Home Cart 0 Sign in  

[ CAS No. 15761-38-3 ]

{[proInfo.proName]} ,{[proInfo.pro_purity]}
Cat. No.: {[proInfo.prAm]}
Chemical Structure| 15761-38-3
Chemical Structure| 15761-38-3
Structure of 15761-38-3 * Storage: {[proInfo.prStorage]}

Quality Control of [ 15761-38-3 ]

Related Doc. of [ 15761-38-3 ]

SDS
Alternatived Products of [ 15761-38-3 ]
Alternatived Products of [ 15761-38-3 ]

Product Details of [ 15761-38-3 ]

CAS No. :15761-38-3 MDL No. :MFCD00037225
Formula : C8H15NO4 Boiling Point : 320.9°C at 760 mmHg
Linear Structure Formula :- InChI Key :-
M.W :189.21 g/mol Pubchem ID :85082
Synonyms :

Safety of [ 15761-38-3 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 15761-38-3 ]

  • Upstream synthesis route of [ 15761-38-3 ]
  • Downstream synthetic route of [ 15761-38-3 ]

[ 15761-38-3 ] Synthesis Path-Upstream   1~27

  • 1
  • [ 6066-82-6 ]
  • [ 15761-38-3 ]
  • [ 3392-05-0 ]
Reference: [1] Journal of Pharmaceutical Sciences, 1987, vol. 76, # 2, p. 134 - 140
[2] Chemical and pharmaceutical bulletin, 2002, vol. 50, # 2, p. 239 - 252
[3] Journal of the Chemical Society, Chemical Communications, 1985, # 8, p. 473
[4] Carbohydrate Research, 1984, vol. 132, p. 275 - 286
[5] Journal of the American Chemical Society, 1992, vol. 114, # 17, p. 6653 - 6661
[6] Journal of the American Chemical Society, 1996, vol. 118, # 29, p. 6975 - 6985
[7] Journal of Medicinal Chemistry, 1997, vol. 40, # 15, p. 2386 - 2397
[8] Chemistry of Natural Compounds, 1997, vol. 33, # 5, p. 568 - 570
[9] Chemistry of Natural Compounds, 1998, vol. 34, # 1, p. 78 - 79
[10] Journal of Medicinal Chemistry, 2003, vol. 46, # 21, p. 4543 - 4551
[11] Patent: EP2123283, 2009, A1, . Location in patent: Page/Page column 17-18
[12] Patent: US2009/325894, 2009, A1, . Location in patent: Page/Page column 11-12
[13] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 12, p. 3220 - 3224
[14] Biomacromolecules, 2010, vol. 11, # 2, p. 496 - 504
[15] Organic and Biomolecular Chemistry, 2011, vol. 9, # 11, p. 4182 - 4187
[16] Synlett, 2012, # 1, p. 142 - 144
[17] Chinese Chemical Letters, 2011, vol. 22, # 12, p. 1443 - 1446
[18] Biochimie, 2013, vol. 95, # 6, p. 1120 - 1126
[19] Chinese Chemical Letters, 2016, vol. 27, # 3, p. 357 - 360
[20] Patent: EP2612857, 2017, B1, . Location in patent: Paragraph 0137
[21] Journal of Molecular Biology, 2018, vol. 430, # 6, p. 842 - 852
  • 2
  • [ 15761-38-3 ]
  • [ 107960-02-1 ]
  • [ 3392-05-0 ]
YieldReaction ConditionsOperation in experiment
94% With 4-methyl-morpholine In tetrahydrofuran; ethyl acetate; Petroleum ether EXAMPLE 11:
PREPARATION OF N-SUCCINIMIDYL N-TERT-BUTYLOXYCARBONYL-L-ALANINATE
0.95 g (5 mmol) of N-tert-butyloxycarbonyl-L-alanine and 0.66 ml (5.5 mmol) of N-methylmorpholine are dissolved in 6 ml of THF, and 1.8 g (5.5 mmol) of N-succinimidyl 1,2,2,2-tetrachloroethyl carbonate is added in a single portion.
The mixture is stirred for two hours at 20° C.
Approximately 25 ml of ethyl acetate are added and the organic phase is washed rapidly with N HCl solution, then with potassium bicarbonate solution and finally twice with water.
The organic phase is dried over magnesium sulphate and evaporated.
The residue is crystallized in an ethyl acetate/petroleum ether mixture and 1.25 g (Y=87percent) of white crystals are obtained.
Evaporation of the mother liquors and crystallisation enables a further 0.1 g to be recovered, and this brings the yield to 94percent.
M.p. (melting point)=158° C. [α]D20 =50.7 (c=2, dioxane)
Reference: [1] Journal of Organic Chemistry, 1987, vol. 52, # 12, p. 2364 - 2367
[2] Patent: US4782164, 1988, A,
  • 3
  • [ 15761-38-3 ]
  • [ 3392-05-0 ]
Reference: [1] Tetrahedron Letters, 2002, vol. 43, # 9, p. 1661 - 1664
  • 4
  • [ 15761-38-3 ]
  • [ 75513-55-2 ]
  • [ 3392-05-0 ]
Reference: [1] Journal of Organic Chemistry, 1982, vol. 47, # 15, p. 2982 - 2987
[2] Tetrahedron Letters, 1980, vol. 21, # 15, p. 1467 - 1468
  • 5
  • [ 15761-38-3 ]
  • [ 90704-86-2 ]
  • [ 3392-05-0 ]
Reference: [1] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1984, vol. 33, p. 1067 - 1070[2] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1984, # 5, p. 1163 - 1165
