* 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.
Example 1N-(5-{3-benzyl-2-[(2-methanesulfonylethyl)amino]-4-oxo-3,4-dihydro methoxypyridin-3-yl)-2,4-difluorobenzene-1-sulfonamideStep A6-bromo-2,4( 1 H, 3H)-quinazolinedione [00123] A mixture of methyl 2-amino-5-bromobenzoate (50 g, 217 mmol) and urea (65.3 g, 1087 mmol) were ground together and heated to 200 °C for 2 hours with stirring and while under nitrogen. The mixture went fully into solution after 10 minutes, and then solidified after 40 minutes. The reaction was cooled and the resulting solid was washed with water (1 L). The solid was then filtered and the remaining solids rinsed with more water and broken up into fine particles. The residue was triturated with EtOAc (ca 300 mL) and dried to yield 6-bromo- 2,4(1 H,3H)-quinazolinedione (42g, 80percent). ES-LCMS: 241.0, 243.1 (M+1 ).
Reference：
[1] Patent: WO2012/87938, 2012, A1, . Location in patent: Page/Page column 113-114
[2] Journal of Medicinal Chemistry, 2007, vol. 50, # 10, p. 2297 - 2300
[3] Patent: WO2008/152387, 2008, A1, . Location in patent: Page/Page column 26; 29
2
[ 52727-57-8 ]
[ 88145-89-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 21, p. 4904 - 4907
[2] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 24, p. 6680 - 6694
3
[ 52727-57-8 ]
[ 29632-82-4 ]
[ 62473-92-1 ]
Yield
Reaction Conditions
Operation in experiment
9%
With ammonia; acetic acid; sodium nitrite In tetrahydrofuran; hydrogenchloride; methanol; water; sodium hydrogencarbonate
Step b: 6-Bromo-1,1-dioxo-1,2-dihydro-1λ6-benzo[d]isothiazol-3-one A solution of the methyl 2-amino-5-bromobenzoate (20.0 g, 86.9 mol) in 20percent hydrochloric acid (60 mL) was warmed until all solids were dissolved. The solution was cooled to 0° C. with stirring to precipitate the hydrochloride salt. To this suspension was added a solution of sodium nitrite (6.10 g, 8.84 mol) in water (20 mL) dropwise at such a rate that the internal reaction temperature did not exceed 5° C. The mixture was stirred at 0° C. for 45 minutes to afford a clear solution. Sulfur dioxide was bubbled into a mixture of acetic acid (100 mL) and water (10 mL) at 0° C. Copper (I) chloride (8.6 g, 0.088 mol) was then added to the sulfur dioxide solution. The mixture was then cooled to 0° C. To this mixture was added the diazonium salt solution portion-wise with vigorous stirring over a period of 30 minutes. The reaction mixture was stirred at 0° C. for 1 h and then the mixture was allowed to warm to room temperature. The mixture was stirred at room temperature for 2 h before it was quenched with ice water (500 mL). The mixture was extracted with EtOAc (3*) and the extracts were washed with sat. NaHCO3 and dried over anhydrous Na2SO4. The solvent was removed in vacuo to afford an oily residue. The residue was dissolved in THF (60 mL) and the solution was cooled to 0° C. To this mixture was added a cold (0° C.) solution of sat. NH3 (50 mL) in MeOH portion-wise at such a rate that the internal reaction temperature was maintained below 10° C. After the addition was complete, the mixture was allowed to warm to room temperature and was stirred for 1 h. The solvent was removed in vacuo and the residue was dissolved in saturated aqueous sodium bicarbonate (60 mL) and washed with diethyl ether (80 mL). The aqueous layer was acidified with concentrated HCl to pH to 1. The resulting precipitate was collected by filtration and was dried in vacuo to afford 6-bromo-1,1-dioxo-1,2-dihydro-1λ6-benzo[d]isothiazol-3-one (2.1 g, 9percent yield). 1H NMR (300 MHz, CDCl3) δ 8.18 (d, J=1.8, 1H), 8.03 (dd, J=8.1, 1.8, 1H), 7.79 (d, J=8.1, 1H).
Reference：
[1] Patent: US2011/98311, 2011, A1,
4
[ 52727-57-8 ]
[ 21440-97-1 ]
Reference：
[1] Journal of Medicinal Chemistry, 2005, vol. 48, # 16, p. 5092 - 5095
5
[ 134-20-3 ]
[ 52727-57-8 ]
Yield
Reaction Conditions
Operation in experiment
90%
With bromine In tetrachloromethane
1. Add carbon tetrachloride (100 mL) and methyl 2-aminobenzoate (149 mmol) to a 250 mL four-necked flask.The stirring was started, and bromine (156.45 mmol) was added dropwise. After the addition was completed, the sample was followed by HPLC to follow the reaction.After the reaction was completed, the reaction solution was filtered, and the filter cake was rinsed with 200 mL of isopropyl ether and dried.A yellow solid was obtained with a purity of 96.5percent and a yield of 90percent.
78%
With acetic acid; potassium bromide In water at 30℃; for 1 h;
302 mg (2 mmol) of methyl anthranilate,143 mg (1.2 mmol) of potassium bromide was added to a 50 ml three-necked flask,Then add AcOH: H2O = 9: 1 10ml solvent, transferred to constant temperature magnetic stirring water bath, control the good temperature of 30 The reaction was stirred for 1 hour, and 1.8 g (1.8 mmol) of ZnAl-BrO3-LDHs was added slowly in portions 15 minutes before the reaction. Reaction knot After the mixture was extracted with methylene chloride, the reaction mixture was extracted and the organic phases were combined. A solution of silica gel (200-300 mesh) and the dichloromethane was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1 as elution ) To give a pure product, 359 mg. The material was an off-white solid with a yield of 78percent.
Reference：
[1] Patent: CN108164469, 2018, A, . Location in patent: Paragraph 0100; 0101
[2] Patent: CN107089919, 2017, A, . Location in patent: Paragraph 0052; 0053; 0054; 0055
[3] Synthetic Communications, 2007, vol. 37, # 4, p. 581 - 585
[4] Organic and Biomolecular Chemistry, 2017, vol. 15, # 21, p. 4644 - 4654
6
[ 77-78-1 ]
[ 5794-88-7 ]
[ 52727-57-8 ]
Yield
Reaction Conditions
Operation in experiment
56%
With triethylamine In N,N-dimethyl-formamide at 20℃; for 48 h;
Step a: Methyl 2-amino-5-bromobenzoate MeSO4 (26.3 mL, 0.280 mol) was added to a solution of 2-amino-5-bromobenzoic acid (50.0 g, 0.230 mol) in DMF and Et3N (40 mL, 0.28 mol). The reaction mixture was stirred at rt for 48 h. The mixture was quenched with water, extracted with EtOAc and dried over MgSO4. The solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel (5percent EtOAc in petroleum ether) to afford methyl 2-amino-5-bromobenzoate (30 g, 56percent yield). 1H NMR (300 MHz, DMSO) δ 7.74 (d, J=2.7, 1H), 7.35 (dd, J=9.0, 2.1, 1H), 6.78-6.73 (m, 3H), 3.77 (s, 3H).
56%
With triethylamine In N,N-dimethyl-formamide at 20℃; for 48 h;
MeSO4 (26.3 mL, 0.280 mol) was added to a solution of 2-amino-5-bromobenzoic acid (50.0 g, 0.230 mol) in DMF and Et3N (40 mL, 0.28 mol). The reaction mixture was stirred at rt for 48 h. The mixture was quenched with water, extracted with EtOAc and dried over MgSO4. The solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel (5percent EtOAc in petroleum ether) to afford methyl 2-amino-5-bromobenzoate (30 g, 56percent yield). 1H NMR (300 MHz, DMSO) δ 7.74 (d, J=2.7, 1H), 7.35 (dd, J=9.0, 2.1, 1H), 6.78-6.73 (M, 3H), 3.77 (s, 3H).
The commercially available material 2-amino-5-bromobenzoic acid (G-0) (0.2g, 0.93mmol) was dissolved in methanol (10mL) and concentrated H2SO4 (0.2ml, 3.72mmol) was slowly added. The reaction mixture was refluxed for 6h. After cooling, the solvent was evaporated mostly under reduced pressure and then aqueous NaHCO3 was used to adjust the pH to 9–10. The residue was extracted with ethyl acetate (3×20mL) and then the combined organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was recrystallized from ethyl acetate and petroleum ether or purified by column chromatography using ethyl acetate and petroleum ether (1:8) as an eluent to give G-1 as white solid. yield 90.8percent, mp: 64–65°C 1H NMR (400MHz, d6-DMSO) δ 7.77 (s, 1H, PH-H), 7.38 (d, J=8.6Hz, 1H, Ph-H), 6.82 (s, 2H, NH2-H), 6.77 (d, J=8.9Hz, 1H, Ph-H), 3.80 (s, 3H, CH3-H). 13C NMR (100MHz, d6-DMSO) δ 167.14, 150.86, 136.90, 132.76, 119.37, 110.65, 105.22, 52.15
76%
Stage #1: for 72 h; Reflux
2-Amino-5-bromobenzoic acid (8Og, 0.37mmol) was dissolved in MeOH (600 ml.) and a solution of H2SO4 (50 ml.) was slowly added. The reaction mixture was refluxed for 72 h, then concentrated. NaOH solution was added to adjust the pH to 10-11. The mixture was extracted with EtOAc (3 x 500 ml_). The combined organic layer was dried over MgSO4, concentrated to afford the desired compound (65 g, yield: 76 percent) as a colorless oil, which is used directly in the next step without purification.
76%
Stage #1: for 72 h; Reflux
Example 8D: 2-Amino-5-bromo-/V-methylbenzamide2-Amino-5-bromobenzoic acid (80 g, 0.37 mol) was dissolved in MeOH (600 mL) and cone. H2S04 (50 mL) was slowly added. The reaction mixture was refluxed for 72 h, then concentrated. NaOH solution was added to adjust the pH to 10-1 1 . The mixture was extracted with EtOAc (3 χ 500 mL). The combined organic layer was dried over MgS04, concentrated to afford the desired compound (65 g, yield: 76 percent) as a colorless oil, which is used directly in the next step without purification. A mixture of methyl 2-amino-5-bromobenzoate and CH3NH2.H2O (1000 mL) was stirred at 80 C overnight in a pressure tube. The mixture was diluted with H20 (1000 mL) and extracted with EtOAc (3 χ 500 mL). The combined organic layers were dried over MgS04, concentrated to afford the title compound (55 g, yield: 87 percent) as a gray solid. 1H NMR (CDCI3, 400 MHz): δ 2.93 (d, J = 5.2 Hz, 3H), 5.48 (s, br, 2H), 6.04 (s, br, 1 H), 6.54 (d, J == 2.0, 8.4 Hz, 1 H), 7.38 (d, J = 2.0 Hz, 1 H).
Reference：
[1] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 20, p. 5779 - 5789
[2] Patent: WO2010/141406, 2010, A2, . Location in patent: Page/Page column 97
[3] Patent: WO2012/74951, 2012, A1, . Location in patent: Page/Page column 50-51
[4] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 13, p. 3574 - 3577
[5] Chemistry of Heterocyclic Compounds, 2006, vol. 42, # 1, p. 64 - 69
[6] Journal of Heterocyclic Chemistry, 2010, vol. 47, # 2, p. 415 - 420
[7] Journal of Medicinal Chemistry, 2013, vol. 56, # 21, p. 8332 - 8338
[8] European Journal of Medicinal Chemistry, 2014, vol. 76, p. 343 - 351
8
[ 5794-88-7 ]
[ 52727-57-8 ]
Yield
Reaction Conditions
Operation in experiment
56%
With triethylamine In ethyl acetate; N,N-dimethyl-formamide; Petroleum ether
Step a: Methyl 2-amino-5-bromobenzoate MeSO4 (26.3 mL, 0.280 mol) was added to a solution of 2-amino-5-bromobenzoic acid (50.0 g, 0.230 mol) in DMF and Et3N (40 mL, 0.28 mol). The reaction mixture was stirred at rt for 48 h. The mixture was quenched with water, extracted with EtOAc and dried over MgSO4. The solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel (5percent EtOAc in petroleum ether) to afford methyl 2-amino-5-bromobenzoate (30 g, 56percent yield). 1H NMR (300 MHz, DMSO) δ 7.74 (d, J=2.7, 1H), 7.35 (dd, J=9.0, 2.1, 1H), 6.78-6.73 (m, 3H), 3.77 (s, 3H).
Reference：
[1] Bulletin de la Societe Chimique de France, 1911, vol. <4> 9, p. 605[2] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1910, vol. 150, p. 1179
18
[ 52727-57-8 ]
[ 39263-32-6 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2014, vol. 76, p. 343 - 351
19
[ 52727-57-8 ]
[ 29124-57-0 ]
Reference：
[1] Journal of Medicinal Chemistry, 2011, vol. 54, # 16, p. 5836 - 5857
20
[ 52727-57-8 ]
[ 16313-66-9 ]
Yield
Reaction Conditions
Operation in experiment
11%
With ammonia In methanol at 20℃; for 336 h; Inert atmosphere
Methyl 2-amino-5-bromobenzoate (1 equiv) was added to a solution of NH3 in MeOH (7 M, 10 equiv) under a N2 atmosphere. The reaction mixture was stirred for 2 weeks at room temperature. After evaporation of the solvent the remaining solid was purified by CC (n-hexane/EtOAc 1:1) to provide the pure compound; white solid, yield: 11percent. 1H NMR (500 MHz, DMSO-d6) δ = 7.84 (br. s., 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.25 (dd, J = 8.8, 2.3 Hz, 1H), 7.22-7.09 (m, 1H), 6.70 (s, 2H, NH2), 6.66 (d, J = 8.8 Hz, 1H) ppm. 13C NMR (125 MHz, DMSO-d6) δ = 169.9, 149.4, 134.3, 130.8, 118.5, 115.2, 104.7 ppm. LC/MS: m/z = 215 and 217 [M + H+], 198 and 200 [M+ - NH2]; tR = 6.65 min; 97.0percent pure (UV).
Reference：
[1] Journal of Medicinal Chemistry, 2007, vol. 50, # 10, p. 2297 - 2300
[2] Patent: WO2012/87938, 2012, A1,
[3] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 21, p. 4904 - 4907
[4] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 24, p. 6680 - 6694
[5] Patent: WO2009/143058, 2009, A1,
27
[ 52727-57-8 ]
[ 99767-45-0 ]
Reference：
[1] Journal of Medicinal Chemistry, 2017, vol. 60, # 21, p. 8858 - 8875
28
[ 52727-57-8 ]
[ 159847-81-1 ]
Yield
Reaction Conditions
Operation in experiment
85%
With zinc(II) cyanide In DMF (N,N-dimethyl-formamide) at 90 - 100℃; for 8 h;
Methyl 2-amino-5-bromobenzoate (24.0 g, 104 mmol), zinc cyanide (8.02 g, 68.3 mmol), and Pd (PPh3) 4 (2.02 g) were weighed into a three-necked flask, which was then purged with nitrogen. After adding DMF (130 mL), the reaction mixture was stirred in a hot oil bath [(90°C)] for 8 h. Because TLC revealed no change during the last 3 h, additional catalyst (2.00 g) was added and stirred in the hot oil bath overnight. Additional catalyst (1.00 g) and heating at [100°C] was required to drive reaction to near completion. Reaction was poured into water (400 mL), extracted with EtOAc (700 mL), and the two-phase mixture filtered. The organic layer was removed, washed with saturated brine (4 x 200 mL), dried, filtered, and evaporated on to silica gel, and applied to a column of silica gel. Elution was effected using 4: 1 [HEPTANE/ETOAC] to give 15.60 g (yield of 85percent) of the methyl 5-cyanoanthranilate as a pale yellow solid. [APOS;H NMR] (300 MHz, [CDC13)] 8 8.19 (d, [1H),] 7.45 (dd, 1H), 6.68 (d, 1 H),-6. 3 (very [BRS),] 3.90 (s, [3H).]
