* 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.
Stage #1: at 0 - 90℃; Stage #2: With sodium hydroxide In water; ethyl acetate
Example 21; 7V-(3-Chloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[l,2-fl]pyridine-2-yl)-l,3,4- thiadiazol-2-yl) Phynyl)methanesulfonamide; Methyl-4-amino-2-chlorobenzoate (100).; To a stirred solution of methyl-2-chloro-4- nitro benzoate 99 (0.50 g, 2.3 mmol) in EtOH was added stannous chloride (2.62 g, 11.6 mmol) at 0 0C and the resulting mixture was stirred at 90 0C for 2 h. After completion, the reaction mixture was allowed to cool to room temperature and concentrated in vacuo. 1 M NaOH (20 mL) and EtOAc (30 mL) was added to the residue and the resulting mixture filtered through Celite. The filtrate was extracted with EtOAc (3 X 25 mL) and the combined organic layers were dried over Na2SO4 and concentrated. The crude compound was purified by column chromatography, eluting with 50percent EtOAc/ hexane, to afford the title intermediate 100 as a yellow solid (0.43 Ig, 100percent yield).
90%
With hydrogen In methanol; water at 20℃; for 4 h;
A solution of methyl 2-chloro-4-nitrobenzoate (46,0.116 mol) in methanol and 30percent w/w of Raney 2800 nickel slurry in water (activecatalyst-Aldrich), was stirred under hydrogen in a hydrogenation apparatus atroom temperature for 4 hours. The catalyst was removed by filtration on celiteand solvent removed in vacuum. Recrystallized from methanol gave 90percent yield of a white solid, mp 108.5-109.5 C. 1H NMR (DMSO-d6; 400 MHz): δ 7.64 (d, J = 8.6 Hz, 1H), 6.63 (d, J = 2.2 Hz, 1H), 6.51 (dd, J = 8.7, 2.2 Hz, 1H), 6.17 (s, 2H), 3.73(s, 3H). 13C NMR (DMSO-d6;100 MHz): δ 164.73, 153.48, 134.70, 133.56, 114.51, 113.82, 111.55, 51.40. GC-MSm/z (percent):185 (M+, 30); 154 (M-31+,100); 126 (M-59+, 20).
407 mg
for 1.5 h; Reflux
Step 2: To a stirred solution of methyl 2-chloro-4-nitrobenzoate (468 mg, 2.17 mmol) in ethanol was added Sn(ll) chloride and heated to reflux for 1 .5 h. TLC showed complete consumption of starting material. The reaction mixture was cooled to room temperature. The solvent was removed in vacuo and extracted with EtOAc. The organic layer was washed with water and brine. The extract was dried over MgSO4 and concentrated under reduced pressure to give desired product methyl 4-amino-2-chlorobenzoate (407 mg).
Reference：
[1] Patent: WO2010/65760, 2010, A1, . Location in patent: Page/Page column 150
[2] Journal of Medicinal Chemistry, 2010, vol. 53, # 4, p. 1546 - 1562
[3] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 17, p. 4377 - 4381
[4] Acad. romine Stud. Cerc. Chim., 1956, vol. 4, p. 175,177
[5] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 13, p. 2991 - 3013
[6] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 5, p. 1749 - 1761
[7] Patent: WO2009/126863, 2009, A2, . Location in patent: Page/Page column 164-165
[8] Patent: US2006/63779, 2006, A1, . Location in patent: Page/Page column 112
[9] Patent: US2011/130398, 2011, A1, . Location in patent: Page/Page column 22
[10] Patent: WO2013/68467, 2013, A1, . Location in patent: Page/Page column 64
[11] Patent: WO2018/68296, 2018, A1, . Location in patent: Page/Page column 51; 53
2
[ 67-56-1 ]
[ 2457-76-3 ]
[ 46004-37-9 ]
Yield
Reaction Conditions
Operation in experiment
98%
at 0 - 20℃; for 32 h;
To a solution of 4-amino-2-chlorobenzoic acid (2 g, 1 1.66 mmol) in MeOH (55.5 mL) was added thionyl chloride (3.40 mL, 46.6 mmol) dropwise at 0°C. The resulting solution was stirred at rt. After 32h the solvent was removed. The crude product was taken up in EtOAc and washed with sat. aqueous NaHC03 and brine. The organic layer was dried over MgS04, filtered and evaporated to dryness to give intermediate 125a (2.146 g, 1 1.45 mmol, 98 percent yield) as white solid.1 H NMR (400 MHz, DMSO-c/6) δ ppm 7.64 (d, J=8.56 Hz, 1 H), 6.64 (d, J=2.20 Hz, 1 H), 6.51 (dd, J=8.80, 2.20 Hz, 1 H), 6.16 (bs, 2 H), 3.73 (s, 3 H). Intermediate 125b: methyl 2-chloro-4-cvanobenzoate
97.4%
at 0℃; Heating / reflux
To a 200 mL MeOH solution of 4-amino-2-chlorobenzoic acid (12 g, 67.84 mmol) was added 2 equivalents of SOCl2 (11 mL, 135.7 mmol) at 0° C. The ice-water bath was removed after the addition and the reaction mixture was heated to reflux until the starting material had disappeared, as indicated by LC-MS. After the reaction was cooled back to RT, solvent and excess of SOCl2 were removed under reduced pressure. The residue was suspended in 10percent aqueous Na2CO3 solution. The precipitate that formed was filtered and washed with water until the washes became neutral. The filter cake was then re-dissolved in 200 mL of ethyl acetate, and the ethyl acetate layer was washed with water, brine, and dried over anhydrous Na2SO4. After concentrated under reduced pressure and vacuum drying, 12.27 g of product was obtained (97.4percent). M+H+(186).