[3] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1984, vol. 33, p. 1067 - 1070[4] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1984, # 5, p. 1163 - 1165
  • 6
  • [ 15761-38-3 ]
  • [ 1115-59-9 ]
  • [ 27317-69-7 ]
Reference: [1] Patent: US5162307, 1992, A,
  • 7
  • [ 15761-38-3 ]
  • [ 27317-69-7 ]
Reference: [1] Russian Journal of Bioorganic Chemistry, 1995, vol. 21, # 9, p. 590 - 595[2] Bioorganicheskaya Khimiya, 1995, vol. 21, # 9, p. 684 - 690
[3] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1970, # 12, p. 2657 - 2659[4] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1970, # 12, p. 2820 - 2821
[5] Tetrahedron Asymmetry, 2011, vol. 22, # 1, p. 22 - 25
[6] Chemical Communications, 2018, vol. 54, # 18, p. 2280 - 2283
  • 8
  • [ 486449-25-6 ]
  • [ 15761-38-3 ]
  • [ 637-89-8 ]
Reference: [1] The Journal of organic chemistry, 2002, vol. 67, # 25, p. 9103 - 9106
  • 9
  • [ 15761-38-3 ]
  • [ 28782-78-7 ]
Reference: [1] Journal of Organic Chemistry, 1997, vol. 62, # 5, p. 1356 - 1362
[2] Pharmazie, 1982, vol. 37, # 6, p. 403 - 407
[3] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 11, p. 3055 - 3064
[4] Chemistry - An Asian Journal, 2017, vol. 12, # 12, p. 1326 - 1337
  • 10
  • [ 15761-38-3 ]
  • [ 74-88-4 ]
  • [ 16948-16-6 ]
YieldReaction ConditionsOperation in experiment
93% With sodium hydride In tetrahydrofuran at 0 - 20℃; for 26 h; Inert atmosphere General procedure: (S)-2-(Tert-butoxycarbonyl(methyl)amino)-3-hydroxypropanoic acid(6a) Gummy substance (This compound was prepared byadding neat sodium hydride (10 equiv.) in portion wiseover a period of 2.0 h to a cooled (0 °C) solution of (S)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid (1equiv.) and iodomethane (10 equiv.) in dry THF under astream of nitrogen. The reaction mixture was stirred at room temperature for 24 h under nitrogen atmosphere andthen diluted with ether (20 mL) and quenched with water(30 mL). The layers were separated and the aqueous layerwas extracted with ether (2 x9 15 mL), acidified to pH 3with a 20 percent aqueous solution of citric acid and extractedwith EtOAc (3 x 20 mL). The combined organic phasewas dried over Na2SO4 and evaporated to afford thecorresponding N-methylated product in 90 percent yield asGummy substance.)
Reference: [1] Tetrahedron, 2006, vol. 62, # 2-3, p. 264 - 284
[2] Chemistry - A European Journal, 2013, vol. 19, # 32, p. 10619 - 10624
[3] British Journal of Pharmacology, 2016, p. 2657 - 2668
[4] Medicinal Chemistry Research, 2016, vol. 25, # 6, p. 1148 - 1162
[5] Canadian Journal of Chemistry, 1977, vol. 55, p. 906 - 910
[6] Tetrahedron, 1991, vol. 47, # 29, p. 5453 - 5462
[7] Tetrahedron Letters, 1998, vol. 39, # 40, p. 7373 - 7376
[8] Journal of Physical Organic Chemistry, 2004, vol. 17, # 5, p. 448 - 457
[9] Helvetica Chimica Acta, 2012, vol. 95, # 6, p. 973 - 982
[10] Current Medicinal Chemistry, 2013, vol. 20, # 9, p. 1183 - 1194
  • 11
  • [ 15761-38-3 ]
  • [ 77-78-1 ]
  • [ 16948-16-6 ]
Reference: [1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1995, vol. 34, # 1, p. 45 - 47
  • 12
  • [ 15761-38-3 ]
  • [ 16948-16-6 ]
Reference: [1] Tetrahedron, 2012, vol. 68, # 35, p. 7070 - 7076
  • 13
  • [ 67-56-1 ]
  • [ 15761-38-3 ]
  • [ 2491-20-5 ]
Reference: [1] Journal of Organic Chemistry, 1999, vol. 64, # 25, p. 9294 - 9296
  • 14
  • [ 15761-38-3 ]
  • [ 124-41-4 ]
  • [ 2491-20-5 ]
Reference: [1] Amino Acids, 2012, vol. 43, # 4, p. 1779 - 1790
  • 15
  • [ 15761-38-3 ]
  • [ 53267-93-9 ]
  • [ 37169-36-1 ]
Reference: [1] RSC Advances, 2015, vol. 5, # 74, p. 60354 - 60364
  • 16
  • [ 15761-38-3 ]
  • [ 78981-25-6 ]
YieldReaction ConditionsOperation in experiment
89%
Stage #1: With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at -10℃; for 1 h; Inert atmosphere
Stage #2: With ammonia In tetrahydrofuran at -10 - 20℃; Inert atmosphere