Stage #1: for 5 h; Heating / reflux Stage #2: With hydrogenchloride; iron(III) chloride In 1-methyl-pyrrolidin-2-one; water at 60℃; for 1 h;
a. 2-AMINO-5-CYANO-BENZOIC acid methyl ester A mixture of 2-amino-5-bromo-benzoic acid methyl ester (5.00 g, 21.7 mmol) and CUCN (2.34 g, 26.1 mmol, 2.0 M) in 25 ml OF NMP was stirred at reflux for 5 h, then cooled to rt. The mixture was poured into a solution of hydrated FeCl3 (15 g of FeCl3. 6H20) and conc. HC1 (2.2 ml) in 15 ml of H20. The resulting mixture was stirred at 60 °C for 1 h, cooled to rt. Treated with 200 ml of EtOAc, the mixture was washed with H20 (40 ml), 1N NAOH (3X30 ml), brine (30 ml) and dried (NA2SO4). Removal of the solvent under reduced pressure gave a slightly dark solid. Recrystalization of the solid in HEXANES/DCM/ETOAC yielded 3.25 g (85 percent) of product as a yellow solid : H-NMR (CDCl3 ; 400 MHz) 8 8.20 (d, 1H, J= 1.9 Hz), 7.45 (dd, 1 H, J = 8.9, 1.9 Hz), 6.67 (d, 1H, J = 8.9 Hz), 6.29 (br s, 2H), 3.90 (s, 3H). Mass spectrum (ESI, m/z) : Calcd. for C9H8N202, 177.1 (M+H), found 177.2.
52%
at 200℃; Heating / reflux
A mixture of methyl 2-amino-5-bromobenzoate [(50G,] [217MMOL)] and [CUCN] [(19.] 7g, [220MMOL)] in [200ML] of N-methyl-2-pyrrolidinone are stirred at reflux [(-200OC)] for overnight, and cooled to room temperature. The dark mixture is slowly added to [1800ML] of Et20 with vigorous stirring. Dark sticky oil at the bottom is discarded and the upper cloudy solution (2000ml) is washed consecutively with brine [(200ML),] 1M [NAOH] [(200ML)] and brine [(2X200ML),] dried over [NA2S04,] then evaporated to dryness to [GIVE-20G] of yellow solids, methyl 2-amino-5-cyanobenzoate. Yield for crude product: [52percent.]
Copper(I) cyanide (available from Alfa Aesar; 10.71 g, 0.12 mol) was added to a stirred solution of methyl 2-amino-5-bromobenzoate (available from Aldrich Chemical Company, Inc.; 25.0 g, 0.11 mol) in N-methyl-2-pyrrolidone (50 mL) and the mixture was stirred at 180° C. for 4 h. The reaction mixture was cooled to room temperature, diluted with aqueous ethylenediamine (water:ethylenediamine=1:1; 250 mL), and filtered through pad of Celite. The filtrate was extracted with EtOAc (3*100 mL), and the combined organic layers were washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, filtered, evaporated under reduced pressure, and purified by silica gel chromatography (100-200 mesh), using 5-10percent ethyl acetate/hexanes as eluent, to give 2-amino-5-cyanobenzoic acid methyl ester (14.0 g, 73percent) as a yellow powder. 1H NMR (400 MHz, DMSO-d6) δ 8.05 (d, J=1.9 Hz, 1H), 7.57 (dd, J=1.9, 8.8 Hz, 1H), 7.44 (br s, 2H), 6.88 (d, J=8.8 Hz, 1H), 3.81 (s, 3H).
Reference：
[1] Patent: CN108164469, 2018, A, . Location in patent: Paragraph 0103; 0104
[2] Patent: US2013/79346, 2013, A1, . Location in patent: Paragraph 0277-0278
[3] Angewandte Chemie - International Edition, 2013, vol. 52, # 40, p. 10593 - 10597[4] Angew. Chem., 2013, vol. 125, # 40, p. 10787 - 10791
[5] Journal of Medicinal Chemistry, 2017, vol. 60, # 21, p. 8858 - 8875
31
[ 52727-57-8 ]
[ 20712-12-3 ]
Yield
Reaction Conditions
Operation in experiment
59%
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 2 h; Inert atmosphere Stage #2: With water; sodium hydroxide In tetrahydrofuran
To a suspension of lithium aluminium hydride (0.33 g, 8.7 mmol) in THF (10 ml) was added a solution of methyl 2-amino-5-bromobenzoate (2.0 g, 8.7 mmol) in 20 ml THF at 0° C. under nitrogen. Then stirring was continued for 2 h. 0.64 ml water, 2 M solution of sodium hydroxide (0.64 ml) and again 1.28 ml water were added before the resulting mixture was filtered through celite. Evaporation of the solvent and purification of the crude product by flash chromatography on silica gel (dichloromethane/ethyl acetate, 2/1) yielded (2-amino-5-bromophenyl)methanol (1.0 g, 5.2 mmol, 59percent) as off-white solid.
59%
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 2 h; Inert atmosphere Stage #2: With water; sodium hydroxide In tetrahydrofuran
To a suspension of lithium aluminium hydride (0.33 g, 8.7 mmol) in THF (10 ml) was added a solution of methyl 2-amino-5-bromobenzoate (2.0 g, 8.7 mmol) in 20 ml THF at 0 0C under nitrogen. Then stirring was continued for 2 h. 0.64 ml water, 2 M solution of sodium hydroxide (0.64 ml) and again 1.28 ml water were added before the resulting mixture was filtered through celite. Evaporation of the solvent and purification of the crude product by flash chromatography on silica gel (dichloromethane/ethyl acetate, 2/1) yielded (2-amino-5- bromophenyl)methanol (1.0 g, 5.2 mmol, 59 percent) as off-white solid.
Reference：
[1] Tetrahedron Letters, 2002, vol. 43, # 7, p. 1171 - 1174
[2] Journal of Organic Chemistry, 2014, vol. 79, # 3, p. 1235 - 1246
[3] Patent: WO2007/115408, 2007, A1, . Location in patent: Page/Page column 136
[4] Organic Letters, 2016, vol. 18, # 21, p. 5572 - 5575
[5] Patent: US2011/112067, 2011, A1, . Location in patent: Page/Page column 33; 34
[6] Patent: WO2009/135651, 2009, A1, . Location in patent: Page/Page column 51
[7] Patent: WO2006/50940, 2006, A1, . Location in patent: Page/Page column 59-60
[8] Patent: WO2009/7749, 2009, A2, . Location in patent: Page/Page column 108
[9] Journal of Organic Chemistry, 2010, vol. 75, # 4, p. 1188 - 1196
[10] Organic Letters, 2010, vol. 12, # 5, p. 1084 - 1087
[11] Patent: WO2006/50943, 2006, A1, . Location in patent: Page/Page column 45
[12] Patent: WO2011/19090, 2011, A1, . Location in patent: Page/Page column 47-48
[13] European Journal of Medicinal Chemistry, 2014, vol. 90, p. 788 - 796
Reference：
[1] Journal of Medicinal Chemistry, 2007, vol. 50, # 10, p. 2297 - 2300
[2] Patent: WO2012/87938, 2012, A1,
34
[ 52727-57-8 ]
[ 289039-83-4 ]
Yield
Reaction Conditions
Operation in experiment
82%
at 20℃; for 17 h;
Example S9; Preparation of 5-bromo-1H-indole-7-carboxylic acid; 371 mg of 2-amino-5-bromo-benzoic acid methyl ester (2 mmol) was dissolved in 2 ml conc acetic acid and treated with 495 mg of N-iodosuccinimide (2.2 mmol) at rt for 17 h. The reaction mixture was then poured on 5 ml saturated sodium bicarbonate solution and ice, extracted twice with EtOAc. The combined organic phases were then washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo, leading to 585 mg 2-amino-5-bromo-3-iodo-benzoic acid methyl ester (82percent) as a light brown solid. MS (EI) 354.9 (M)+.
7.49 g
at 20℃; Inert atmosphere
To a stirring of solution of methyl 2-amino-5-bromobenzoate (5 g, 21.73 mmol) in TFA(20 mL, 260 mmol) is added NIS (4.99 g, 22.17 mmol) in one portion. After I h, the reactionmixture is concentrated under reduced pressure. The residue is dissolved in EtOAc and washedsequentially with saturated Na2CO3 solution (2x), 10percent aq. sodium dithionite (2x) and brine (lx),dried over Na2504,filtered and concentrated to give the title compound (7.47 g, 18.89 mmol,90percent purity) as a dark brown solid. LCMS (ES API) MH+ = 356 & 358 for Br isotopes.
Stage #1: at 20℃; for 17 h; Inert atmosphere Stage #2: at 20℃; for 1.5 h; Inert atmosphere
463.5 mg of methyl 5-bromoanthranilate was placed in an argon atmosphere and dissolved in 2 mL of acetic acid. 499.5 mg of N-iodosuccinimide was added thereto, and the mixture was stirred at room temperature for 17 hours. The reaction solution was added dropwise to a saturated aqueous sodium hydrogen carbonate solution (5 mL) to neutralize acetic acid. This was extracted with ethyl acetate, and the ethyl acetate phase obtained was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and ethyl acetate was distilled off under reduced pressure.The obtained material was placed in an argon atmosphere and dissolved in 6.6 mL of triethylamine. 74.2 mg of bis (triphenylphosphine) palladium (II) dichloride, 22.3 mg of copper (I) iodide and 0.34 mL of trimethylsilylacetylene were added thereto, and the mixture was stirred at room temperature for 90 minutes. The reaction solution was diluted with dichloromethane, washed sequentially with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.The obtained substance dissolved in 9 mL of N-methyl-2-pyrrolidone was added dropwise to a mother liquor in which 512.3 mg of potassium tert-butoxide was changed to 0 ° C. under an argon atmosphere and 7 mL of N-methyl-2-pyrrolidone was added , Stirred for 1 hour, and then stirred at room temperature for 90 minutes. The reaction solution was again brought to 0 ° C., 32 mL of water was added, and the temperature was returned to room temperature. The diethyl ether phase extracted with diethyl ether was washed with water, saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, And the solvent was distilled off. The residue was dissolved in methanol, the insoluble matter was removed by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography using 10percent ethyl acetate / hexane as a developing solvent, and the solvent was distilled off .62.5 mg of the obtained substance was placed under an argon atmosphere, 2 N sodium hydroxide 2.4 mL and 2.4 mL ethanol were added and the temperature was adjusted to 40 ° C. and stirred for 2 hours. The reaction solution was brought to room temperature, the pH was made acidic using 3 N hydrochloric acid, sodium chloride was added until saturation, and the ethyl acetate phase eluted with ethyl acetate was dried with anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, it was suspended in diethyl ether, the brown solids in the insoluble matter was removed, and the remaining insoluble matter was washed with warm hexane. The solvent was distilled off, dissolved in ethyl acetate, activated charcoal was added to adsorb impurities, and the activated carbon was removed by filtration. The residue obtained by distilling off the solvent was dissolved in diethyl ether, the insoluble matter was removed by filtration, and the solvent was distilled off. As a result, 54.2 mg (yield 11.3percent) of a compound was obtained.
Reference：
[1] Patent: JP2018/52865, 2018, A, . Location in patent: Paragraph 0039
37
[ 52727-57-8 ]
[ 860624-90-4 ]
Reference：
[1] Patent: WO2016/87975, 2016, A1,
38
[ 52727-57-8 ]
[ 1196155-68-6 ]
Reference：
[1] Journal of Medicinal Chemistry, 2011, vol. 54, # 16, p. 5836 - 5857
39
[ 52727-57-8 ]
[ 1220418-77-8 ]
Reference：
[1] Journal of Medicinal Chemistry, 2011, vol. 54, # 16, p. 5836 - 5857
Compound 25 (10 g, 43.5 mmol) and NaOH (5.2 g, 130.4 mmol) were dissolved in H20 (60 mL), CH3CH2OH (60 mL) and THF (180 mL). The reaction mixture was stirred for 12 hours at room temperature. The organic solvent was removed in vacuo. The mixture was then extracted with ethyl acetate (2 xlOO mL). The water layer was neutralized with 1 N HC1 (till pH=4) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were concentrated under vacuum resulting in compound 26 (9.1 g, 97 % yield).
97%
With water; sodium hydroxide; In tetrahydrofuran; ethanol; at 20℃; for 12h;
12460] A solution of compound 69-3 (10.0 g, 43.5 mmol) and NaOH (5.20 g, 130.4 mmol) in H20 (60.0 mE), EtOH (60.0 mE) and THF (180 mE) was stirred at rt for 12 hrs. After the reaction was completed, the solvent was removed. The residue was extracted with EtOAc (100 mEx2). The aqueous phase was adjusted to pH 4 with hydrochloric acid (1 M) and extracted with EtOAc (25 mEx3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound 69-4 (9.1 g, 97%). The compound was characterized by the following spectroscopic data:12461] MS (ESI, pos.ion) mlz: 216.5 [M+H]12462] ?H NMR (400 MHz, CDC13) oe (ppm): 8.03 (d, 1H),7.34, 7.31 (d, d, 1H), 6.97 (brs, 3H), 6.86, 6.84 (d, d, 1H).
72%
With water; sodium hydroxide; In tetrahydrofuran; at 60℃;Inert atmosphere; Sealed tube;
To a solution of compound 28-6 (2.1 g, 9.17 mmol) in THF (20 mL) was added a aqueous solution of NaOH (2.1 g, 20 mL). At the end of the addition, the mixture was stirred at 60 C overnight. After the reaction was completed, the THF solvent was removed. The residue was dissolved in EtOAc (50 mL) and washed with water (50 mL x 3). The combined aqueous phase was adjusted to pH 4 with hydrochloric acid (1 M) and the solid was precipitated. The resulting mixture was filtered to give the title compound as a pale yellow solid (1.42 g, 72%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 217 [M+H] +; and ln NMPv (400 MHz, CDC13) delta (ppm): 7.59 (d, 1H, J= 8.0 Hz), 6.96 (d, 1H, J= 1.6 Hz), 6.64 (dd, 1H, J= 8.0 Hz, 2.0 Hz).
72%
With water; sodium hydroxide; In tetrahydrofuran; at 60℃;
(2.1 g, 9.17 mmol) in THF (20.0 mL) was added a aqueous solution of NaOH (2.1 g.20.0 mL). At the end of the addition, the mixture was stirred at 60 C overnight. After the reaction was completed, the solvent was removed. The residue was dissolved in EtOAc (50 mL) and extracted with water (50 mL x 3). The combined aqueous phase was adjusted to pH 4 with hydrochloric acid (1M) and the solid was precipitated. The resulting mixture was filtered to give the title compound as a yellow solid ( 1.4 g.72%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 217 [M+H] ": and NMR (400 MHz. CDC 1.0 delta (ppm): 7.59 (d, 1H, J= 8.0 Hz).6.96 (d, 1H, J= 1.6 Hz), 6.64 (dd.1H. J = 8.0 Hz, 2.0 Hz).
72%
With sodium hydroxide; In tetrahydrofuran; water; at 60℃;
To a solution of compound 24-1 (2.1 g, 9.17 mmol) in THF (20 mL) was added an aqueous NaOH solution (2.1 g, 20 mL) and the mixture was stirred at 60 C overnight. After the mixture was completed, the THF was removed in vacuo. The residue was dissolved in EtOAc (50 mL) and the solution was extracted with water (50 mL x 3). The combined aqueous layers were acidified with aqueous HC1 (1 M) till pH = 4 and solid precipitated out. The mixture was filtered to afford the title compound as a pale yellow solid (1.4 g, 72%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 217 [M+H]+; and lli NMR (400 MHz, CDC13): delta 7.59 (d, IH, J= 8.0 Hz), 6.96 (d, IH, J= 1.6 Hz), 6.64 (dd, IH, J= 8.0 Hz, 2.0 Hz) ppm.
To a suspension of lithium aluminium hydride (0.33 g, 8.7 mmol) in THF (10 ml) was added a solution of methyl 2-amino-5-bromobenzoate (2.0 g, 8.7 mmol) in 20 ml THF at 0° C. under nitrogen. Then stirring was continued for 2 h. 0.64 ml water, 2 M solution of sodium hydroxide (0.64 ml) and again 1.28 ml water were added before the resulting mixture was filtered through celite. Evaporation of the solvent and purification of the crude product by flash chromatography on silica gel (dichloromethane/ethyl acetate, 2/1) yielded (2-amino-5-bromophenyl)methanol (1.0 g, 5.2 mmol, 59percent) as off-white solid.