97%
for 18 h; Heating / reflux
Example E 4-Amino-2-chlorobenzoic acid methyl ester Acetyl chloride (2.5ml) was added drop-wise to a stirred solution of 4-amino-2-chlorobenzoic acid (2.22g, 12.9mmol) in methanol (75ml). The mixture was heated at reflux for 18h, cooled and reduced in vacuo. The residue was taken up in EtOAc, washed with saturated sodium hydrogen carbonate solution and brine, dried and reduced in vacuo to afford a beige solid identified as 4-amino-2-chlorobenzoic acid methyl ester, yield 2.32g, 97percent.
20.9 g
Stage #1: at 0 - 20℃; for 0.5 h; Stage #2: for 18 h; Reflux
To methanol at 0 °C was added dropwise acetyl chloride (314.7 mmol, 22.4 mL). After the addition of acetyl chloride, the reaction mixture was stirred at rt for30 mm, then 4-amino-2-chlorobenzoic acid 1(116.6 mmol, 20.0 g) was added in one portion. The reaction mixture was heated at reflux for 18 hours, cooled to 0 °C, and concentrated under vacuum. The residue was suspended in 250 mL of ethyl acetate, cooled to 0 °C, and saturated aqueous NaHCO3 was added (pH was 8). The mixture was partitioned and extracted with ethyl acetate (200 mL). Combined organic layers were washed with brine, dried over MgSO4, and concentrated under vacuum to afford 20.9 g of title compound as a yellow solid which was used as such in next step without purification. 1H NMR (400 MHz, CDCI3): 67.78 (d, J= 8.6 Hz, 1H), 6.70 (d, J= 2.3 Hz, 1H), 6.52 (dd, J= 8.6, 2.3 Hz, 1H), 4.09 (bs, 1H), 3.86 (s, 3H). LCMS (M+1) 186.1,188.1.
Stage #1: With lithium hydroxide In tetrahydrofuran at 20℃; for 0.333333 h; Stage #2: for 2 h; Heating / reflux
4-Amino-2-chloro-benzoic acid (2.50 g) and lithium hydroxide monohydrate (611 mg) were suspended in tetrahydrofuran (20 ml), and the suspension was stirred at room temperature for 20 min. Thereafter, dimethylsulfuric acid (1.38 ml) was added to the reaction mixture, and the mixture was stirred under reflux for 2 hr. The solvent was removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was neutralized with a saturated aqueous sodium hydrogencarbonate solution and was extracted with diethyl ether. The diethyl ether layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure to give methyl 4-amino-2-chloro-benzoate (1.68 g, yield 62percent). Methyl 4-amino-2-chloro-benzoate (1.68 g) and 5-methoxymethylene-2,2-dimethyl-[1,3]dioxan-4,6-dione (1.53 g) were dissolved in 2-propanol (25 ml), and the mixture was stirred at 100°C for 15.5 hr. The solvent was removed by distillation under the reduced pressure, and the residue was washed with diethyl ether to give methyl 2-chloro-4-[(2,2-dimethyl-4,6-dioxo-[1,3]dioxan-5-ylidenemeth yl)-amino]-benzoate (1.92 g, yield 63percent).
Acetyl chloride (2.5 ml) was added drop-wise to a solution of 2-chloro-4-cyano-benzoic acid (2.22 g, 12.94 mmol) in methanol (75 ml) while stirring. The mixture was heated at reflux for 18 h, cooled and concentrated in vacuo. The residue was taken up in ethyl acetate, washed with saturated NaHCO3 and brine and concentrated in vacuo to give a beige solid identified as 4-amino-2-chloro-benzoic acid methyl ester (2.32 g, 97percent).
Stage #1: With hydrogenchloride; sodium nitrite In water at 0 - 5℃; for 0.25 h; Sonication Stage #2: With potassium cyanide In water at 75℃; for 0.75 h;
2-Chloro-4-cyanobenzoic acid methyl ester 4-Amino-2-chlorobenzoic acid methyl ester (4.7g, 25mmol) was taken up in water (12ml) and concentrated hydrochloric acid (12ml) was added. The mixture was sonicated to form a fine suspension and then cooled to 0°C. A solution of sodium nitrite (1.91g, 27.7mmol) in water (15ml) was then added dropwise so as to maintain the temperature of the reaction between 0-5°C. The mixture was stirred at 0-5°C for 15 minutes and then neutralised by addition of solid sodium bicarbonate. The resulting solution was then added to a solution of copper cyanide (2.79g, 31mmol) and potassium cyanide (4.0g, 61mmol) in water (25ml) at 75°C. The mixture was stirred at 75°C for 45 minutes, allowed to cool and then extracted with toluene (2 times). The combined extracts were washed with brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant 20percent ethyl acetate/ 80percent pet. ether) to give a pale orange solid identified as 2-chloro-4-cyanobenzoic acid methyl ester, yield 2.61g, 53percent.