General procedure: To a stirred solution of N-Boc-(R)-alanine (5.0 g, 26.4 mmol) in dry THF at -10 °C, were added triethylamine (3 mL, 21.12 mmol) and ethyl chloroformate (2.5 mL, 26.4 mmol). The reaction mixture was stirred for 1 h and then NH3 (g) was bubbled for 1.5 h. The mixture was then stirred at room temperature overnight. Next, THF was removed under reduced pressure, after which NaCl sat. sol. (40 mL) was added and extracted with EtOAc (5 * 40 mL). The organic layer was washed with HCl 0.5 M (2 * 30 mL) and dried over Na2SO4, filtered, and evaporated under vacuum, to give the amide
80%
Stage #1: With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran at 0℃; for 0.5 h;
Stage #2: With ammonium hydroxide In tetrahydrofuran; water at 0 - 20℃; for 5 h;
Step 1: tert-Butyl[(1S)-2-amino-1-methyl-2-oxoethyl]carbamate To a stirred solution of (2S)-2-[(tert-butoxycarbonyl)amino]propanoic acid (1 g, 0.005 mol) in THF at 0° C. was added 4-methylmorpholine (0.588 g, 0.00581 mol) followed by dropwise addition of isobutyl chloroformate (0.794 g, 0.00581 mol) over 2 min. The reaction was stirred at 0° C. for 30 min. after which a solution of 30 wt. percent ammonium hydroxide (12.0 mL, 0.0925 mol) was quickly poured into the reaction. The reaction was warmed to room temperature and stirred for 5 h. The reaction mixture was concentrated. Water was added and the mixture extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to afford the crude product which was directly used in the next step reaction without further purification (800 mg, 80percent). 11'-NMR (300 MHz, DMSO-d6): 12.40 (s, 1H), 7.10 (d, J=7.0 Hz, 1H), 3.88 (m, 1H), 1.35 (s, 9H), 1.20 (d, J=7.3 Hz, 3H).
49%
Stage #1: With 1-hydroxy-pyrrolidine-2,5-dione; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran; DMF (N,N-dimethyl-formamide) at 20℃; for 16 h;
Stage #2: With ammonia In tetrahydrofuran; DMF (N,N-dimethyl-formamide); water at 20℃; for 0.5 h;
To a solution containing Boc-L-alanine (1.0 g, 5.29 mmol) in a mixture of tetrahydrofuran (25 mL) and N,N-dimethylformamide (5 mL) were added EDAC (1.5 g, 7.82 mmol) and N-hydroxysuccinimide (0.91 g, 7.91 mmol) and the mixture was stirred at room temperature for 16 hours. Aqueous ammonium hydroxide solution (15 mL, 28percent) was added and the mixture was stirred for 0.5 hours at room temperature. The reaction was partitioned between ethyl acetate and water, and the organic was washed with brine and dried over MgSO4, filtered and evaporated to give the product (0.483 g, 49percent yield), which was used without further purification.
49%
Stage #1: With 1-hydroxy-pyrrolidine-2,5-dione; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 16 h;
Stage #2: With ammonium hydroxide In tetrahydrofuran; water; N,N-dimethyl-formamide at 20℃; for 0.5 h;
Example 474Atert-butyl (1S)-2-amino-1-methyl-2-oxoethylcarbamateTo a solution containing Boc-L-alanine (1.0 g, 5.29 mmol) in a mixture of tetrahydrofuran (25 mL) and N,N-dimethylformamide (5 mL) were added EDAC (1.5 g, 7.82 mmol) and N-hydroxysuccinimide (0.91 g, 7.91 mmol) and the mixture was stirred at room temperature for 16 hours. Aqueous ammonium hydroxide solution (15 mL, 28percent) was added and the mixture was stirred for 0.5 hours at room temperature. The reaction was partitioned between ethyl acetate and water, and the organic was washed with brine and dried over MgSO4, filtered and evaporated to give the product (0.483 g, 49percent yield), which was used without further purification.
4 g
Stage #1: With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at 20℃; for 0.333333 h;
Stage #2: With ammonium hydroxide In tetrahydrofuran at 0 - 5℃; for 0.5 h;
Ethyichioroformate (3.4 g, 31.3 mmol) and Et3N (7.0 mL, 52.8 mmol) were added to a solution of compound la (5.0 g, 26.4 mmol) in THF (20 mL) and stirred at - 20 °C for 20 mm. After 20 minutes 25percent of aqueous ammonia (10 mL, 132.0 mmol) was added to the active mixed anhydride and stirred at 0-5 °C for 30 mm. The completeness of the reaction was confirmed by TLC analysis. The volatiles were evaporated underreduced pressure and partitioned between water and ethyl acetate. The organic layer was washed with NaHCO3 solution followed by citric acid solution and brine solution. The separated organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure to yield 4.0 g of compound lb. LCMS: 89.3 (M-Boc+H).