59%
To a suspension of lithium aluminium hydride (0.33 g, 8.7 mmol) in THF (10 ml) was added a solution of methyl 2-amino-5-bromobenzoate (2.0 g, 8.7 mmol) in 20 ml THF at 0 0C under nitrogen. Then stirring was continued for 2 h. 0.64 ml water, 2 M solution of sodium hydroxide (0.64 ml) and again 1.28 ml water were added before the resulting mixture was filtered through celite. Evaporation of the solvent and purification of the crude product by flash chromatography on silica gel (dichloromethane/ethyl acetate, 2/1) yielded (2-amino-5- bromophenyl)methanol (1.0 g, 5.2 mmol, 59 percent) as off-white solid.
a) (2-Amino-5-bromophenyl)methanol1.0M Lithium aluminium hydride in THF (175 ml_) was added to a solution of methyl 2- amino-5-bromobenzoate (40.37 g) in THF (400 ml_) by cannula at 00C under argon. EPO <DP n="61"/>Stirring was continued for 1 hour after addition. Water (6.4 ml_), 2M sodium hydroxide (6.4 ml_) and water (12.8 mL) were added sequentially and the resultant mixture stirred at 200C for 30 minutes before filtration through celite. The solution was evaporated and the residue crystallised from EtOAc/hexane to give the title compound as a white solid (18.5 g); ESMS m/z 202.1 [M+H]+.
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 25℃; for 1.16667h;
(2-Amino-5-bromo-phenyl)methanol Methyl-2-amino-5-bromobenzoate (1 g) was dissolved in THF (20 mL) and cooled to O0C. Lithium aluminium hydride (8.7 mL, IM solution in THF) was added slowly to the solution over 10 minutes then the reaction allowed to warm room temperature and stirred for a further 1 hour. The reaction was quenched with water, filtered and concentrated in vacuo. The residue was chromatographed on silica, eluting with 2.5percent methanol in DCM, to give the desired material (394 mg) as a white solid.NMR Spectrum: (DMSOd6) 54.35 (2H, d), 5.05 (2H, s), 5.10 (IH, t), 6.58 (IH, d), 7.07 - 7.10 (IH, m), 7.22 (IH, d) Mass Spectrum; M-H+ 200.
) (2-Amino-5-bromophenyl)methanol; 1.0M Lithium aluminium hydride in THF (175 mL, 175 mmol) was added to a solution of 2- amino-5-bromobenzoic acid methyl ester (40.37 g, 175 mmol) in THF (400 mL) by cannula at 00C under argon. Stirring was continued for 1 hour after addition. Water (6.4 mL), 2M sodium hydroxide (6.4 mL) and water (12.8 mL) were added sequentially and the resultant mixture stirred at 20°C for 30 minutes before filtration through celite. The solution was evaporated and the residue crystallised from ethyl acetate/hexane to give the title compound as a white solid (18.50 g); ESMS m/z 202.1 [M+H]+.
(l) To a mixture of lithium aluminum hydride (2.6 g, 69 mmol) in diethyl ether (54 ml) was added dropwise 5-bromoanthranillic acid methyl ester (6.3 g, 27 mmol) in diethyl ether (54 ml) at Ot). The mixture was stirred at O1C for 3 hours. Then water (2.6 ml), 15 wtpercent aqueous solution of sodium hydroxide (2.6 ml) and water (7.8 ml) was addedsequentially at O1C. The mixture was filtrated through a pad of Celite, and concentrated in vacuo. The residue was dissolved into tetrahydrofuran (160 ml), and triethylamine (15 g, 150 mmol) was added. The mixture was cooled to Ot, and trichloromethyl chloroformate (2.9 g, 15 mmol) was added. The mixture was stirred at room temperature for 4 hours. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford crude product. This crude product was washed with diethyl ether to afford6-bromo-l,4-dihydro-2H"3,l-benzoxazin-2-one as a colorless solid (4.7g, 21 mmol, 77percent).
Stage #1: 4,5-dichloro-1,2,3-dithiazolium chloride; 5-bromo-2-aminobenzoic acid methyl ester In dichloromethane at 20℃; for 0.5h; Inert atmosphere;
Stage #2: With pyridine In dichloromethane at 20℃; for 2h;
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃; for 0.5h;
Step 1: Synthetic route for the preparation of compound 5a isshown in Scheme 2. The reaction vessel was charged with methyl 2-amino-5-bromo-benzoate (200 mg), phenylboronic acid (106 mg),Na2CO3 (276.40 mg) and Pd(PPh3)4 (100.46 mg). 1,4-dioxane (3 mL) and water (1 mL) were added. The reaction vessel was sealed, vacuumed,backfilled with argon and submitted to microwave irradiationfor 30 min at 100 C. The reaction mixture was diluted with water andextracted with DCM. Organic layers were combined, dried over sodiumsulphate, filtered and evaporated under reduced pressure to obtaincrude product. Crude product was purified by flash chromatography onsilica column. The gradient was set to 0-50% EtOAc/cyclohexane in 25CVs. Appropriate fractions were combined and evaporated under reducedpressure to obtain intermediate 5i; methyl 2-amino-5-phenylbenzoatein 82% yield, purity 95% by UPLC (UV, 254 nm). Step 2:Methyl 2-amino-5-phenyl-benzoate (5i) (200 mg) was dissolved in dryDMF (2 mL). The reaction mixture was cooled to 0 C, methylimino(oxo)methane (106 mg) was added and allowed to slowly warm to roomtemperature. After 3 h, the reaction was diluted with water and extractedwith EtOAc. Organic layers were combined, dried over sodiumsulphate, filtered and evaporated under reduced pressure to obtaincrude product. Crude product was purified by flash chromatography onsilica column. The gradient was set to 0-50% EtOAc/cyclohexane in 25CVs. Appropriate fractions were combined and evaporated under reducedpressure to obtain intermediate 5ii methyl 2-(methylcarbamoylamino)-5-phenyl-benzoate in 77% yield, purity 75% by UPLC (UV,254 nm). Step 3: Methyl 2-(methylcarbamoylamino)-5-phenylbenzoate(5ii) (20 mg) was dissolved in NaOEt, 20% solution inethanol. Reaction mixture was heated to 60 C. After 3 h reaction mixturewas cooled to room temperature, diluted with water and extractedwith DCM. Organic layers were combined, dried over sodium sulphate,filtered and evaporated under reduced pressure to obtain crude product.Crude product was purified by flash chromatography using silicacolumn. Gradient was set 0-50% EtOAc/cyclohexane in 25 CVs. Appropriatefractions were combined and evaporated under reducedpressure to obtain product 5a, 3-methyl-6-phenyl-1H-quinazoline-2,4-dione in 73% yield, purity 95% by UPLC (UV, 254 nm).
76%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; at 100℃; for 6h;Inert atmosphere;
to with magnetic rotor and the condensation of the 100 ml dry three-mouth bottle is sequentially added in the intermediate 4 (6.90 g, 30 mmol, 1.0 equivalent), phenyl boronic acid (3.84 g, 31.5 mmol, 1 . 05 equivalent), four (triphenylphosphine) palladium (Pd (PPh3)4) (1.04 G, 0.9 mmol, 0 . 03 equivalent), K2CO3(8.29 G, 60 mmol, 2.0 equivalent), replacing the nitrogen three times, under the protection of nitrogen added to the 1, 4 - dioxane (30 ml) and H2O (15 ml). The oil bath temperature is raised to 100 C stirring reaction 6.0 hours, cooling to room temperature, for 30 ml ethyl acetate extraction three times, using anhydrous Na2SO4Drying the organic phase, then filtered, distilled under reduced pressure, the solvent is removed, dry sample, using silica gel column chromatography column to carry out the separation and purification, eluent petroleum ether/ethyl acetate=20 is: 1, to obtain white solid 4.81 g, yield 76%.
76%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 100℃; for 6h;Inert atmosphere;
Intermediate 4 (6.90 g, 30 mmol, 1.0 eq.) was added sequentially to a 100 mL dry three-necked flask with a magnetic rotor and a condensing tube.Phenylboronic acid (3.84 g, 31.5 mmol, 1.05 equivalent),Tetrakis(triphenylphosphine)palladium (Pd(PPh3)4) (1.04 g, 0.9 mmol, 0.03 equivalent),K2CO3 (8.29g, 60mmol, 2.0 equivalents),Swap three times with nitrogen, was added 1,4-dioxane (30mL) and H2O (15mL) under nitrogen.The temperature of the oil bath was raised to 100 C, and the reaction was stirred for 6.0 hours, and cooled to room temperature.Extracted three times with 30mL of ethyl acetate, the organic phase dried over anhydrous Na2SO4, then filtered and evaporated under reduced pressure to remove theThe solvent was dry loaded onto a silica gel column chromatography for separation and purification by column chromatography, eluting with petroleum ether / ethyl acetate = 20: 1,4.81 g of a white solid were obtained in a yield of 76%.
The commercially available material 2-amino-5-bromobenzoic acid (G-0) (0.2g, 0.93mmol) was dissolved in methanol (10mL) and concentrated H2SO4 (0.2ml, 3.72mmol) was slowly added. The reaction mixture was refluxed for 6h. After cooling, the solvent was evaporated mostly under reduced pressure and then aqueous NaHCO3 was used to adjust the pH to 9-10. The residue was extracted with ethyl acetate (3×20mL) and then the combined organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was recrystallized from ethyl acetate and petroleum ether or purified by column chromatography using ethyl acetate and petroleum ether (1:8) as an eluent to give G-1 as white solid. yield 90.8%, mp: 64-65C 1H NMR (400MHz, d6-DMSO) delta 7.77 (s, 1H, PH-H), 7.38 (d, J=8.6Hz, 1H, Ph-H), 6.82 (s, 2H, NH2-H), 6.77 (d, J=8.9Hz, 1H, Ph-H), 3.80 (s, 3H, CH3-H). 13C NMR (100MHz, d6-DMSO) delta 167.14, 150.86, 136.90, 132.76, 119.37, 110.65, 105.22, 52.15
78%
With sulfuric acid; at 70℃; for 2h;
to with magnetic rotor and the condensation of the 500 ml dry three-mouth bottle is sequentially added in the 2 - amino -4 - bromo - benzoic acid (21.60 g, 100 mmol), methanol (300 ml), 98% H2SO4(80 Ml), the oil bath temperature is raised to 70 C reaction 2 days. Cooling to room temperature, and in the NaOH and to 6 - 7, then the extraction of ethyl acetate three times, using anhydrous Na2SO4Drying the organic phase, then filtering, reduced pressure distillation, to remove the solvent, then adding poor solvent hexane, recrystallized 2 times, then use the Buchner funnel the mixtures are filtered, to obtain the product 4, is a white solid 17.98 g, yield is 78%. Directly used for the next step reaction.
78%
With sulfuric acid; at 70℃; for 48h;
2-Amino-4-bromo-benzoic acid (21.60 g, 100 mmol) was added to a 500 mL dry three-necked flask with a magnetic rotor and a condenser.Methanol (300 mL), 98% H2SO4 (80 mL),The temperature of the oil bath was raised to 70 C for 2 days.It was cooled to room temperature and neutralized to 6-7 with NaOH, then extracted three times with ethyl acetate. The organic phase was dried over anhydrous Na 2SO Recrystallization 2 times, then the mixture was filtered using a Buchner funnel to give the product 4,It was 17.98 g of a white solid in a yield of 78%.Used directly in the next step.
76%
2-Amino-5-bromobenzoic acid (8Og, 0.37mmol) was dissolved in MeOH (600 ml.) and a solution of H2SO4 (50 ml.) was slowly added. The reaction mixture was refluxed for 72 h, then concentrated. NaOH solution was added to adjust the pH to 10-11. The mixture was extracted with EtOAc (3 x 500 ml_). The combined organic layer was dried over MgSO4, concentrated to afford the desired compound (65 g, yield: 76 %) as a colorless oil, which is used directly in the next step without purification.
76%
Example 8D: 2-Amino-5-bromo-/V-methylbenzamide2-Amino-5-bromobenzoic acid (80 g, 0.37 mol) was dissolved in MeOH (600 mL) and cone. H2S04 (50 mL) was slowly added. The reaction mixture was refluxed for 72 h, then concentrated. NaOH solution was added to adjust the pH to 10-1 1 . The mixture was extracted with EtOAc (3 chi 500 mL). The combined organic layer was dried over MgS04, concentrated to afford the desired compound (65 g, yield: 76 %) as a colorless oil, which is used directly in the next step without purification. A mixture of methyl 2-amino-5-bromobenzoate and CH3NH2.H2O (1000 mL) was stirred at 80 C overnight in a pressure tube. The mixture was diluted with H20 (1000 mL) and extracted with EtOAc (3 chi 500 mL). The combined organic layers were dried over MgS04, concentrated to afford the title compound (55 g, yield: 87 %) as a gray solid. 1H NMR (CDCI3, 400 MHz): delta 2.93 (d, J = 5.2 Hz, 3H), 5.48 (s, br, 2H), 6.04 (s, br, 1 H), 6.54 (d, J == 2.0, 8.4 Hz, 1 H), 7.38 (d, J = 2.0 Hz, 1 H).
With tetrabutylammomium bromide; copper(ll) bromide; In ethanol; at 45℃;
General procedure: A round bottom flask was charged with Bu4NBr (2 mmol, 0.64 g), EtOH (8 mL) and 2-methylaniline (2 mmol, 0.21 g) followed by CuBr2 (3 mmol, 0.67 g). The resulted mixture was stirred at 25 C. After the completion of the reaction (monitored by TLC), the solvent was evaporated under reduced pressure. To the residue was added ammonium hydroxide (5 mL, 25% w/v) and water (5 mL) with stirring, and the suspension was extracted with DCM(10 mL×4) The organic phase was washed with saturated brine and dried over anhydrous Na2SO4. The product 2b was obtained using flash chromatograph column eluted with PE : EA (5 : 1).
90%
With bromine; In tetrachloromethane;
1. Add carbon tetrachloride (100 mL) and methyl 2-aminobenzoate (149 mmol) to a 250 mL four-necked flask.The stirring was started, and bromine (156.45 mmol) was added dropwise. After the addition was completed, the sample was followed by HPLC to follow the reaction.After the reaction was completed, the reaction solution was filtered, and the filter cake was rinsed with 200 mL of isopropyl ether and dried.A yellow solid was obtained with a purity of 96.5% and a yield of 90%.
78%
With acetic acid; potassium bromide; In water; at 30℃; for 1h;
302 mg (2 mmol) of methyl anthranilate,143 mg (1.2 mmol) of potassium bromide was added to a 50 ml three-necked flask,Then add AcOH: H2O = 9: 1 10ml solvent, transferred to constant temperature magnetic stirring water bath, control the good temperature of 30 The reaction was stirred for 1 hour, and 1.8 g (1.8 mmol) of ZnAl-BrO3-LDHs was added slowly in portions 15 minutes before the reaction. Reaction knot After the mixture was extracted with methylene chloride, the reaction mixture was extracted and the organic phases were combined. A solution of silica gel (200-300 mesh) and the dichloromethane was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1 as elution ) To give a pure product, 359 mg. The material was an off-white solid with a yield of 78%.
With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 48h;
Step a: Methyl 2-amino-5-bromobenzoate MeSO4 (26.3 mL, 0.280 mol) was added to a solution of 2-amino-5-bromobenzoic acid (50.0 g, 0.230 mol) in DMF and Et3N (40 mL, 0.28 mol). The reaction mixture was stirred at rt for 48 h. The mixture was quenched with water, extracted with EtOAc and dried over MgSO4. The solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel (5% EtOAc in petroleum ether) to afford methyl 2-amino-5-bromobenzoate (30 g, 56% yield). 1H NMR (300 MHz, DMSO) delta 7.74 (d, J=2.7, 1H), 7.35 (dd, J=9.0, 2.1, 1H), 6.78-6.73 (m, 3H), 3.77 (s, 3H).
