylamine In dichloromethane at -78 - 20℃; for 1.5 h;
Example 10 1-methyl-5-[4-(thien-2-ylcarbonyl)phenyl]-1H-pyrrole-2-carbonitrile To a stirred solution of 4-bromobenzoyl chloride (20.0 g, 91.1 mmol) in dichloromethane (300 mL) at -78° C. was added triethylamine (28.0 mL, 200.0 mmol), and O,N-dimethylhydroxylamine hydrochloride (9.33 g, 95.6 mmol). The resulting solution was allowed to warm to room temperature, stirred for 1.5 hours, and then concentrated. The residue was triturated in acetone and the resulting solid was dissolved in ethyl acetate washed with water and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give 4-bromo-N-methoxy-N-methylbenzamide (18.6 g, 84percent). To a solution of 4-bromo-N-methoxy-N-methylbenzamide (3.0 g, 12.29 mmol) in THF (30 mL) at 0° C. under nitrogen was added 2-thienyllithium (1.0 M in THF, 15 mL, 15 mmol) slowly over 10 minutes. The solution was stirred at 0° C. for 1 hour, poured into a saturated aqueous ammonium chloride solution (150 mL), and extracted several times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The residue was triturated with ether to give (4-bromophenyl)(thien-2-yl)methanone as a brown solid (1.1 g, 34percent). MS (ES) m/z 266.9. The title compound was prepared from (4-bromophenyl)(thien-2-yl)methanone and 1-methyl-2-cyanopyrrole according to the coupling procedure as described in example 1. MS (ES) m/z 293.1; HRMS: calcd for C17H12N2OS+H+, 293.0743; found (ESI, [M+H]+), 293.0744.
Reference：
[1] Angewandte Chemie - International Edition, 2010, vol. 49, # 17, p. 3073 - 3076
[2] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 17, p. 3694 - 3698
[3] European Journal of Organic Chemistry, 2017, vol. 2017, # 46, p. 6840 - 6850
[4] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 4, p. 1415 - 1419
[5] Patent: US2007/66628, 2007, A1, . Location in patent: Page/Page column 15
[6] Patent: US2007/66675, 2007, A1, . Location in patent: Page/Page column 16
[7] Journal of Medicinal Chemistry, 2012, vol. 55, # 9, p. 4189 - 4204
[8] Chemical Communications, 2012, vol. 48, # 71, p. 8976 - 8978
[9] Patent: WO2016/22448, 2016, A1, . Location in patent: Page/Page column 104
[10] Journal of Organic Chemistry, 2017, vol. 82, # 2, p. 1114 - 1126
Reference：
[1] Australian Journal of Chemistry, 2017, vol. 70, # 1, p. 44 - 51
98
[ 16948-16-6 ]
[ 6638-79-5 ]
[ 170097-58-2 ]
Reference：
[1] British Journal of Pharmacology, 2016, p. 2657 - 2668
[2] Journal of Natural Products, 2003, vol. 66, # 2, p. 183 - 199
[3] British Journal of Pharmacology, 2015, vol. 172, # 3, p. 883 - 894
99
[ 68947-43-3 ]
[ 6638-79-5 ]
[ 215950-19-9 ]
Yield
Reaction Conditions
Operation in experiment
80%
Stage #1: With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In DMF (N,N-dimethyl-formamide) for 63 h; Stage #2: With sodium hydroxide In water
1-Methylisonipecotic acid (5.5 g, 38.4 mmol) was dissolved in dimethylformamide (100 ml) with heating. Diisopropylethylamine (8.0 ml, 46.1 mmol), 1-hydroxybenzotriazole (5.2 g, 38.4 mmol), and N,O-dimethylhydroxylamine hydrochloride (4.1 g, 42.2 mmol) were added and the reaction mixture was stirred 5 min. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.4 g, 38.4 mmol) was added and the resulting homogeneous solution was stirred for 63 hours at ambient temperature. The solvent was removed under reduced pressure. The residue was dissolved in water and the solution was basified to pH 9 with 5N sodium hydroxide solution. This aqueous solution was extracted with methylene chloride then saturated with sodium chloride and extracted with chloroform/isopropanol (3/1). The combined organic extracts were dried over sodium sulfate and the solvent was removed under reduced pressure to give 9.5 g of a yellow liquid. Purification by flash chromatography (silica gel, methylene chloride:methanol:ammonium hydroxide, 100:10:1) gave 5.7 g (80percent) of product as a light yellow liquid. [00381] MS (m/e): 186(M+). [00382] Analysis for C9H18N2O2:
Stage #1: With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 20 - 55℃; for 2.25 h; Stage #2: at 20 - 65℃;
SYNTHETIC PREPARATION 63-Carboxyindazole (10 g, 61.7 mmol) in DMF (100 mL) was treated with carbonyldiimidazole (11 g, 67.84 mmol) at rt with gas evolution for 15 min, after which the reaction mixture was heated up to 65 0C for 2 hours. After cooling to rt, N1O- dimethylhydroxyamine-HCI (4.14 g, 67.8 mmol) was added and the mixture was heated to 65 0C overnight. The reaction was cooled, quenched with water, extracted with CH2CI2 and washed with water. The combined organic phase was dried and concentrated to afford N- methoxy-N-methyl-1 H-indazole-3-carboxamide (10.3 g, 81.4percent).
79%
Stage #1: With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 60 - 65℃; for 2 h; Stage #2: at 65℃; for 3 h;
lH-indazole-3-carboxylic acid (CX) (100 g, 617 mmol) in DMF was treated with carbonyldiimidazole (110 g, 678 mmol) at room temperature until the evolution of gas ceased (ca. 15 minutes). The reaction was heated to 60-65°C for 2 h and then allowed to cool to room temperature. Ν,Ο-Dimethylhydroxylamine-HCl (66.2 g, 678 mmol) was added as a solid and the mixture was heated to 65 °C for 3 h. The reaction was concentrated to a paste, taken up in DCM and washed subsequently with water and 2 N HC1. The product could be seen coming out of solution. The solid was filtered and rinsed separately with EtOAc. The EtOAc and DCM layers were separately washed with sodium bicarbonate followed by brine, dried over MgS04 and concentrated under reduced pressure. The resulting solids were combined, triturated with 1:1 mixture of DCM-ether, filtered, and dried to produce N-methoxy-N-methyl-lH-indazole-3- carboxamide (CXI) as a white solid (100 g, 487 mmol, 79percent yield). 1H NMR (DMSO-d6) δ ppm 3.46 (s, 3H), 3.69-3.85 (m, 3H), 7.13-7.31 (m, 1H), 7.41 (t, J=7.25 Hz, 1H), 7.56- 7.65 (m, 1H), 7.93-8.08 (m, 1H); ESIMS found for CioHiiN302 mlz 206 (M+H).
79%
Stage #1: With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 60 - 65℃; for 2 h; Stage #2: at 65℃; for 3 h;
1H-indazole-3-carboxylic acid (XV) (100 g, 617 mmol) in DMF was treated with carbonyldiimidazole (110 g, 678 mmol) at room temperature until the evolution of gas ceased (ca. 15 minutes). The reaction was heated to 60-65° C. for two hours and then allowed to cool to room temperature. N,O-Dimethylhydroxylamine-HCl (66.2 g, 678 mmol) was added as a solid and the mixture was heated to 65° C. for 3 hours. The reaction was concentrated to a paste and taken up in DCM, and washed subsequently with water and 2N HCl. The product could be seen coming out of solution. The solid was filtered and rinsed separately with EtOAc. The EtOAc and DCM layers were separately washed with sodium bicarbonate followed by brine, dried over MgSO4 and concentrated under reduced pressure. The resulting solids were combined, triturated with 1:1 mixture of DCM-ether, filtered, and dried to produce N-methoxy-N-methyl-1H-indazole-3-carboxamide (XVI) as a white solid (100 g, 487 mmol, 79percent yield). 1H NMR (DMSO-d6) δ ppm 3.46 (s, 3H), 3.69-3.85 (m, 3H), 7.13-7.31 (m, 1H), 7.41 (t, J=7.25 Hz, 1H), 7.56-7.65 (m, 1H), 7.93-8.08 (m, 1H); ESIMS found for C10H11N3O2 m/z 206 (M+H).
79%
Stage #1: With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 60 - 65℃; for 2 h; Stage #2: at 65℃; for 3 h;
Step a ;1H-indazole-3-carboxylic acid (VIII) (100 g, 617 mmol) in DMF was treated with carbonyldiimidazole (110 g, 678 mmol) at r.t. until the evolution of gas ceased (ca. 15 minutes). The reaction was heated to 60-65°C for two hours and then allowed to cool to r.t. N,O-Dimethylhydroxylamine-HCl (66.2 g, 678 mmol) was added as a solid and the mixture was heated to 65°C for 3 hours. The reaction was concentrated to a paste and taken up in DCM, and washed subsequently with water and 2N HCl. The product could be seen coming out of solution. The solid was filtered and rinsed separately with EtOAc. The EtOAc and DCM layers were separately washed with sodium bicarbonate followed by brine, dried over MgSO4 and concentrated under reduced pressure. The resulting solids were combined, triturated with 1:1 mixture of DCM-ether, filtered, and dried to produce N-methoxy-N-methyl-1H-indazole-3-carboxamide (IX) as a white solid (100 g, 487 mmol), 79percent yield). 1H NMR (DMSO-d6) δ ppm 3.46 (s, 3H), 3.69-3.85 (m, 3H), 7.13-7.31 (m, 1H), 7.41 (t, J=7.25 Hz, 1H), 7.56-7.65 (m, 1H), 7.93-8.08 (m, 1H); ESIMS found for C10H11N3O2 m/z 206 (M+H).
79%
Stage #1: With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 60 - 65℃; for 2 h; Stage #2: at 65℃; for 3 h;
lH-indazole-3-carboxylic acid (CX) (100 g, 617 mmol) in DMF was treated with carbonyldiimidazole (110 g, 678 mmol) at room temperature until the evolution of gas ceased (ca. 15 minutes). The reaction was heated to 60-65°C for 2 h and then allowed to cool to room temperature. N,0-Dimethylhydroxylamine-HCl (66.2 g, 678 mmol) was added as a solid and the mixture was heated to 65°C for 3 h. The reaction was concentrated to a paste, taken up in DCM and washed subsequently with water and 2 N HC1. The product could be seen coming out of solution. The solid was filtered and rinsed separately with EtOAc. The EtOAc and DCM layers were separately washed with sodium bicarbonate followed by brine, dried over MgS04 and concentrated under reduced pressure. The resulting solids were combined, triturated with 1 : 1 mixture of DCM-ether, filtered, and dried to produce N-methoxy- N-methyl-lH-indazole-3-carboxamide (CXI) as a white solid (100 g, 487 mmol, 79percent yield). NMR (DMSO-de) δ ppm 3.46 (s, 3H), 3.69-3.85 (m, 3H), 7.13-7.31 (m, 1H), 7.41 (t, J=7.25 Hz, 1H), 7.56-7.65 (m, 1H), 7.93-8.08 (m, 1H); ESIMS found for C10H11N3O2 mlz 206 (M+H).
75.4%
Stage #1: With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 65℃; for 2 h; Stage #2: at 65℃; for 12 h;
A solution of 1H-indazole-3-carboxylic acid (1.0 g, 6.17 mmol, 1.0 eq.) and CDI (1.1 g, 6.78 mmol, 1.leq.) in DMF (20 mL) was stirred at 65°C for 2h, then cooled down to r.t., N,O-dimethylhydroxylamine hydrochloride (661 mg, 6.78 mmol, 1.1 eq.) was added and the mixture was stirred at 65 °C for 12 h. The solvent of the mixture was removed under vacuum and the residue was purified by flash chromatography (elute: EAPE = 1/2) to give N-methoxy-N-methyl -1 H-indazole-3 -carboxamide (950mg, 75.4 percent yield) as a yellow solid.
361 mg
Stage #1: With pyridine In tetrahydrofuran at 0 - 26℃; for 3 h; Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 22 - 26℃; for 16 h;
Step 2: N-Methoxy-N-methyl-lH-indazole-3-carboxamide: To a stirred solution of step 1 intermediate (500 mg, 3.083 mmol) in THF (20 mL) was added N, 0-dimethylhydroxylamine hydrochloride (360 mg, 3.70 mmol). The reaction mixture was cooled to 0 °C and added pyridine (2.5 mL). The reaction mixture was stirred at the same temperature for 2 h and then at room temperature for 1 h. To the reaction mixture was added some more pyridine (2 mL) followed by EDCI.HC1 (1.18 g, 6.167 mmol) and further stirred at RT for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with water (2 x 15 mL), brine (20 mL) and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure and the residue thus obtained was purified by silica gel column chromatography to yield 361 mg of the title product as off white solid. 1H NMR (300 MHz, DMSO-i) δ 3.55 (s, 3H), 3.82 (s, 3H), 7.32 (t, J = 7.5 Hz, 1H), 7.49 (t, J = 6.9 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H), 13.62 (br s, 1H).
Reference：
[1] European Journal of Medicinal Chemistry, 2011, vol. 46, # 10, p. 5138 - 5145
102
[ 6638-79-5 ]
[ 1711-07-5 ]
[ 226260-01-1 ]
Yield
Reaction Conditions
Operation in experiment
86.5%
With triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere
To a solution of Ν,Ο-dimethylhydroxylamine hydrochloride (138 g, 1.42 mol) in DCM (1.5 L) was added Et3N (383 g, 3.78 mol) at room temperature (RT). To the stirred mixture, 1-1 (150 g, 946 mmol) was added dropwise at 0 °C under N2 atmosphere. The solution was stirred at the same temperature for 1 h, and then slowly warmed to RT for 10 h. The mixture was added to water (~1L) and extracted with EtOAc (2 x 500 mL). The combined organic phases were dried with Na2S04, filtered and concentrated. The residue was purified by flash column chromatography (eluent: PE) to give 1-2 as a white solid (150 g, yield: 86.5percent). 1H NMR (400 MHz, CDC13): δ 7.49-7.43 (1 H, m), 7.41-7.32 (2 H, m), 7.18- 7.10 (1 H, m), 3.54 (3 H, s), 3.34 (3 H, s).
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 75 h;
EXAMPLE 4 3-Fluoro-N-methoxy-N-methylbenzamide To a suspension of 3-fluorobenzoic acid (140 mg, 1 mmol) and N dimethylhydroxylamine hydrochloride (107 mg, 1.1 mmol) in dichloromethane (2.5 mL) was added 1- [3- (dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride (EDC) (211 mg, 1.1 mmol) and the mixture stirred at room temperature for 75 h. The solvents were removed under reduced pressure and the residue chromatographed using ethyl acetate- hexane (4: 6) to separate the pure product (130 mg, 71percent). H-n. m. r. (CDC13) 8 3.36 (s, 3H, N-Me), 3.55 (s, 3H, N-OMe), 7. 1. -7.2 (m, 1H, ArH), 7.3-7. 5 (m, 3H, Ar)
71%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 25℃; for 75 h;
Example 4 3-Fluoro-N-methoxy-N-methylbenzamide To a suspension of 3-fluorobenzoic acid (140 mg, 1 mmol) and AC (7 dimethylhydroxylamine hydrochloride (107 mg, 1.1 mmol) in dichloromethane (2.5 mL) was added 1- [3- (DIMETHYLAMINO) PROPYL]-3-ETHYLCARBODIIMIDE hydrochloride (EDC) (211 mg, 1.1 mmol) and the mixture stirred at room temperature for 75 h. The solvents were removed under reduced pressure and the residue chromatographed using ethyl acetate- hexane (4: 6) to separate the pure product (130 mg, 71percent). APOS;H-N. m. r. (CDCL3) 8 3.36 (s, 3H, N-Me), 3.55 (s, 3H, N-OMe), 7.1.-7. 2 (m, 1H, Ar), 7.3-7. 5 (m, 3H, Ar)
61%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 3 h; Inert atmosphere
3-fluoro-N-methoxy-N-methylbenzamide To a solution of 3-fluorobenzoic acid (30 g, 214.1 mmol) in DCM (300 mL) were added EDC.HCl (45 g, 235 mmol) and N,O-dimethylhydroxylamine.HCl (23 g, 235 mmol) at 0° C. under N2. The reaction mixture was stirred at rt for 3 h, then diluted with water (1000 mL) and extracted with DCM (3*200 mL). The organics were washed with brine, dried over Na2SO4, and concentrated to obtain the 3-fluoro-N-methoxy-N-methylbenzamide (24 g, 61percent). (183.91 [M+H]) 1H NMR: (400 MHz, CDCl3) δ: 3.38 (s, 3H), 3.57 (s, 3H), 7.14-7.19 (m, 1H), 7.37-7.43 (m, 2H), 7.48-7.50 (d, J=7.6, 1H).