Reference: [1] Tetrahedron, 1999, vol. 55, # 42, p. 12301 - 12308
[2] Tetrahedron Letters, 2007, vol. 48, # 4, p. 603 - 607
[3] Synthetic Communications, 2013, vol. 43, # 7, p. 993 - 1006
[4] Bulletin of the Chemical Society of Japan, 1988, vol. 61, # 7, p. 2647 - 2648
[5] Tetrahedron Asymmetry, 2013, vol. 24, # 24, p. 1572 - 1575
[6] Tetrahedron Letters, 1995, vol. 36, # 39, p. 7115 - 7118
[7] Angewandte Chemie - International Edition, 2008, vol. 47, # 23, p. 4331 - 4334
[8] Patent: US2011/212967, 2011, A1, . Location in patent: Page/Page column 11
[9] Inorganic Chemistry, 2016, vol. 55, # 2, p. 877 - 886
[10] Patent: US2005/131042, 2005, A1, . Location in patent: Page/Page column 124
[11] Patent: US2011/3827, 2011, A1, . Location in patent: Page/Page column 111-112
[12] Tetrahedron Letters, 2007, vol. 48, # 8, p. 1465 - 1468
[13] Chemical Communications, 2006, # 4, p. 460 - 462
[14] Synthetic Communications, 2009, vol. 39, # 3, p. 395 - 406
[15] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 16, p. 4878 - 4881
[16] Journal of Organic Chemistry, 2011, vol. 76, # 23, p. 9845 - 9851
[17] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 24, p. 7355 - 7358
[18] Organic Letters, 2012, vol. 14, # 5, p. 1198 - 1201
[19] Organic Letters, 2013, vol. 15, # 18, p. 4638 - 4641
[20] European Journal of Organic Chemistry, 2013, # 36, p. 8154 - 8161
[21] Tetrahedron Letters, 2014, vol. 55, # 15, p. 2389 - 2393
[22] Tetrahedron Letters, 2014, vol. 55, # 50, p. 6831 - 6835
[23] MedChemComm, 2015, vol. 6, # 2, p. 300 - 305
[24] Patent: WO2016/142833, 2016, A1, . Location in patent: Page/Page column 69
[25] ACS Medicinal Chemistry Letters, 2017, vol. 8, # 4, p. 401 - 406
[26] Patent: WO2009/146112, 2009, A1, . Location in patent: Page/Page column 29; 33
  • 17
  • [ 15761-38-3 ]
  • [ 124-38-9 ]
  • [ 1529-17-5 ]
  • [ 6003-05-0 ]
  • [ 115-11-7 ]
Reference: [1] Tetrahedron Letters, 1988, vol. 29, # 3, p. 303 - 306
  • 18
  • [ 112392-66-2 ]
  • [ 15761-38-3 ]
  • [ 91103-47-8 ]
YieldReaction ConditionsOperation in experiment
99.7 % ee With lyophilized cells of Bacillus amyloliquefaciens WZZ002 In aq. phosphate buffer at 35℃; for 10 h; Enzymatic reaction Enantioselective hydrolysis was performed on Boc-dl-Ala-OMe by adding both a substrate with a concentration range of 0.1 to 4.0M and a 500mg lyophilized cell of B. amyloliquefaciens WZZ002 in a 10mL (50mL flask) phosphate buffer solution (0.2M, pH6.0–12.0) at 20°C to 60°C. The solution was stirred at 400rpm. The pH level was controlled through automatic titration using different alkali solutions (2M). The samples were withdrawn at regular intervals and were immediately acidified with HCl (2M) to stop the reaction and to enhance the extractability of Boc-dl-Ala. The sample was extracted using ethyl acetate, whereas the organic phase was isolated and dried using anhydrous Na2SO4 for gas chromatography (GC) analysis. All experiments were conducted in triplicate, unless specified. The time course of enantioselective hydrolysis reaction was performed by adding 2M of Boc-dl-Ala-OMe and 5g of the lyophilized cell of B. amyloliquefaciens WZZ002 in 100mL (250mL flask) phosphate buffer solution (0.2M, pH8.0). The pH of the reaction was controlled through automatic titration using 6M of NH3·H2O to reduce the increasing amount of the neutralizer.
Reference: [1] Catalysis Communications, 2014, vol. 60, p. 134 - 137
  • 19
  • [ 15761-38-3 ]
  • [ 6638-79-5 ]
  • [ 146553-06-2 ]
YieldReaction ConditionsOperation in experiment
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: 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. 12 The 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.