Reference：
[1] Patent: EP1512687, 2005, A1, . Location in patent: Page/Page column 9-10
[2] Journal of Medicinal Chemistry, 2008, vol. 51, # 24, p. 8124 - 8134
10
[ 773837-37-9 ]
[ 46004-37-9 ]
[ 98592-34-8 ]
Yield
Reaction Conditions
Operation in experiment
41.1%
Stage #1: With hydrogenchloride; sodium nitrite In water at 0 - 5℃; for 0.75 h; Stage #2: With sodium hydrogencarbonate In water at 75 - 80℃; for 1.5 h;
Intermediate 125a (2.146 g, 1 1.56 mmol) was dispersed in water (8 mL) and HCI (12 ml, 96 mmol) and the mixture was cooled to 0°C. An aqueous solution of sodium nitrite (0.885 g, 12.83 mmol) was added dropwise in such a manner that the temperature never exceeded 5°C. The resulting solution was stirred at 0-5°C for 45 min. and neutralized by addition of solid NaHC03. The diazonium salt was added to an aqueous solution of copper (I) cyanide (1.294 g, 14.45 mmol) and sodium cyanide (1.383 g, 28.2 mmol) in water (25 mL) at 75°C. The contents were stirred for 1.5 hr at 75-80°C. After cooling the reaction mixture to rt, the product was extracted with toluene (4x100ml). The combined organic layers were washed with brine, dried over MgS04, filtered and the solvent was removed in vaccum. The crude product was purified by flash chromatography with Isco Combiflash: 80 g Redisep column, eluent Heptane / Ethyl acetate (A / B), detection at 254 nm. Mobile phase: 5 min. (0percent B), from 0 t o 20percent B for 10 min. then 20percent B for 10 min. The priduct containing fractions were combined and evaporated to dryness to yield intermediate 125b (939 mg, 4.76 mmol, 41.1 percent yield) as orange solid.1 H NMR (400 MHz, DMSO-c/6) δ ppm 8.23 (s, 1 H), 7.96 (bs, 2 H), 3.91 (s, 3 H).RtMSi= 1 -80 min., [M+H]+ = 196.1
Methyl-2-chloro-4-(methylsulfonamido) benzoate (101).; To a stirred solution of methyl-2-chloro-4-amino benzoate 100 (0.457 g, 2.45 mmol) in DCM cooled to 0 0C was added pyridine (2 mL) followed by dropwise addition of methanesulphonyl choride (0.2 mL, 2.5 mmol). After addition was complete, the reaction was allowed to warm to room temperature and stirred for 2 h. After completion, the reaction mixture was concentrated in vacuo. 1 N HCl (5 mL) was added to the residue and the mixture extracted with EtOAc (10 mL). The organic phase was dried over Na2SO4 and concentrated under high vacuum. The crude compound was purified by column chromatography to afford the title intermediate 101 as a solid (0.54 g, 84percent yield).
Example 21; 7V-(3-Chloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[l,2-fl]pyridine-2-yl)-l,3,4- thiadiazol-2-yl) Phynyl)methanesulfonamide; Methyl-4-amino-2-chlorobenzoate (100).; To a stirred solution of methyl-2-chloro-4- nitro benzoate 99 (0.50 g, 2.3 mmol) in EtOH was added stannous chloride (2.62 g, 11.6 mmol) at 0 0C and the resulting mixture was stirred at 90 0C for 2 h. After completion, the reaction mixture was allowed to cool to room temperature and concentrated in vacuo. 1 M NaOH (20 mL) and EtOAc (30 mL) was added to the residue and the resulting mixture filtered through Celite. The filtrate was extracted with EtOAc (3 X 25 mL) and the combined organic layers were dried over Na2SO4 and concentrated. The crude compound was purified by column chromatography, eluting with 50% EtOAc/ hexane, to afford the title intermediate 100 as a yellow solid (0.43 Ig, 100% yield).
90%
With hydrogen; In methanol; water; at 20℃; for 4h;
A solution of methyl 2-chloro-4-nitrobenzoate (46,0.116 mol) in methanol and 30% w/w of Raney 2800 nickel slurry in water (activecatalyst-Aldrich), was stirred under hydrogen in a hydrogenation apparatus atroom temperature for 4 hours. The catalyst was removed by filtration on celiteand solvent removed in vacuum. Recrystallized from methanol gave 90% yield of a white solid, mp 108.5-109.5 C. 1H NMR (DMSO-d6; 400 MHz): delta 7.64 (d, J = 8.6 Hz, 1H), 6.63 (d, J = 2.2 Hz, 1H), 6.51 (dd, J = 8.7, 2.2 Hz, 1H), 6.17 (s, 2H), 3.73(s, 3H). 13C NMR (DMSO-d6;100 MHz): delta 164.73, 153.48, 134.70, 133.56, 114.51, 113.82, 111.55, 51.40. GC-MSm/z (%):185 (M+, 30); 154 (M-31+,100); 126 (M-59+, 20).
With tin(ll) chloride; In ethanol; at 55℃;
Example 164 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(2-methoxyethyl)methyl- sulfonamido)benzamide <n="166"/> To 5 g of methyl 2-chloro-4-nitrobenzoate in 100 mL of EtOH was added 20 g of Tin (II) Chloride in portions. The reaction was heated to 55C and monitored by TLC until complete. Solvent was concentrated and extraction was performed in Ethyl Acetate and water with TEA to reduce emulsions. The organic layer was dried over Magnesium Sulfate, filtered and concentrated to give 3.9 g of methyl 4-amino-2-chlorobenzoate.
With ethanol; tin(ll) chloride; at 55℃;
To 5 g of methyl 2-chloro-4-nitrobenzoate in 100 mL of EtOH was added 20 g of Tin (II) Chloride in portions. The reaction was heated to 55 C. and monitored by TLC until complete. Solvent was concentrated and extraction was performed in Ethyl Acetate and water with TEA to reduce emulsions. The organic layer was dried over Magnesium Sulfate, filtered and concentrated to give 3.9 g of methyl 4-amino-2-chlorobenzoate. 1 g of methyl 4-amino-2-chlorobenzoate was cooled to 0 C. in DCM with 485 muL of Pyridine before Methanesulfonyl Chloride was added dropwise. The reaction was allowed to warm to room temperature and stir overnight. Solvent was concentrated and the crude material was dissolved in Ethyl Acetate and extracted with saturated bicarbonate 10' solution and then brine. The crude material was dried over Magnesium Sulfate, filtered and concentrated to give 1.54 g of methyl 2-chloro-4-(methylsulfonamido)benzoate. 107 muL of 1-bromo-2-methoxyethane and 556 mg of Cesium Carbonate were added to 150 mg of methyl 2-chloro-4-(methylsulfonamido)benzoate in DMF and stirred at room temperature for 16 hours. The reaction mixture was extracted in Ethyl Acetate twice with saturated bicarbonate and once with brine, dried over Magnesium Sulfate, filtered and concentrated to give methyl 2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoate. 182 mg of methyl 2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoate was hydrolyzed via Procedure M to yield 169 mg of crude 2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoic acid. 65 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(2-methoxyethyl)methylsulfonamido)benzamide. MS (Q1) 494 (M)+.