56%
With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 48h;
MeSO4 (26.3 mL, 0.280 mol) was added to a solution of 2-amino-5-bromobenzoic acid (50.0 g, 0.230 mol) in DMF and Et3N (40 mL, 0.28 mol). The reaction mixture was stirred at rt for 48 h. The mixture was quenched with water, extracted with EtOAc and dried over MgSO4. The solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel (5% EtOAc in petroleum ether) to afford methyl 2-amino-5-bromobenzoate (30 g, 56% yield). 1H NMR (300 MHz, DMSO) delta 7.74 (d, J=2.7, 1H), 7.35 (dd, J=9.0, 2.1, 1H), 6.78-6.73 (M, 3H), 3.77 (s, 3H).
Step b: 6-Bromo-1,1-dioxo-1,2-dihydro-1lambda6-benzo[d]isothiazol-3-one A solution of the methyl 2-amino-5-bromobenzoate (20.0 g, 86.9 mol) in 20% hydrochloric acid (60 mL) was warmed until all solids were dissolved. The solution was cooled to 0 C. with stirring to precipitate the hydrochloride salt. To this suspension was added a solution of sodium nitrite (6.10 g, 8.84 mol) in water (20 mL) dropwise at such a rate that the internal reaction temperature did not exceed 5 C. The mixture was stirred at 0 C. for 45 minutes to afford a clear solution. Sulfur dioxide was bubbled into a mixture of acetic acid (100 mL) and water (10 mL) at 0 C., Copper (I) chloride (8.6 g, 0.088 mol) was then added to the sulfur dioxide solution. The mixture was then cooled to 0 C. To this mixture was added the diazonium salt solution portion-wise with vigorous stirring over a period of 30 minutes. The reaction mixture was stirred at 0 C. for 1 h and then the mixture was allowed to warm to room temperature. The mixture was stirred at room temperature for 2 h before it was quenched with ice water (500 mL). The mixture was extracted with EtOAc (3*) and the extracts were washed with sat. NaHCO3 and dried over anhydrous Na2SO4. The solvent was removed in vacuo to afford an oily residue. The residue was dissolved in THF (60 mL) and the solution was cooled to 0 C. To this mixture was added a cold (0 C.) solution of sat. NH3 (50 mL) in MeOH portion-wise at such a rate that the internal reaction temperature was maintained below 10 C. After the addition was complete, the mixture was allowed to warm to room temperature and was stirred for 1 h. The solvent was removed in vacuo and the residue was dissolved in saturated aqueous sodium bicarbonate (60 mL) and washed with diethyl ether (80 mL). The aqueous layer was acidified with concentrated HCl to pH to 1. The resulting precipitate was collected by filtration and was dried in vacuo to afford 6-bromo-1,1-dioxo-1,2-dihydro-1lambda6-benzo[d]isothiazol-3-one (2.1 g, 9% yield). 1H NMR (300 MHz, CDCl3) delta 8.18 (d, J=1.8, 1H), 8.03 (dd, J=8.1, 1.8, 1H), 7.79 (d, J=8.1, 1H).
9%
A solution of the methyl 2-amino-5-bromobenzoate (20.0 g, 86.9 mol) in 20% hydrochloric acid (60 mL) was warmed until all solids were dissolved. The solution was cooled to 0 C. with stirring to precipitate the hydrochloride salt. To this suspension was added a solution of sodium nitrite (6.10 g, 8.84 mol) in water (20 mL) dropwise at such a rate that the internal reaction temperature did not exceed 5 C. The mixture was stirred at 0 C. for 45 minutes to afford a clear solution. Sulfur dioxide was bubbled into a mixture of acetic acid (100 mL) and water (10 mL) at 0 C. Copper (1) chloride (8.6 g, 0.088 mol) was then added to the sulfur dioxide solution. The mixture was then cooled to 0 C. To this mixture was added the diazonium salt solution portion-wise with vigorous stirring over a period of 30 minutes. The reaction mixture was stirred at 0 C. for 1 h and then the mixture was allowed to warm to room temperature. The mixture was stirred at room temperature for 2 h before it was quenched with ice water (500 mL). The mixture was extracted with EtOAc (3*) and the extracts were washed with sat. NaHCO3 and dried over anhydrous Na2SO4. The solvent was removed in vacuo to afford an oily residue. The residue was dissolved in THF (60 mL) and the solution was cooled to 0 C. To this mixture was added a cold (0 C.) solution of sat. NH3 (50 mL) in MeOH portion-wise at such a rate that the internal reaction temperature was maintained below 10 C. After the addition was complete, the mixture was allowed to warm to room temperature and was stirred for 1 h. The solvent was removed in vacuo and the residue was dissolved in saturated aqueous sodium bicarbonate (60 mL) and washed with diethyl ether (80 mL). The aqueous layer was acidified with concentrated HCl to pH to 1. The resulting precipitate was collected by filtration and was dried in vacuo to afford 6-bromo-1,1-dioxo-1,2-dihydro-1lambda6-benzo[d]isothiazol-3-one (2.1 g, 9% yield). 1H NMR (300 MHz, CDCl3) delta 8.18 (d, J=1.8, 1 H), 8.03 (dd, J=8.1, 1.8, 1H), 7.79 (d, J=8.1, 1H).
Example 1N-(5-{3-benzyl-2-[(2-methanesulfonylethyl)amino]-4-oxo-3,4-dihydro methoxypyridin-3-yl)-2,4-difluorobenzene-1-sulfonamideStep A6-bromo-2,4( 1 H, 3H)-quinazolinedione [00123] A mixture of methyl 2-amino-5-bromobenzoate (50 g, 217 mmol) and urea (65.3 g, 1087 mmol) were ground together and heated to 200 C for 2 hours with stirring and while under nitrogen. The mixture went fully into solution after 10 minutes, and then solidified after 40 minutes. The reaction was cooled and the resulting solid was washed with water (1 L). The solid was then filtered and the remaining solids rinsed with more water and broken up into fine particles. The residue was triturated with EtOAc (ca 300 mL) and dried to yield 6-bromo- 2,4(1 H,3H)-quinazolinedione (42g, 80%). ES-LCMS: 241.0, 243.1 (M+1 ).
A mixture of methyl-2-amino-5-bromobenzoate (12.5 g), and urea (18.5 g) was heated in a melt at 180-185C for 4.5 hours. The mixture was cooled and the white solid residue treated with 2M sodium hydroxide (400 ml) for 6hours at room temperature, then acidified with concentrated hydrochloric acid at 00C to give a white solid which was collected by filtration, washed with water and dried to give the title compound (12.5 g), as a white solid. deltaH (400 MHz, DMSO) 7.06 (d, IH)5 7.68 (dd, IH), 7.88 (s, IH).
Multi-step reaction with 4 steps
1.1: 88 percent / pyridine / 1 h / 55 °C
2.1: NaH / dimethylformamide / 1 h / 20 °C
2.2: NaI / dimethylformamide / 14 h / 80 °C
3.1: 25.1 g / NaH / dimethylformamide / 15 h / 80 °C
4.1: 21 percent / H2SO4; AcOH / 2.5 h / 90 °C
Multi-step reaction with 2 steps
1.1: 5 h / 25 - 55 °C
2.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 2 h / 0 - 25 °C / Inert atmosphere
2.2: 60 h / 0 - 80 °C / Inert atmosphere
2.3: 15 h / 0 - 80 °C
a. 2-AMINO-5-CYANO-BENZOIC acid methyl ester A mixture of 2-amino-5-bromo-benzoic acid methyl ester (5.00 g, 21.7 mmol) and CUCN (2.34 g, 26.1 mmol, 2.0 M) in 25 ml OF NMP was stirred at reflux for 5 h, then cooled to rt. The mixture was poured into a solution of hydrated FeCl3 (15 g of FeCl3. 6H20) and conc. HC1 (2.2 ml) in 15 ml of H20. The resulting mixture was stirred at 60 C for 1 h, cooled to rt. Treated with 200 ml of EtOAc, the mixture was washed with H20 (40 ml), 1N NAOH (3X30 ml), brine (30 ml) and dried (NA2SO4). Removal of the solvent under reduced pressure gave a slightly dark solid. Recrystalization of the solid in HEXANES/DCM/ETOAC yielded 3.25 g (85 %) of product as a yellow solid : H-NMR (CDCl3 ; 400 MHz) 8 8.20 (d, 1H, J= 1.9 Hz), 7.45 (dd, 1 H, J = 8.9, 1.9 Hz), 6.67 (d, 1H, J = 8.9 Hz), 6.29 (br s, 2H), 3.90 (s, 3H). Mass spectrum (ESI, m/z) : Calcd. for C9H8N202, 177.1 (M+H), found 177.2.
52%
In 1-methyl-pyrrolidin-2-one; at 200℃;Heating / reflux;
A mixture of methyl 2-amino-5-bromobenzoate [(50G,] [217MMOL)] and [CUCN] [(19.] 7g, [220MMOL)] in [200ML] of N-methyl-2-pyrrolidinone are stirred at reflux [(-200OC)] for overnight, and cooled to room temperature. The dark mixture is slowly added to [1800ML] of Et20 with vigorous stirring. Dark sticky oil at the bottom is discarded and the upper cloudy solution (2000ml) is washed consecutively with brine [(200ML),] 1M [NAOH] [(200ML)] and brine [(2X200ML),] dried over [NA2S04,] then evaporated to dryness to [GIVE-20G] of yellow solids, methyl 2-amino-5-cyanobenzoate. Yield for crude product: [52%.]
Stage #1: O-acetylsalicyloyl chloride; 5-bromo-2-aminobenzoic acid methyl ester With pyridine In dichloromethane
Stage #2: With polyamine resin In dichloromethane for 4h;
9 Synthesis of Acetate 15
Synthesis of Acetate 15. To a [250-ML] round bottom flask was added a solution of [METHYL-2-AMINO-5-BROMOBENZOATE] [14,5. 0 g, 21.7 mmol dissolved in pyridine (10 mL) and [CH2C12] (10 mL) ], followed by o-acetoxybenzoyl chloride5 (4.7 g, 33.8 mmol dissolved in 60 mL of [CH2CL2).] The mixture was stirred overnight under a nitrogen atmosphere. Polyamine resin (4.0 g) was then added to the reaction mixture and the reaction was stirred for 4 h. After filtration and concentration of the reaction mixture, a white residue was obtained. The residue was recrystallized from [CH2C12 TO AFFORD] 8.0 g (94%) of 15 as a white solid [: 1H] NMR (DMSO-d6) [8] 2.24 (s, 3H), 3.86 (s, 3H), 7. [30] (d, [J=] 8.1, [1H),] 7.46 (dt, [J=] 1.1, 7.6, [1H),] 7.66 (dt, [J=] 1.7, 8.0, [1H),] 7.82 (dd, J= 1. 7,7. 7, [1H),] 7.86 (dd, J= 2.5, 8.9, 1H), 8.06 (d, J= 2.5, [1H),] 8.38 (d, J= 8.9, 1H)
With zinc(II) cyanide;tetrakis(triphenylphosphine) palladium(0); In DMF (N,N-dimethyl-formamide); at 90 - 100℃; for 8h;
<strong>[52727-57-8]Methyl 2-amino-5-bromobenzoate</strong> (24.0 g, 104 mmol), zinc cyanide (8.02 g, 68.3 mmol), and Pd (PPh3) 4 (2.02 g) were weighed into a three-necked flask, which was then purged with nitrogen. After adding DMF (130 mL), the reaction mixture was stirred in a hot oil bath [(90C)] for 8 h. Because TLC revealed no change during the last 3 h, additional catalyst (2.00 g) was added and stirred in the hot oil bath overnight. Additional catalyst (1.00 g) and heating at [100C] was required to drive reaction to near completion. Reaction was poured into water (400 mL), extracted with EtOAc (700 mL), and the two-phase mixture filtered. The organic layer was removed, washed with saturated brine (4 x 200 mL), dried, filtered, and evaporated on to silica gel, and applied to a column of silica gel. Elution was effected using 4: 1 [HEPTANE/ETOAC] to give 15.60 g (yield of 85%) of the methyl 5-cyanoanthranilate as a pale yellow solid. ['H NMR] (300 MHz, [CDC13)] 8 8.19 (d, [1H),] 7.45 (dd, 1H), 6.68 (d, 1 H),-6. 3 (very [BRS),] 3.90 (s, [3H).]
CuCN; In water; ethylenediamine;
a) Methyl 2-amino-5-cyanobenzoate b) Methyl 2-amino-3-ethyl-5-cyanobenzoate A mixture of methyl 2-amino-5-bromobenzoate (4.6 g, 20 mmol), and CuCN (1.97 g, 22 mmol) in NMP (20 mL) was heated to 190 C. and 3 h. The reaction mixture was poured into a solution of ethylene diamine 4 mL) in H2O(16 mL) and extracted with toluene (4*20 mL). The extracts were dried (Na2SO4). Removal of the solvent gave the title compound a) (i.e., R8 is hydrogen). Use of methyl 2-amino-5-bromo-3-ethyl bromobenzoate gave the title compound b) (iLe., R8 is ethyl).