Stage #1: With triethylamine In dichloromethane at 0℃; for 0.166667 h; Stage #2: at 0 - 20℃;
Triethylamine (5.32 mL, 37.84 mmol) was added dropwise to a solution of Ν,Ο-dimethylhydroxylamine hydrochloride (2.768 g, 28.38 mmol) in anhydrous dichloromethane (45 mL) at 0 °C. After stirring for 10 min, 2-fluorobenzoyl chloride (0.303 mL, 2.52 mmol) in anhydrous dichloromethane (15 mL) was added dropwise. The reaction mixture was returned to room temperature and stirred for 5 h. The reaction mixture was quenched with water (60 mL) and the products were extracted with dichloromethane (2 x 60 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Purification using flash chromatography (silica gel, hexanes:ethyl acetate, gradient 93:7 to 60:40) afforded 2-Fluoro-N-methoxy-N-methyl-benzamide (3.1 16, 17 mmol) in a 90percent yield. [0
90%
Stage #1: With triethylamine In dichloromethane at 0℃; for 0.166667 h; Inert atmosphere Stage #2: at 0 - 20℃; for 5 h; Inert atmosphere
Triethylamine (5.32 mL, 37.8 mmol) was added dropwise to a solution of N,O-dimethylhydroxylamine hydrochloride (2.77 g, 28.4 mmol) in anhydrous dichloromethane (45 mL) at 0 °C. After stirring for 10 min, 2-flurobenzoyl chloride (0.303 mL, 2.52 mmol) in anhydrous dichloromethane (15 mL) was added dropwise. The reaction mixture was returned to room temperature and stirred for 5 h. The reaction mixture was quenched with water (60 mL) and the products were extracted with dichloromethane (2 * 60 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Purification using flash chromatography (silica gel, hexanes/ethyl acetate, gradient 93:7 to 60:40) afforded 2-Fluoro-N-methoxy-N-methyl-benzamide (3.12 g, 17.0 mmol, 90percent yield). 1H NMR (500 MHz, CDCl3): δ 7.44-7.38 (2H, m), 7.19 (1H, t, J = 7.5 Hz), 7.10 (1H, t, J = 8.9 Hz), 3.55 (3H, br s), 3.35 (3H, br s). 13C NMR (125 MHz, CDCl3): δ 166.40, 158.66, (d, J = 249 Hz), 131.50, 128.90, 124.11, 123.52 (d, J = 17 Hz), 115.69 (d, J = 21 Hz), 61.21, 32.31. 19F NMR (470 MHz, CDCl3): δ -114.04 (1F, s). HRMS (ESI) calculated for C9H10FNO2H+ (M+H)+ 184.07683, found 184.07702.
62%
With pyridine In tetrahydrofuran at 0 - 20℃; for 2.25 h;
N,O-Dimethylhydroxylamine hydrochloride (23.4 g, 240 mmol) was suspended inTHF (100 ml) and cooled to 0 °C under nitrogen. Pyridine (32 ml, 400 mmol) was addedslowly. A solution of 2-fluorobenzoyl chloride (9.5 ml, 80 mmol) in THF (50 ml) was addedover 15 min. The reaction was removed from the ice bath and stirred at rt for 2 h. Water (100ml) and AcOEt (100 ml) were added, and the phases were separated. The aq. phase wasextracted with AcOEt (100 ml). The organic phases were pooled and washed with 1 N HCI (2x 100 ml) and 1 N NaOH (100 ml). After drying over MgSO4, the sample was concentrated toyield a yellow oil (10.7 g). The oil was purified by vacuum distillation, and a colorless oil wascollected (0.22 torr, 57-59 °C, 9.1 g, 62percent yield)2-fluoro-N-methoxy-N-methylbenzamide1H-NMR (300MHz, CDCI3) 53.34 (s, 3H), 3.54 (br, 3H), 7.10 (m, 1H), 7.19 (m, 1H),7.42 (m, 2H)
Reference：
[1] RSC Advances, 2013, vol. 3, # 26, p. 10158 - 10162
[2] Patent: WO2013/142038, 2013, A2, . Location in patent: Paragraph 0130
[3] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 21, p. 6974 - 6992
[4] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 4, p. 1415 - 1419
[5] Patent: WO2006/3096, 2006, A1, . Location in patent: Page/Page column 73
[6] Chemical Communications, 2012, vol. 48, # 71, p. 8976 - 8978
105
[ 6638-79-5 ]
[ 445-29-4 ]
[ 198967-24-7 ]
Yield
Reaction Conditions
Operation in experiment
73%
With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane at 20℃; for 2 h;
2-Fluoro-N-methoxy-N-methylbenzamide was prepared in 73percent yield according to the Example 1 , Step A substituting 6-bromopicolinic acid for 2-fluorobenzoic acid.
With 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 17 h;
To a solution of CH2C12 (1L) was addded 3-fluoro-4-nitrobenzoic acid (100 g, 540 mmol) and EDCI (155.3 g, 810 mmol) followed by NMM (178 mL, 1.62 mol) and N-methoxymethanamine hydrochloride (79.0 g, 810 mmol). The solution was allowed to stir under N2 at rt for 17h. The reaction mixture was then diluted with IN HCI (1 L), transferred to separatoiy funnel, and separated. The organic phase was washed with IN NaOH (2 x 500 mL) and water (250 mL). All aqueous layers were back extracted with EtOAc (2 x 500 mL). The organic layers were combined, dried (MgS04), filtered, and concentrated in vacuo. to afford 102.3 g of the above compound as a yellow solid (448 mmol, yield 83percent). (at)H-NMR (DMSO-d6) No. 8.22 to 8.18 (t, J = 8.0 Hz, 1H), 7.79 to 7.76 (d, J = 11.5 Hz, 1H), 7.60 to 7.58 (d, J = 8.3 Hz, 1H), 3.56 (s, 3H), 3.28 (s, 3H) ; MS [M+H]+ = 229.1; LCMS RT = 2.27 min.
56%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;
N-[methyl]-N-[methoxy] 3-fluoro-4-nitrobenzamide; Dissolve 3-Fluoro-4-nitro-benzoic acid (10. 7 g, 57. 71 mmol) in 1000 mL anhydrous dichloromethane. Add N, O-Dimethylhydroxylamine hydxochloride (4. 5 g, 46. 17 mmol), followed by 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (16. 60 g, 86. 57 mmol) and and 4-dimethylaminopyridine (6. 77 g, 55. 4 mmol). Stir at room temperature under nitrogen atmosphere overnight. Concentrate under reduced pressure and partition the residue between ethyl acetate (300 mL) and water (lOOmL). Wash the organic layer with saturated aqueous sodium chloride (4x 30mL) and dry over magnesium sulfate. Concentrate under reduced pressure to provide the desired compound (7. 4 g, 56percent). MS (ES) : m/z = 229. 1; N- [Methyl]-N-[methoxy]-3-fluoro-4-nitrobenzamide; Add triethylamine (17 mL, 120 mmol) dropwise to a stirring solution of 3-fluoro- 4-nitrobenzoic acid (17. 8 g, 96 mmol), 1- (3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (23 g, 120 mmol), N, O-dimethylamine hydrochloride (11. 25 g, 115. 2 moles) and 4-N, N-dimethylaminopyridine (1, 17 g, 9. 6 mmol) in 300 mL dry dichloromethane under a nitrogen atmosphere. Stir at room temperature overnight. Add 10percent hydrochloric acid (200 mL), dichloromethane (200 mL) and water (200 mL). Separate the phases and extract the aqueous phase twice with dichloromethane. Wash the combined organic phases sequentially with 10 percent aqueous hydrochloric acid, water, and saturated aqueous sodium chloride. Dry over magnesium sulfate and concentrate under reduced pressure to provide the desired compound (90percent).
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In dichloromethane; water at 0 - 20℃; for 2 h;
N,N- diisopropylethylamine (8.1 mL, 46 mmol) was slowly added to a cold (0 °C) solution of tetrahydro-2H-pyran-4-carboxylic acid (2 g, 15 mmol) and O,N-Dimethyl-hydroxylamine hydrochloride (2.25 g, 23.05 mmol) in DCM (20 mL). To the above solution was added 2,4,6- tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (11 mL, 50 percentw/w; 18.4 mmol) slowly while at 0 °C. The mixture was warmed to rt and allowed to stir for 2 h. The reaction mixture was quenched with ice cubes then diluted with water (10 mL) and extracted with DCM (2 X 30 mL). The organic fractions were combined, washed with aq. sodium bicaronate solution, dried (Na2SO4), filtered, and concentrated under reduced pressure to provide the title compound as an oily liquid (2.56 g, 96percent). 1H NMR (400MHz, CD3OD) ^ = 3.96 (ddd, J = 1.7, 4.0, 11.5 Hz, 2H), 3.75 (s, 3H), 3.49 (dt, J = 2.4, 11.7 Hz, 2H), 3.19 (s, 3H), 3.10 - 2.92, (m, 1H), 1.83 - 1.60 (m, 4H); [M+H] = 174.2.
89%
Stage #1: With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 2 h; Stage #2: at 20℃;
In a 1 L RB flask, a solution of tetrahydro-2H-pyran-4-carboxylic acid (46.0 g, 353 mmol) in dichloromethane (250 mL) was treated with 1,1′-carbonyldiimidazole (63.0 g, 389 mmol) portion-wise—caution bubbling. After the addition was complete the mixture was stirred at room temperature for 2 h and then treated portion wise with N,O-dimethylhydroxylamine, HCl (37.9 g, 389 mmol) and then stirred overnight at room temperature. Washed with water and brine, dried over MgSO4, filtered, and concentrated to give N-methoxy-N-methyloxane-4-carboxamide (55.0 g, 302 mmol, 85percent) as light amber oil. 1H NMR (400 MHz, CDCl3) δ 4.02 (ddd, J=11.4, 4.2, 2.1 Hz, 2H), 3.71 (s, 3H), 3.46 (td, J=11.8, 2.2 Hz, 2H), 3.19 (s, 3H), 1.93-1.80 (m, 2H), 1.69-1.62 (m, 2H).
81%
With 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 18 h;
[0239] To a solution of tetrahydro-2H-pyran-4-carboxylic acid 1 (4.0 g, 31 mmol) in DCM (65 mL) was added sequentiallyN,O-dimethylhydroxylamine hydrochloride (3.3 g, 34 mmol), 4-methylmorpholine (7.4 mL, 68 mmol), and N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (6.5 g, 34 mmol). The resulting mixture was stirred at RT for 18 h. Atthat time, the reaction was diluted with 1 N HCl and EtOAc and stirred vigorously until both phases cleared. The phases were separated, and the aqueous layer was extracted with EtOAc. The organic portions were combined, washed withbrine, dried over MgSO4, filtered, and concentrated. The crude residue was subjected to column chromatography (120g silica, 80 mL/min, 0percent to 100percent EtOAc/hexanes) to give N-methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide 2(4.3 g, 24.8 mmol, 81percent). LCMS for 2 (conditions D): tR = 1.12 min, m/e = 174.3 (M+H, base).
73.3%
With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 16 h;
The racemate of the methyl ester of the title compound was prepared according the literature using the scheme described above (US 2016/0176864). [00237] Methyl 3-(3,5-dimethylisoxazol-4-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)- 5H-pyrido[3,2-b]indole-7-carboxylate (0.22 g, prepared according to literature and the synthetic route above) was separated by chiral HPLC to give (R)-methyl 3-(3,5- dimethylisoxazol-4-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7- carboxylate (0.095 g) and (S)-methyl 3-(3,5-dimethylisoxazol-4-yl)-5-(phenyl(tetrahydro-2H- pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate (0.090 g) as a yellow solid. H NMR (racemate) (400 MHz, CDC13) δ 0.98-1.02 (IH, m), 1.32-1.36 (2H, m), 1.95 (IH, s), 2.15 (3H, s), 2.31 (3H, s), 3.00-3.08 (IH, m), 3.24-3.31 (IH, m), 3.45-3.51 (IH, m), 3.76-3.80 (IH, m), 3.96 (3H, s), 4.00-4.01 (IH, m), 5.52 (IH, d, J = 10.8 Hz), 7.22-7.29 (3H, m), 7.38-7.40 (2H, m), 7.51 (IH, d, J = 1.6 Hz), 7.99 (IH, dd, / = 8.0, 1.2 Hz), 8.36 (IH, d, J = 8.0 Hz), 8.39 (2H, s); LC/MS 496.3 [M+H]+. [00238] The chiral material ester was hydrolyzed under basic condition (aq. NaOH in MeOH) to provide (R)-PTM-3-l-A and (S)-PTM-3-l-B.
831 mg
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 10 - 35℃;
A) N-methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide To a solution of tetrahydro-2H-pyran-4-carboxylic acid (800 mg) in N,N-dimethylformamide (60.0 mL) were added 1-hydroxybenzotriazole monohydrate (1.17 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.44 g), N,O-dimethylhydroxylamine hydrochloride (600 mg) and triethylamine (1.73 mL). The reaction mixture was stirred overnight at room temperature, water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (831 mg). MS (API+): [M+H]+174.3.
With isopropylmagnesium chloride In tetrahydrofuran at -30 - -5℃; for 1 h;
Step 1 Methyl tetrahydropyran-4-carboxylate (1.33 mL, 10.0 mmol) was dissolved in THF (20 mL), N,O-dimethylhydroxylamine hydrochloride (1.51 g, 15.5 mmol) was added thereto, and the mixture was stirred. A THF solution (15.0 mL, 30.0 mmol) of 2.0 mol/L isopropyl magnesium chloride was added dropwise to the reaction mixture at -30°C under an argon atmosphere, and the mixture was stirred at -5°C for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and then the solvent was removed in vacuo. The resulting residue was purified by distillation under reduced pressure, whereby N-methoxy-N-methyl tetrahydropyran-4-carboxylic acid amide (1.00 g, 58percent) was obtained. Boiling point: 125 to 129°C/8.0 hPa 1H NMR (CDCl3, δ ppm): 1.57-1.66 (m, 2H), 1.77-1.93 (m, 2H), 2.85-2.94 (m, 1H), 3.18 (s, 3H), 3.44 (ddd, J = 2.4, 11.9, 11.9 Hz, 2H), 3.69 (s, 3H), 4.00 (ddd, J = 2.4, 11.9, 11.9 Hz, 2H)
58%
With isopropylmagnesium chloride In tetrahydrofuran at -30 - -5℃; for 1 h; Inert atmosphere
Methyl tetrahydropyran-4-carboxylate (1.33 mL, 10.0 mmol) was dissolved in THF (20 mL), and N,O-dimethylhydroxylamine hydrochloride (1.51 g, 15.5 mmol) added thereto , then the mixture was stirred. Under an argon atmosphere, THF solution of isopropyl magnesium chloride (2.0 mol/L; 15.0 mL, 30.0 mmol) was added dropwise to the reaction mixture at -30°C, and the mixture was stirred at -5°C for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure. The resulting residue was purified by distillation under reduced pressure to give N-methoxy-N-methyltetrahydropyran-4-carboxamide (1.00 g, 58percent). Boiling point: 125-129 °C / 8.0 hPa, 1H NMR (CDCl3, δ ppm): 1.57-1.66 (m, 2H), 1.77-1.93 (m, 2H), 2.85-2.94 (m, 1H), 3.18 (s, 3H), 3.44 (ddd, J = 2.4, 11.9, 11.9 Hz, 2H), 3.69 (s, 3H), 4.00 (ddd, J = 2.4, 11.9, 11.9 Hz, 2H).
With 4-methyl-morpholine In dichloromethane for 2 h;
N,O-Dimethylhydroxylamine hydrochloride (1.23 g, 12.7 mmol) and N-methyl morpholine (3.80 mL, 34.5 mmol) were dissolved in DCM (20 mL) and a solution of oxane-4-carbonyl chloride (1.71 g, 11.5 mmol) in DCM (20 mL) was added drop-wise. The reaction mixture was stirred for 2 h, then diluted to 200 mL with DCM, washed with 1 M aq HCl (2*100 mL), 1M aq Na2CO3 (100 mL) and water (100 mL), dried (MgSO4) and concentrated in vacuo to give the crude title compound as a yellow oil (1.87 g, 94percent). LCMS (ES+): 174.1 [MH]+.