With hydrogen;palladium 10% on activated carbon; In ethyl acetate; under 2585.81 Torr; for 3h;
A solution of 4-nitro-2-chlorobenzoic acid methyl ester (Aldrich, 700 mg, 3.24 mmol) in ethyl acetate (50 mL) was added 10% Pd/C (50 mg). The mixture was vigorously shaken in a Parr under an atmosphere of hydrogen (50 psi) for 3 h. The mixture was filtered through a short pad of celite and the filtrate was concentrated to give 4-amino-2-chlorobenzoic acid methyl ester as a light yellow solid which was directly used for the next step.
407 mg
With ethanol; tin(ll) chloride; for 1.5h;Reflux;
Step 2: To a stirred solution of methyl 2-chloro-4-nitrobenzoate (468 mg, 2.17 mmol) in ethanol was added Sn(ll) chloride and heated to reflux for 1 .5 h. TLC showed complete consumption of starting material. The reaction mixture was cooled to room temperature. The solvent was removed in vacuo and extracted with EtOAc. The organic layer was washed with water and brine. The extract was dried over MgSO4 and concentrated under reduced pressure to give desired product methyl 4-amino-2-chlorobenzoate (407 mg).
To a solution of 4-amino-2-chlorobenzoic acid (2 g, 1 1.66 mmol) in MeOH (55.5 mL) was added thionyl chloride (3.40 mL, 46.6 mmol) dropwise at 0C. The resulting solution was stirred at rt. After 32h the solvent was removed. The crude product was taken up in EtOAc and washed with sat. aqueous NaHC03 and brine. The organic layer was dried over MgS04, filtered and evaporated to dryness to give intermediate 125a (2.146 g, 1 1.45 mmol, 98 % yield) as white solid.1 H NMR (400 MHz, DMSO-c/6) delta ppm 7.64 (d, J=8.56 Hz, 1 H), 6.64 (d, J=2.20 Hz, 1 H), 6.51 (dd, J=8.80, 2.20 Hz, 1 H), 6.16 (bs, 2 H), 3.73 (s, 3 H). Intermediate 125b: methyl 2-chloro-4-cvanobenzoate
97.4%
With thionyl chloride; at 0℃;Heating / reflux;
To a 200 mL MeOH solution of 4-amino-2-chlorobenzoic acid (12 g, 67.84 mmol) was added 2 equivalents of SOCl2 (11 mL, 135.7 mmol) at 0 C. The ice-water bath was removed after the addition and the reaction mixture was heated to reflux until the starting material had disappeared, as indicated by LC-MS. After the reaction was cooled back to RT, solvent and excess of SOCl2 were removed under reduced pressure. The residue was suspended in 10% aqueous Na2CO3 solution. The precipitate that formed was filtered and washed with water until the washes became neutral. The filter cake was then re-dissolved in 200 mL of ethyl acetate, and the ethyl acetate layer was washed with water, brine, and dried over anhydrous Na2SO4. After concentrated under reduced pressure and vacuum drying, 12.27 g of product was obtained (97.4%). M+H+(186).
97%
With acetyl chloride; for 18h;Heating / reflux;
Example E 4-Amino-2-chlorobenzoic acid methyl ester Acetyl chloride (2.5ml) was added drop-wise to a stirred solution of 4-amino-2-chlorobenzoic acid (2.22g, 12.9mmol) in methanol (75ml). The mixture was heated at reflux for 18h, cooled and reduced in vacuo. The residue was taken up in EtOAc, washed with saturated sodium hydrogen carbonate solution and brine, dried and reduced in vacuo to afford a beige solid identified as 4-amino-2-chlorobenzoic acid methyl ester, yield 2.32g, 97%.
With acetyl chloride; In methanol; for 18h;Reflux;
A. Methyl 4-amino-2-chloro-benzoate, 23b. Acetyl chloride (35.2 mmol, 2.5 mL) was added dropwise to a stirring solution of 4-amino-2-chloro-benzoic acid 23a (12.9 mmol, 2.22 g) in methanol (50 mL). The mixture was heated at reflux for 18 h, cooled, and concentrated under vacuum. The residue was taken up in EtOAc, washed with saturated aqueous NaHCO3 and brine, dried, and concentrated under vacuum. The crude product was purified by flash column chromatography (silica gel, 30% EtOAc/hexanes) to give compound 23b.
With acetyl chloride; for 18h;Reflux;
Acetyl chloride (35.2 mmol, 2.5 mL) was added dropwise to a stirring solution of 4-amino-2-chloro-benzoic acid 23a (12.9 mmol, 2.22 g) in methanol (50 mL). The mixture was heated at reflux for 18 h, cooled, and concentrated under vacuum. The residue was taken up in EtOAc, washed with saturated aqueous NaHCO3 and brine, dried, and concentrated under vacuum. The crude product was purified by flash column chromatography (silica gel, 30% EtOAc/hexanes) to give compound 23b.