9-fluorenyl-methoxycarbonyl-cyclohexyl alanine[ No CAS ]
[ 462-94-2 ]
[ 1458-98-6 ]
[ 78-77-3 ]
[ 1809-10-5 ]
[ 110-53-2 ]
[ 592-55-2 ]
[ 7328-91-8 ]
[ 871-76-1 ]
[ 105-83-9 ]
[ 144-48-9 ]
[ 929-59-9 ]
[ 107-59-5 ]
[ 5324-30-1 ]
[ 5428-54-6 ]
[ 27129-86-8 ]
[ 2417-72-3 ]
[ 2581-34-2 ]
[ 554-84-7 ]
[ 3385-21-5 ]
[ 126-38-5 ]
[ 636-93-1 ]
[ 88-30-2 ]
[ 620-13-3 ]
[ 823-78-9 ]
[ 5035-82-5 ]
[ 29022-11-5 ]
[ 539-48-0 ]
[ 35661-39-3 ]
[ 26759-46-6 ]
[ 20439-47-8 ]
[ 2615-25-0 ]
[ 6393-01-7 ]
[ 5372-81-6 ]
[ 35661-40-6 ]
[ 100-39-0 ]
[ 611-17-6 ]
[ 23915-07-3 ]
[ 71989-23-6 ]
[ 35737-15-6 ]
[ 2592-95-2 ]
[ 18880-00-7 ]
[ 88681-68-9 ]
[ 100063-22-7 ]
[ 75-03-6 ]
[ 106-94-5 ]
[ 104-81-4 ]
[ 589-10-6 ]
[ 107-15-3 ]
[ 109-76-2 ]
[ 110-60-1 ]
[ 7051-34-5 ]
[ 106-95-6 ]
[ 622-95-7 ]
[ 589-15-1 ]
[ 134-20-3 ]
[ 2550-36-9 ]
[ 89-92-9 ]
[ 456-41-7 ]
[ 766-80-3 ]
[ 459-46-1 ]
[ 874-98-6 ]
[ 402-49-3 ]
[ 870-63-3 ]
[ 85118-01-0 ]
[ 22115-41-9 ]
[ 3958-57-4 ]
[ 100-11-8 ]
[ 107-82-4 ]
[ 6482-24-2 ]
[ 3132-64-7 ]
[ 112883-41-7 ]
[ 3433-80-5 ]
[ 52727-57-8 ]
C18H15N2O3PolS[ No CAS ]
C20H20N3OPolS[ No CAS ]
C23H19N2O2PolS[ No CAS ]
C18H23ClN3OPolS[ No CAS ]
C22H26N3OPolS[ No CAS ]
C22H23N2O5PolS[ No CAS ]
C20H26ClN2O3PolS[ No CAS ]
C23H22ClN2O3PolS[ No CAS ]
C20H21FN3O3PolS[ No CAS ]
C22H29N2O3PolS[ No CAS ]
C21H28N3O3PolS[ No CAS ]
C19H26N3O4PolS2[ No CAS ]
C22H30N3OPolS[ No CAS ]
C21H28N3O4PolS[ No CAS ]
C26H26N3OPolS[ No CAS ]
C23H15ClF3N2O2PolS[ No CAS ]
C24H22N3O3PolS[ No CAS ]
C23H16ClF2N2O2PolS[ No CAS ]
C22H22Br2N3OPolS[ No CAS ]
C24H26FN2O5PolS[ No CAS ]
C25H22FN2O4PolS[ No CAS ]
C26H22N3O4PolS[ No CAS ]
C25H25ClN3O3PolS[ No CAS ]
C25H18ClF2N2O3PolS[ No CAS ]
C29H26N3O3PolS[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With piperidine; Carbonyldiimidazole; tin-2-ethylhexanoate dihydrate; potassium tert-butylate; water; N-ethyl-N,N-diisopropylamine; trifluoroacetic acid; diisopropyl-carbodiimide; dibromotriphenylphosphorane; In DMF (N,N-dimethyl-formamide); dichloromethane; N,N-dimethyl acetamide; 1,2-dichloro-ethane;Combinatorial reaction / High throughput screening (HTS);
EXAMPLE 1 [0213] This example shows the synthesis of a combinatorial library of thioquinazolinone derivatives. [0214] Step 1a: Preparation of Wang Bromide Resin [0215] 40 tea bags containing 2 g each of Wang resin (80 g, 120 mmol) was taken in a 5 L PP container. A solution of triphenylphosphine dibromide (152 g, 0.15 M, 3 eq., 360 mmol) in 2000 ml DCM was added and the solution was shaken at room temperature overnight. The resin was sequentially washed with DCM (4×, 1.5 L each) and diethylether (6×, 1.5 L each) and dried under vacuum, to give the bromo wang resin. [0216] Step 1b: Loading of the Nitrophenol on Bromo Wang [0217] 20 g of the Bromo wang resin (1.5 meq/g) was taken in a 2 L wide-mouthed glass container and 1000 mL DMA was addded to it followed by the addition of the nitro phenol (10 eq., 0.3M, 300 mmol). Potasium t-butoxide (33.46 g, 10 eq., 300 mmol) was then added to it and the bottles were heated at 50 C. overnight. The bags were washed alternatively with DMF (500 mL) and DCM (500 mL) 3 cycles followed by 6 cycles of MeOH (500 mL). The tea bags were then dried overnight in air. The following nitrophenols were used: [0218] 2-METHYL-5-NITROPHENOL [0219] 5-HYDROXY-2-NITROBENZOTRIFLUORIDE [0220] 3-METHYL-4-NITROPHENOL [0221] 2-METHOXY-5-NITROPHENOL [0222] M-NITROPHENOL [0223] Step 1c: Reduction of the Nitro Group to Amine [0224] A 2.0 M solution of tin-2-ethylhexanoate dihydrate was prepared in DMF containing 0.5% H2O. The tea bags were added and the solution is heated at 50 C. for 40 hours. After cooling the bags are washed with DMF/10% HOAc (3×), DMF (3×), 5% DIEA/DCM (2×), DCM (2×) and MeOH (2×) and dried in air overnight. [0225] Step 1d: Coupling N-FMOC Protected Amino Acid to Wang Resin. [0226] 20 g of Wang resin (1.5 meq/g) was placed in a porous polypropylene packet (Tea-bag, 60 mm×60 mm, 65mu) and taken in a 1000 mL plastic bottle. DMF (300 mL), DCM (300 mL), FMOC-Cyclohexyl alanine (70.82 g, 6 eq., 0.3M, 180 mmol), DIC (22.71 g, 6 eq., 180 mmol), HOBt (24.32 g, 6 eq., 180 mmol) were added sequentially. After shaking for 12 hours, the packet was washed alternatively with DMF (500 mL) and DCM (500 mL) 3 cycles followed by 6 cycles of MeOH (500 mL). The packet was then dried overnight in air. The tea bags containing the amino acids were then treated with 20% piperidine/DMF for 2 h at room temperature to deblock the FMOC group. The following amino acids were used: [0227] FMOC-GLY-OH [0228] FMOC-ALA-OH [0229] FMOC-L-ISOLEUCINE [0230] FMOC-L-PHENYLALANINE [0231] FMOC-D-NLE-OH [0232] FMOC-CHA-OH [0233] FMOC-L-TRYPTOPHAN [0234] Step 1e: Coupling of the Diamines to Wang Resin [0235] 20 g of Wang resin (1.5 meq/g) was placed in a porous polypropylene packet (Tea-bag, 60 mm×60 mm, 65mu) and taken in a 1000 mL Nalgene bottle. 600 mL of DCM was added followed by the addition of the carbonyl diimidazole (29.9 g, 6 eq., 0.3M, 180 mmol) and the flasks were shaken at room temperature for 3 hours after which they were decanted and washed with DCM (2×, 600 mL). To these Nalgene bottles were added the diamines (6 eq., 0.4M, 180 mmol) in 450 mL of DCM (0.4M) and they were shaken at room temperature overnight. The diamines used were as follows: [0236] 2,2-DIMETHYL-1,3-PROPANEDIAMINE [0237] 1,3-CYCLOHEXANEDIAMINE [0238] (1R,2R)-(-)-1,2-DIAMINOCYCLOHEXANE [0239] TRANS-1,4-DIAMINOCYCLOHEXANE [0240] P-XYLYLENEDIAMINE [0241] 1,4-BIS(3-AMINOPROPYL)PIPERAZINE [0242] ETHYLENEDIAMINE [0243] 1,3-DIAMINOPROPANE [0244] 1,8-DIAMINO-3,6-DIOXAOCTANE [0245] 1,4-DIAMINOBUTANE [0246] 1,5-DIAMINOPENTANE [0247] 1,6-HEXANEDIAMINE [0248] N,N-BIS(3-AMINOPROPYL)METHYLAMINE [0249] 2,2'-THIOBIS(ETHYLAMINE) [0250] 2,5-DIMETHYL-1,4-PHENYLENEDIAMINE [0251] After shaking overnight, the packets was washed alternatively with DMF (500 mL) and DCM (500 mL) 3 cycles followed by 6 cycles of MeOH (500 mL). The packet was then dried in air. [0252] Step 2: Formation of the Isothiocyanate [0253] The o-amino benzoate ester (136 g, 10 eq., 900 mmol) was taken in a 5 L wide-mouthed glass bottle and 2.7 L of dichloroethane was added to it (0.3M). The following esters were used: [0254] METHYL ANTHRANILATE [0255] METHYL 2-AMINO-4-CHLOROBENZOATE [0256] 2-AMINO-4,5-DIMETHOXYBENZOIC ACID [0257] METHYL ESTER [0258] METHYL 3,4,5-TRIMETHOXYANTHRANILATE [0259] DIMETHYL AMINOTEREPHTHALATE [0260] METHYL 2-AMINO-5-BROMOBENZOATE [0261] METHYL 3-AMINOTHIOPHENE-2-CARBOXYLATE [0262] METHYL 3-AMINO-5-PHENYLTHIOPHENE-2-CARBOXYLATE [0263] Thiocarbonyl diimidazole (160 g, 10 eq., 900 mmol) was added to it and the solution was heated at 55 C. overnight to form the isothiocyanate. [0264] Step 3: Formation of the Thioquinazolinone [0265] The next day the tea bags containing the amino acids, diamines and the amino phenols on wang resin (90 mmol) was added to the isothiocyanate solution from reaction 2 and the glass bottles were heated at 55 C. overnight. After cooling the bags was washed alternatively with DMF (2000 mL) and DCM (2000 mL) 3 cycles followed by 6 cycles of MeOH...
With N-iodo-succinimide; acetic acid; at 20℃; for 17h;
Example S9; Preparation of 5-bromo-1H-indole-7-carboxylic acid; 371 mg of 2-amino-5-bromo-benzoic acid methyl ester (2 mmol) was dissolved in 2 ml conc acetic acid and treated with 495 mg of N-iodosuccinimide (2.2 mmol) at rt for 17 h. The reaction mixture was then poured on 5 ml saturated sodium bicarbonate solution and ice, extracted twice with EtOAc. The combined organic phases were then washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo, leading to 585 mg 2-amino-5-bromo-3-iodo-benzoic acid methyl ester (82%) as a light brown solid. MS (EI) 354.9 (M)+.
7.49 g
With N-iodo-succinimide; trifluoroacetic acid; at 20℃;Inert atmosphere;
To a stirring of solution of methyl 2-amino-5-bromobenzoate (5 g, 21.73 mmol) in TFA(20 mL, 260 mmol) is added NIS (4.99 g, 22.17 mmol) in one portion. After I h, the reactionmixture is concentrated under reduced pressure. The residue is dissolved in EtOAc and washedsequentially with saturated Na2CO3 solution (2x), 10% aq. sodium dithionite (2x) and brine (lx),dried over Na2504,filtered and concentrated to give the title compound (7.47 g, 18.89 mmol,90% purity) as a dark brown solid. LCMS (ES API) MH+ = 356 & 358 for Br isotopes.
With pyridine; In dichloromethane; at 20℃; for 1.5h;
Example 1; Synthesis of (+/-)-Isopropyl 5-[(3,5-bistrifluoromethylbenzyl)-(2-methyl-2//-tetrazol-5-yl)ammo]-7-bromo-2,3,4,5-tetrahydrobenzo[Z?]azepine-l-carboxylate; Step 1; Preparation of Methyl 5-bromo-2-isopropoxycarbonylaminobenzoate; Add isopropyl chloroformate (36.9 mL, 36.9 mmol, 1.0 M in toluene) dropwise to asolution of methyl 2-amino-5-bromobenzoate (5.0 g, 24.6 mmol) and pyridine (80.0 mL,36.9 mmol) in dichloromethane (80 mL) at room temperature under an atmosphere ofnitrogen and stir for 1.5 h. Pour the reaction into water (100 mL) and separate the layers.Extract the aqueous layer with dichloromethane (2 x 40 mL) and combine the organicextracts and wash with 2 N hydrochloric acid, saturated sodium hydrogen carbonate, andbrine (80 mL each). Dry the organic layer over anhydrous sodium sulfate, filter, andremove the solvent under reduced pressure to afford the title compound as a pale yellowsolid (6.68 g, 86%).
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 100℃;
a) Methyl 4-amino-4'-(trifluoromethyl)-3-biphenylcarboxylate A mixture of 4-trifluoromethylbenzeneboronic acid (440 mg, 2.31 mmol), methyl 2-amino-5-bromobenzoate (535 mg, 2.31 mmol), sodium carbonate (730 mg, 6.9 mmol) and tetrakis(triphenylphosphine)palladium (0) (80 mg, 0.07 mmol) in water (2 mL) and dimethylformamide (5 ml_) was sealed in pressure bottle under argon and heated at 1000C overnight. The mixture was cooled and diluted with water and extracted twice with ethyl acetate, the combined extracts washed with water and brine, dried and evaporated. Flash chromatography (silica gel, hexane to 10% ethyl acetate in hexane) gave the title compound (600 mg, 88%). 1 H NMR (400MHz, DQ-DMSO) delta 8.13 (d, J = 2.3 Hz, 1 H), 7.84 (d, J = 8.6 Hz, 2H), 7.79 (d, J = 8.3 Hz, 2H), 7.76 (dd, J = 8.6 and 2.3 Hz, 1 H), 6.9-7.0 (m, 3H), 3.90 (s, 3H).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 65℃; for 16h;Inert atmosphere;
A suspension of methyl 2-amino-5-bromobenzoate (460 mg, 2.0 mmol), potassium acetate (441 mg, 4.5 mmol) and pinacol diborane (1.52 g, 6.0 mmol) in 1,4-dioxane (20 mL) was degassed under a flow of N2 for 15 minutes. PdCb(dppf) (73 mg, 0.1 mmol) was added and the mixture heated to 95C for 16 hours. The reaction was deemed complete by LCMS. After cooling, the contents were partitioned between CH2C12 and water. The organic layer was washed with water, dried over anhydrous MgS04, filtered and evaporated. The product was purified by automated silica-gel chromatography eluting with a hexanes/EtOAc gradient. The fractions containing methyl 2- amino-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate were concentrated to yield the product as a colorless oil = 560 mg (2.00 mmol, quant.). (0566) LC/MS - HPLC (254 nm) - Rt 3.32 min. MS (ESI) m/z 278.3 [M + H]+.
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 80℃; for 2.5h;
Example 88:Methyl 2-amino-5-[4-(methylsulfonyImethyl)-6-morpholin-4-yl-pyrimidin-2- yljbenzoateA mixture of methyl-2-amino-5-bromobenzoate (250 mg), potassium acetate (320 mg) and bis(pinacolato)diboron (332 mg) in 1,4-dioxane (10 mL) was degassed for 5 minutes. 1,1'- Bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane adduct (54 mg) was added and the reaction was heated to 8O0C for 2.5 hours. 2-Chloro-4-(methylsulfonylmethyl)-6-mophiholin-4-yl-pyrimidine (381 mg), ethanol (0.75 mL), a 2M solution of sodium carbonate (2.7 mL) and additional 1,1'- bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane adduct (54 mg) were added and the heating was continued for a further 3.5 hours. The cooled reaction mixture was loaded on a SCX-2 (10 g), removed with 7N ammonia in methanol and the solution concentrated in vacuo. The residue was chromatographed on silica, eluting with 50% ethyl acetate in DCM, to give the desired material as a yellow solid (82 mg). Mass Spectrum; MH+ 407 NMR Spectrum: 1H NMR (DMSO-d6) 53.22 (3H, s), 3.69 (4H, s), 3.73 (4H, s), 3.84 (3H, s), 4.49 (2H, s), 6.77 (IH, s), 6.87 (IH, d), 7.05 (2H, s), 8.24 (IH, d), 8.79 (IH, s)
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 85℃; for 18h;Inert atmosphere;
A mixture of methyl 2-amino-5-bromobenzoate (5.0 g, 21.7 mmol),4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (6.6 g, 26.1 mmol), dichloro l,l'-bis(diphenylphosphino)ferrocene palladium (II) (0.89 g, 1.1 mmol), and potassium acetate (6.4 g, 65.2 mmol) under an inert atmosphere in a 500 mL RBF was treated with dioxane (130 mL). The suspension was heated to 85 C for 18 h. The reaction mixture was concentrated in vacuo then diluted with EtOAc. The organic layer was washed with water and brine then dried over MgS04 and concentrated in vacuo to give a sticky tan solid which was used in the next step without further purification.
Methyl 5-bromo-2-[4-(chlorosulfonyl) benzoyl] amino} benzoate (1) was prepared as a common intermediate for the formation of sulfonamides by the procedure below: 4- (chlorosulfonyl) benzoic acid (18.37 g, 8.33 mmol) was suspended in [CH2C12] (140 mL) [AND 4 DROPS OF DMF.] The solution was cooled to [0 C] and oxalyl chloride (1.8 mL, 20.6 mmol) was added and stirred for 1 hour, removed from ice bath, and stirred overnight. The clear solution was concentrated in vacuo, redissolved in [CH2C12,] and concentrated in vacuo. The resulting product was dissolved in toluene (140 [ML)] and refluxed for 30 minutes to remove any HC1 gas. After cooling to room temperature, [METHYL-2-AMINO-5-BROMOBENZOATE] (15.96 g, 69.4 mmol) was added, and the suspension was refluxed overnight. The suspension was cooled to [0] C and filtered, washing with toluene and quickly with ethyl acetate. The solid was dried in a vacuum oven overnight to obtain sulfonyl chloride 1 (19.8 g, 66%). 1H NMR [(CDC13)] 8 12.19, 8.82, 8.27-8. 19,7. 73,4. 00; IR 1700,1683, 1604,1585, 1524 (s), cm [1 ;] MS (ESI-) for [CLSHMBRCINO5S M/Z] 429.8 [(M-H)'.]
methyl 5-bromo-2-[3-(morpholin-4-ylsulfonyl)benzoyl]amino}benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
3- (morpholin-4-ylsulfonyl) benzoic acid (271 mg, 1.0 mmol) was suspended in [CH2C12] (10 mL) and (COCl) 2 added (725 mg, 5.7 mmol). A catalytic amount [OF DMF] was then added and the mixture stirred for 4 hrs. The solvent was then removed in vacuo to give the acid chloride as an oil. The oil was dissolved in [CHC13] (10 mL). Methyl 2- amino-5-bromobenzoate (230 mg, 1.0 mmol) was added followed by pyridine [(1] mL). The solution was stirred at room temperature for an additional 12 hrs then poured into 1 M HC1 (20 [ML)] and extracted with EtOAc (3 x 20 mL). The combined organic solutions were dried over Na2S04 and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (20% EtOAc in hexane) to provide 367 mg of the desired methyl ester (76%). The ester was treated with [LIOH] in 1: 1: 1 THF/MeOH/H20 for 12 hrs followed by acidification and extraction with EtOAc. The organic solution was dried over NazS04 and then concentrated in vacuo. The title compound (328 mg, 92%, 70% overall) was obtained as a white solid after recrystalization from [MEOH.] H NMR (400 MHz, DMSO) 2.93 (m, [4H),] 3.65 [(M,] 4H), 7.88 (dd, 1H), 7.90 (d, 1H), 8.00 (d, [1H),] 8.13 (d, 1H), 8.25-8. 29 [(M,] [2H),] 8. 59 (d, 1H), 12.21 (s, 1H).