Stage #1: With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 0 - 10℃; for 1 h; Stage #2: at 20 - 30℃;
1C (33 g, 0.155 mol) was dissolved in N,N-dimethylformamide (200 ml), the temperature was controlled below10°C, and N,N’-carbonyldiimidazole (32.58 g, 0.201 mol) was added to the reaction solution, followed by reaction at 0°Cfor 1 hour. N,O-dimethylhydroxylamine hydrochloride (19.6 g, 0.186 mol) was added to the reaction solution, followedby stirring at room temperature overnight. Water (150 ml) was added dropwise, followed by stirring for 1 hour andextraction with ethyl acetate (100 ml32). The organic phases were combined, washed with a saturated sodium bicarbonatesolution (60 ml33) and with a saturated sodium chloride solution (60 ml33), and dried by addition of anhydrousmagnesium sulfate thereto. Filtration was performed, and the filtrate was concentrated and separated by column chromatography(petroleum ether/ethyl acetate (v/v) = 10:1) to obtain a white solid 1D (35 g, yield 88.2percent).MS m/z (ESI): 156.9 [M-99].
88.2%
Stage #1: With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 0 - 10℃; for 1 h; Stage #2: at 20℃;
1C (33 g, 0.155 mol) was dissolved in N, N-dimethylformamide (200 mL)The reaction temperature was less than 10 ° C, and N, N'-carbonyldiimidazole (32.58 g, 0.201 mol) was added to the reaction solution, and the reaction was carried out at 0 ° C for 1 hour.N, O-dimethylhydroxylamine hydrochloride (19.6 g, 0.186 mol) was added to the reaction solution and stirred at room temperature overnight.Water (150 mL) was added dropwise, stirred for 1 hour, extracted with ethyl acetate (100 mL x 2), the organic phases were combined, washed with saturated sodium bicarbonate solution (60 mL x 3)The organic phase was washed with saturated sodium chloride solution (60 mL x 3), and the organic phase was dried over anhydrous magnesium sulfate.The filtrate was concentrated and separated by column chromatography (petroleum ether / ethyl acetate (v / v) = 10: 1) to give 1D (35 g, 88.2percent yield) as a white solid.
88.2%
Stage #1: With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 0 - 10℃; for 1 h; Stage #2: at 20℃;
1C (33 g, 0.155 mol) was dissolved in N,N-dimethylformamide (200 mL) at a controlled temperature of less than 10 °C, N, N'-carbonyldiimidazole (32.58 g, 0.201 mol) was added to the reaction solution and reacted at 0 °C for 1 hour. N,O-dimethylhydroxylamine hydrochloride (19.6 g, 0.186 mol) was added to the reaction solution and stirred at room temperature overnight.Water (150 mL) was added dropwise, stirred for 1 hour, extracted with ethyl acetate (100 mL x 2) and the combined organic phases were washed with saturated sodium bicarbonate solution (60 mL x 3), saturated sodium chloride solution (60 mL x 3) The organic phase was added to the organic phase and dried over anhydrous magnesium sulfate. The filtrate was concentrated and separated by column chromatography (petroleum ether / ethyl acetate (v / v) = 10: 1) to give 1D (35 g, 88.2percent yield) as a white solid.
88.2%
Stage #1: With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 0 - 10℃; for 1 h; Stage #2: at 20℃;
1C(33g, 0.155 µM) dissolved in N, N - dimethyl formamide(200 ml), control temperature is less than 10 °C, will N, N' - carbonyl diimidazole (32.58g, 0.201 µM) is added to the reaction solution, the reaction of the 0 °C under 1 hour. The N, O - dimethyl hydroxylamine hydrochloride (19.6g, 0.186 µM) is added to the reaction solution, stir at room temperature overnight. Water (150 ml) is added dropwise, stirring 1 hour, ethyl acetate (100mL × 2) extraction, the combined organic phase, saturated sodium bicarbonate solution (60mL × 3), saturated sodium chloride solution (60mL × 3) washing the organic phase, the organic phase adding anhydrous magnesium sulfate drying. Filtering, the filtrate is concentrated, for column chromatography (petroleum ether/ethyl acetate (v/v)=10:1), to obtain white solid1D(35g, yield 88.2percent).
88.2%
With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 0 - 20℃; for 2 h;
1C (33 g, 0.155 mol) was dissolvedN, N-dimethylformamide (200 mL)Control the temperature is less than 10 ,N, N'-carbonyldiimidazole (32.58 g, 0.201 mol) was added,0 & lt; 0 & gt; C for 1 hour,JoinN, O-dimethylhydroxyammonium hydrochloride (19.6 g, 0.186 mol)Stir overnight at room temperature.Water (150 mL) was added dropwise to the reaction solution,Stirring for 1 hour,Extracted with ethyl acetate (100 mL x 2)Combined organic phase,The organic phase was washed successively with saturated sodium bicarbonate solution (60 mL x 3)Saturated sodium chloride solution (60 mL x 3)Dried over anhydrous magnesium sulfate,filter,concentrate,The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10: 1)A white solid 1D (35 g, yield 88.2percent) was obtained.
81%
With triethylamine; HATU In acetonitrile at 20℃; for 2 h;
To a solution of 2-(tert-butoxycarbonylamino)pent-4-ynoic acid (20.22 g, 94.9 mmol) in acetonitrile (200 mL) were added 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (43.27 g, 113.9 mmol), N,O-dimethylhydroxylamine hydrochloride (11.11 g, 113.9 mmol) and triethylamine (46.2 mL, 332.2 mmol), and stirred at room temperature for 2 hours. The reaction solution was poured into 1500 mL water, and extracted three times with ethyl acetate. The combined organic phase was washed sequentially with IN hydrochloric acid, water, saturated sodium bicarbonate solution and saturated brine, dried and concentrated, and then the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate), 5:1 to 4:1) to give the product 2-(tert-butoxycarbonylamino)pent-4-ynylacyl-(N-methoxy-N-methyl)amine (19.6 g). Yield: 81percent. 1H-NMR (400 MHz, CDCl3): δ= 5.45 (1H, d, J=8.0Hz), 4.82 (1H, m), 3.77(3H, s), 3.24(3H, s), 2.66 (2H, m), 2.04(1H, s), 1.45 (9H, s).
73%
Stage #1: With pivaloyl chloride; N-ethyl-N,N-diisopropylamine In dichloromethane at -10 - -5℃; for 2 h; Stage #2: at -10 - -5℃;
Trimethylacetyl chloride (24.50 mL) was added to a solution of 2-[(tert-butoxycarbonyl)amino]pent-4-ynoic acid (40 g; Formula IV, Example 2) in dichloromethane (280 mL) and DIPEA (98.50 mL) at -10°C to -5°C, and the mixture was stirred for 2 hours. N,O-Bismethylhydroxylamine hydrochloride (18.30 g) was added to the reaction mixture, and then the mixture was stirred for 3 hours to 4 hours at -10°C to-5°C. After completion of the reaction, water (200 mL) was added to the reaction mixture, and then the mixture was stirred for 30 minutes. The reaction mixture was allowed to settle, and the layers were separated. The organic layer was washed with water (200 mL),and then concentrated under reduced pressure at 40°C to 45°C to obtain a residue. MTBE (12.5 mL) was added to the residue, and then the mixture was stirred for 2 hours at 0°C to 5°C. The solid obtained was filtered, then washed with MTBE (50 mL), and then dried under reduced pressure at 40°C to 50°C to obtain the title compound.Yield: 73percent
8.2%
Stage #1: With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 0 - 10℃; for 1 h; Stage #2: at 20℃;
1C (33 g, 0.155 mol) was dissolved in N, N-dimethylformamide (200 mL)The reaction temperature was less than 10 ° C and N, N'-carbonyldiimidazole (32.58 g, 0.201 mol) was added to the reaction solution and reacted at 0 ° C for 1 hour. N, O-dimethylhydroxyamine hydrochloride (19.6 g, 0.186 mol) was added to the reaction solution and stirred at room temperature overnight. (150 mL), saturated with sodium chloride solution (60 mL), and the mixture was extracted with ethyl acetate (100 mL χ2). The organic phase was combined with saturated sodium bicarbonate solution (60 mL χ 3) Χ 3) The organic phase was washed and the organic phase was dried over anhydrous magnesium sulfate. The filtrate was concentrated and separated by column chromatography (petroleum ether / ethyl acetate (ν / ν) = 10: 1) to give a white solid 1D (35 g, yield 8.2percent).
Reference：
[1] Organic Letters, 2010, vol. 12, # 4, p. 684 - 687
[2] Patent: EP3159344, 2017, A1, . Location in patent: Paragraph 0096; 0097; 0100
[3] Patent: TW2017/8221, 2017, A, . Location in patent: Page/Page column 33; 34
[4] Patent: TW2017/8220, 2017, A, . Location in patent: Page/Page column 56; 57; 58
[5] Patent: TW2017/8222, 2017, A, . Location in patent: Paragraph 34; 35
[6] Patent: CN106632349, 2017, A, . Location in patent: Paragraph 0077; 0078; 0079; 0080; 0081
[7] Patent: EP3257857, 2017, A1, . Location in patent: Paragraph 0084; 0088
[8] Patent: WO2017/81590, 2017, A1, . Location in patent: Page/Page column 18; 19
[9] Patent: TW2017/8224, 2017, A, . Location in patent: Page/Page column 28; 29; 30
[10] Patent: US2009/187028, 2009, A1, . Location in patent: Page/Page column 7
[11] Organic Letters, 2014, vol. 16, # 20, p. 5422 - 5425
[12] Organic Process Research and Development, 2015, vol. 19, # 11, p. 1760 - 1768
112
[ 6638-79-5 ]
[ 61172-66-5 ]
[ 530-62-1 ]
[ 1172623-95-8 ]
Yield
Reaction Conditions
Operation in experiment
88.2%
Stage #1: at 0 - 10℃; for 1 h; Stage #2: at 20℃;
1C (33 g, 0.155 mol) was dissolved in N, N-dimethylformamide (200 mL)Control the temperature is less than 10 ,N, N'-carbonyldiimidazole (32.58 g, 0.201 mol) was added,1 hour at 0 ,N, O-dimethylhydroxylamine hydrochloride (19.6 g, 0.186 mol) was added and stirred at room temperature overnight.Water (150 mL) was added dropwise to the reaction solution, stirred for 1 hour and extracted with ethyl acetate (100 mL x 2). The organic phases were combined and the organic phase was washed with saturated sodium bicarbonate solution (60 mL x 3), saturated sodium chloride (40 mL x 3), dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10: 1) to give 1D (35 g , Yield 88.2percent).
Reference：
[1] Patent: TW2017/8223, 2017, A, . Location in patent: Page/Page column 38
Stage #1: With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0℃; for 0.166667 h; Stage #2: With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 16 h;
To a solution of Ν,Ο-dimethyl hydroxyl amine hydrochloride (4.6 g, 47.61 mmol) in DMF (50 ml_) was added DIPEA (16.9 ml_, 95.23 mmol) at 0°C and the mixture stirred for 10 minutes. 4-chloropyridine-2-carboxylic acid (5.0 g, 31 .74 mmol) was then added followed by HATU (17.8 g, 47.61 mmol) and the reaction stirred at room temperature for 16 hours. The reaction was concentrated in vacuo and purified using silica gel column chromatography eluting with 15-20percent EtOAc in hexane to afford the title compound (4.8 g, 96percent). 1H NMR (400 MHz, CDCl3): δ ppm 3.37 (s, 3H), 3.72 (s, 3H), 7.35 (d, 1 H), 7.63 (br s, 1 H), 7.48 (d, 1 H). LCMS Rt = 2.30 minutes MS m/z 201 [M+H]+
46%
With 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃;
Preparation 6 4-Chloro-N-methoxy-N-meth l-pyridine-2-carboxamide 4-Chloropyridine-2-carboxylic acid (40.9 g, 259.59 mmol) is suspended in anhydrous dichloromethane (700 mL) with stirring and with exclusion of moisture (silica gel drying tube is used). The resulting solution is cooled to 0 °C and N- methylmorpholine (129 mL, 1.17 mol), N,0-dimethylhydroxylamine hydrochloride (35.45 g, 363.43 mmol) are added followed by portion wise addition of l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (69.67 g, 363.43 mmol). After this addition is complete, the reaction is warmed to room temperature and stirred at that temperature overnight. Water (600 mL) is added and the layers are separated. The aqueous layer is re-extracted twice with dichloromethane (300mL). The organic layers are combined, washed with brine (400mL) and dried over anhydrous sodium sulphate. The solvent is removed under reduced pressure to give a dark oil. This is purified by silica gel column chromatography using a gradient of 0 to 50percent ethyl acetate in iso hexane to give the title compound (23.7 g, 46percent). ES/MS (m/e) 201/203.
With potassium carbonate; In tert-butyl methyl ether; water; at -5 - 20℃; for 3.5h;
Example 139 N-methoxy-N-methylchloroacetamide A solution of N,O-dimethylhydroxylamine hydrochloride (200 g, 2.05 mol) and tert-butyl methyl ether (2 L) was added to a cooled (0°C) solution of potassium carbonate (624 g, 4.1 mol) in water (2 L). The mixture was cooled to -5°C and chloroacetyl chloride added such that the temperature remained below 5°C. The vigorously stirred mixture was allowed to warm to room temperature and stirred for an additional 3.5 hours. The phases were separated and the aqueous phase was extracted with tert-butyl methyl ether (3 x 1 L). The combined organic phase was washed with saturated aqueous sodium chloride solution (2 x 1 L), dried (MgSO4), and concentrated. The residue was dried in vacuo to yield a white solid (257 g, 92percent). Mp 39-40.5°C; 1H NMR (CDCl3, 300 MHz) delta 4.24 (s, 2 H), 3.74 (s, 3 H), 3.22 (s, 3 H); MS (CI) 138 (MH+); Anal. calcd for C4H8ClNO2: C, 34.92; H, 5.86; N, 10.18. Found: C, 35.06; H, 5.88; N, 10.23.
92%
With potassium carbonate; In tert-butyl methyl ether; water;
EXAMPLE 139 STR92 N-methoxy-N-methylchloroacetamide A solution of N,O-dimethylhydroxylamine hydrochloride (200 g, 2.05 mol) and tert-butyl methyl ether (2 L) was added to a cooled (0° C.) solution of potassium carbonate (624 g, 4.1 mol) in water (2 L). The mixture was cooled to -5° C. and chloroacetyl chloride added such that the temperature remained below 5° C. The vigorously stirred mixture was allowed to warm to room temperature and stirred for an additional 3.5 hours. The phases were separated and the aqueous phase was extracted with tert-butyl methyl ether (3*1 L). The combined organic phase was washed with saturated aqueous sodium chloride solution (2*1 L), dried (MgSO4), and concentrated. The residue was dried in vacuo to yield a white solid (257 g, 92percent). Mp 39-40.5° C.; 1 H NMR (CDCl3, 300 MHz) delta 4.24 (s, 2 H), 3.74 (s, 3 H), 3.22 (s, 3 H); MS (CI) 138 (MH+); Anal. calcd for C4 H8 ClNO2: C, 34.92; H, 5.86; N, 10.18. Found: C, 35.06; H, 5.88; N, 10.23.
90%
With potassium carbonate; In tert-butyl methyl ether; water; at -5 - 0℃; for 2h;
A 3 L four necked flask equipped with Teflon-blade stirrer, reflux condenser and thermo-pocket was charged with N-methoxymethanamine hydrochloride (345g), water (1 .6 litre) and the resulting reaction mixture was cooled to 0 to -5 °C. Then potassium carbonate (1466 g) was added in lots to the above reaction mixture followed by the addition of methyl tert-butyl ether (1 .4 litre). The chloroacetyl chloride (400 g) was dissolved in tert-butyl methyl ether (0.2 litre) and added dropwise in to the above kept reaction mixture at - 5°C to 0°C and the reaction mixture was stirred for 2 h at 0°C. The reaction mixture was allowed to come to ambient temperature and two phases were separated. The organic layer was dried over sodium sulfate, filtered and evaporated to provide 2-chloro-N-methoxy-N-methyl-acetamide as white solid (440 g, 90percent yield and 98.0percent area purity by HPLC).
With potassium carbonate; In water; at -5 - 20℃; for 2h;
2-Chloro-N-methoxy-N-methylacetamide To a solution of potassium carbonate (93 g, 750 mmol) in H2O (300 mL) was added N,O-dimethylhydroxylamine hydrochloride (30 g, 300 mmol) at 0° C. The mixture was further cooled to -5° C., and 2-chloroacetyl chloride (40.6 g, 360 mmol) was added. The solution was stirred at room temperature for 2 h. The aqueous mixture was extracted with toluene (3*300 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to give the crude product (35 g, 85percent) as a white solid. LC/MS: m/e=138 (M+H)+.