With acetyl chloride; for 18h;Reflux;
Acetyl chloride (2.5 mL, 35.2 mmol) was added dropwise to a stirring solution of 4-amino-2-chloro-benzoic acid 22i (2.22 g, 12.9 mmol) in methanol (50 mL). The mixture was heated at reflux for 18 h, cooled, and concentrated under reduced pressure. The residue was dissolved in EtOAc, washed sequentially with saturated aqueous NaHCO3 and brine, dried, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 30% EtOAc/hexanes) to give compound 22j.
With acetyl chloride; for 5h;Reflux;
To a solution of 4-amino-2-chlorobenzoic acid (54.2 mmol) in MeOH (325 mL) was added dropwise acetylchloride (163 mmol) and the mixture was refluxed for 5h. It was concentrated in vacuo and partitioned between EtOAc and a sat. solution of NaHC03. The organic phase was washed with a sat. solution of NaHC03, dried over MgS04 and concentrated in vacuo to give the title compound as beige solid. LC-MS (B): tR = 0.57 min; [M+CH3CN+H]+: 227.29
20.9 g
To methanol at 0 C was added dropwise acetyl chloride (314.7 mmol, 22.4 mL). After the addition of acetyl chloride, the reaction mixture was stirred at rt for30 mm, then 4-amino-2-chlorobenzoic acid 1(116.6 mmol, 20.0 g) was added in one portion. The reaction mixture was heated at reflux for 18 hours, cooled to 0 C, and concentrated under vacuum. The residue was suspended in 250 mL of ethyl acetate, cooled to 0 C, and saturated aqueous NaHCO3 was added (pH was 8). The mixture was partitioned and extracted with ethyl acetate (200 mL). Combined organic layers were washed with brine, dried over MgSO4, and concentrated under vacuum to afford 20.9 g of title compound as a yellow solid which was used as such in next step without purification. 1H NMR (400 MHz, CDCI3): 67.78 (d, J= 8.6 Hz, 1H), 6.70 (d, J= 2.3 Hz, 1H), 6.52 (dd, J= 8.6, 2.3 Hz, 1H), 4.09 (bs, 1H), 3.86 (s, 3H). LCMS (M+1) 186.1,188.1.
With thionyl chloride; at 0℃;Reflux;
To a solution of 4-amino-2-chlorobenzoic acid (116 mmol, 20 g) in MeOH (200 mL) was added SOC12 (234 mmol, 27 g) at 00 C. The ice-water bath was removed after the addition and the mixture was heated to reflux until the starting material had disappeared, as indicated by LC-MS. The reaction was cooled to rt and the solvent and excess of SOC12 were evaporated under reduced pressure. The residue was suspended in 10 percent aqueous Na2CO3 solution. The precipitate that formed was filtered and washed with water until the washes became neutral. The filter cake was then re-dissolved in 500 mL of ethyl acetate. The mixture was washed with water, brine, and dried over anhydrous Na2SO4. The ethyl acetate was evaporared under reduced pressue to give the product. ESI: m/z 186.1 (M+H)+
With Iodine monochloride; calcium carbonate; In methanol; dichloromethane; at 20℃; for 1.5h;
B. Methyl 4-amino-2-chloro-5-iodo-benzoate, 23c. To a suspension of compound 23b (1.18 g, 6.38 mmol) and CaCO3 (12.8 mmol, 1.28 g) in MeOH (13 mL) was added a solution of iodine monochloride (6.70 mmol, 1.09 g) in CH2Cl2 (6 mL) dropwise at room temperature. The resulting reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated and then partitioned between EtOAc and water. The organic layer was concentrated and purified by flash column chromatography (silica gel, 20-25% EtOAc/hexanes) to provide methyl 4-amino-2-chloro-5-iodo-benzoate 23c as the major the product and methyl 4-amino-2-chloro-3-iodo-benzoate 23d as the minor product.
With Iodine monochloride; calcium carbonate; In methanol; dichloromethane; at 20℃; for 1.5h;
To a suspension of compound 23b (1.18 g, 6.38 mmol) and CaCO3 (12.8 mmol, 1.28 g) in MeOH (13 mL) was added a solution of iodine monchloride (6.70 mmol, 1.09 g) in CH2Cl2 (6 mL) dropwise at room temperature. The resulting reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated and then partitioned between EtOAc and water. The organic layer was concentrated and purified by flash column chromatography (silica gel, 20-25% EtOAc/hexanes) to provide methyl 4-amino-2-chloro-5-iodo-benzoate 23c as the major the product and methyl 4-amino-2-chloro-3-iodo-benzoate 23d as the minor product.
With Iodine monochloride; calcium carbonate; In methanol; dichloromethane; at 20℃; for 1.5h;
To a suspension of compound 22j (1.18 g, 6.38 mmol) and CaCO3 (1.28 g, 12.8 mmol) in MeOH (13 mL) was added a solution of iodine monochloride (1.09 g, 6.70 mmol) in CH2Cl2 (6 mL) dropwise at room temperature. The resulting reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated and then partitioned between EtOAc and water. The organic layer was concentrated and purified by flash column chromatography (silica gel, 20-25% EtOAc/hexanes) to provide methyl 4-amino-2-chloro-5-iodo-benzoate 22k as the major product and methyl 4-amino-2-chloro-3-iodo-benzoate 221 as the minor product.