Reference: [1] Angewandte Chemie - International Edition, 2013, vol. 52, # 34, p. 8957 - 8960[2] Angew. Chem., 2013, vol. 125, # 34, p. 9126 - 9129,4
[3] Journal of Labelled Compounds and Radiopharmaceuticals, 2014, vol. 57, # 4, p. 275 - 278
[4] Organic Letters, 2002, vol. 4, # 16, p. 2665 - 2668
[5] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 15, p. 3582 - 3586
[6] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 15, p. 3582 - 3586
[7] Patent: CN104211663, 2017, B, . Location in patent: Paragraph 0039; 0040
[8] Organic and Biomolecular Chemistry, 2011, vol. 9, # 6, p. 1823 - 1830
[9] Organic and Biomolecular Chemistry, 2012, vol. 10, # 18, p. 3739 - 3748
[10] Patent: US2012/184568, 2012, A1, . Location in patent: Page/Page column 78
[11] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 3, p. 897 - 911
[12] Patent: WO2009/142569, 2009, A1, . Location in patent: Page/Page column 50
[13] Journal of Medicinal Chemistry, 2017, vol. 60, # 21, p. 8963 - 8981
[14] Organic Letters, 2010, vol. 12, # 23, p. 5576 - 5579
[15] Chemistry - A European Journal, 2011, vol. 17, # 48, p. 13544 - 13552
[16] European Journal of Organic Chemistry, 2014, vol. 2014, # 8, p. 1672 - 1683
[17] European Journal of Organic Chemistry, 2014, vol. 2014, # 8, p. 1672 - 1683
[18] British Journal of Pharmacology, 2016, p. 2657 - 2668
[19] Patent: US2015/87658, 2015, A1, . Location in patent: Paragraph 0538; 0539; 0540
[20] Synthesis, 1983, # 8, p. 676 - 678
[21] Angewandte Chemie - International Edition, 2010, vol. 49, # 38, p. 6856 - 6859
[22] Helvetica Chimica Acta, 1998, vol. 81, # 5, p. 983 - 1002
[23] Tetrahedron Letters, 2001, vol. 42, # 30, p. 5013 - 5016
[24] Patent: WO2006/76595, 2006, A1, . Location in patent: Page/Page column 154
[25] Patent: EP3036251, 2017, B1, . Location in patent: Paragraph 0022
[26] Synthetic Communications, 1995, vol. 25, # 8, p. 1255 - 1264
[27] Tetrahedron Letters, 2010, vol. 51, # 14, p. 1819 - 1821
[28] Tetrahedron Letters, 1994, vol. 35, # 29, p. 5173 - 5176
[29] Angewandte Chemie - International Edition, 2016, vol. 55, # 19, p. 5842 - 5845[30] Angew. Chem., 2016, vol. 128, # 19, p. 5936 - 5939,4
[31] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 14, p. 4047 - 4057
[32] Patent: WO2016/20836, 2016, A1, . Location in patent: Page/Page column 53; 54
[33] European Journal of Medicinal Chemistry, 2015, vol. 106, p. 15 - 25
[34] Journal of the American Chemical Society, 1999, vol. 121, # 13, p. 2974 - 2986
[35] Chemical and Pharmaceutical Bulletin, 1999, vol. 47, # 3, p. 423 - 427
[36] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 18, p. 4777 - 4779
[37] Organic Letters, 2006, vol. 8, # 23, p. 5357 - 5360
[38] Journal of Medicinal Chemistry, 2000, vol. 43, # 18, p. 3434 - 3442
[39] European Journal of Organic Chemistry, 2008, # 27, p. 4655 - 4664
[40] Journal of Organic Chemistry, 2009, vol. 74, # 15, p. 5614 - 5617
[41] Organic and Biomolecular Chemistry, 2010, vol. 8, # 21, p. 4855 - 4860
[42] Organic and Biomolecular Chemistry, 2011, vol. 9, # 19, p. 6566 - 6574
[43] Tetrahedron Letters, 2012, vol. 53, # 11, p. 1313 - 1315
[44] Patent: WO2012/68343, 2012, A1, . Location in patent: Page/Page column 29; 30
[45] Patent: WO2013/1294, 2013, A1, . Location in patent: Page/Page column 42-43
[46] European Journal of Organic Chemistry, 2014, vol. 2014, # 15, p. 3067 - 3071
[47] Patent: US2014/309225, 2014, A1, . Location in patent: Paragraph 0926
[48] Patent: WO2014/184365, 2014, A1, . Location in patent: Page/Page column 43
[49] Patent: WO2014/184350, 2014, A1, . Location in patent: Page/Page column 192
[50] Patent: WO2015/11281, 2015, A1, . Location in patent: Page/Page column 64-65
[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
  • 20
  • [ 15761-38-3 ]
  • [ 1117-97-1 ]
  • [ 146553-06-2 ]
YieldReaction ConditionsOperation in experiment
95% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 0 - 20℃; 10 g (52.85 mmol, 1.0 equivalent) of (S)-2-((tert-butoxycarbonyl)amino)propanoic acid was dissolved in anhydrous dichloromethane (250 ml), to which 29.5 ml (211.40 mmol, 4.0 equivalent) of triethylamine and 7.14 g (52.85 mmol, 1.0 equivalent) of hydroxybenzotriazole (HOBt) were added at 0° C. 20.3 g (105.70 mmol, 2.0 equivalent) of EDCI.HCl was added thereto, followed by stirring at room temperature for 30 minutes. 5.7 g (58.14 mmol, 1.1 equivalent) of N,O-dimethylhydroxylamine was added thereto, followed by stirring at room temperature for hours.
Water was added to the reaction mixture, followed by extraction using ethyl acetate.
The organic layer was separated, dried (Na2SO4), filtered, and concentrated under reduced pressure.
The obtained solid was recrystallized with hexane/ethyl acetate to give 11.7 g of the target compound tert-butyl (S)-(1-(methoxy(methyl)amino)-1-oxopropane-2-yl)carbamate as a white solid (50.37 mmol, yield: 95percent).
1H NMR(300 MHz, CDCl3) δ 5.23 (s, 1H), 4.68-4.70 (m, 1H) , 3.77 (s, 3H) , 3.12 (s, 3H) , 1.44 (s, 9H) , 1.31 (d, J=3.5 Hz, 3H).
93%
Stage #1: at 0℃; for 0.166667 h;
Stage #2: With phosphorus trichloride In toluene at 20 - 60℃; for 0.5 h;
General procedure: A solution of NHMe(OMe) (0.360 g, 6.0 mmol) and benzoic acid (0.244 g, 2.0 mmol) was stirred in dry toluene (10 mL) at 0 °C for 10 min. A solution of PCl3 (0.137 g, 1.0 mmol) in dry toluene (2 mL) was then added dropwise to the mixture. The mixture was warmed to r.t. slowly and then stirred at 60 °C for 0.5 h. When the reaction was complete (TLC monitoring), the mixture was cooled to r.t. The mixture was then quenched with sat. NaHCO3 soln (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried (anhyd MgSO4). The solvent was removed in vacuo.The product was purified by column chromatography (silica gel, petroleum ether–EtOAc, 3:2) to give pure 3a as a colorless oil; yield: 320 mg (97percent).