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
Commercially available (2S)-2-[(tert-butoxycarbonyl)amino]pentanoic acid (1.0 g, 4.6 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.47 g, 4.8 mmol) were dissolved in DMF <n="131"/>(18 ml). O-benzofriazole-l-yl-N,N,N',N'-te1xamethyl-uronium hexafluorophosphate (1.92 g, 5.06 mmol) and N,N-diisopropylethylamine (2.47 ml, 14.5 mmol) were added. The reaction was stirred at r.t. over night. The reaction was poured into a mixture of water and ethyl acetate. The mixture was shaken, the layers separated and the water layer washed twice with ethyl acetate. The collected organic phase was washed with a small portion of water and dried over sodium sulphate. The solvent was removed under educed pressure and the crude product was purified by flash chromatography. Yield. 1.02 g, 85 percent APCI-MS: m/z 261 [MH+]1H NMR (400 MHz, DMSOd6) delta 6.96 (d, J= 8.3 Hz, IH), 4.37 (m, IH), 3.72 (s, 3H), 3.09 (s, 3H), 1.36 (m, 13H), 0.85 (t, J= 7.3 Hz, 3H)
With 4-methyl-morpholine; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; In DMF (N,N-dimethyl-formamide); dichloromethane; at 50℃;
Step H A solution of acid 1 k (2 g) in 100 mL of dry dichloromethane and 5 mL of DMF was treated with N, O-dimethylhydroxylamine hydrochloride (1.1 eq, 986 mg), BOP reagent (1.1 eq, 4.47 g), and N-methylmorpholine (3.3 eq, 3.3 mL, d 0.920) in that order. The mixture was heated to 50 °C overnight. The reaction mixture was concentrated to half its volume and diluted with 400 mL of ethyl acetate. The organic layer was washed with water (80 mL), aqueous 1M HCI (80 mL), aqueous saturated sodium bicarbonate solution (80 mL.), and brine (80 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel (gradient: acetone/hexanes; 5: 95 to 3: 7) to afford the product 11 as a clear oil.
A solution of acid 12a (2 g) in 100 mL of dry dichloromethane and 5 mL of DMF was treated with N,O-dimethylhydroxylamine hydrochloride (1.1 eq, 986 mg), BOP reagent (1.1 eq, 4.47 g), and N-methylmorpholine (3.3 eq, 3.3 mL, d 0.920) in that order. The mixture was heated to 50° C. overnight. The reaction mixture was concentrated to half its volume and diluted with 400 mL of ethyl acetate. The organic layer was washed with water (80 mL), aqueous 1 M HCl (80 mL), aqueous saturated sodium bicarbonate solution (80 mL), and brine (80 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel (gradient: acetone/hexanes; 5:95 to 3:7) to afford the product 12b as a clear oil.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 2.5h;
To the mixture of Boc-NVa-OH (25 g, 0.115 mol), Lambdazeta,O-dimethylhydroxyamine hydrochloride (12.34 g, 0.127 mol), EDC (33.07 g, 0.173 mol), HOBt (22.9 g, 0.15 mol) in dichloromethane (300 mL), was slowly added NMM (34.9g, 0.35 mol) under stirring in 30 min. The reaction was left at room temperature for 2 h, then diluted with 2000 mL EtOAc, washed with NaHCpsi3, H2O, and brine, and dried over MgSO4. The solvent was removed on rotovap to give [^-(methoxymethylcarbamoytybutyljcarbamic acid tert-bntyl ester (20 g) as colorless oil.
To a solution of the BOC-amino acid 323 (25 g) in THF (250 mL) was added in portions, solid carbonyldiimidazole (CDI) (22.4 g). After 0.5 h a mixture of N-methyl-N-methoxyamine hydrochloride in DMA/DIEA (30 mL) was added and the resulting mixture was stirred at room temperature overnight. The reaction was washed by adding water (250 mL) and Et2O/EtOAc (1:1, 500 mL) and then back-extracted once. The organic portion was washed with 0.5 N HlC, followed by brine and dried over sodium sulfate. The mixture was then filtered and the filtrate was concentrated in vacuo to afford 324 as a yellow oil (20 g).
With 4-methyl-morpholine; benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In dichloromethane; at 20℃; for 2.5h;
Preparation 1; Preparation of OSVS-amino-N-cvclopropyl-Z-hvdroxyhexanamide hydrochloride, the compound of Formula (12); Step 1; [0100] To a mixture of Boc-NVa-OH (25 g, 0.115 mol), 7V,O-dimethylhydroxyamine hydrochloride (12.34 g, 0.127 mol), l-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (33.07 g, 0.173 mol) and 1-hydroxybenzotriazole (22.9 g, 0.15 mol) in dichloromethane (300 mL), was slowly added N-methylmorpholine (34.9g, 0.35 mol) under stirring over a 30 minute period. The reaction was stirred at room temperature for 2 hours, then diluted with 2000 mL ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate, water, and brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure to provide [l.pound.-(methoxymethylcarbamoyl)butyl]carbamic acid tert-butyl ester (20 g) as a colorless oil.
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine; In dichloromethane; for 24h;
To a stirred solutionof N-BOC-L-Norvaline (25 g, 0.12 mol) inCH2C12 (300mL) were added triethylamine (47mL, 0.34 mol), N,O-dimethylhydroxylamine hydrochloride (14 g, 0.14 mol), andPyBOP (60 g, 0.12 mol). The reaction mixture was left to stir for1 d, treated with 1 NNaOH solution, and left to stir for 1 h. The aqueous layer was extracted with EtOAc (x 3). The combined organics were washed with brine, dried(Na2S04), concentrated, and purified by flash chromatography to giveN2- (tert-butoxycarbonyl)-Nl-methoxy-Nl-methyl-L-norvalinamide. 1H NMR (CDC13, 500 MHz) 8 5.15 (br s,1H), 4.70 (br s, 1H), 3.80 (s, 3H), 3.23 (s, 3H), 1.40-1. 80 (m, 4H), 1. 46 (s, 9H), 0.95 (t, 3H).
With 4-methyl-morpholine; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; In dichloromethane; N,N-dimethyl-formamide; at 50℃;
A solution of acid 1k (2 g) in 100 mL of dry dichloromethane and 5 mL of DMF was treated with N,O-dimethylhydroxylamine hydrochloride (1.1 eq, 986 mg), BOP reagent (1.1 eq, 4.47 g), and N-methylmorpholine (3.3 eq, 3.3 mL, d 0.920) in that order. The mixture was heated to 50° C. overnight. The reaction mixture was concentrated to half its volume and diluted with 400 mL of ethyl acetate. The organic layer was washed with water (80 mL), aqueous 1M HCl (80 mL), aqueous saturated sodium bicarbonate solution (80 mL), and brine (80 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel (gradient: acetone/hexanes; 5:95 to 3:7) to afford the product 1l as a clear oil.
With 4-methyl-morpholine; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; In dichloromethane; N,N-dimethyl-formamide; at 50℃;
A solution of acid 1k (2 g) in 100 mL of dry dichloromethane and 5 mL of DMF was treated with N,O-dimethylhydroxylamine hydrochloride (1.1 eq, 986 mg), BOP reagent (1.1 eq, 4.47 g), and N-methylmorpholine (3.3 eq, 3.3 mL, d 0.920) in that order. The mixture was heated to 50° C. overnight. The reaction mixture was concentrated to half its volume and diluted with 400 mL of ethyl acetate. The organic layer was washed with water (80 mL), aqueous 1M HCl (80 mL), aqueous saturated sodium bicarbonate solution (80 mL), and brine (80 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel (gradient: acetone/hexanes; 5:95 to 3:7) to afford the product 1l as a clear oil.
With 4-methyl-morpholine; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; In dichloromethane; N,N-dimethyl-formamide; at 50℃;
A solution of acid 1k (2 g) in 100 mL of dry dichloromethane and 5 mL of DMF was treated with N,O-dimethylhydroxylamine hydrochloride (1.1 eq, 986 mg), BOP reagent (1.1 eq, 4.47 g), and N-methylmorpholine (3.3 eq, 3.3 mL, d 0.920) in that order. The mixture was heated to 50° C. overnight. The reaction mixture was concentrated to half its volume and diluted with 400 mL of ethyl acetate. The organic layer was washed with water (80 mL), aqueous 1M HCl (80 mL), aqueous saturated sodium bicarbonate solution (80 mL), and brine (80 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel (gradient: acetone/hexanes; 5:95 to 3:7) to afford the product 1l as a clear oil.
With 4-methyl-morpholine; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; In dichloromethane; N,N-dimethyl-formamide; at 50℃;
A solution of acid 1k (2 g) in 100 mL of dry dichloromethane and 5 mL of DMF was treated with N,O-dimethylhydroxylamine hydrochloride (1.1 eq, 986 mg), BOP reagent (1.1 eq, 4.47 g), and N-methylmorpholine (3.3 eq, 3.3 mL, d 0.920) in that order. The mixture was heated to 50° C. overnight. The reaction mixture was concentrated to half its volume and diluted with 400 mL of ethyl acetate. The organic layer was washed with water (80 mL), aqueous 1M HCl (80 mL), aqueous saturated sodium bicarbonate solution (80 mL), and brine (80 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel (gradient: acetone/hexanes; 5:95 to 3:7) to afford the product 1l as a clear oil.
With 4-methyl-morpholine; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; In dichloromethane; N,N-dimethyl-formamide; at 50℃;
Step HA solution of acid 1k (2 g) in 100 mL of dry dichloromethane and 5 ml_ of DMF was treated with N,O-dimethylhydroxylamine hydrochloride (1.1 eq, 986 mg), BOP reagent (1.1 eq, 4.47 g), and N-methylmorpholine (3.3 eq, 3.3 mL, d 0.920) in that order. The mixture was heated to 50 0C overnight. The reaction mixture was concentrated to half its volume and diluted with 400 mL of ethyl acetate. The organic layer was washed with water (80 mL), aqueous 1M HCI (80 mL), aqueous saturated sodium bicarbonate solution (80 mL), and brine (80 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel (gradient: acetone/hexanes; 5:95 to 3:7) to afford the product 11 as a clear oil.
With 4-methyl-morpholine; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; In dichloromethane; N,N-dimethyl-formamide; at 50℃;
Step HA solution of acid 1k (2 g) in 100 mL of dry dichloromethane and 5 ml_ of DMF was treated with N,O-dimethylhydroxylamine hydrochloride (1.1 eq, 986 mg), BOP reagent (1.1 eq, 4.47 g), and N-methylmorpholine (3.3 eq, 3.3 mL, d 0.920) in that order. The mixture was heated to 50 0C overnight. The reaction mixture was concentrated to half its volume and diluted with 400 mL of ethyl acetate. The organic layer was washed with water (80 mL), aqueous 1M HCI (80 mL), aqueous saturated sodium bicarbonate solution (80 mL), and brine (80 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel (gradient: acetone/hexanes; 5:95 to 3:7) to afford the product 11 as a clear oil.
With 4-methyl-morpholine; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; In dichloromethane; N,N-dimethyl-formamide; at 50℃;
A solution of acid 1k (2 g) in 100 mL of dry dichloromethane and 5 mL of DMF was treated with N,O-dimethylhydroxylamine hydrochloride (1.1 eq, 986 mg), BOP reagent (1.1 eq, 4.47 g), and N-methylmorpholine (3.3 eq, 3.3 mL, d 0.920) in that order. The mixture was heated to 50° C. overnight. The reaction mixture was concentrated to half its volume and diluted with 400 mL of ethyl acetate. The organic layer was washed with water (80 mL), aqueous 1M HCl (80 mL), aqueous saturated sodium bicarbonate solution (80 mL), and brine (80 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel (gradient: acetone/hexanes; 5:95 to 3:7) to afford the product 1l as a clear oil.
With 4-methyl-morpholine; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; In dichloromethane; N,N-dimethyl-formamide; at 50℃;
A solution of acid 1k (2 g) in 100 mL of dry dichloromethane and 5 mL of DMF was treated with N,O-dimethylhydroxylamine hydrochloride (1.1 eq, 986 mg), BOP reagent (1.1 eq, 4.47 g), and N-methylmorpholine (3.3 eq, 3.3 mL, d 0.920) in that order. The mixture was heated to 50° C. overnight. The reaction mixture was concentrated to half its volume and diluted with 400 mL of ethyl acetate. The organic layer was washed with water (80 mL), aqueous 1M HCl (80 mL), aqueous saturated sodium bicarbonate solution (80 mL), and brine (80 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel (gradient: acetone/hexanes; 5:95 to 3:7) to afford the product 11 as a clear oil.
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 2.5h;
Reference A; Synthesis of [1S-(cyclopropylcarbamoylhydroxymethyl)butyl]carbamic acid tert-butyl ester is provided in the scheme for Reference intermediate A (see FIG. 4).; Step 1; To the mixture of Boc-NVa-OH (25 g, 0.115 mol), N,O-dimethylhydroxyamine hydrochloride (12.34 g, 0.127 mol), EDC (33.07 g, 0.173 mol), HOBt (22.9 g, 0.15 mol) in dichloromethane (300 mL), was slowly added NMM (34.9 g, 0.35 mol) under stirring in 30 min. The reaction was left at room temperature for 2 h, then diluted with 2000 mL EtOAc, washed with NaHCO3, H2O, and brine, and dried over MgSO4. The solvent was removed on rotovap to give [1S-(methoxymethylcarbamoyl)butyl]carbamic acid tert-butyl ester (20g) as colorless oil.
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;
Compound (S)-3-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)propanoic acid (10 g, 38.27 mmol), in a 500 mL single-necked flaskDimethylhydroxylamine hydrochloride (4.48 g, 45.92 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (14.7 g, 76.68 mmol)And 4-dimethylaminopyridine (2.33g, 19mmol) dissolved in anhydrous dichloromethane (200mL), the reaction was stirred at room temperature until complete,Ethyl acetate and extracted with water, brine, dried, and concentrated to give the title compound 13a.
Synthesis of ylide 21. To a solution of N-methoxy-N-methylhydroxylamine hydrochloride (48.52 g, 500 mmol, 1.0 equiv) in CH2Cl2 (1.0 L) at 0°C were added pyridine (80.63 mL, 1.0 mol) and chloroacetic anhydride (85.14 g, 500 mmol, 1.0 equiv). The resulting mixture was stirred for 15 min at 00C, then warm up to 23°C and stirred overnight. The reaction mixture was then poured carefully into sat. NaHCpsi3aq solution (1.0 L) and stirred 1 hour, after which the layers were separated, the aqueous phase was extracted with CHaCl2 (400 mL) and the combined organic layers were washed with IN HCl (200 mL x 2), brine (200 mL x 2), dried over Na2SO4 (10 g) and filtered. Evaporation of the solvents under reduced pressure afforded the corresponding acetamide (N-rnethoxy-N-methyl acetamide-2-chloride) as a green oil which was used in the next step without further purification. To a solution of this acetamide in CH3CN (800 mL) was added Ph3P (107.98 g, 411.7 mmol, 0.82 equiv) and the resulting mixture was refluxed for 18 hours. Then the solvents were removed under vacuum and the resulting viscous oil was dissolved in CH2Cl2 (1.0 L), washed with 2N KOH (400 mL x 2), brine (400 mL) and dried over Na2SO4 (10.0 g). Filtration and evaporation of the solvents under reduced pressure afforded ylide 21 as a thick oil which solidified by standing (146.5 g, 80percent over two steps). This compound was used in the next step without further purification. Rf = 0.85 (Hexane/EtOAc 3/1); 1H NMR (CDCl3, 400 MHz, 25 0C) 57.71-7.65 (m, 6H), 7.55-7.50 (m, 3H), 7.48-7.42 (m, 6H), 3.74 (s, 3H), 3.08 (s, 3H), 1.86 (s, IH); 13C NMR <n="150"/>(CDCl3, 100 MHz, 25 0C) 133.3 (x 3), 133,2 (x 3), 131.9 (x 3), 128.9 (x 3), 128.8 (x 3), 127.9, 61.3, 35.9.
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃;
2-METHYLTHIAZOLE-4-CARBOXYLIC acid (2 g, 13.9 mmol) was combined with N, N- (methoxy) methylamine HCL (1.78 g, 18.18 mmol), N-hydroxybenzotriazole (2.83 g, 20.98 mmol), diluted into CH2C12 (30 mL), treated with diisopropylethylamine (6.1 ML, 34.97 mmol) and then treated with solid BOP reagent (6.80 g, 15.38 mmol) at 0 °C. The reaction mixture was warmed to room temperature and maintained under TLC control (SI02, 20percent acetone-hexanes). The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution and CH2CL2, the organic phase dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and purified (Biotage 40M SIO2, 20-25percent acetone-hexanes) to provide the N-methoxy-N- methyl amide as a pale yellow oil (2.04 g, 78percent).