With iodine; silver sulfate; In ethanol; for 0.25h;Inert atmosphere;
To a suspension of <strong>[46004-37-9]methyl 4-amino-2-chlorobenzoate</strong> (55.8 mmol) in EtOH (558 mL) was added silver sulfate (55.8 mmol) and iodine (58.6 mmol) under argon. The mixture was stirred for 15 min, filtered and the filtrate was concentrated in vacuo. The residue was partitioned between DCM and a 1 M aq. solution of NaOH. The organic phase was washed with a 1 M aq. solution of NaOH, dried over MgS04 and concentrated in vacuo. The crude was purified by CC (SNAP KP-SIL from Biotage) using Hept/EtOAc/MeOH from 89/11/1 to 81/19/1 to give the mixture of regioisomers as salmon solid. The mixture was enriched from 59 to 66% in methyl 4-amino-2-chloro-3-iodobenzoate by recrystallisation in Hept/EtOAc 75/25, separation of the solid methyl 4-amino-2-chloro-5-iodobenzoate by filtration and evaporation of the mother liquid. LC-MS (B): tR = 0.72 min; [M+CH3CN+H]+: 352.79 In addition, pure methyl 4-amino-2-chloro-5-iodobenzoate regioisomer was isolated as pink to orange solid. LC-MS (B): tR = 0.75 min; [M+CH3CN+H]+: 352.80
With sodium periodate; iodine; In DMF (N,N-dimethyl-formamide); at 50℃; for 2h;
To a solution of <strong>[46004-37-9]methyl 2-chloro-4-aminobenzoate</strong> (109 g, 587 mmol) in 440 mL DMF was added NaIO4 (50 g) and iodine (119 g). The mixture was warmed at 50 C. for 2 h. It was then cooled and diluted with water and filtered. The solid was treated with sodium hydrogensulfite (19 g) in water (110 mL) at 40 C. for 1 h. The mix was filtered again and washed with water, followed by isopropanol. Upon drying, the product was obtained in 56% yield. M+H+(312).
17 g
With Iodine monochloride; calcium carbonate; In methanol; dichloromethane; at 20℃; for 5h;
To a suspension of methyl 4-amino-2- chlorobenzoate (20.0 g, 107.75 mmol) and CaCO3 (21.58 g, 215.5 mmol) in MeOH (216 mL) was added a solution of iodine monochloride (20.0 g, 123.2 mmol) in CH2CI2 (102 mL). The resulting reaction mixture was stirred at room temperature for 5 h, and quenched by adding cooled water (700 mL) and ethyl acetate (700 mL). It was filtered through celite, the filtrate was treated with 300 mL of 10% sodium thiosulfate, partitioned, and the aqueous layer was extracted with ethyl acetate (400 mL). The combined organic layers were washed with 10% sodium thiosulfate (2x), and brine. The organic layer was dried over Mg504, and concentrated to dryness under vacuum. The residue was adsorbed in silica gel, loaded into flash column which was eluted with 5, 7.5, and 10% ethyl acetate/toluene to afford 17.0 g of title compound as a yellow solid. 1H NMR (400 MHz, CDCI3): 6 8.26 (s, 1H),6.75 (s, 1H), 4.52 (bs, 1H), 3.87 (s, 3H). LCMS (M+1) 312.0, 314.0.
5.86 g
With sodium periodate; iodine; In N,N-dimethyl-formamide; at 65℃; for 2h;
Step 1: A stirred solution of compound 6 (5.00 g, 26.9 mmol) in N,N- dimethylformamide (DMF: 18.9 mL) was treated with sodium periodate (2.30 g, 10.8 mmol) and iodine (5.50 g, 21.6 mmol) at room temperature. The resulting brown solution was heated to 65C for 2 hours, and then allowed to cool to room temperature. The reaction mixture was then poured slowly into water (150 mL) with rapid stirring, and the resulting dark brown precipitate was collected by filtration (washing with water) and dried under suction. The resultant dark brown solid was added to 5% aqueous sodium metabisulfite solution with stirring, and the resulting suspension heated at 45-50C for 30 minutes. The brown solid was then collected by filtration (washing with water) and dried under suction. The solid was triturated with isopropanol (30 mL), with stirring, for 30 minutes, and was then filtered and dried under suction to afford compound 7 (5.86 g) as a brown solid. 1H NMR (400 MHz, CDC13) delta 8.26 (s, 1H), 6.75 (s, 1H), 3.87 (s, 3H)
2-chloro-4-aminobenzoic acid, methyl ester (13.95 g) was suspended in a mixture of water (65 ml) and concentrated hydrochloric acid (15.7 ml). After stirring at room temperature for 10 minutes, the suspension was cooled to 0 C. A solution of sodium nitrite (5.71 g) in water (37 ml) was gradually added over 20 minutes, maintaining a reaction temperature of 0 C. After stirring at 0 C. for 35 minutes, the reaction mixture was partially neutralized by the addition of solid sodium carbonate (3.16 g) to afford a cold solution of the diazonium salt.
With hydrogenchloride; sodium nitrite; In water; acetic acid; at 0 - 20℃; for 0.25h;
A solution of 818 mg of Sodium Nitrite in 13 mL of water was added dropwise to a solution of 2 g of <strong>[46004-37-9]methyl 4-amino-2-chlorobenzoate</strong> in 5 mL of HCl and 15 mL of AcOH at 0 C. The reaction was removed from the ice bath and stirred at room temperature for 15 minutes. Simultaneously a solution of 460 mg of Copper II Chloride Dihydrate in 1 mL of water was added to a saturated solution of sulfur dioxide gas in 10 mL of AcOH at 0 C. The cooled solution containing Copper II Chloride and sulfur dioxide gas was slowly added to the re-cooled initial solution containing Sodium Nitrite. The reaction was warmed to room temperature and stirred until gas no longer evolved. The reaction was filtered through celite and poured into a beaker of stirred icewater until a yellow-orange solid crashed out. The icewater solution was filtered thru a Buchner funnel to collect the methyl 2-chloro-4-(chlorosulfonyl)benzoate precipitate and was dried for 24 hours under vacuum. 1 g of methyl 2-chloro-4-(chlorosulfonyl)benzoate was added to a solution of 2 mL of 2M solution of Ammonia in MeOH and 970 muL DIPEA in 5 mL MeOH. Upon completion the reaction was concentrated, extracted twice with saturated bicarbonate, dried with Magnesium Sulfate, filtered and concentrated to give methyl 2-chloro-4-sulfamoylbenzoate. 777 mg of methyl 2-chloro-4-sulfamoylbenzoate was hydrolyzed via Procedure M to yield crude 2-chloro-4-sulfamoylbenzoic acid. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 91 mg of crude 2-chloro-4-sulfamoylbenzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-sulfamoylbenzamide. MS (Q1) 422 (M)+.