[3-F [ (4-CHLOROPHENYL)] (methyl) amino] [SULFONYL}-2-METHYLBENZOATE] (404 mg, 1.19 mmol) was suspended in dry [CH2C12] (10 mL) and DMF (10 [. L) UNDER N2.] The solution was treated with oxalyl chloride (Aldrich, 0.192 mL, 2.2 mmol) and stirred while gas evolved. After one hour the excess solvent and oxalyl chloride were evaporated and the resultant residue was taken up in dry [CH2C12] (10 mL). [METHYL-2-AMINO-5-] bromobenzoate (Aldrich, 230 mg, 1.0 mmol) was added as a solution in pyridine (3 mL) and the amber solution stirred at RT. After 2 hours [HPLC] indicated the reaction was complete. The mixture was diluted with CH2Cl2 (100 [ML)] and washed 2x with 1. OM HC1 followed by brine (100 mL each). The organic layer was evaporated and purified on a Biotage Flash 25M+ (40 g) silica cartridge using [CH2C12.] The combined fractions were evaporated and the product was dried under vacuum at [100 C] to afford 535mg (97%) of a glass-like [SOLID. 1H NMR] (400 MHz, DMSO-d6) 8 10.88 (s, 1 H), 8.05 (d, J= 8.9 Hz, [1] H), 7.99 (d, J= 2.3 Hz, 1 H), 7.93 (D, J= 7.5 Hz, 1 H), 7.86 (dd, J= 8.8, 2.4 Hz, 1 H), 7.80 (d, J= 7.3 Hz, 1 H), 7.57 (t, J= 7.9 Hz, 1 H), 7.45 (d, [J=8. 7HZ, 2H),] 7.29 (d, [J=8. 7HZ, 2H),] 3.83 (s, [3H),] 3.24 (s, [3H),] 2. [39] (s, [3 H).] 322 mg of the methyl ester solid was dissolved in hot dioxane (10 mL), and after cooling was treated with 1. OM [LIOH] (1.0 [ML,] 1.0 [MMOL).] After stirring overnight at RT the reaction was complete by [HPLC] and OAMS showed correct [M/Z] for the product. The solvent was evaporated and the residue was poured into 1. OM HC1 (100 mL) to afford a white precipitate. The product was extracted into EtOAc (125 [ML)] and washed 3x with [1.] OM HCl, and lx with brine (100 mL each). The organic layer was dried over [NA2S04,] filtered and evaporated to dryness. The crude product was re- [ CRYSTALLIZEDFROMHOTMEOH/ETOH. THERESULTANTPRODUCTWAS DRIEDAT 100 CUNDER] vacuum to afford 213 mg (68%) of white [CRYSTALS. 1H] NMR (400 MHz, DMSO-d6) [B] 11. [35] (s, 1 H), 8. [39] (d, [J=] 8.9 Hz, 1 H), 8.07 (d, [J=] 2.5 Hz, 1 H), 7.92 (dd, [J=] 8.1, 1. [0 HZ, 1 H),] 7.81-7. 89 (m, 2 H), 7.56 (t, [J= 7. 8 HZ, 1 H),] 7.41-7. 48 (m, 2 H), 7.24- 7.34 (m, 2 H), 3.23 (s, 3 H), 2.39 (s, [3 H).]
[1,] [2-BENZISOXAZOLE-3-CARBOXYLIC] acid (815 mg, 5.0 mmol) was suspended in dichloroethane (DCE) (10 mL). Oxalyl chloride (0.545 [ML,] 6.25 mmol) was added followed by a catalytic amount of DMF. The reaction was stirred at room temperature for 5 hrs. The solvent was removed in vacuo, and the resulting oil was redissolved in [DCB] (10 mL). Methyl [2-AMINO-5-BROMOBENZOATE] was added dropwise as a solution in [THF/PYRIDINE] [(5 ML/2 ML).] The mixture was stirred for 48 hrs. The resulting solid was filtered and washed with MeOH, giving 925 mg (50%) of the desired amide.
[ETHYL-1,] 2-benzisoxazole-3-carboxylate (10 g, 52 mmol) was dissolved in 100 mL of [CHLOROSULFONIC] acid and heated to 80 C. After 16 h the reaction was cooled to room temperature, poured onto ice and then extracted with EtOAc. The organic solution was dried over [NA2S04] and then concentrated to a brown oil. This oil was dissolved in 60 [ML] of thionyl chloride and heated to 50 C. After 6 h excess reagent was removed in vacuo and the remaining residue dissolved in 300 mL [CHCLS.] [METHYL-2-AMINO-5-] bromobenzoate was added as a solution in 100 mL CHCl3 and 10 [ML] pyridine. After stirring overnight at room temperature the resulting precipitate was filtered providing 3.96 g of the title compound. H NMR (400 MHz, CDCl3) 3.80 (s, [3H),] 7.77 (dd, [1H),] 7.92 (d, [1H),] 8.27 (d, [1H),] 8.32 (dd, [1H),] 8.82 (d, [1H),] 9.12 (d, [1H),] 12.63 (s, [1H)]
To a suspension of acid [10250-64-3] (150 mg, 0.74 mmol) in CH2Cl2 is added oxalyl chloride (65 muL, 0.74 mmol) and DMF (1 drop). The reaction mixture is stirred at rt for 90 min. It is concentrated to give an oil. The oil is dissolved in [CHZCLX] (5 mL), and methyl 5-bromoanthranilate (17 mg, 0.74 [MMOL),] [NET3 (207, UL,] 1.48mmol), and DMAP (10 mg, 0.074 mol) are added. The reaction mixture is stirred at rt for 72h. It is quenched with aqueous 1 M HCl (10 mL). The aqueous mixture is extracted with EtOAc. The EtOAc extracts are dried and concentrated to give an oil. The oil is dissolved in [CH2CL2,] and 4b is precipitated as a solid by the addition of hexanes : MS (ESI+) m/z 415.3.
3-[ (5-CHLORO-2, 3-DIHYDRO-1H-INDOL-1-YL) SULFONYL] benzoic acid[ No CAS ]
[ 52727-57-8 ]
[ 666859-50-3 ]
Yield
Reaction Conditions
Operation in experiment
78%
[3- [ (5-chloro-2, 3-dihydro-LH-indol-1-YL) sulfonyl]] benzoic acid, 1.0 g, 2.96 mmol) was suspended in dry [CH2C12] (20 mL) under N2 and treated with DMF (5 RL) followed by oxalyl chloride (0.5 mL, 5.70 mmol). Gas evolved as the mixture rapidly became homogenous. After stirring for 40 minutes at RT, the solvent and excess oxalyl chloride were evaporated and the resultant residue was taken up in [CH2C12] (20 mL).methyl 2-amino-5-bromobenzoate (656 mg, 2.85 mmol, Avocado) was added as a solution in dry pyridine (5 mL) and the amber solution was stirred at RT until TLC showed the absence of the aniline. The reaction was diluted to 300 mL with CH2Cl2, and was washed 2x with [1.] OM HCl (150 mL) and lx with brine (200 mL). The organic layer was dried over [MGS04,] filtered and the solvent was evaporated. The resultant residue was purified on a Biotage Flash 40M (90g) silica cartridge using [CH2C12.] The solvent was evaporated and the resultant product dried under vacuum at [120 C] to afford 1.22 g [(78%)] of white [SOLID. 1H NMR] (400 MHz, [CDC13)] [# 12 ]07 (s, 1 H), 8.79 (d, J= 8.6 Hz, [1] H), 8.50 (s, [1] H), 8.19-8. 23 [(M,] 2 H), 7.95 (d, J= 7.6 Hz, 1 [H),] 7.72 (dd, J= 9.2, 2.5 Hz, 1 H), 7.59-7. 66 [(M,] 2 H), 7.16 (d, J= 8.6 Hz, [1] H), 7.05 (s, [1] H), 4.05 (t, J= 8.4 Hz, 2 H), 4.00 (s, 3 H), 2.94 (t, J= 8.4 Hz, 2 H).
Compound 1a (18.60 g, 80.85 mmol) was dissolved in concentrated hydrochloric acid (200 mL, 12N), and an aqueous solution of sodium nitrite (6.69 g, 97.02 mmol) was slowly added dropwise at -10 to 0C. The reaction solution was at 0C. Stir for 1 hour. This reaction was added dropwise to a mixture of cuprous chloride (800 mg, 8.09 mmol) and sulfur dioxide (15.54 g, 242.55 mmol) at 0C. The resulting reaction solution was stirred at 0 C. for 1 hour and further warmed to 20 C. and stirred for 3 hours. After the reaction was completed, it was extracted with ethyl acetate (200 mL×3). The organic phases were combined, dried, concentrated to dryness under reduced pressure, and separated and purified by column chromatography on silica gel (petroleum ether/ethyl acetate=100-0%) to give Compound 1b (4.10 g).
To a solution of 2-amino-5-bromo-benzoic acid methyl ester (25.0 g, 109 mmol) in aqueous hydrochloric acid (10 M, 100 ml) a solution of NaNU2 (8.3 g, 1 19 mmol) in water (25 ml) was slowly added at 0 0C. After stirring 1 hour at 0 0C the obtained reaction mixture was added to a saturated solution of SO2 in 1 ,2-dichloroethane (75 ml) containing CuCb (0.50 g, 3.7 mmol) and benzyltrimethmethylammonium chloride (1.41 g, 7.6 mmol) cooled to a temperature of 0 0C. After the addition the reaction mixture was heated to 50 0C for 1 hour, cooled to ambient temperature and extracted with CH2CI2 (250 ml). The organic phase was washed with an aqueous saturated solution of NaHCtheta3, dried over Na2SU4, filtered and concentrated in vacuo. 5-Bromo-2-chloro- sulfonyl-benzoic acid methyl ester was obtained as the residue in an amount of 3.6 g.
4.1 g
Compound 47a (18.60 g, 80.85 mmol) was dissolved in concentrated hydrochloric acid (200 mL, 12 N), and an aqueous solution of sodium nitrite (6.69 g, 97.02 mmol) was slowly added dropwise at -10C to 0 C. The resulting reaction mixture was stirred for 1 hr at 0 C. The reaction mixture was added dropwise to a mixture of cuprous chloride (800 mg, 8.09 mmol) and sulfur dioxide (15.54 g, 242.55 mmol) at 0 C. The resulting reaction mixture was stirred for 1 hr at 0 C, warmed to 20 C, and stirred for 3 hr. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (200 mL×3). The organic phases were combined, dried, concentrated under reduced pressure to dryness, and separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate=100-0%), to give Compound 47b (4.10 g). 1H NMR (400 MHz, CDCl3) delta 8.03 (d, J=8.4 Hz, 1H), 7.83-7.91 (m, 2H), 4.01 (s, 3H). MS-ESI calculated value [M+ H]+ 314, measured value 314.
Intermediate 108To a solution of methyl 2-amino-5-bromobenzoate (7.38 g, 32.0 mmol) and pyridine (6.3 mL, 81.5 mmol) in 100 mL of anhydrous CH2CL2, was added slowly methane sulfonylchloride (6.5 mL, 79.9 mmol). After stirring overnight, reaction mixture was quenched with 100 mL of IN HC1 (aq). Aqueous mixture was extracted with ethyl acetate (3x120 mL) and combined organic layers were washed 200 mL brine. Organics were dried (MgS04), filtered, and concentrated under reduced pressure to yield intermediate 108 as an off white solid. Silica gel column chromatography (0-30% Ethyl Acetate in Hexanes), yielded intermediate C-C (9.35 g, 95 %) as a white off- white solid.1 H-NMR (CDC13, 300 MHz): delta 10.4 (s, IH), 8.22 (s, IH), 7.63 (s, 2H), 3.96 (s, 3H), 3.05 (s, 3H) LCMS m/z [M+H]+ C9Hi0BrNO4S requires: 307.95. Found 308.06
82%
With pyridine; at 0 - 20℃;Inert atmosphere;
Step A: Methyl 5-bromo-2-(methylsulfonamido) benzoate. A N2 degassed solution of methyl 2-amino-5-bromobenzoate (2.8 g) in 10 mL 1 pyridine was cooled to 0C before the drop wise addition of methane sulfonyl chloride (0.9 mL). The reaction mixture was stirred overnight at rt, then diluted with 50 mL ethyl acetate. The organic layer was washed with a saturated solution of Na2CO3, with brine, then dried over MgSO4 and evaporated to dryness (yield: 82%). LCMS (method B): 305.6 (M-H)- at 1.55 min.
82%
With pyridine; at 0 - 20℃;
A N2 degassed solution of methyl 2-amino-5-bromobenzoate (2.8 g) in 10 mL 1 pyridine was cooled to 0C before the drop wise addition of methane sulfonyl chloride (0.9 mL). The reaction mixture was stirred overnight at rt, then diluted with 50 mL ethyl acetate. The organic layer was washed with a saturated solution of Na2C03, with brine, then dried over MgS04 and evaporated to dryness (yield: 82%). LCMS (method B): 305.6 (M-H)" at 1.55 min.
80%
To an ice-cooled mixture of methyl 2-amino-5-bromobenzoate (3) (50.0 g, 217 mmol) and triethylamine (90.0 ml, 646 mol) in THF (650 ml) was added dropwise methanesulfonyl chloride (34.0 ml, 436 mmol) over 10 min. The mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo and the residue was suspended in MeOH (800 ml). To the suspension was added a solution of K2CO3 (200 g, 1450 mmol) in water (600 ml), and resulting white suspension was stirred at room temperature for 16 h. Resulting solid was collected by filtration and washed with water to give a crude product. The filtrate was concentrated in vacuo, and the residue was suspended in water. Insoluble solid was collected by filtration and combined with the crude product. The product was washed with water and dried in vacuo to give the desired methansulfonamide as a white powder (53.3 g, 80%). 1H NMR (DMSO-d6) delta 3.18 (3H, s), 3.88 (3H, s), 7.54 (1H, d, J = 8.9 Hz), 7.83 (1H, dd, J = 8.9, 2.5 Hz), 8.02 (1H, d, J = 2.5 Hz), 9.99 (1H, s).
With pyridine; In toluene; at 90℃; for 24h;
Step 1-Formation of the Sulfonamide Moiety; To a solution of the bromoaniline compound 123 (1.0 g, 4.37 mmol) in toluene (20 mL), methanesulfonyl chloride (2.5 g, 22 mmol, 5 eq) was added followed by pyridine (5 mL) and the reaction mixture was heated at 90 C. for 24 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL). The combined organic solvents were washed with water, dil. HCl, water, brine, and dried over sodium sulfate. Solvent was distilled off, and the residue was charged on a silica gel column and eluted with dichloromethane to get the methyl sulfonamide derivative 124.1HNMR (400 MHz; CDCl3) delta 10.40 (s, 1H); 8.25 (d, J=4.0 Hz, 1H); 7.70 (d, 8 Hz, 1H); 7.62 (dd, J1=8 Hz, J2=4 Hz, 1H), 3.96 (s, 3H); 3.12 (s, 31-1)
With pyridine; In dichloromethane; at 0 - 20℃; for 18h;
Methanesulfonyl chloride (5.40 mL, 69.5 mmol) was added slowly to a solution of methyl 2-amino-5-bromobenzoate (8.0 g, 34.8 mmol) and pyridine (8.44 mL, 104 mmol) in 50 mL CH2CI2 at 0 C. The solution was stirred at room temperature for 18 hours. The reaction mixture was acidified with 1M HC1 (aq) and extracted into CH2CI2. The combined extracts were washed with brine, dried over a2S04, filtered, and concentrated. The residue was purified by flash chromatography (2-40% ethyl acetate/hexane) to afford the title compound.