78%
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃;
Thioacetamide (75 g, 1 mol) was suspended in CC14 (250 mL), and a solution of ethyl bromopyruvate (205 g, 1.05 mol) in CC14 (250 mL) was added by portions with intensive stirring. An exothermic reaction was observed, resulting in formation of a layer of heavy orange- red oil, that was separated, washed with ether (3X250 mL) and heated in a boiling water bath for 1 hour. Then water was added (1 L), followed by solid sodium bicarbonate addition to alkaline pH. The ethyl ester was extracted with ether (5X250 mL), the extracts dried over anhydrous sodium sulfate, concentrated in vacuo and the residue was distilled under vacuum. Ethyl 2-methylthiazole-4-carboxylate (100 g, 0.58 mol) was dissolved in a minimum amount of cold methanol, and a solution of potassium hydroxide (36 g, 0.64 mol) in a minimum amount of cold methanol was added. The hydrolysis of the ester was rapid, and the potassium salt of the target acid precipitated from the mixture. Water was added to homogeneity, and the methanol was evaporated. The aqueous was acidified carefully with concentrated hydrochloric acid, the preciptant acid filtered off, washed with cold water, and recrystallized with water to provide 55 g of <strong>[35272-15-2]2-methylthiazole-4-carboxylic acid</strong>. 2-Methylthiazole-4-carboxylic acid (2 g, 13.9 mmol) was combined with N, N- (methoxy) methylamine HC1 (1.78 g, 18.18 mmol), N-hydroxybenzotriazole (2.83 g, 20.98 mmol), diluted into methylene chloride (30 mL), treated with diisopropylethylamine (6.1 ML, 34.97 mmol) and then treated with solid BOP reagent (6.80 g, 15.38 mmol) at 0 °C. The reaction mixture was warmed to room temperature and maintained under TLC control (SI02, 20percent acetone-hexanes). The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution and methylene chloride, the organic phase dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and purified (Biotage 40M SI02, 20-25percent acetone- hexanes) to provide the N-methoxy-N-methyl amide as a pale yellow oil (2.04 g, 78percent). 2-Methylthiazole-4-N-methoxy-N-methyl amide (2.05 g, 11.02 mmol) was diluted into dry toluene (30 mL), chilled TO-78 °C, and treated with fresh DIBAL-H (8.4 ML, 1.5 M toluene) under nitrogen. The reaction mixture was maintained 10 minutes under TLC control (SI02, 20percent acetone-hexanes), quenched at-78 °C with saturated aqueous Rochelle salt, warmed to room temperature, partitioned between water and chloroform, and the organic phase dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and dried under vacuum to provide the aldehyde as a yellow oil which was used directly in the next reaction without purification. 2-Methylthiazole-4-carboxaldehyde (1.4 g, 11.02 mmol) was diluted into dry toluene (30 mL), treated with the solid stabilized ylide (Ph3P=CHC (O) N (CH3) (OCH3), 4.6 g, 12.67 mmol) at 23 °C, and the reaction mixture heated at 60 °C overnight under nitrogen. The reaction mixture was concentrated in vacuo and purified (Biotage 40M SI02, 15-20percent acetone- hexanes) to provide the N-methoxy-N-methyl acrylamide as a white solid (1.43 g, 61percent).
Analogous to the general method described in J. Med. Chem., (2005), 48(6), 2134-2153. To a flask containing <strong>[35272-15-2]2-methylthiazole-4-carboxylic acid</strong> (1.10 g, 7.68 mmol) was added DCM (30 mL) and the homogeneous solution was stirred at room temperature as carbonyldiimidazole (1.30 g, 8.02 mmol) was added. A white opaque suspension resulted. After the mixture was stirred at room temperature for 2.25 hours a colorless homogeneous solution resulted and then N,O-dimethylhydroxylamine hydrochloride (820 mg, 8.41 mmol) was added which caused an opaque solution to result once again. The mixture was stirred at room temperature for 18 hours, then diluted with water and 1 N NaOH (to pH 9) and extracted with DCM (4×50 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated to give a colorless oil, which was passed through a plug of silica gel eluting with (20percent THF-DCM) to provide the title compound as a colorless oil.
1-Methylisonipecotic acid (5.5 g, 38.4 mmol) was dissolved in dimethylformamide (100 ml) with heating. Diisopropylethylamine (8.0 ml, 46.1 mmol), 1-hydroxybenzotriazole (5.2 g, 38.4 mmol), and N,O-dimethylhydroxylamine hydrochloride (4.1 g, 42.2 mmol) were added and the reaction mixture was stirred 5 min. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.4 g, 38.4 mmol) was added and the resulting homogeneous solution was stirred for 63 hours at ambient temperature. The solvent was removed under reduced pressure. The residue was dissolved in water and the solution was basified to pH 9 with 5N sodium hydroxide solution. This aqueous solution was extracted with methylene chloride then saturated with sodium chloride and extracted with chloroform/isopropanol (3/1). The combined organic extracts were dried over sodium sulfate and the solvent was removed under reduced pressure to give 9.5 g of a yellow liquid. Purification by flash chromatography (silica gel, methylene chloride:methanol:ammonium hydroxide, 100:10:1) gave 5.7 g (80percent) of product as a light yellow liquid. [00381] MS (m/e): 186(M+). [00382] Analysis for C9H18N2O2:
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 14h;Inert atmosphere;
Step A: Preparation of N-methoxy-N-methylpyrirnidine-5-carboxamide. [00245] To a stirred mixture of <strong>[4595-61-3]pyrimidine-5-carboxylic acid</strong> (2.5 g, 20.15 mmol), and N,0- dimethyl hydroxylamine hydrochloride (2.49 g, 25.5 mmol) in DCM (50 mL), EDC HC1 (4.63 g, 24.17 mmol) and DMAP (3.69 g, 30.2 mmol) were added under a nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 14 h. The reaction mixture was concentrated under reduced pressure; the obtained crude material was purified by flash column chromatography (100-200, Si02, 50-70 percent EA/Hexanes) to get N-methoxy-N-methylpyrimidine-5- carboxamide as a pale brown liquid. The product was confirmed by 1H NMR and LCMS. (2.8 g, 83percent). 1H NMR (400MHz, CDC13) delta 9.28 (s, 1H), 9.10 (s, 2H), 3.59 (s, 3H), 3.41 (s, 3H); ESIMS m/z 167.97 [M+H]+.
21%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 24h;
Combine EDCI (0.99 g, 5.18 mmol) with a solution OF O, N- dimethylhydroxylamine hydrochloride (0.51 g, 5.23 MMOL), PYRIMIDINE-5-CARBOXYLIC (540 mg, 4.35 MMOL), triethylamine (1.5 mL, 10.4 mmol), and DMAP (0.64 g, 5.24 mmol) in DMF (10 mL) and stir at RT. After 24 h, treat the reaction mixture with saturated NAHC03 and extract with CH2CI2. Wash the organic layer with water, dry over sodium sulfate, filter, and concentrate under reduced pressure. Purification by flash chromatography eluting with a linear gradient of 15percent to 30percent EtOAc in hexanes gives the title compound (0.15 g, 21percent). MS (ES) 168.2 (M+1) + ;'H NMR (400 MHz, CHCI3) 8 9.21 (s, 1H), 9.02 (s, 2H), 3.53 (s, 3H), 3.34 (s, 3H).
1,1?-carbonyldiimidazole (1.23 g, 7.57 mmol) was added to a suspension of <strong>[4595-61-3]pyrimidine-5-carboxylic acid</strong> (783 mg, 6.31 mmol) in DCM (20 mL) and the mixture was stirred at room temperature for 15 min before addition of N,O-dimethylhydroxylamine hydrochloride (739 mg, 7.57 mmol). The mixture was stirred at room temperature for 5 d, then was diluted with saturated aqueous NH4Cl and water and extracted with DCM. The organic phase was washed with water, and the aqueous phases were back-extracted with DCM. The organic phase was dried (Na2SO4), filtered, and concentrated, affording the crude title compound as a light yellow oil which was used without further purification in the next reaction
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; at 20℃; for 4h;
EXAMPLE 57; (alphaR,gammaS,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-gamma-hydroxy-4-[1-methyl-1-[3-methyl-5-(4-pyridinyl)-2-furanyl]ethyl]-alpha-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide; To a solution of commercially available methyl 3-methylfuroate (20.0 g, 140 mmol) in 100 mL of MeOH, NaOH (11.43 g, 280 mmol) in 20 mL of water was added. The yellowish solution was stirred at room temperature for 3 hours. TLC (1:9 EtOAc/hexane) showed no starting material. MeOH was removed and the pH of the aqueous solution was adjusted to 4 with 1N HCl. The slurry was extracted with ethyl acetate (5.x.100 mL). The combined ethyl acetate layers were washed brine, and dried over sodium sulfate. 3-methyl furoic acid was obtained as a white solid (13.2 g, 73percent) after evaporation of the solvent. To a mixture of 3-methyl furoic acid (8.60 g, 68 mmol), N,O-dimethylhydroxylamine hydrochloride (8.0 g, 82 mmol), EDC (15.7 g, 82 mmol), and HOBT (11.07 g, 82 mmol) in dichloromethane (200 mL), triethylamine (14.4 mL, 100 mmol) was added. The solution was stirred at room temperature for 4 hours, and washed with 1N NaOH (50 mL), 1N HCl (50 mL), brine, and dried over sodium sulfate. The title compound was obtained as a colorless liquid upon removal of the solvent.
With N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; triethylamine; In dichloromethane; at 20℃; for 3h;
Example 1 Production of N-benzyl-2-[3-benzyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanamine a) Production of N-methoxy-N-methylisoquinoline-3-carboxyamide [Show Image]; 200 mg of <strong>[6624-49-3]3-isoquinolinecarboxylic acid</strong>, 169 mg of N,O-dimethylhydroxylamine monohydrochloride, 332 mg of WSC, and 582 mg of triethylamine were dissolved in 2 mL of dichloromethane, followed by stirring at room temperature for 3 hours. Water was added to the reaction liquid, followed by extraction with chloroform. The organic layer was then washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue obtained was purified using silica gel chromatography (chloroform alone) to obtain 169 mg (yield 67percent) of a title compound as a pale yellow solidified product. 1H-NMR (CDCl3) delta: 3.47 (3H, s), 3.80 (3H, s), 7.69 (1H, ddd, J = 1.2, 8.0, 8.0 Hz), 7.76 (1H, ddd, J =1.2, 8.0, 8.0 Hz), 7.92 (1H, d, J = 8.0 Hz), 8.02 (1H, d, J = 8.0 Hz), 8.14 (1H, s), 9.25 (1H, s).
With triethylamine; 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride; In acetonitrile; for 48h;Product distribution / selectivity;
Step 1: Isoquinoline-3-carboxylic acid methoxy-methyl-amide In 50 mL of acetonitrile was dissolved 0.49 g (2.60 mmol) of <strong>[6624-49-3]isoquinoline-3-carboxylic acid</strong> monohydrate. To this 0.28 g (2.87 mmol) of O,N-dimethyl-hydroxylamine hydrochloride, 0.4 mL (2.87 mmol) triethylamine and 0.921 g (3.13 mmol) of 4-(4,6-dimethoxy-[1,3,5]triazin-2-yl)-4-methyl-morpholin-4-ium chloride hydrate were added and stirred for 2 days and then evaporated. A mixture of dichloromethane and water was added to it and the organic layer was evaporated and purified using flash chromatography (0-20percent methanol in dichloromethane). Fractions containing pure product were evaporated to yield 210 mg of the free base as a white solid. LC-MSD, m/z for C12H12N2O2 [M+H]+: 217.4, [M+Na]+: 239.4
Preparation 34: 6-Chloronaphthalcnc-2-carboxylic acid mcthoxymcthylamidcTo a solution of -chloronaphthalene^-carboxylic acid (Preparation 33, 1.65g,8.0mmol) in DMF (1OmL) was added N,O-dimethylhydroxylamine (0.78g 8mmol), HOBt (1.08g, 8mmol) and DIPEA (4.3mL, 25mmol). After 5min EDCI (2.Og, lO.Ommol) was added and the reaction mixture stirred at rt under argon for 24hr. The solvent was removed in vacuo and the residue partitioned between EtOAc (3 x 10OmL) and water (10OmL). The combined organic phase was dried (MgSO4) and concentrated in vacuo. The residue was dissolved inEtOAc (10OmL) and washed with HCl (2M, 5OmL). The organic layer was washed with sodium hydroxide (2M, 5OmL), dried (MgSO4) and concentrated in vacuo to afford the title compound. deltaH (CDCl3): 3.42 (3H, s), 3.56 (3H, s), 7.48 (IH, dd), 7.83, (4H, m), 8.21 (IH, s).
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃; for 4h;
A mixture of Compound 106B (3.00 g, 14.56 mmol), N,O- dimethylhydroxylamine hydrochloride (1.71 g, 17.47 mmol), Et3N (4.41 g, 43.68 mmol), and HATU (8.30 g, 21.84 mmol) in dichloromethane (30 mL) was stirred at room temperature for 4 hours. The mixture was diluted with ethyl acetate (160 mL), washed with water (100 mL) and brine (100 mL), and concentrated. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether from 0% to 80% v/v) to yield Compound 106C. LC-MS (ESI) m/z: 250 [M+H]+; 1H-NMR (DMSO-4, 400 MHz): d (ppm) 3.31 (s, 3H), 3.56 (s, 3H), 7.59-7.62 (m, 1H), 7.71-7.74 (m, 1H), 7.97 (d, J= 8.8 Hz, 1H), 8.08-8.12 (m, 2H), 8.24 (s, 1H).
4-chloro-3-iodo-N-methoxy-N-methylbenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With benzotriazol-1-ol; 1,2-dichloro-ethane; triethylamine; In water; ethyl acetate; N,N-dimethyl-formamide;
EXAMPLE 3B 4-chloro-3-iodo-N-methoxy-N-methylbenzamide A mixture of Example 3A (2.82 g, 10 mmol), EDC (2.11 g, 11 mmol), HOBt (1.68 g, 11 mmol), and N,O-dimethylhydroxylamine hydrochloride (1.26 g, 13 mmol) in DMF (30 mL) was stirred until all of the reagents dissolved, treated with triethylamine (2.54 mL, 18 mmol), stirred for 3 days at room temperature, treated with 1:1/ethyl acetate:water, stirred for 1 hour, poured into water, and extracted with ethyl acetate. The extract was washed sequentially with 2M Na2CO3, water, and brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 3:1/hexanes:ethyl acetate to provide the desired product. MS (DCI/NH3) m/z 343 (M+NH4)+; 1H NMR (300 MHz, CDCl3) delta 8.2 (d, 1H), 7.65 (dd, 1H), 7.5 (s, 1H), 3.55 (s, 3H), 3.35 (s, 3H).
With hydrogenchloride; In pyridine; dichloromethane; N,N-dimethyl-formamide; toluene;
Preparation 3 N-Methoxy-N-methyl-1-ethyl-5-methylpyrazole-3-carboxamide <strong>[50920-46-2]1-Ethyl-5-methylpyrazole-3-carboxylic acid</strong> (5.25 g) in dry dichloromethane (100 ml) containing N,N-dimethylformamide (0.26 ml) was cooled in an ice-bath and treated with a solution of oxalyl chloride (3.27 ml) in dichloromethane (25 ml), added dropwise. The mixture was stirred in the cold for 25 min, and then allowed to warm to room temperature, when evolution of a gas was observed. After 10 min the solvent was removed by evaporation in vacuo and toluene was added and removed (*2) to ensure any residual HCl and oxalyl chloride had been removed. The resultant acid chloride was redissolved in dry dichloromethane and then treated with N,O-dimethylhydroxylamine hydrochloride (3.61 g). The mixture was cooled in an ice-bath and treated with pyridine (6.0 ml), the mixture was then allowed to stir at room temperature for 1.5 h and then diluted with ether (100 ml) and washed with brine. The organic layer was then dried (MgSO4) and evaporated to leave an oil. This was the chromatographed on silica gel, loading in dichloromethane, and eluding with ethyl acetate/hexane mixtures to give, after evaporation of requisite fractions, the hydroxamate (5.2 g) as a solid: numax (CH2 Cl2) 2982, 2937, 1641, 1489, 1445, 1379, and 975 cm-1; delta(CDCl3) 1.43 (3H, t, J 7.3 Hz), 2.29 (3H, s), 3.42 (3H, s), 3.76 (3H, s,), 4.13 (2H, q, J 7.3 Hz), 6.49 (1H, s); (Found m/z 197.1164. C9 H15 N3 O2 requires m/z 197.1164).
EXAMPLE 7 Preparation of N-methoxy-N-methylchloroacetamide (3b). To a cold (0° C.), stirred solution of K2 CO3 (62.4 g, 450 mmol) in H2 O (250 mL) was added, successively, N,O-dimethylhydroxylamine hydrochloride (20 g, 205 mmol) and organic solvent (250 mL, toluene or MTBE). The resulting two phase mixture was cooled to -5° C. and chloroacetyl chloride (19.6 ml, 246 mmol) was added over 5 min (solution temperature maintained below 0° C.). The vigorously stirred mixture was allowed to warm to 15° C. over 30 min, the layers were separated, and the aqueous layer was extracted with organic solvent (3*100 mL, toluene or MTBE). The combined organic extracts were concentrated (MTBE used as solvent) to give the amide 3b (26.8 g, 95percent) as a white solid. Alternatively, the combined organic extracts (toluene used as solvent) were concentrated to 250 mL to effect azeotropic drying (water content 100 mug/mL) and the solution of 3b was used directly in reactions with organometallic reagents.