91%
Stage #1: With 1,1'-carbonyldiimidazole In dichloromethane at 0℃; for 0.5 h;
Stage #2: With triethylamine In dichloromethane at 20℃;
General procedure: This procedure has been carried out according to the following article: J. Am. Chem. Soc.,1999, 121 (13), pp 2974–2986.To a stirred solution of the corresponding Boc-protected amino acid (Boc-D-Ala-OH, Boc-LAla-OH or Boc-Gly-OH) (1.00 equiv) in anhydrous dichloromethane (0.3 M) at 0°C wasadded 1,1’-carbonyldiimidazole (1.40 equiv). After 30 min at 0°C, Et3N (1.40 equiv) and N,Odimethylhydroxylamine(1.40 equiv) were added. After 30 min, the reaction was stirred at r.tovernight. Et2O (for each 1.00 mmol of protected amino acid, add 6.70 mL of Et2O) wasadded and the organic layer was washed (x3) with a solution of HCl (1N) (for each 1.00mmol of protected amino acid, wash with 2.50 mL of HCl 1N), saturated solution of NaHCO3,brine and dried over MgSO4, filtered and concentrated to give the desired product ascolorless solid yield without further purification.
81.5% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 26℃; [00277] Compound 253: To a mixture of Boc-L-Ala-OH (50.0 g, 0.265 mol), Compound 253B (16.1 g, 0.265 mol), and DIEA (102.4 g, 0.794 mol) in DMF (600 mL) was added HOBt (39.3 g, 0.291 mol) and EDCI (66.0 g, 0.344 mol) at 0 °C. The mixture was stirred overnight at 26 °C. After LCMS showed the reaction was complete, the mixture was extracted with t- BuOMe and H20. The combined organic layers were washed with brine, dried over Na2S04 and concentrated to give Compound 253 A2 (50.0 g, yield: 81.5 percent).
81% With 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 16 h; To a mixture of (tert-butoxycarbonyl)-L-alanine (10.0 g, 4.64 mmol) in dry DCM (100 mL), N,O-dimethylhydroxylamine (5.69 g, 5.80 mmol), NMM (5.87 g, 5.80 mmol) and EDC (15.22 g, 7.90 mmol) were added at 0°C and reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completionof the reaction, the reaction mixture was quenched with water and extracted with DCM. The combined organic layer were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford IV.[0372] Yield: 10 g, 81 percent; ‘H NMR (400 MHz, CDC13) 5.25 (d, J= 8.2 Hz, 1H), 4.73— 4.62 (m, 1H), 3.77 (s, 3H), 3.21 (s, 3H), 1.44 (s, 9H), 1.31 (dd, J= 6.8, 1.0 Hz, 3H).
81% With 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 16 h; [0393] To a mixture of (tert-butoxycarbonyl)-Z-alanine (10.0 g, 4.64 mmol) in dry DCM (100 mL), N,O-dimethylhydroxylamine (5.69 g, 5.80 mmol), NMM (5.87 g, 5.80 mmol) and EDC (15.22 g, 7.90 mmol) were added at 0°C and reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with DCM. The combined organic layer were washed with brine, dried over anhydrous Na2S04 and concentrated under reduced pressure to afford IV. (0642) [0394] Yield: 10 g, 81 percent; 1H MR (400 MHz, CDC13) δ 5.25 (d, J= 8.2 Hz, 1H), 4.73- 4.62 (m, 1H), 3.77 (s, 3H), 3.21 (s, 3H), 1.44 (s, 9H), 1.31 (dd, 7= 6.8, 1.0 Hz, 3H).
63% With 1-[(1-cyano-2-ethoxy-2-oxoethylideneaminooxy)-morpholinomethylene]dimethylammonium hexafluorophosphate.; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 20℃; for 2.83333 h; Inert atmosphere General procedure: A mixture of DMF (120 mL) containing N,O-dimethylhydroxylamine hydrochloride (1.56 g, 0.016 mol) and redistilled diisopropylethylamine (6.16 g, 0.0477 mol) were cooled to 0 °C in an ice-bath under a nitrogen atmosphere. To the mixture was added alanine (3 g, 0.0159 mol) followed by COMU (0.016 mol). The solution immediately turned yellow and the solution was left stirring in the ice-bath for a further 20 min. The ice-bath was removed and the reaction mixture was allowed to reach ambient temperature. After about 2 h the colour of the reaction mixture became orange and stirring was continued for a further 30 min. The solution was diluted with H2O (200 mL) and extracted with Et2O (3 .x. 100 mL). The combined organic fractions were washed with dilute HCl (1 M) (20 mL), saturated Na2CO3 solution (3 .x. 20 mL) and finally a saturated brine solution (20 mL). The organic layer was dried over anhydrous MgSO4, filtered in vacuo and the solvent removed at the pump to afford the title compound as a white crystalline solid 2.32 g, 63percent. Mp 147.2-148.6 °C, lit. 148-153 °C;25 [α]D -26, c 1, (MeOH), lit. [α]D -26, c 1, (MeOH);25 HRMS (EI, M+) calcd for C10H21O4N2 233.1496, found 233.1497; 1H NMR (CDCl3, 400 MHz) δ 5.18 (1H, br s, N-H), 4.62 (1H, br s, C-H), 3.70 (3H, s, O-CH3), 3.14 (3H, s, CH3), 1.37 (9H, s, CH3), 1.24 (3H, d J = 7.03 Hz, CH3); 13C (CDCl3 101 MHz) δ 18.69, 28.36, 32.16, 46.52, 61.61, 79.50. 155.12,26 173.69.2724 HPLC was determined using a (Chiralcel-OD-H column) with a Waters 996 photodiode array diode detector. Measurements were made at 230 nm at a flow rate of 0.5 ml/min. Solvent, hexane/IPA (98:2).
21 g With triethylamine; HATU In tetrahydrofuran at 0 - 20℃; for 15 h; Inert atmosphere To a stirred solution of (2S)-2-(tert-butoxycarbonylamino)propanoic acid (compound 12a, 20.0 g, 105.7 mmol) in THF (300 mL) were added HATU (60.3 g, 158.5 mmol), TEA (26.7 g, 264.2 mmol) and N-methoxymethanamine (15.5 g, 158.5 mmol) at 0 oC. The reaction mixture was stirred under nitrogen atmosphere at room temperature for 15 hours, and then diluted with EA (200 mL), was washed with brine (200 mL), dried over filtered and concentrated. The residue was purified by column chromatography (PE: EtOAc=1:1) to give compound 12b (21.0 g) as a white solid.