With pyridine; In dichloromethane;
Example 14 Preparation of Intermediate 14 [0469] [0470] To a solution of methyl 2-amino-5-bromobenzoate (7.38 g, 32.0 mmol) and pyridine (6.3 mL, 81.5 mmol) in 100 mL of anhydrous CH2Cl2, was added slowly methane sulfonylchloride (6.5 mL, 79.9 mmol). After stirring overnight, reaction mixture was quenched with 100 mL of 1N HCl(aq). Aqueous mixture was extracted with ethyl acetate (3×120 mL) and combined organic layers were washed 200 mL brine. Organics were dried (MgSO4), filtered, and concentrated under reduced pressure to yield intermediate 14. Silica gel column chromatography (0-30% Ethyl Acetate in Hexanes), yielded intermediate 14. [0471] 1H-NMR (CDCl3, 300 MHz): delta 10.4 (s, 1H), 8.22 (s, 1H), 7.63 (s, 2H), 3.96 (s, 3H), 3.05 (s, 3H) [0472] LCMS m/z [M+H]+C9H10BrNO4S requires: 307.95. Found 308.06.
With pyridine; In dichloromethane; at 20℃;
To a solution of methyl 2-amino-5-bromobenzoate (7.38 g, 32.0 mmol) and pyridine (6.3 mE, 81.5 mmol) in 100 mE ofanhydrous CH2C12, was added slowly methane sulfonylchloride (6.5 mE, 79.9 mmol). After stirring overnight, reaction mixture was quenched with 100 mE of iN HClQ,q) Aqueous mixture was extracted with ethyl acetate (3x120 mE) and combined organic layers were washed 200 mE brine. Organics were dried (MgSO4), filtered, and concentrated under reduced pressure to yield intermediate 14. Silica gel colunmchromatography (0-30% Ethyl Acetate in Hexanes), yieldedintermediate 14.?H-NMR (CDC13, 300 MHz): oe 10.4 (s, 1H), 8.22 (s, 1H), 7.63 (s, 2H), 3.96 (s, 3H), 3.05 (s, 3H)ECMS mlz [M+H] C9H1013rNO4S requires: 307.95. Found 308.06.
Example 8D: 2-Amino-5-bromo-/V-methylbenzamide2-Amino-5-bromobenzoic acid (80 g, 0.37 mol) was dissolved in MeOH (600 mL) and cone. H2S04 (50 mL) was slowly added. The reaction mixture was refluxed for 72 h, then concentrated. NaOH solution was added to adjust the pH to 10-1 1 . The mixture was extracted with EtOAc (3 χ 500 mL). The combined organic layer was dried over MgS04, concentrated to afford the desired compound (65 g, yield: 76 %) as a colorless oil, which is used directly in the next step without purification. A mixture of methyl 2-amino-5-bromobenzoate and CH3NH2.H2O (1000 mL) was stirred at 80 C overnight in a pressure tube. The mixture was diluted with H20 (1000 mL) and extracted with EtOAc (3 χ 500 mL). The combined organic layers were dried over MgS04, concentrated to afford the title compound (55 g, yield: 87 %) as a gray solid. 1H NMR (CDCI3, 400 MHz): δ 2.93 (d, J = 5.2 Hz, 3H), 5.48 (s, br, 2H), 6.04 (s, br, 1 H), 6.54 (d, J == 2.0, 8.4 Hz, 1 H), 7.38 (d, J = 2.0 Hz, 1 H).
106
A mixture of methyl 2-amino-5-bromobenzoate (Compound 106B, 65 g) and CH3NH2-H2O (1000 mL) was stirred at 80 0C overnight in a pressure tube. The mixture was diluted with H2O (1000 mL) and extracted with EtOAc (3 x 500 mL). The combined organic layers were dried over MgSO4, concentrated to afford the title compound (55 g, yield: 87 %) as a gray solid. 1H NMR (CDCI3, 400 MHz): δ = 2.93 (d, J = 5.2 Hz, 3 H), 5.48 (s, br, 2 H), 6.04 (s, br, 1 H), 6.54 (d, J = 8.4 Hz, 1 H), 7.24 (dd, J = 2.0, 8.4 Hz, 1 H), 7.38 (d, J = 2.0 Hz, 1 H).
With lithium hexamethyldisilazane; In tetrahydrofuran; at 0℃; for 2h;
General procedure: 1.5 equiv of PMBONH3+Cl- plus 4.5 equiv of LiHMDS (at 0 C for 2 h) or 4.1 equiv of LDA (from -78 C to -10 C, 0.5 h); yields were similar.
With ammonia; acetic acid; sodium nitrite; In tetrahydrofuran; hydrogenchloride; methanol; water; sodium hydrogencarbonate;
Step b:6-Bromo-1,1-dioxo-1,2-dihydro-1lambda6-benzo[d]isothiazol-3-oneA solution of the methyl 2-amino-5-bromobenzoate (20.0 g, 86.9 mol) in 20percent hydrochloric acid (60 mL) was warmed until all solids were dissolved.The solution was cooled to 0° C. with stirring to precipitate the hydrochloride salt.To this suspension was added a solution of sodium nitrite (6.10 g, 8.84 mol) in water (20 mL) dropwise at such a rate that the internal reaction temperature did not exceed 5° C.The mixture was stirred at 0° C. for 45 minutes to afford a clear solution.Sulfur dioxide was bubbled into a mixture of acetic acid (100 mL) and water (10 mL) at 0° C. Copper (I) chloride (8.6 g, 0.088 mol) was then added to the sulfur dioxide solution.The mixture was then cooled to 0° C.To this mixture was added the diazonium salt solution portion-wise with vigorous stirring over a period of 30 minutes.The reaction mixture was stirred at 0° C. for 1 h and then the mixture was allowed to warm to room temperature.The mixture was stirred at room temperature for 2 h before it was quenched with ice water (500 mL).The mixture was extracted with EtOAc (3*) and the extracts were washed with sat.NaHCO3 and dried over anhydrous Na2SO4.The solvent was removed in vacuo to afford an oily residue.The residue was dissolved in THF (60 mL) and the solution was cooled to 0° C.To this mixture was added a cold (0° C.) solution of sat. NH3 (50 mL) in MeOH portion-wise at such a rate that the internal reaction temperature was maintained below 10° C.After the addition was complete, the mixture was allowed to warm to room temperature and was stirred for 1 h.The solvent was removed in vacuo and the residue was dissolved in saturated aqueous sodium bicarbonate (60 mL) and washed with diethyl ether (80 mL).The aqueous layer was acidified with concentrated HCl to pH to 1.The resulting precipitate was collected by filtration and was dried in vacuo to afford 6-bromo-1,1-dioxo-1,2-dihydro-1lambda6-benzo[d]isothiazol-3-one (2.1 g, 9percent yield).1H NMR (300 MHz, CDCl3) delta 8.18 (d, J=1.8, 1H), 8.03 (dd, J=8.1, 1.8, 1H), 7.79 (d, J=8.1, 1H).
(iii) Methyl 5-bromo-2-([3-(furan-3-yl)phenoxy]acetyl}amino)benzoate Under ice-cooling, 1.53 g (7.97 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to a DMAc (5 mL) solution comprising 1.45 g (6.64 mmol) of [3-(furan-3-yl)phenoxy]acetic acid, 1.60 g (6.97 mmol) of methyl 2-amino-5-bromobenzoate, and 1.08 g (7.97 mmol) of 1-hydroxybenzotriazole, and the mixture was stirred at room temperature for 4 hours. Under ice-cooling, 1.63 g (19.9 mmol) of 1-methylimidazole was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was stirred for 1 hour. The precipitates were collected by filtration and washed with water and IPE, followed by drying under reduced pressure at 50 C. for 3 hours, thereby giving 2.30 g of methyl 5-bromo-2-([3-(furan-3-yl)phenoxy]acetyl}amino)benzoate (yield: 81%). 1H-NMR (CDCl3) delta: 3.97 (3H, s), 4.68 (2H, s), 6.72 (1H, dd, J=1.7, 1.0 Hz), 6.97 (1H, ddd, J=7.9, 2.6, 1.0 Hz), 7.19 (1H, ddd, J=7.9, 1.5, 1.0 Hz), 7.23 (1H, dd, J=2.6, 1.5 Hz), 7.35 (1H, t, J=7.9 Hz), 7.49 (1H, t, J=1.7 Hz), 7.67 (1H, dd, J=9.0, 2.4 Hz), 7.76 (1H, dd, J=1.4, 1.0 Hz), 8.19 (1H, d, J=2.4 Hz), 8.74 (1H, d, J=9.0 Hz), 12.08 (1H, s).
With ammonia; In methanol; at 20℃; for 336h;Inert atmosphere;
<strong>[52727-57-8]Methyl 2-amino-5-bromobenzoate</strong> (1 equiv) was added to a solution of NH3 in MeOH (7 M, 10 equiv) under a N2 atmosphere. The reaction mixture was stirred for 2 weeks at room temperature. After evaporation of the solvent the remaining solid was purified by CC (n-hexane/EtOAc 1:1) to provide the pure compound; white solid, yield: 11%. 1H NMR (500 MHz, DMSO-d6) delta = 7.84 (br. s., 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.25 (dd, J = 8.8, 2.3 Hz, 1H), 7.22-7.09 (m, 1H), 6.70 (s, 2H, NH2), 6.66 (d, J = 8.8 Hz, 1H) ppm. 13C NMR (125 MHz, DMSO-d6) delta = 169.9, 149.4, 134.3, 130.8, 118.5, 115.2, 104.7 ppm. LC/MS: m/z = 215 and 217 [M + H+], 198 and 200 [M+ - NH2]; tR = 6.65 min; 97.0% pure (UV).
With potassium hexamethylsilazane; In tetrahydrofuran; at 20℃; for 0.166667h;Inert atmosphere;
General procedure: To a solution of methyl 2-amino-4-chlorobenzoate (300 mg, 1.6 mmol) and ethyl 2-phenoxyacetate (320 mg, 1.8 mmol) in anhydrous THF (9 mL) was added KHMDS (4.8 mL, 1.0 M in THF, 4.8 mmol) in one portion with vigorous stirring under a nitrogen atmosphere. The reaction mixture was stirred at rt until completion of the reaction (10 min) then MeOH was added. The reaction mixture was concentrated under reduced pressure and the resulting residue was taken up in water and acidified with 1 N HCl until precipitation occurred. The precipitate was filtered, washed with EtOH then dried to give 7-chloro-4-hydroxy-3-phenoxyquinolin-2(1H)-one (Table 2, entry 1) as a pale pink powder (449 mg, 92%).
B) To a solution of cyanoacetic acid (0.92 g, 10.87 mmol) in 20 mL dichloromethane and dimethylacetamide (4:1) was added HATU (4.13 g,10.87 mmol) and diisopropylethyl amine (1.75 g, 13.49 mmol) and the reaction mixture stirred for 15 minutes. To the above solution was added 4 (1.00 g, 4.35 mmol) in 10 mL dichloromethane and the reaction mixture heated at 6O0C. After completion, the reaction mixture was cooled to room temperature and was washed with saturated sodium bicarbonate (2 x 25 mL), water (2 x 25 mL), brine (1 x 15 mL), dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by silica gel column chromatography to give almost quantitative yield of 5. 1H NMR (CDCl3+ CD3OD, 400 MHz) delta 8.41 (d, J = 9.2 Hz, IH), 8.08 (d, J= 2.4 Hz, IH), 7.58 (dd, J= 2.4 Hz, 9.2 Hz, IH), 3.58 (s, 2H).
With triethylamine; In dichloromethane; at 0 - 20℃;
Methyl-2-(2-cyanoacetamido)-5-bromobenzoate (5)The title compound can be prepared by two alternative methods: A) To a solution of 4 (1.00 g, 4.35 mmol) in 16 mL of dichloromethane was added triethylamine (1.32 g, 13.05 mmol) and the reaction mixture was cooled to 0 0C. To the above solution was added cyanoacetyl chloride (10.87 mmol) (prepared freshly from cyanoacetic acid (0.92 g, 10.87 mmoles) and oxalyl chloride (10.87 mmoles) in 16 mL dichloromethane and catalytic amounts of DMF). The reaction mixture was allowed to warm at room temperature. After completion, dichloromethane was removed in vacuo and the crude residue was taken up in ethylacetate (50 mL) and the organic layer was washed with saturated sodium bicarbonate (2 x 25 mL), water (2 x 25 mL), brine (1 x 15 mL), dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by silica gel column chromatography to give almost quantitative yield of 5. 1U NMR (CDCl3, 400 MHz) delta 8.41 (d, J = 9.2Hz, IH), 8.08 (d, J = 2.4 Hz, IH), 7.58 (dd, J = 2.4 Hz, 9.2 Hz, IH), 3.58 (s,2H).
Copper(I) cyanide (available from Alfa Aesar; 10.71 g, 0.12 mol) was added to a stirred solution of methyl 2-amino-5-bromobenzoate (available from Aldrich Chemical Company, Inc.; 25.0 g, 0.11 mol) in N-methyl-2-pyrrolidone (50 mL) and the mixture was stirred at 180 C. for 4 h. The reaction mixture was cooled to room temperature, diluted with aqueous ethylenediamine (water:ethylenediamine=1:1; 250 mL), and filtered through pad of Celite. The filtrate was extracted with EtOAc (3*100 mL), and the combined organic layers were washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, filtered, evaporated under reduced pressure, and purified by silica gel chromatography (100-200 mesh), using 5-10% ethyl acetate/hexanes as eluent, to give 2-amino-5-cyanobenzoic acid methyl ester (14.0 g, 73%) as a yellow powder. 1H NMR (400 MHz, DMSO-d6) delta 8.05 (d, J=1.9 Hz, 1H), 7.57 (dd, J=1.9, 8.8 Hz, 1H), 7.44 (br s, 2H), 6.88 (d, J=8.8 Hz, 1H), 3.81 (s, 3H).
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℃;
Into a 250-mL round-bottom flask was placed a solution of methyl 2-amino-5-bromobenzoate (5 g, 21.73 mmol, 1.00 equivalent), <strong>[6419-36-9]2-<strong>[6419-36-9](pyridin-3-yl)acetic acid hydrochloride</strong></strong> (4.5 g, 25.92 mmol, 1.20 equivalents), HATU (10 g, 26.30 mmol, 1.20 equivalents), and DIEA (8.5 g, 65.77 mmol, 3.00 equivalents) in N,N-dimethylformamide (100 mL). After stirring overnight at 20 C., the reaction was quenched with 100 mL of water and extracted with 3×100 mL of dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:2-1:1) to give the title compound as a yellow solid.
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;
Into a 250-mL round-bottom flask was placed a solution of methyl 2-amino-5-bromobenzoate (5 g, 21.73 mmol, 100%), <strong>[6419-36-9]2-<strong>[6419-36-9](pyridin-3-yl)acetic acid hydrochloride</strong></strong> (4.5 g, 25.92 mmol), HATU (10 g, 26.30 mmol 100%) and DIEA (8.5 g, 65.77 mmol, 100%) in N,N-dimethylformamide (100 mL). The resulting solution was stirred overnight at 20 C. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 3*100 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2-1:1) to provide the title compound as a yellow solid.