EXAMPLE 7 Preparation of N-methoxy-N-methylchloroacetamide (3b). To a cold (0°C), stirred solution of K2CO3 (62.4 g, 450 mmol) in H2O (250 mL) was added, successively, N,O-dimethylhydroxylamine hydrochloride (20 g, 205 mmol) and organic solvent (250 mL, toluene or MTBE). The resulting two phase mixture was cooled to -5°C and chloroacetyl chloride (19.6 ml, 246 mmol) was added over 5 min (solution temperature maintained below 0°C). The vigorously stirred mixture was allowed to warm to 15°C over 30 min, the layers were separated, and the aqueous layer was extracted with organic solvent (3x100 mL, toluene or MTBE). The combined organic extracts were concentrated (MTBE used as solvent) to give the amide 3b (26.8 g, 95percent) as a white solid. Alternatively, the combined organic extracts (toluene used as solvent) were concentrated to 250 mL to effect azeotropic drying (water content 100mug/mL) and the solution of 3b was used directly in reactions with organometallic reagents.
With 4-methyl-morpholine; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; In dichloromethane; N,N-dimethyl-formamide; at 50℃;
A solution of acid 1k (2 g) in 100 mL of dry dichloromethane and 5 mL of DMF was treated with N,O-dimethylhydroxylamine hydrochloride (1.1 eq, 986 mg), BOP reagent (1.1 eq, 4.47 g), and N-methylmorpholine (3.3 eq, 3.3 mL, d 0.920) in that order. The mixture was heated to 50° C. overnight. The reaction mixture was concentrated to half its volume and diluted with 400 mL of ethyl acetate. The organic layer was washed with water (80 mL), aqueous 1M HCl (80 mL), aqueous saturated sodium bicarbonate solution (80 mL), and brine (80 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel (gradient: acetone/hexanes; 5:95 to 3:7) to afford the product 1l as a clear oil.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃;
1) N-Methoxy-N-methyl-1-methyl-1H-imidazole-4-carboxamide 1-Methyl-1H-imidazole-4-carboxylic acid (1.26 g), N,O-dimethylhydroxylamine hydrochloride (1.17 g), 1-hydroxybenzotriazole (1.84 g), triethylamine (2.09 mL), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.30 g) were dissolved in N,N-dimethylformamide (50 mL), and the solution was stirred overnight at room temperature. The reaction solvent was evaporated under reduced pressure, and ethanol was added to the residue. Insoluble matter was removed through filtration, and the solvent was evaporated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform - methanol - water, lower phase), to thereby give N-methoxy-N-methyl-1-methyl-1H-imidazole-4-carboxamide as a solid product (1.08 g, 64percent). 1H-NMR(400MHz,CDCl3)delta:3.45(3H,s), 3.73(3H,s), 3.78(3H,s), 7.45(1H,s),7.54(1H,s).
With triethylamine; HATU; In dichloromethane; at 0 - 20℃; for 0.833333h;
Step 2: Benzyl (1R.2R)-l-hydroxy-l-phenylpent-4-en-2-ylcarbamate. To a mixture of HATU (0.915 g, 2.41 mmol), (R)-2-(benzyloxycarbonyl)pent-4- enoic acid (0.400 g, 1.60 mmol), N-methoxymethanamine hydrochloride (0.188 g, 1.93 mmol) in CH2Cl2 (20 mL) at 0 0C was added triethylamine (0.558 ml, 4.01 mmol). The mixture was allowed to stir at 0 0C for 20 min then warmed to RT for 30 min. The reaction was diluted with CH2Cl2 (20 mL) and washed with 1 M HCl (30 mL), 9%Na2CO3 (30 mL), brine (30 mL), dried over Na2SO4, filtered through a small plug of silica gel and washed with ether (10 mL) and concentrated. The crude material was used without further purification. MS m/z = 293 [M+l]+. Calc'd for Ci5H2ON2O4: 292. To a solution of (R)-benzyl l-(methoxy(methyl)amino)-l-oxopent-4-en-2- ylcarbamate (0.468 g, 1.60 mmol) in THF (10 mL) at 0 0C was added phenylmagnesium bromide (1.0 M in THF, 4.80 ml, 4.80 mmol). The mixture was allowed to warm to room temperature and stir overnight. To the mixture was added saturated aqueous NH4Cl (10 mL). The volatiles were removed under reduced pressure. The residue was diluted with water and extracted with Et2O (3 x 20 mL). The combined organics were washed with HCl (1 M, 20 mL), water (20 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated. The crude was used without further purification. MS m/z = 310 [M+l]+. Calc'd for C19H19NO3: 309.To (R)-benzyl 1 -oxo-1 -phenylpent-4-en-2-ylcarbamate (2.13 g, 6.89 mmol) in THF (50 mL) at -78 0C under argon was added lithium tri-sec-butylborohydride (20.7 ml, 20.7 mmol). Allowed the mixture to stir for 45 min. Quenched the reaction with saturated aqueous Rochelle's salt (50 mL) and the volatiles were removed in vacuo. The aqueous residue was extracted with ether (3 x 50 mL). The ether was combined and washed with brine (20 mL), dried over Na2SO4 and filtered. The filtrate was evaporated onto silica gel and purified via flash chromatography (0% to 20%; EtOAc in hexanes). MS m/z = 334 [M+Na]+. Calc'd for C19H2iNO3: 311.
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 18h;
Intermediate 1[00338] 2-Fluoro-N-methoxy-N-methylnicotinamide: TBTU coupling agent (13g, 40mmol) was added to a solution of <strong>[393-55-5]2-fluoronicotinic acid</strong> (5.6g, 40 mmol), N-methoxy-N- methylamine hydrochloride (4.4g, 45mmol) and diisopropylethylamine (16ml, O.lmol) in dichloromethane (100ml) under nitrogen. The reaction mixture was stirred at room temperature for eighteen hours. It was diluted with more dichloromethane (200ml), washed with a 2M aqueous hydrochloric acid solution (50ml), a saturated sodium bicarbonate solution (100ml), and brine (100ml). The organic was dried over magnesium sulfate and, after filtration, concentrated in vacuo. The residue was purified by flash chromatography (120g SiO2, pentane/ethyl acetate) to afford the title compound as a colourless oil (6g, 80percent). 1H NMR(CDCl3): 3.40-3.45 (3H, s), 3.55-3.65 (3H, s), 7.75-7.80 (IH, t), 7.90-7.95 (IH, t), 8.28-8.30 (IH, d).
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 10 - 22℃;
2-fluoro-7V-methoxy-7V-methylpyridine-3-carboxamide<strong>[393-55-5]2-fluoropyridine-3-carboxylic acid</strong> (100 g, 708.7 mmol) was dissolved in THF (1.5 L). DMAP (86.58 g, 708.7 mmol) was added followed by N-methoxymethanamine hydrochloride (76.05 g, 779.6 mmol) . The mixture was cooled to 10°C then DIPEA (100.8 g, 135.8 mL, 779.6 mmol) was added followed by EDC (149.5 g, 779.6 mmol) portionwise. The mixture was stirred for 30 minutes, then warmed rapidly to ambient temp (22°C) and stirred overnight. Lc/Ms after this time showed no acid remaining. The reaction mixture was diluted with ethyl acetate (1L) and water (1.5L). The mixture was stirred for 10 minutes then the organic phase was isolated. The aqueous was extracted with ethyl acetate (2x500ml) and the combined organics washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude was purified through a silica plug, eluting with 50-70percent ethyl acetate/petrol. This afforded the title compound as a pale yellow oil (81g, 62percent); 3/4 NMR (CDC13) 3.39 (3H, s), 3,68 (3H, brs), 7.29 (1H, m), 7.92 (1H, m), 8.32 (1H, m); MS ES (+) 184.9 (M+l).
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃; for 2h;
Synthesis Example 8; Synthesis of methyl 2(S)-2-amino-5,5-difluoroheptanoate;A mixture of 2-tert -butyl N-carbobenzoxy-L-glutamate (3.03 g, 10 mmol) and methoxymethylamine HCl (1.17 g, 12 mmol) in HOBt (1.62 g, 12 mmol), EDC (2.3 g, 12 mmol) and NMM (3.3 mL, 30 mmol) was stirred at RT for 2 hr. The reaction was washed with IN-HCl, NaHCO3 and sat. NaCl and dried over MgSO4. The solvent was removed to give 3.67 g of (2S)-2-benzyloxycarbonylamino-4-(N-methoxy-N-methylaminocarbonyl)- butanoic acid tert-butyl ester, as a colorless oil. See, Syn. Lett. 2003, 10: 1411-1414.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In acetonitrile; at 20℃; for 14h;
(Step 1)To a solution of the compound (13.8 g) obtained in Reference Example 95, step 3, N,O-dimethylhydroxylamine hydrochloride (7.88 g) and Et3N (11.3 mL) in CH3CN (100 mL) were added WSC.HCl (25.8 g) and HOBt.H2O (15.5 g), and the mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5?20% ethyl acetate/hexane) to give 3-chloro-N-methoxy-N-methyl-5-(trifluoromethyl)benzamide (15.09 g, 84%) as a pale-yellow oil.1H-NMR (300 MHz, CDCl3):delta 3.38 (3H, s), 3.56 (3H, s), 7.69 (1H, s), 7.86 (2H, m)
To <strong>[402-69-7]6-fluoropicolinic acid</strong> (980 mg, 6.95 mmol) was in DCM (50 mL) was added DMF (50 mu., 0.65 mmol), followed by dropwise addition of oxalyl chloride (650 mu, 7.43 mmol). After 1.2 h, N,O-dimethylhydroxyl amine HC1 (1.05 g, 10.8 mmol) was added and the reaction mixture was cooled to 0°C. Pyridine (2.6 mL, 32 mmol) was added and the reaction mixture was allowed to warm to room temperature and stir 72 h. The reaction mixture was quenched by the addition of water and the layers were partitioned. The aqueous phase was extracted with dichlorom ethane and the combined organic layer was washed with brine, dried (MgS04), filtered and concentrated under reduced pressure to afford 6-fluoro-N-methoxy-N-methylpicolinamide (1.09 g, 85.0 percent yield) as a clear pale yellow oil. NMR (500 MHz, CD3C1) delta 7.88 (q, J=7.8 Hz, 1 H), 7.56 (br. s., 1 H), 7.02 (dd, J=8.2, 2.4 Hz, 1 H), 3.79 (br. s., 3 H), 3.37 (br. s., 3 H). LCMS m/z = 185.0 (M+H).+
84%
Step A-6-Fluoro-N-methyl-M-(methyloxy)-2-pyridinecarboxamide 2-Fluoropyridine-6-carboxylic acid (1.00 g, 7.09 mmol) was dissolved in 50 mL of DCM with stirring. DMF (3 drops) was added. Gxalyi chloride (4.3 mL, 2M in DCM, 8.6 mmol) was added dropwise via syringe. The reaction was stirred for 1 h and cooled to 0° C. N,O-Dimethylhydroxylamine hydrochloride (0.761 g, 7.80 mmol) was added in a single portion. Pyridine (1.26 mL, 15.6 mmol) was added via syringe, and the reaction was allowed to warm to room temperature. The reaction was stirred for 16 h and poured into half-saturated NaHCO3 solution and DCM. The layers were separated, and the aqueous layer was washed with EtOAc, The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash chromatography provided 1.10 g (84percent) of the title compound. 1H NMR (400 MHz, DMSO-d6) delta 8.11 (m, 1H), 7.56 (m, 1H), 7.32 (dd, J=8.2, 2.4 Hz, 1H), 3.65 (s, 3H), 3.25 (s, 3H).
67%
A solution of 6-methoxypicolinic acid (2.018g,13.2 mmol) in DCM (70 mL) was treated with DMF (0.1 mL, 1.3 mmol) and oxalylchloride (1.34 mL, 15.8 mmol), after 1 h the solution was cooled to 0 °C and N,O-dimethylhydroxylamineHCl (1.42 g, 14.6 mmol) and pyridine (2.34 mL, 28.9 mmol) were added. Themixture was stirred at room temperature for 18 h, sat. aq. NaHCO3 (200mL) was added and the mixture was partitioned between DCM and water. Theorganic fractions were dried and evaporated, column chromatography (97.5:2.5DCM:MeOH) gave N,6-dimethoxy-N-methylpicolinamide (2.372 g, 92percent) asan oil. 1H NMR (CD3SOCD3) delta 7.86 (dd, J = 8.3, 7.3 Hz, 1H), 7.66 (dd, J = 7.3, 0.7 Hz, 1H), 7.05 (dd, J = 8.3, 0.7 Hz, 1H), 3.90 (s, 3H), 3.28(bs, 3H). Found: [M+H] = 197.2.
With triethylamine; HATU; In dichloromethane; at 20℃; for 24h;
A solution of <strong>[402-69-7]6-fluoropicolinic acid</strong> (20.0 g, 142 mmol), Nu,Omicron- dimethylhydroxylamine hydrochloride (16.6 g, 170 mmol), 0-(7-azabenzotriazol-l-yl)- Nu,Nu,Nu,Nu-tetramethyluronium hexafluorophosphate (HATU) (80.8 g, 213 mmol) and triethylamine (59.1 mL, 425 mmol) in dichloromethane (500 mL) was stirred for 24 h at RT and treated with 200 mL of saturated aq. H4CI solution. The resulting solution was extracted with dichloromethane (2 x 500 mL). The organic layers were combined, dried over Na2S04 and concentrated. The residue obtained was purified on silica gel with EtO Ac/petroleum ether (15-50percent) to give the title compound as a yellow oil. LCMS, ESI pos. : Calcd. for C8H9FN2O2: 185.0 (M+H)+; found: 184.9.
Thiazole-2-carboxylic acid (5 g, 38.7 mmol) and CDMT (7.47 g, 42.6 mmol) were suspended in THF under N2 at O0C. After 15 min NMM (11.7 g, 12.76 mL, 116 mmol) was added dropwise. The reaction mixture was stirred for 1.5 hr at RT, and then N- <n="23"/>methoxymethanamine hydrochloride was added at 0 0C. The reaction mixture was stirred over night at room temperature and was then concentrated under reduced pressure. The residue was redissolved in ethyl acetate and the solution was washed with water and brine, dried over anhydrous sodium sulfate. The residue after evaporation of solvents was purified by column chromatography eluting with 30percent EtOAc/hexanes to give 4.6 g (70percent) of the desired product as pale yellow oil.