With hydrogenchloride; sodium nitrite; In methanol; water; at 0℃; for 1.5h;
8 g of <strong>[46004-37-9]methyl 4-amino-2-chlorobenzoate</strong> was dissolved in 16 mL of MeOH, 8 mL of H2O and 8 mL of concentrated hydrochloric acid and was then cooled to 0C. A solution of 3.9 g of sodium nitrite in 15 mL of H2O was added dropwise over 30 min. The reaction was stirred at 0 C. for an additional 1 h. The cold diazonating mixture was added to a solution of 13.8 g of potassium ethyl xanthate in 10 mL of H2O at 5060 C. The reaction was heated to 65 C. for 2 h and monitored by TLC until complete. The mixture was cooled to 25 C. and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. Purified by silica gel chromatography (0-10% ethyl acetate/hexane) to afford methyl 2-chloro-4-(ethoxycarbonothioylthio)benzoate. A solution of 2.6 g of sodium hydroxide in 20 mL of H2O was added to 5.9 g of methyl 2-chloro-4-(ethoxycarbonothioylthio)benzoate in 40 mL of EtOH The reaction mixture was heated to 70 C. for 1 h. Upon completion, the mixture was cooled to 25 C., and then acidified to pH 3 by the addition of 10 N HCl. The solid was filtered and washed with H2O to give 2-chloro-4-mercaptobenzonic acid. 3.8 g of 2-chloro-4-mercaptobenzonic acid in 40 mL of 5% sulfuric acid-methanol was refluxed under nitrogen atmosphere for 3 h. After concentration of the reaction mixture, 10 mL of H2O was added and the resulting mixture was made alkaline with sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated to yield methyl 2-chloro-4-mercaptobenzoate. 80 mg of isobutylene oxide was reacted with methyl 2-chloro-4-mercaptobenzoate via Procedure S to afford methyl 2-chloro-4-(2-hydroxy-2-methylpropylthio)benzoate. 190 mg of methyl 2-chloro-4-(2-hydroxy-2-methylpropylthio)benzoate was hydrolyzed via Procedure M to give 2-chloro-4-(2-hydroxy-2-methylpropylthio)benzoic acid. 160 mg of 2-chloro-4-(2-hydroxy-2-methylpropylthio)benzoic acid was reacted via procedure R to give 2-chloro-4-(2-hydroxy-2-methylpropylsulfonyl)benzoic acid.
With 2,6-dimethylpyridine; sodium iodide; In N,N-dimethyl-formamide; at 80℃; for 14h;
To a mixture of <strong>[46004-37-9]methyl 4-amino-2-chlorobenzoate</strong> (0.500 g) and sodium iodide (0.404 g) in N,N-dimethylformamide (8.0 mL) were successively added 2, 6-lutidine (0.433 g) and ethyl 4-bromobutylate (0.578 g) at room temperature, and the solution was stirred at an external temperature of 80 C for 14 hours. To the solution were added water and ethyl acetate at room temperature. The organic layer was separated. The organic layer was successively washed with water and brine, dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The obtained crude product was purified by column chromatography on aminopropylsilylated silica gel (eluent:ethyl acetate-hexane) to give methyl 2-chloro-4-(3-ethoxycarbonylpropylamino) benzoate (0.178 g). ethoxycarbonylpropylamino)benzoate (0.178 g). 1H-NMR(CDCl3) delta ppm: 1.26 (3H, t, J=7.2Hz), 1.90-2.00 (2H, m), 2.43 (2H, t, J=6.9Hz), 3.15-3.25 (2H, m), 3.85 (3H, s), 4.15 (2H, q, J=7.2Hz), 4.35-4.45(1H, br), 6.44 (1H, dd, J=8.7, 2.4Hz), 6.59 (1H, d, J=2.4Hz), 7.79 (1H, d, J=8.7Hz). MS(ESI, m/z) : 300 (M+H)+
2-chloro-<i>N</i>-[3-(1-hydroxy-ethyl)-phenyl]-4-[6-methyl-3-oxo-4-(3-trifluoromethyl-phenyl)-3,6-dihydro-1<i>H</i>-1,2,5,6,7-pentaaza-<i>as</i>-indacen-2-yl]-benzamide[ No CAS ]
2.0 g of <strong>[46004-37-9]methyl 4-amino-2-chlorobenzoate</strong> were dissolved in 10 ml of acetic acid, 2.0 ml of 2,5-dimethoxytetrahydrofuran were added thereto, and the mixture was heated under reflux for 15 minutes.. After cooling the reaction solution, the solvent was evaporated.. The obtained residue was mixed with EtOAc and saturated NaHCO3 aq. and extracted.. The organic layer was washed with brine, and dried over sodium sulfate anhydride.. After evaporating the solvent, the residue was purified by silica gel column chromatography (hexane-EtOAc (4:1)) to obtain 2.1 g of methyl 2-chloro-4-(1H-pyrrol-1-yl)benzoate.