Reference: [1] Patent: US2018/105527, 2018, A1, . Location in patent: Paragraph 0550-0552
[2] Heteroatom Chemistry, 2003, vol. 14, # 7, p. 603 - 606
[3] Synthesis (Germany), 2014, vol. 46, # 3, p. 320 - 330
[4] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 12, p. 2180 - 2183
[5] Organic Letters, 2000, vol. 2, # 25, p. 4091 - 4093
[6] Patent: WO2013/123456, 2013, A1, . Location in patent: Paragraph 00277
[7] Patent: WO2017/6271, 2017, A1, . Location in patent: Paragraph 0371; 0372
[8] Patent: WO2018/98209, 2018, A1, . Location in patent: Paragraph 0393-0394
[9] Tetrahedron Letters, 2011, vol. 52, # 3, p. 369 - 372
[10] Journal of the American Chemical Society, 1992, vol. 114, # l6, p. 6568 - 6570
[11] Journal of Medicinal Chemistry, 1999, vol. 42, # 19, p. 3779 - 3784
[12] Patent: WO2018/11160, 2018, A1, . Location in patent: Page/Page column 50
  • 21
  • [ 15761-38-3 ]
  • [ 146553-06-2 ]
YieldReaction ConditionsOperation in experiment
78.8% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 0 - 20℃; for 16 h; N-(3-dimethylaminopropyl)-N’-ethylcarboiimide hydrochloride (455 g, 2378.4 mmol), 1- hydroxybenzotriazole (214.3 g, 1585.6 mmol) and triethylamine (571.9 mL, 3964 mmol) were added to a stirred solution of (25)-2-(tert-butoxycarbonylamino)propanoic acid (300 g, 1585.6 mmol) in dichloromethane (3L) at 0 °C, followed by N, 0-dimethylhydroxylamine hydrochloride (185.6 g, 1902.7 mmol). The reaction mixture was allowed to stir at room temperature for 16h. On completion, the reaction mixture was concentrated under reduced pressure. Water (1 L) was added to the resulting crude and the mixture stirred for 0.5 hr, filtered and dried to afford the titled compound as a white solid (290 g, 78.8percent).TLC system: 3Qpercent ethyl acetate in petroleum ether, Rf: 0.2.1H NMR (400MHz, CDCI3) O = 5.25 (br d, J=6.1 Hz, 1H), 4.68 (br s, 1H), 3.77 (s, 3H),3.21 (s, 3H), 1.44 (s, 9H), 1.31 (d, J=6.7 Hz, 3H).
Reference: [1] Patent: WO2017/46096, 2017, A1, . Location in patent: Page/Page column 40; 41
  • 22
  • [ 15761-38-3 ]
  • [ 146553-06-2 ]
Reference: [1] Journal of Medicinal Chemistry, 1997, vol. 40, # 25, p. 4113 - 4135
[2] Tetrahedron Asymmetry, 1996, vol. 7, # 4, p. 985 - 988
[3] Journal of Organic Chemistry, 2011, vol. 76, # 15, p. 6209 - 6217
[4] Zeitschrift fur Naturforschung - Section B Journal of Chemical Sciences, 2014, vol. 69, # 5, p. 615 - 626
  • 23
  • [ 4530-20-5 ]
  • [ 15761-38-3 ]
  • [ 13734-34-4 ]
  • [ 15260-10-3 ]
  • [ 23680-31-1 ]
  • [ 18942-46-6 ]
  • [ 54613-99-9 ]
  • [ 13139-14-5 ]
  • [ 65420-40-8 ]
  • [ 38916-34-6 ]
Reference: [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 17, p. 5981 - 5987
  • 24
  • [ 186581-53-3 ]
  • [ 15761-38-3 ]
  • [ 158851-30-0 ]
Reference: [1] Journal of Peptide Science, 2012, vol. 18, # 9, p. 556 - 559
  • 25
  • [ 15761-38-3 ]
  • [ 158851-30-0 ]
Reference: [1] Journal of Peptide Science, 2012, vol. 18, # 9, p. 556 - 559
[2] Angewandte Chemie - International Edition, 2014, vol. 53, # 14, p. 3594 - 3598[3] Angew. Chem., 2014, vol. 126, # 14, p. 3668 - 3672,5
  • 26
  • [ 15761-38-3 ]
  • [ 146552-71-8 ]
Reference: [1] Patent: US2015/141323, 2015, A1,
  • 27
  • [ 15761-38-3 ]
  • [ 170097-58-2 ]
Reference: [1] British Journal of Pharmacology, 2016, p. 2657 - 2668
Historical Records