6-fluoro-pyridine-2-carboxylic acid methoxy-methyl-amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
18%
Add N-methylmorpholine (6 ml, 52 mmol) and isobutylchloroformate (3.5 ml, 26.9 mmol) to a solution of <strong>[402-69-7]6-fluoropyridine-2-carboxylic acid</strong> (3.8 g, 26.9 mmol) in methylene chloride at 0 C. After 15 minutes add O,N-dimethylhydroxylamine hydrochloride (2.6 g, 26.9 mmol) and N-methylmorpholine (3 ml, 26.9 mmol). Stir the reaction at 0 C for 15 minutes and then room temperature for 17 hours. Dilute the reaction with methylene chloride and wash sequentially with water (1 x 50 ml), 10 percent aqueous citric acid (1 x 50 ml), brine (1 x 50 ml), saturated aqueous sodium bicarbonate (1 x 50 ml), and brine (1 x 50 ml). Dry the resulting organic solution with Na2SO4, filter, and purify by flash column chromatography (Silica Gel, 20 percent acetone/hexanes) to provide the title compound 0.97g (18 percent from 2-fiuoro-5-methylpyridine) as a clear, yellow oil. MS APCI+ m/e 185 (M+1). TLC (SiO2): Rf 0.40 (1:3 acetone/hexanes)
1.5 (1-Benzylpiperidin-4-yl)-N-methoxy-N-methylcarboxamide A solution of 4.17 g (42.8 mmol) of N,O-dimethylhydroxylamine hydrochloride in 195 mL of THF is cooled to -20 C., and 6.51 g (28 mmol) of methyl (1-benzylpiperidin-4-yl)carboxylate are added. Next, 85 mL of a 1M solution of isopropylmagnesium bromide in THF are added over 20 minutes while keeping the temperature in the region of 5 C. The mixture is stirred at -10 C. for 20 minutes. The reaction medium is hydrolyzed with 40 mL of 20% ammonium chloride solution and then extracted with ethyl acetate. The combined organic phases are washed with water and with brine, and then dried over anhydrous sodium sulfate and evaporated under reduced pressure. 6.9 g of an oily product are obtained.1H NMR (DMSO-d6, 250 MHz) delta ppm: 1.5-1.75 (m, 4H); 1.9-2.05 (m, 2H); 2.55-2.7 (m, 1H); 2.8-2.9 (m, 2H); 3.09 (s, 3H); 3.46 (s, 2H); 3.67 (s, 3H); 7.2-7.4 (m, 5H).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; for 24h;
A N, N-dimethylformamide solution (3 mL) of 4- <n="216"/>pyrazolecarboxylic acid (150 mg, 1.34 mmol) , N,0- dimethylhydroxylamine hydrochloride (261.4 mg, 2.68 mmol), 1 -ethyl -3- (3-dimethylaminopropyl) carbodiimide, hydrochloride (513.8 mg, 2.68 mmol), 1- hydroxybenzotriazoleimidazole anhydride (54.2 mg, 0.40 mmol), and triethylamine (0.38 mL, 2.68 mmol) was stirred for 1 day. After completion of the reaction, the reaction solution was mixed with ethyl acetate and washed with saturated aqueous sodium chloride. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting crude reaction product containing the desired product was used for the next step (142.7 mg) .Morphology: colorless oil 1H-NMR(CDCl3) delta: 2.89 (s, 3H), 2.96 (s, 3H), 8.03 (s, 1H), 8.13 (s, 1H).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0℃; for 12h;
3-Bromo-4-chlorobenzoic acid (1.0 g, 4.24 mmol, 1.0 eq) was dissolved in dry DMF and stirred for 10 minutes. The solution was cooled to 0 °C and treated with N,O-dimethyI hydroxylamine hydrochloride (0.828 mg, 8.48 mmol, 2.0 eq), 1-hydroxybenzotrizole (860 mg, 6.36 mmol, 1.5 eq), N,JV-diisopropyl ethylamine (820 mg, 6.37 mmol, 1.5 eq), and EDC HCl (1.2 g, 6,37 mmol, 1.5 eq). The reaction mixture was stirred for 12 h, evaporated under reduced pressure and diluted with water (25 mL). The aqueous layer was extracted with ethyl acetate. The organic layer was dried under anhydrous Na2SQi and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (60-120) eluting with 5-10 percent ethyl acetate/hexane to afford the desired product (1 g, 85percent). 1H NMR (400 MHz, <n="203"/>CD3OD) delta 3.34 (s, 3H), 3.57 (beta, 3H), 7.47-7.49 (d, 1H), 7.71-7.74 (d, 1H), 7.85-7.88 (d, 1H). MS (ESI): 278.2 (M+).
79%
(RS)-4-(3-Bromo-4-chloro-phenyl)-4-(4-methoxy-3-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine 3-Bromo-4-chloro-N-methoxy-N-methylbenzamide [203179-00-4] Carbonyldiimidazole (7.2 g, 0.045 mol) was added in portions to a stirred suspension of <strong>[42860-10-6]3-bromo-4-chlorobenzoic acid</strong> (10.0 g, 0.042 mol) in dichloromethane (120 mL). The reaction mixture was stirred at room temperature for 30 minutes then at reflux for 30 minutes. Triethylamine (6.3 mL, 0.045 mol) and N,O-dimethylhydroxylamine hydrochloride (4.2 g, 0.043 mol) were added and the reaction mixture was stirred at room temperature overnight, then diluted with water (75 mL) and the layers separated. The aqueous fraction was extracted with dichloromethane (2*50 mL) and the combined organic extracts were washed with citric acid (10percent; 2*50 mL), NaHCO3 (50 mL) and brine (50 mL), dried (sodium sulfate) and concentrated to give 3-bromo-4-chloro-N-methoxy-N-methylbenzamide as a colourless oil (9.3 g, 79percent). 1H NMR (300 MHz; DMSO-d6) 7.98 (1H, s, Ar), 7.60 (1H, d, J 7.2, Ar), 7.48 (1H, d, J 7.2, Ar), 3.54 (3H, s, Me), 3.36 (3H, s, Me).
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 60℃; for 10 - 15h;
A mixture of 2-amino-4-chloromethyl-thiazole hydrochloride (27.8 g, 0.15 mol), N,O-dimethylhydroxylamine hydrochloride (87.8 g, 0.90 mol), and anhydrous THF (300 mL) was rapidly stirred and DIPEA (157 mL, 0.90 mol) was added. The resulting mixture was heated at 60 0C for 10-15 hours. The mixture was cooled in an ice/salt bath and the solid byproduct (DIPEA hydrochloride) was removed by filtration and washed with cold THF (300 mL). The combined filtrate was concentrated to afford the N- (2- amino-thiazol-4-ylmethyl)-O,N-dimethyl-hydroxylamine as a dark oil (31 g, >100percent theory), which partially crystallized on standing. This product was used in the next step without further purification.
With 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 3h;
The mixture was stirred for 5 minutes, to which were added N-(3- dimethylaminopropyl )-N'-ethylcarbodi imide hydrochloride (1.05g, 5.33mmol). The mixture was stirred for 3 hours at room temperature, and then diluted with EtOAc. The organic layer was washed with IN HCl, water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The product was vacuum-dried to give the 3-hydroxy-N-methoxy-N- methyl-5-trif1uoromethyl-benzamide.
To a solution of S-bromoisoxazole-S-carboxylic acid (2.85 g, 14.8 mmol) in DMF (74 niL) was added 2-(7-aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (EtaATU) (6.89 g, 18.1 mmol). The solution was cooled (O0C) and DIPEA (10.5 mL, 60.3 mmol) was added followed by iV,0-dimethylhydroxylamine hydrochloride (1.81 g, 18.6 mmol) and the reaction was maintained at room temperature. After 25 hours, DMAP (183 mg, 1.50 mmol) was added. After 38 hours, the mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3, saturated aqueous NH4Cl, water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with a gradient of 0%-100% EtOAc in heptane to afford <strong>[6567-35-7]3-bromo-isoxazole-5-carboxylic acid</strong> methoxy-methyl-amide as a pale yellow solid. MS m/z 235 (M), 237 (M+2).
HATU (14.9 g, 39.3 mmol, 1.1 equiv) and N,O-dimethylhydroxylamine hydrochloride (3.9 g, 39.3 mmol, 1.1 equiv) were charged into a round-bottomed flask containing 200 mL dichloromethane. Triethylamine (14.9 mL, 107 mmol, 3.0 equiv) was added, and then a solution of <strong>[277756-45-3](1-trifluoromethyl)cyclobutanecarboxylic acid</strong> (6.0 g, 35.7 mmol, 1.0 equiv) in DCM (25 mL) was added. The reaction was stirred at room temperature until complete consumption of the carboxylic acid. The solution was concentrated in vacuo to remove volatiles and the residue was partitioned between DCM (200 mL) and saturated NH4Cl (100 mL). The aqueous was extract with DCM (200 mL) and the combined organics were dried over Na2SO4 and then concentrated. The crude was purified by silica gel chromatography to afford the product (5.64 g, 27 mmol, 75percent yield) as colorless oil.
A pre-formed solution of <strong>[13211-32-0]tert-butoxyacetic acid</strong> 1 (26.4 g, 200 mmol) and 4-methylmorpholine (20.2 g 200 mmol) in 50 ml dichloromethane was added at 0° C. to a solution of isobutyl chloroformiate (27.3 g 200 mmol) in 150 ml dichloromethane. After additional stirring at 0° C. for 30 min, N,O-dimethylhydroxylamine hydrochloride (21.5 g, 220 mmol) was added all at once followed by the drop wise addition of 4-methylmorpholine (24.3 g, 240 mmol) over ~30 min. Stirring at 0° C. was continued for 30 min and at RT for 30 min. The reaction mixture was washed with 100 ml 1 M HCl and 100 ml 10percent brine. Both aqueous layers were extracted with 100 ml dichloromethane and the combined organic layers were dried (Na2SO4) and evaporated to dryness affording 34.7 g ("99.1percent") brown oil. Vacuum distillation over a 18 cm Vigreux column yielded 29.9 g (85.3percent) Weinrebamide 2 as a colorless oil, bp. 71° C./0.5 mbar. 1H NMR (CDCl3, 400 MHz) delta 1.26 (s, 9H), 3.19 (s, 3H), 3.71 (s, 3H), 4.17 (s, 2H).
b 1 ) 2-tert-Butoxy-N-methoxy-N-methyl-acetamideA performed solution of <strong>[13211-32-0]tert-butoxyacetic acid</strong> 1 (26.4 g, 200 mmol) and 4- methylmorpholine (20.2 g 200 mmol) in 50 ml dichloromethane was added at 00C to a solution of isobutyl chloroformiate (27.3 g 200 mmol) in 150 ml dichloromethane. After additional stirring at 00C for 30 min, N,O-dimethylhydroxylamine hydrochloride (21.5 g, 220 mmol) was added all at once followed by the drop wise addition of 4-methylmorpholine (24.3 g, 240 mmol) over ~30 min. Stirring at 00C was continued for 30 min and at RT for 30 min. The reaction mixture was washed with 100 ml 1 M HCl and 100 ml 10percent brine. Both aqueous layers were extracted with 100 ml dichloromethane and the combined organic layers were dried (Na2SO4) and evaporated to dryness affording 34.7 g ("99.1percent") brown oil. Vacuum distillation over a 18 cm Vigreux column yielded 29.9 g (85.3percent) Weinrebamide 2 as a colorless oil, bp. 71°C/0.5 mbar. 1H NMR (CDCl3, 400 MHz) delta 1.26 (s, 9H), 3.19 (s, 3H), 3.71 (s, 3H), 4.17 (s, 2H).
With 4-methyl-morpholine; 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride; In acetonitrile; at 20℃; for 17h;
(1a) 2-Bromo-N,3-dimethoxy-N-methylbenzamide <strong>[88377-29-1]2-Bromo-3 methoxy benzoic acid</strong> (14.2 g, 61.5 mmol) was dissolved in acetonitrile (250 mL), added with 4-methylmorpholine (13.5 mL, 123 mmol), N-methoxy methanamine hydrochloride (7.19 g, 73.8 mmol), and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (20.4 g, 73.8 mmol), and stirred for 17 hours at room temperature. 1 N aqueous hydrochloric acid solution was added to the reaction solution, which was then extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane : ethyl acetate, 85 : 15 to 25 : 75, V/V) to give the title compound as a colorless oily substance (16.8 g, quantitative).
To a suspension of <strong>[27398-39-6]3-chloropyrazine-2-carboxylic acid</strong> (5.46 g) in THF (100 mL) was added CDI (6.14 g) at room temperature, and the mixture was stirred at room temperature for 30 min and heated to 50 °C. After stirring at 50 °C for 1 h, the mixture was cooled to room temperature. To the mixture were added N, O-dimethylhydroxylamine hydrochloride (5.04 g) and DIPEA (9.02 mL) at room temperature, and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (3.05 g) .MS (API+) : [M+H]+ 202.1.H NMR (300 MHz, CDC13) delta 3.43 (3H, s) , 3.58 (3H, s), 8.44 (1H, d, J = 2.3 Hz>, 8.52 (1H, d, J = '2.3 Hz).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 9 - 17℃;
[00194] Step 1: Synthesis of N-methoxy-N,l-dimethyl-lH-pyrazole-4- carboxamide: A mixture of l-methyl-lH-pyrazole-4-carboxylic acid (5.0 g, 39.6 mmol), N, O-dimethylhydroxylamine hydrochloride (4.8 g, 48.0 mmol), l-(3-dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride (9.2 g, 48.0 mmol), hydroxybenzotriazole (6.5 g, 48.0 mmol) and triethylamine (12.1 g, 120 mmol) in dichloromethane (100 mL) was stirred at 9- 17°C overnight. The reaction mixture was diluted with water (50 mL) and the resulting mixture was extracted with EtOAc (30 mL x 3), the combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2S04, filtered and concentrated in vacuo (an example of a standard aqueous/EtOAc procedure), then purified by silica gel column chromatography (PE: EtOAc = 5: 1) to give product (4.6 g, yield 69percent).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In acetonitrile; at 20℃; for 15h;
Method 31 Synthesis of 2-bromo-1-(6-methyl-3-pyridyl)ethanone (Intermediate 45) To a solution of R-12 (10 g, 79.3 mmol) in MeCN (200 mL) at 0° C. is added N,O-dimethylhydroxylaminehydrochloride (8.5 g, 87.2 mmol), EDCI (18.2 g, 95.2 mmol), 1-hydroxybenzotriazole (3.2 g, 23.8 mmol) followed by triethylamine (20.5 mL, 158 mmol) and stirred at room temperature 15 h. The reaction mixture is partitioned between water and EtOAc. The collected organics are dried with anhydrous Na2SO4, filtered, and concentrated in vacuo to give I-43 (12 g) m/z 170.0 [M+H].
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 20h;
Example 99[0344] [Formula 123] [0345] 1) In N,N-dimethylformamide (24 mL) was dissolved 5-bromo-3-chloropyridine-2- carboxylic acid (2.36 g), 1-hydroxybenzotriazole (2.2 g) and 3-ethyl-3-(3-dimethyl- aminopropyl)carbodiimide hydrochloride (2.87 g), Nu,Omicron-dimethylhydroxylamine hydrochloride (1.27 g) and triethylamine (1.95 mL) was added to the solution, and the resulting mixture was stirred at room temperature for 20 hours. Water was added to the obtained residue, extracted with ethyl acetate, and the organic layer was washed with water and then with a saturated brine. After drying the mixture over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure to obtain 5- bromo-3-chloro-N-methoxy-N-methylpyridine-2-carboxamide (2.67 g).MS (m/z): 279/281/283 [M+H]+
9.11 g
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; for 16h;Cooling with ice;
9.02 g of <strong>[1189513-51-6]5-bromo-3-chloropyridine-2-carboxylic acid</strong>, 9.10 g of 1-ethyl-3- (3- dimethylaminopropyl) carbodiimide hydrochloride, 4.11 g of N, O-dimethylhydroxylamine hydrochloride, To a mixture of 0.93 g of 4- (dimethylamino) pyridine and 100 mL of chloroform, 10.6 mL of triethylamine was added dropwise under ice cooling. After raising the temperature to room temperature and stirring for 16 hours, a saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with chloroform. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to column chromatography to obtain Intermediate 11 represented by the following formula9.11 g was obtained.
[0060] Preparation of N-Methoxy-N-methyl-lH-Pyrrolo 2.3-blpyridine-3-carboxamide[00611 To a solution of <strong>[156270-06-3]7-azaindole-3-carboxylic acid</strong> (324 mg, 2.00 mmol) in dioxane (lOmL) was added HO At (300 mg, 2.20 mmol), N, O-Dimethylhydroxylamine hydrochloride (214 mg, 2.00 mmol) and EDC (422 mg, 2.20 mmol). The mixture was stirred at rt for 15 minutes then DIPEA (853 mg, 6.60 mmol) added slowly over 5 minutes. The reaction was then stirred at rt for an additional 18 hrs. The reaction was then poured into 25percent ammonium chloride solution (lOmL) and extracted with EtOAc (3 x lOmL). The combined extracts were dried over magnesium sulfate, filtered and concentrated to a brown oil. This oil was purified via column chromatography (Si02, EtOAc) to afford the title compound as a viscous clear oil which solidified on standing. Yield = 86percent1H NMR (CDC13): delta = 12.48 (bs, 1H), 8.60 (dd, J = 7.9, 1.4Hz, 1H), 8.24 (bd, J = 3.8Hz, 1H), 8.15 (s, 1H), 7.10 (dd, J = 7.9, 4.7Hz, 1H), 3.66 (s, 3H) and 3.31 ppm (s, 3H).
Step 1 : 5-Bromo-/V1 ,/V3-dimethoxy-A 1.A/3-dimethylisophthalamide (P32a)1 , 1 '-Carbonyldiimidazole (2.53 g, 25 mmol) was added portionwise to a solution of 5- bromoisophthalic acid (2.45 g, 10 mmol) in DCM and the mixture was stirred at rt for 1 h, then a suspension of Lambda/,Omicron-dimethylhydroxylamine (2.34 g, 24 mmol) in DCM was added, stirred at rt overnight, washed with water and brine, dried over Na2S04 and concentrated to afford compound P32a (3.2 g, 97percent) as a pale oil.