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;
intermediate 10: step amethyl 5-bromo-2-(2-(pyridin-3-yl)acetamido)benzoateInto a 250-mL round-bottom flask was placed a solution of methyl 2-amino-5-bromobenzoate (5 g, 21.73 mmol, 100%), <strong>[6419-36-9]2-<strong>[6419-36-9](pyridin-3-yl)acetic acid hydrochloride</strong></strong> (4.5 g, 25.92 mmol), HATU (10 g, 26.30 mmol 100%) and DIEA (8.5 g, 65.77 mmol, 100%) in N,N-dimethylformamide (100 mL). The resulting solution was stirred overnight at 20 C. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 3x100 mL of dichioro methane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :2-1 : 1) to provide the title compound as a yellow solid.
methyl 5-bromo-2-(4,4,4-trifluorobutanamido)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine In dichloromethane at 0 - 20℃;
69.b Methyl 5-bromo-2-(4,4,4-trifluorobutanamido)benzoate
Methyl 2-amino-5-bromobenzoate (26.0 g, 113 mmol), triethylamine (18.9 mL, 136 mmol), and dichloromethane (400 mL) were combined in a round bottom flask. The contents were cooled to 0° C. in an ice water bath, then a solution of 4,4,4-trifluorobutanoyl chloride in dichloromethane (137 mmol, Intermediate 69: step a) was cannulated into the reaction vessel over approximately 15 minutes. The reaction solution was stirred at 0° C. for one hour, then the ice bath was removed and the contents allowed to warm to room temperature gradually, then stirred at room temperature overnight. Reaction contents were quenched with the addition of saturated, aqueous NH4Cl solution then transferred to a separatory funnel with EtOAc dilution. The organic phase was separated and the aqueous layer was extracted twice with additional EtOAc. The combined organic phases were dried over MgSO4, filtered and rotovapped to dryness to afford the title compound.
General procedure for the preparation of methyl 5-bromo-2-isothiocyanatobenzoate (2)
A solution of methyl 2-amino-5-bromobenzoate 1 (3.05 g, 13.04 mmol) in dichloromethane (40 mL) was added dropwise at room temperature to a solution of di-2-pyridyl thionocarbonate(DPT) (3.0 g, 13.03 mmol) in dichloromethane(40 mL) in substitution of the tedious previous method using thiophosgene, a potential air pollutant (Hodgkins and Ettilinger,1956). The mixture was stirred at room temperature for 24 h. The resulting solution was evaporated under reduced pressure, to give a residue that was dissolved with propan-2-one and added in water. The resulting solid was collected, washed with water, dried, and crystallized from petroleum ether to give isothiocyanate 2 as yellow crystals.
4'-chloro-2-fluoro-4-iodo-5-methoxy-3'-methyl-1,1'-biphenyl[ No CAS ]
[ 52727-57-8 ]
methyl 5-bromo-2-((4'-chloro-2-fluoro-5-methoxy-3'-methyl-[1,1'-biphenyl]-4-yl)amino)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 2h;
A sealable vial was charged vial with methyl 2-amino-5-bromobenzoate (3.63 g, 15.80 mmol), cesium carbonate (8.75 g, 26.9 mmol), Pd2(dba)3 (0.362 g, 0.395 mmol), xantphos (0.457 g, 0.790 mmol), and 4'-chloro-2-fluoro-4-iodo-5-methoxy-3'-methyl-1,1'-biphenyl (7.14 g, 18.96 mmol). The vial was sealed with septum cap and CPME (31.6 ml) was added. The mixture was heated at 100 C. for 2 h. The mixture was cooled and partitioned between water (30 mL) and EtOAc (50 mL). There was an insoluble solid that was suspended between the layers. The organic layer and the solid were collected together and the mixture was concentrated. The resulting yellow solid was taken up in DCM (100 mL) and filtered through a plug of celite. The mother liquor was concentrated to give a yellow solid that was slurried in IPA (100 mL) and collected by vacuum filtration to provide methyl 5-bromo-2-((4'-chloro-2-fluoro-5-methoxy-3'-methyl-[1,1'-biphenyl]-4-yl)amino)benzoate (7.15 g, 14.94 mmol, 95% yield) as a yellow solid. (ESI) 476.1 (M-H)-.
Stage #1: 5-bromo-2-aminobenzoic acid methyl ester With sodium hydride In tetrahydrofuran for 0.333333h;
Stage #2: 3-chlorosulfonyl-4-methylbenzoic acid chloride In tetrahydrofuran at 20℃;
With potassium phosphate monohydrate; dichloro bis((p-dimethylaminophenyl)-?-di-tert-butylphosphine)palladium(II); In 1,4-dioxane; water; at 100℃; for 16h;
To a mixture of methyl 2-amino-5-bromobenzoate (2.32 g, 10.1 mmol), 4-fluorophenylboronic acid (1.70 g, 12.1 mmol, 1.20 equiv), PdCl2(amphos)2 (79.0 mg, 0.112mmol, 1.1 mol %), and tripotassium phosphate n-hydrate (3.28 g, ca. 12 mmol, ca. 1.2 equiv)were added 1,4-dioxane (40 mL) and H2O (4 mL) at room temperature and the mixture washeated at 100 C with stirring for 16 h. After cooling to room temperature, the mixture wasconcentrated under reduced pressure. The mixture was extracted with EtOAc (10 mL × 3),and the combined organic extract was washed with brine (5 mL), dried (Na2SO4), and, afterfiltration, the filtrate was concentrated under reduced pressure. The residue was purified byrecrystallization from n-hexane to give methyl 2-amino-5-(4-fluorophenyl)benzoate (2.01 g,8.20 mmol, 82.0%) as a pale yellow solid.
463.5 mg of methyl 5-bromoanthranilate was placed in an argon atmosphere and dissolved in 2 mL of acetic acid. 499.5 mg of N-iodosuccinimide was added thereto, and the mixture was stirred at room temperature for 17 hours. The reaction solution was added dropwise to a saturated aqueous sodium hydrogen carbonate solution (5 mL) to neutralize acetic acid. This was extracted with ethyl acetate, and the ethyl acetate phase obtained was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and ethyl acetate was distilled off under reduced pressure.The obtained material was placed in an argon atmosphere and dissolved in 6.6 mL of triethylamine. 74.2 mg of bis (triphenylphosphine) palladium (II) dichloride, 22.3 mg of copper (I) iodide and 0.34 mL of trimethylsilylacetylene were added thereto, and the mixture was stirred at room temperature for 90 minutes. The reaction solution was diluted with dichloromethane, washed sequentially with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.The obtained substance dissolved in 9 mL of N-methyl-2-pyrrolidone was added dropwise to a mother liquor in which 512.3 mg of potassium tert-butoxide was changed to 0 C. under an argon atmosphere and 7 mL of N-methyl-2-pyrrolidone was added , Stirred for 1 hour, and then stirred at room temperature for 90 minutes. The reaction solution was again brought to 0 C., 32 mL of water was added, and the temperature was returned to room temperature. The diethyl ether phase extracted with diethyl ether was washed with water, saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, And the solvent was distilled off. The residue was dissolved in methanol, the insoluble matter was removed by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography using 10% ethyl acetate / hexane as a developing solvent, and the solvent was distilled off .62.5 mg of the obtained substance was placed under an argon atmosphere, 2 N sodium hydroxide 2.4 mL and 2.4 mL ethanol were added and the temperature was adjusted to 40 C. and stirred for 2 hours. The reaction solution was brought to room temperature, the pH was made acidic using 3 N hydrochloric acid, sodium chloride was added until saturation, and the ethyl acetate phase eluted with ethyl acetate was dried with anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, it was suspended in diethyl ether, the brown solids in the insoluble matter was removed, and the remaining insoluble matter was washed with warm hexane. The solvent was distilled off, dissolved in ethyl acetate, activated charcoal was added to adsorb impurities, and the activated carbon was removed by filtration. The residue obtained by distilling off the solvent was dissolved in diethyl ether, the insoluble matter was removed by filtration, and the solvent was distilled off. As a result, 54.2 mg (yield 11.3%) of a compound was obtained.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 100℃; for 6h;Inert atmosphere;
to with magnetic rotor and the condensation of the 100 ml dry three-mouth bottle is sequentially added in the intermediate 4 (6.90 g, 30 mmol, 1.0 equivalent), 2, 5 - dimethyl phenyl boronic acid (3.84 g, 31.5 mmol, 1 . 05 equivalent), Pd (PPh3)4(1.04 G, 0.9 mmol, 0 . 03 equivalent), K2CO3(8.29 G, 60 mmol, 2.0 equivalent), replacing the nitrogen three times, under the protection of nitrogen added to the 1, 4 - dioxane (30 ml) and H2O (15 ml). The oil bath temperature is raised to 100 C stirring reaction 6.0 hours, cooling to room temperature, for 30 ml ethyl acetate extraction three times, using anhydrous Na2SO4Drying the organic phase, then filtered, distilled under reduced pressure, the solvent is removed, dry sample, using silica gel column chromatography column to carry out the separation and purification, eluent petroleum ether/ethyl acetate=20 is: 1, to obtain white solid 5.29 g, yield 69%. Directly used for the next step reaction.
69%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 100℃; for 6h;Inert atmosphere;
Intermediate 4 (6.90 g, 30 mmol, 1.0 eq.) was added sequentially to a 100 mL dry three-necked flask with a magnetic rotor and a condensing tube.2,5-Dimethylbenzeneboronic acid (3.84 g, 31.5 mmol, 1.05 equivalent),Pd(PPh3)4 (1.04g, 0.9mmol, 0.03 equivalents),K2CO3 (8.29g, 60mmol, 2.0 equivalents),Swap three times with nitrogen, was added 1,4-dioxane (30mL) and H2O (15mL) under nitrogen.The temperature of the oil bath was raised to 100 C and the reaction was stirred for 6.0 hours.After cooling to room temperature, it was extracted three times with 30 mL of ethyl acetate.Then, filtration, distillation under reduced pressure, removal of the solvent, dry-loading, separation and purification using a silica gel column chromatography column, the eluent is petroleum ether / ethyl acetate = 20:1,5.29 g of a white solid were obtained in a yield of 69%. Used directly in the next step.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; at 100℃; for 6h;Inert atmosphere;
to with magnetic rotor and the condensation of the 100 ml dry three-mouth bottle is sequentially added in the intermediate 4 (5.75 g, 25 mmol, 1.0 equiv), 2 - methyl boronic acid (3.60 g, 26.3 mmol, 1 . 05 equiv), Pd (PPh3) 4 (866.7 mg, 0 . 75 mmol, 0 . 03 equiv), K2CO3 (6.91 g, 50 mmol, 2.0 equiv), replacing the nitrogen three times, under the protection of nitrogen added 1, 4 - dioxane (25 ml) and H2O (10 ml). The oil bath temperature is raised to 100 C stirring reaction 6.0 h, cooling to room temperature, for 30 ml ethyl acetate extraction three times, the organic phase with anhydrous Na2SO4 drying, then filtered, distilled under reduced pressure, the solvent is removed, dry sample, using silica gel column chromatography column to carry out the separation and purification, eluent petroleum ether/ethyl acetate=20 is: 1, to obtain white solid 4.71 g, yield 78%.
78%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 100℃; for 6h;Inert atmosphere;
Intermediate 4 (5.75 g, 25 mmol, 1.0 equiv) was added sequentially to a 100 mL dry three-necked flask with a magnetic rotor and a condenser.2-methylphenylboronic acid (3.60 g, 26.3 mmol, 1.05 equiv),Pd(PPh3)4 (866.7 mg, 0.75 mmol, 0.03 equiv),K2CO3 (6.91g, 50mmol, 2.0equiv),Swap three times with nitrogen, was added 1,4-dioxane (25mL) and H2O (10mL) under nitrogen.The temperature of the oil bath was raised to 100 C and the reaction was stirred for 6.0 h.After cooling to room temperature, it was extracted three times with 30 mL of ethyl acetate.Then filtered, distilled under reduced pressure, solvent removed, dry loading,Separation and purification by silica gel column chromatography, the eluent is petroleum ether / ethyl acetate = 20:1,4.71 g of a white solid were obtained in a yield of 78%.
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 In water; N,N-dimethyl-formamide at 100℃; for 1.25h; Inert atmosphere;
186.1 Step 1: Preparation of methyl 4-amino-4'-fluoro-[1,1'-biphenyl]-3-carboxylate
Nitrogen was bubbled for 5 min through a mixture of methyl 2-amino-5- bromobenzoate (2.00 g, 8.69 mmol), 4-fluorophenylboronic acid, pinacol ester (2.90 g, 12.04 mmol), potassium phosphate tribasic (3.69 g, 17.39 mmol), water (3.5 mL) in N,N- dimethylformamide (10.5 mL), then [1,1 - bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (710 mg, 0.87 mmol) was added. The resulting mixture was heated to 100 °C for 1.25 hours. After return to room temperature, the reaction was diluted with water (100 mL) and diethyl ether (100 mL) and the organic phase was separated. The aqueous phase was extracted further with diethyl ether (100 mL) and then Ethyl acetate (100 mL). The organic phases were combined, washed with water (100 mL), dried over MgSO4 and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel eluting with 5-35% Ethyl acetate in cyclohexane to give the title compound as an off- white solid (2.08 g, 97%). H NMR (400 MHz, CDCl3): d 8.06 (d, J = 2.3 Hz, 1 H), 7.50-7.44 (m, 3 H), 7.08 (dd, J = 8.7, 8.7 Hz, 2 H), 6.74 (d, J = 8.6 Hz, 1 H), 5.78 (s, 2 H), 3.90 (s, 3 H).
methyl 5-bromo-2-(2-chloronicotinamido)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃;
4.1.1 General procedure for the synthesis of compounds 15, 19, 27 and 29
General procedure: The appropriate acid (1mmol) was dissolved in 5ml of DCM and added nearly 0.5ml of DMF (for stability of acid chlorides) and mixture was cooled to 10°C, added oxalyl chloride (2mmol) dropwise for about 10min. The reaction was continued to stir until all the acid content converted into acid chloride and monitored using TLC. The Solvent used DCM was evaporated using Rota vapor to remove excess oxalyl chloride and dried under vacuum to give yellowish oil, which further took forward without any purification. (0015) The Acid chloride (1mmol) was dissolved in 10ml of THF, N, N-Diisopropylethylamine (3mmol) was added slowly and stirred for 30min before adding methyl 2-amino-5-bromobenzoate (1mmol). The reaction was stirred for 2hrs at room temperature by regular monitoring using TLC and finally evaporated to get a fine solid. The hydrolysis of methyl esters (1mmol) was carried out by dissolving the methyl esters in 9:1 ratio of THF: H2O followed by addition of Lithium hydroxide monohydrate (2mmol) and allowed to stir for overnight (12hr) at room temperature. The crude mixture was acidified with 2N HCl to bring the solution to acidic pH and extracted with Ethyl acetate. The organic layers were collected, washed with brine, dried over Na2SO4 and evaporated to get solid.
90%
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃;
4.1.1 General procedure for the synthesis of compounds 15, 19, 27 and 29
General procedure: The appropriate acid (1mmol) was dissolved in 5ml of DCM and added nearly 0.5ml of DMF (for stability of acid chlorides) and mixture was cooled to 10°C, added oxalyl chloride (2mmol) dropwise for about 10min. The reaction was continued to stir until all the acid content converted into acid chloride and monitored using TLC. The Solvent used DCM was evaporated using Rota vapor to remove excess oxalyl chloride and dried under vacuum to give yellowish oil, which further took forward without any purification. (0015) The Acid chloride (1mmol) was dissolved in 10ml of THF, N, N-Diisopropylethylamine (3mmol) was added slowly and stirred for 30min before adding methyl 2-amino-5-bromobenzoate (1mmol). The reaction was stirred for 2hrs at room temperature by regular monitoring using TLC and finally evaporated to get a fine solid. The hydrolysis of methyl esters (1mmol) was carried out by dissolving the methyl esters in 9:1 ratio of THF: H2O followed by addition of Lithium hydroxide monohydrate (2mmol) and allowed to stir for overnight (12hr) at room temperature. The crude mixture was acidified with 2N HCl to bring the solution to acidic pH and extracted with Ethyl acetate. The organic layers were collected, washed with brine, dried over Na2SO4 and evaporated to get solid.
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