Similar Product of
[ 15761-38-3 ]

Chemical Structure| 285978-11-2

A1269717[ 285978-11-2 ]

(tert-Butoxycarbonyl)-L-alanine-2-13C-15N

Reason: Stable Isotope

Chemical Structure| 340320-94-7

A1269704[ 340320-94-7 ]

(tert-Butoxycarbonyl)-L-alanine-13C3-15N

Reason: Stable Isotope

Chemical Structure| 335081-02-2

A1269703[ 335081-02-2 ]

Boc-Ala-OH-13C3

Reason: Stable Isotope

Chemical Structure| 201612-65-9

A1502806[ 201612-65-9 ]

(tert-Butoxycarbonyl)-L-alanine-2-13C

Reason: Stable Isotope

Chemical Structure| 139952-87-7

A460589[ 139952-87-7 ]

L-Alanine-15N, N-[(1,1-dimethylethoxy)carbonyl]-

Reason: Stable Isotope

Chemical Structure| 201740-78-5

A393268[ 201740-78-5 ]

N-(tert-butoxycarbonyl)-L-alanine-1-13c

Reason: Stable Isotope

Chemical Structure| 201740-79-6

A250804[ 201740-79-6 ]

N-(tert-butoxycarbonyl)-L-alanine-3-13c

Reason: Stable Isotope

Related Functional Groups of
[ 15761-38-3 ]

Amino Acid

Chemical Structure| 13726-84-6

[ 13726-84-6 ]

Boc-Glu(OtBu)-OH

Similarity: 0.80

Chemical Structure| 149794-10-5

[ 149794-10-5 ]

Boc-N-Ethylglycine

Similarity: 0.80

Chemical Structure| 34582-32-6

[ 34582-32-6 ]

Boc-Asp-OtBu

Similarity: 0.79

Chemical Structure|

[ ]

Similarity: 0.71

Chemical Structure| 71449-08-6

[ 71449-08-6 ]

Z-D-Asp(OtBu)-OH

Similarity: 0.66