89%
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; acetonitrile; at 20℃; for 16h;
To a stirred solution of <strong>[23351-91-9]5-bromoisophthalic acid</strong>(4.00 g, 16.3 mmol) in ACN (32 mL) and DCM (32 mL) was added EDC*HCl (8.14 g, 42.40 mmol), HOBt-H2O (5.74 g, 42.40 mmol), N-mthylmorpholine(23.3 mL, 212.00 mmol) and N,O-dimethylhydroxylamine*HCl (6.69 g, 68.60 mmol). The mixture was stirred at room temperature for 16 h. The mixture was washed with a saturated solution of NaHCO3 (2 50 mL), a 1 M solution of HCl (2 50 mL) and 50 mL of brine. The organic layer was dried over MgSO4, filtered and evaporated. The compound was used without further purification in the next step. The title compound (4.80 g,14.49 mmol, 89percent) was obtained as a yellow oil. 1H NMR (300MHz), d (ppm, CDCl3): 7.94 (t, J = 1.4 Hz, 1H); 7.91 (d, J = 1.4 Hz,2H); 3.54 (s, 6H); 3.35 (s, 6H). 13C NMR (75 MHz), d (ppm, CDCl3):167.4; 135.5; 133.3; 126.8; 121.7; 61.3; 33.5. LC?MS (ESI) m/z Calculated:331.0?333.0, Found: 331.0?333.0 [M+H]+.
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;
A mixture of (2S,4S)-l -(tert-butoxycarbonyl)-4-methylpyrrolidine-2-carboxylic acid (5.2g, 22.7 mmol), Omicron,Nu-dimethylhydroxylamine hydrochloride (2.4g, 24.9mmol), HATU (10.4g, 27.2mmol) and DIPEA (9.5mL, 54.5mmol) in 114mL DMF was stirred at room temperature overnight. The mixture was extracted into ethyl acetate and washed with saturated bicarbonate and water, dried over sodium sulphate, filtered, and concentrated. It was then dissolved in diethyl ether (lOOmL) and washed with water to remove residual DMF, dried, filtered, and concentrated to a pale yellow oil (5.30g, 19.5mmol) of (2S,4S)-tert-butyl 2-(methoxy(methyl)carbamoyl)-4-methylpyrrolidine-l- carboxylate.
5.3 g
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;
A mixture of <strong>[364750-81-2](2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidine-2-carboxylic acid</strong> (5.2 g, 22.7 mmol), O,N-dimethylhydroxylamine hydrochloride (2.4 g, 24.9 mmol), HATU (10.4 g, 27.2 mmol) and DIPEA (9.5 mL, 54.5 mmol) in 114 mL DMF was stirred at room temperature overnight. The mixture was extracted into ethyl acetate and washed with saturated bicarbonate and water, dried over sodium sulphate, filtered, and concentrated. It was then dissolved in diethyl ether (100 mL) and washed with water to remove residual DMF, dried, filtered, and concentrated to a pale yellow oil (5.30 g, 19.5 mmol) of (2S,4S)-tert-butyl 2-(methoxy(methyl)carbamoyl)-4-methylpyrrolidine-1-carboxylate. [0453] (2S,4S)-tert-butyl 2-(methoxy(methyl)carbamoyl)-4-methylpyrrolidine-1-carboxylate (5.30 g, 19.5 mmol) was dissolved in 120 mL THF, cooled to ?78° C. and treated with lithium aluminium hydride (1M in THF, 19.5 mL, 19.5 mmol) dropwise via addition funnel. After 1 hour, the mixture was brought to 0° C. and kept at that temperature for 2 hours. It was quenched by dropwise addition of a 50 mL solution of 3.0 g KHSO4 in water, removed from the ice bath, and stirred 15 minutes at room temperature. The product was extracted with three 75 mL portions of ethyl acetate and washed with brine. The organic phase was dried over sodium sulphate, filtered, and concentrated to give crude (2S,4S)-tert-butyl 2-formyl-4-methylpyrrolidine-1-carboxylate. (4.89 g)
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 18h;
To a suspension of 5.00 g (29.7 mmol) <strong>[950858-65-8]1-tert-butyl-1H-pyrazole-4-carboxylic acid</strong> and 5.80 g (59.5 mmol) Nu,Omicron-dimethylhydroxylamine hydrochloride in 60 ml dichloromethane are added 12.5 g (65.4 mmol) N-(3-dimethylaminopropyl)- N'-ethylcarbodiimide hydrochloride, 4.42 g (32.7 mmol) 1-hydroxybenzotriazol and 16.5 ml (119 mmol) triethylamine. The reaction mixture is stirred for 18 hours at room temperature. It is quenched with saturated sodium hydrogen carbonate solution and the mixture is partitioned between water and dichloromethane. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to afford 1-tert-butyl-1H-pyrazole-4- carboxylic acid methoxy-methyl-amide as colorless crystals; HPLC/MS 1.91 min (B), [M+H] 212.
To a flask containing <strong>[90322-32-0]2-methylbenzo[d]oxazole-5-carboxylic acid</strong> (1.00 g, 5.64 mmol) was added DCM (40 mL) to give a suspension. Carbonyldiimidazole (1.01 g, 6.21 mmol) was added and the mixture remained homogeneous and was stirred at room temperature for 17 hours, then N,O-dimethylhydroxylamine hydrochloride (688 mg, 7.06 mmol) was added and the mixture was stirred at room temperature for 18 hours. The contents were diluted with water and 1 N NaOH and extracted with DCM (4×50 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. Flash chromatography on silica gel (10-40percent EtOAc-DCM) gave the title compound as an amber oil.
5-amino-2-chloro-N-methoxy-N-methylisonicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With N-ethyl-N,N-diisopropylamine; 1,1'-carbonyldiimidazole; In dimethyl sulfoxide; at 20℃;
5-Amino-2-chloro-isonicotinic acid (109mg, 0.600mmol), N, 0-dimethylhydroxylamine hydrochloride (62mg, 0.617mmol), Iota, -carbonyldiimidazole (131mg, 0.800mmol) and diisopropylethamine (0.38mL, 2.200 mmol) are stirred in DMSO (lmL) at room temperature overnight. The mixture is diluted with water then the aqueous phase is extracted with dichloromethane. The organic phase is dried over magnesium sulfate and the solvent is concentrated to dryness. The residue is purified using silica gel chromatography (dichloromethane/methanol gradient). This provides the desired compound. Yield: 103.5mg (80percent) HPLC-MS: M+H=216/218; tRet =0.43 min; AMI
80%
With N-ethyl-N,N-diisopropylamine; 1,1'-carbonyldiimidazole; In dimethyl sulfoxide; at 20℃;
5-Amino-2-chloro-isonicotinic acid (109 mg, 0.600 mmol), N,O-dimethylhydroxylamine hydrochloride (62 mg, 0.617 mmol), 1,1'-carbonyldiimidazole (131 mg, 0.800 mmol) and diisopropylethamine (0.38 mL, 2.200 mmol) are stirred in DMSO (1 mL) at room temperature overnight. The mixture is diluted with water then the aqueous phase is extracted with dichloromethane. The organic phase is dried over magnesium sulfate and the solvent is concentrated to dryness. The residue is purified using silica gel chromatography (dichloromethane/methanol gradient). This provides the desired compound. Yield: 103.5 mg (80percent) HPLC-MS: M+H=216/218; tRet=0.43 min; AM1
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; N,N-dimethyl-formamide; at 20℃;
[888] N,O-dimethylhydroxylamine hydrochloride (520 mg, 5.33 mmol), 5-aminopyridine-2- carboxylic acid (491 mg, 3.55 mmol), HBTU (2.02 g, 5.33 mmol) and diisopropylethylamine (2.48 mL, 14.2 mmol) were stirred in a mixture of DCM/DMF (5/1, 23.7 mL) at room temperature overnight. The reaction mixture was poured into a saturated solution of NaHC03 (50 mL) and the product extracted 4 times with 2-methyltetrahydrofuran (50 mL). Organics were combined, washed with water, brine, dried over MgS04, filtered and concentrated under reduced pressure to afford the title compound as an orange foamy solid (643 mg, 3.55 mmol, 100percent).
N,4-dimethoxy-N-methylpyrimidine-5-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
36%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 18℃; for 64h;
Step A: Preparation of N,4-dimethoxy-N-methylpyrimidine-5-carboxamide. [00254] In a 500 mL single-neck flask equipped with a stir bar, 4-methoxypyrimidine-5- carboxylic acid (8.0 g, 33.2 mmol) and N,0-dimethylhydroxylamine hydrochloride (4.30 g, 43.2 mmol) were stirred in DCM (166 ml). DMAP (6.15 g, 49.8 mmol) and EDC hydrochloride (7.72 g, 39.9 mmol) were added. The mixture was stirred at 18 °C for 64 h, then silica (-50 g) was added to the reaction mixture. The yellow suspension was concentrated then loaded onto silica (-100 g). Chromatographed through a silica column (80 g) using EtOAc. The product fractions were concentrated to provide 2.4 g (36percent) of the title compound a colorless oil which was used without further purification. 1H NMR (400 MHz, CDC13) delta 8.81 (s, 1H), 8.48 (s, 1H), 4.05 (d, J = 0.7 Hz, 3H), 3.55 (s, 3H), 3.35 (s, 3H).
(S)-tert-butyl (3-methoxy-1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 25℃; for 12h;Inert atmosphere;
N,O-dimethylhydroxylamine hydrochloride (13.35 g, 136.84 mmol) was added to (S)-2- ((tert-butoxycarbonyl)amino)-3-methoxypropanoic acid (20 g, 91.23 mmol), HATU (38.2g, 100.35 mmol) and DIPEA (47.8 mL, 273.68 mmol) in DMF (100 mL) at 25°C under air. The resulting mixture was then stirred at 25 °C for 12 hours. The reaction mixture was then concentrated and diluted with EtOAc (500 mL), and the organic phases washed sequentially with water (150 mL) and saturated brine (2 x 200 mL). The organic layers were dried over Na2SO4, filtered and evaporated to afford crude product. The crudeproduct was purified by flash silica chromatography, elution gradient 0 to 25percent THF in petroleum ether. Pure fractions were evaporated to dryness to afford (S)-tert-butyl (3- methoxy- 1 -(methoxy(methyl)amino)- 1 -oxopropan-2-yl)carbamate (24 g, 100 percent) as a colourless oil. 1HNMR (400 MHz, CDC13, 22°C) oe 1.46(9 H, s), 3.25 (3 H, s), 3.37(3 H, s), 3.62 (2 H, ddd), 3.72 - 3.82 (3 H, m), 4.86 (1 H, s), 5.43 (1 H, d). mlz (ES+), [M+H]+ =263.
2-bromo-4-chloro-N-methoxy-N-methylbenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; HATU; In dichloromethane; at 15℃; for 18h;
Step 1 : 2-bromo-4-chloro-N-methoxy- N-methylbenzamide To a round bottom flask was added <strong>[936-08-3]2-bromo-4-chlorobenzoic acid</strong> (10 g, 42.50 mmol), DCM (150 mL), HATU (19.38 g, 51.00 mmol), Nu,Omicron-dimethylhydroxylamine hydrogen chloride (12.43 g, 127 mmol) and triethylamine (29.60 mL, 212 mmol). The reaction mixture was stirred for 18 h at 15°C. LCMS showed the reaction was complete. The mixture was quenched with water (200 mL) and extracted with DCM (100 mL x 3). The combined organic layers were dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (PE: EtOAc = 10: 1) to give the title compound. MS (ESI) m/z 280.1 (M+H).
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃; for 18h;
To a round bottom flask were added <strong>[936-08-3]2-bromo-4-chlorobenzoic acid</strong> (10 g, 42.5 mmol), DCM (150 mL), HATU (19.38 g, 51.0 mmol), N,O-dimethylhydroxylamine hydrochloride (12.43 g, 127 mmol) and triethylamine (29.6 mL, 212 mmol). The reaction mixture was stirred for 18 h at rt. The mixture was quenched with water (200 mL) and extracted with DCM (100 mLx3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with petroleum ether: EtOAc = 10:1 v/v) to give the title compound. MS (ES+) m/z: 278, 280 [M+H].
With 1,1'-carbonyldiimidazole; In dichloromethane; at 0 - 30℃; for 3h;
General procedure: Step 1: N, 0-Dimethylhydroxylamine hydrochloride (25.14 g, 257.69 mrnol, 1.72 eq), HATU (56.97 g, 149.82 mrnol, 1.00 eq) and TEA (45.48 g, 449.46 mrnol, 3.00 eq) were added to a solution of 2-cyclopropylacetic acid (15.00 g, 149.82 mrnol, 1.00 eq) in DCM (500 mL) at 0 °C, and then the mixture was stirred at 30 °C for 3 h. The resulting mixture was poured into water (500 mL). The aqueous washing phase was extracted with DCM (3*250 mL). The combined organic layers were dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by column 02429524\45-01 chromatography (S1O2, petroleum ether(PE): ethyl acetate (EA) = 50: 1 to 10: 1) to give the desired compound 2 (13.20 g, 82.97 mmol, 55.4percent yield) as colorless liquid. NMR (CDCb, 400 MHz) delta 3.65 (s, 3H), 3.17 (s, 3H), 2.33 (d, / = 6.8 Hz, 2H), 1.09-1.06 (m, 1H), 0.54-0.50 (m, 2H), 0.16-0.14 (m, 2H).
N-methoxy-N,2-dimethylbenzo[d]thiazole-5-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With bromine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; for 12h;Inert atmosphere;
[0784] To a stirred solution of 2-methylbenzo [di thiazole-5-carboxylic acid (6.5 g, 34 mmol) in CH2C12 (65 mL) at 0 C under an argon atmosphere were added N,Odimethylhydroxylamine hydrochloride (3.6 g, 37 mmol), EDCI. HC1 (7.72 g, 40 mmol) and bromine (20.4 mg, 0.1 mmol). The reaction mixture was warmed to room temperature and stirred for 12 h. After consumption of starting material (by TLC), the reaction mixture was diluted with saturated sodium bicarbonate solution (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain N-methoxy-N,2-dimethylbenzo [di thiazole-5-carboxamide (6.2 g, crude) as a pale yellow solid. LCMS: 52.9%; 236.9 (M+1); (column; Ascentis Express C-18 (50 x 3.0 mm, 2.7 tm); RT 1.81 mm; mobile phase: 0.025% Aq TFA+5%ACN: ACN+5% 0.025% Aq TFA; T/B%: 0.01/5, 0.5/5, 3/100, 5/100; flow rate: 1.2 mL/min) (Gradient);TLC: 5% MeOH/CH2C12 (R1: 0.3).
To a mixture of 5.0 g of <strong>[6880-04-2]4-methoxy-3-methylbenzoic acid</strong> and 100 ml of tetrahydrofuran, 4.0 g of oxalyl chloride and 0.2 ml of DMF were added at room temperature, followed by stirring for 2.5 hours and further concentration under reduced pressure. To this mixture, 150 ml of chloroform, 3.5 g of N,O-dimethylhydroxylamine hydrochloride, and 9.3 g of diisopropylethylamine were added at room temperature, followed by stirring for 4 hours. Water was added and the mixture was extracted with chloroform, and the organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to column chromatography to obtain 6.1 g of a compound represented by formula shown below (hereinafter referred to as the intermediate (2A)). 1H-NMR (CDCl3) delta: 7.61-7.58 (1H, m), 7.54 (1H, dd, J=2.1, 0.6 Hz), 6.81 (1H, d, J=8.5 Hz), 3.87 (3H, s), 3.57 (3H, s), 3.35 (3H, s), 2.23 (3H, s).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 16h;Inert atmosphere;
To a stirred solution compound 98 (19 g, 132.86 mmol) in DMF (300 mL) under inert atmosphere were added EDCI.HCl (38.06 g, 199.26 mmol), HOBt (26.9 g, 199.25 mmol) N, O-dimethylhydroxylamine hydrochloride (15.3 g, 158.54 mmol) and diisopropylethylamine (69.48 mL, 398.44 mmol) at 0 oC, followed by warming to room temperature and stirred for 16 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice-cold water and extracted using EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel flash column chromatography using 50percent EtOAc/ hexanes to afford compound 99 (13 g, 53percent) as thick syrup. TLC: 10percent MeOH/ CH2Cl2 (Rf: 0.7); 1H NMR (500 MHz, DMSO-d6): delta 8.26 (s, 1H), 3.75 (s, 3H), 3.27 (s, 3H), 2.68 (s, 3H); LCMS Calculated for C7H10N2O2S: 186.05; Observed: 187.1 (M+1)+.
N-methoxy-N-methyl-4-nitro-1H-pyrazole-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
926 mg
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0.1 - 0.35℃; for 14h;
To a mixture of <strong>[5334-40-7]4-nitro-1H-pyrazole-3-carboxylic acid</strong> (1.02 g), N,O-dimethylhydroxylamine hydrochloride (689 mg), 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (3.39 g) and DMF (10 mL) was added N,N-diisopropylethylamine (2.80 mL). After being stirred at room temperature for 14 hr, the mixture was poured into aqueous saturated ammonium chloride and extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/hexane and NH, MeOH) to give the title compound (926 mg). MS m/z 201.1 [M+1]+.
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