Acetyl chloride (2.5 ml) was added drop-wise to a solution of 2-chloro-4-cyano-benzoic acid (2.22 g, 12.94 mmol) in methanol (75 ml) while stirring. The mixture was heated at reflux for 18 h, cooled and concentrated in vacuo. The residue was taken up in ethyl acetate, washed with saturated NaHCO3 and brine and concentrated in vacuo to give a beige solid identified as 4-amino-2-chloro-benzoic acid methyl ester (2.32 g, 97%).
To a solution of <strong>[46004-37-9]4-amino-2-chloro-benzoic acid methyl ester</strong> (12.27 g, 66.11 mmol) and pyruvic aldehyde dimethyl acetal (15.62 g, 132.22 mmol) in 260 mL glacial acetic acid was added anhydrous Na2SO4 (93.9 g, 661.1 mmol). The reaction mixture was stirred at room temperature for 3 hours. Powered sodium triacetoxy borohydride (42 g, 198.33 mmol) was then added in portions for a period of 10 min. Stirring was continued overnight. After the acetic acid was removed under reduced pressure, the remaining residue was made basic by adding a sufficient amount of saturated Na2CO3 solution. The product was then extracted with ethyl acetate. The organic layer was then dried over anhydrous Na2SO4 and concentrated in vacuo. Flash column chromatography separation (30% ethyl acetate/hexane) then afforded 16.5 g product as colorless oil (87%). M+H+(288).
With N-Bromosuccinimide; In tetrahydrofuran; at -20 - 20℃; for 0.166667h;
To a solution of Compound 61 (900mg, 4.85mmol) in tetrahydrofuran (10mL) was added N-bromosuccinimide(906mg, 15.09mmol) at -20C, the solution was warmed to room temperature, and stirred for 10 minutes. To the reactionmixture was added 10% sodium thiosulfate aqueous solution, and extracted with ethyl acetate. The organic layer wasdried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gelchromatography (ethyl acetate / hexane) to yield Compound 62 (600mg, yield: 47%) as a white solid.LC/MS Method: B, LC-MS: m/z=263. [M+H]+, retention time: 1.86min1H-NMR (DMSO-D6) delta: 7.91 (1H, s), 6.86 (1H, s), 6.38 (2H, s), 3.76 (3H, s).
33%
With N-Bromosuccinimide; In dichloromethane; at 20℃;
Example 31: N-f5-Chloro-2 (at)(E -3-f3-(at)4-fluoro-benzvl)-3,8-diaza-bicvclof3.2.11oct-8-yll-3-oxo- proaen I(at)(1-h droxy-1-methvl-ethyl -ahenyl-acetamide; a) 4-Amino-5-bromo-2-chloro-benzoic acid methyl ester; 4-Amino-2-chloro-benzoic acid methyl ester (7.8 g, 42.0 mmol) is dissolved in 300 ml THF. At room temperature 8.97 g (50.4 mmol) N-bromsuccinimide are added in portions. After stirring over night at room temperature, 200 ml ethyl acetate are added and the organic layer is washed first with 10% sodium thiosulfate solution followed by 10% sodium carbonate solution and saturated sodium chloride solution. The title compound is purified by chromatography (Si02, ethyl acetate/c-hexane 1/9) and is isolated as a yellow solid (3.70 g, 33%) 1 H-NMR (400MHz; DMSO-d6) : 3.75 (s, 3H) ; 3.15-3.25 (m, 1 H); 6.35 (s, 1 NH); 6.83 (s, 1 H); 7.88 (s, 1 H). MS (m/z) ES-: 264 ([M-H] -, 100).
9.58 g
With N-Bromosuccinimide; In tetrahydrofuran; at 20℃;
To a stirred solution of <strong>[46004-37-9]methyl 4-amino-2-chlorobenzoate</strong> (10.9 g, 58.73 mmol) in 196 mL of THF at rt was added NBS (11.5 g, 64.6 mmol). The reaction mixture was stirred at rt over weekend, 200 mL of EtOAc were added, and the organic layer was washed with 10% sodium thiosulfate, followed by 10% sodium carbonate, and brine. The organic layer was dried over MgSO4 and concentrated to dryness under vacuum. The residue was adsorbed on silica gel, loaded onto a flash column and eluted with 10- 30% EtOAc/hexanes. Mixed fractions were purified again by flash chromatography eluting with 8% EtOAc/toluene to afford in total 9.58 g of the title compound as a light yellow solid. 1H NMR (400 MHz, CDCI3): 68.03 (s, 1H), 6.79 (s, 1H), 4.52 (bs, 2H), 3.87 (s, 3H). LCMS (M+1) = 263.9, 265.9.
N-[2-chloro(4-methoxycarbonyl)phenyl]-6-chloro-3-oxo-4-aza-5α-androst-5-en-17β-acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine;dmap; In dichloromethane; at 20℃; for 18h;
To a stirred solution of 6-chloro-3-oxo-4-aza-5alpha-androst-5-en-17ss;-acetic acid (60- 4)(0.05 g, 0.14 mmol) in anhydrous CH2C12 (1 ml) at 0 C was added anhydrous DMF (10 mul) and thionyl chloride (15 mul, 0.21 mmol). The resulting orange solution was warmed to ambient temperature and stirred for 1 h. Anhydrous toluene (2 ml) was added and removed under vacuum at ambient temperature to give an orange oil which was dissolved in anhydrous CH2C12 (0.5 ml). DIPEA (0.12 ml, 0.68 mmol), DMAP (0.002 g, 0.014 mmol), and methyl 4-amino-3-chlorobenzoate (0.08 g, 0.41 mmol) was added. After stirring at ambient temperature for 18 h, CH2C12 was removed under vacuum. The residue was purified on reversed phase silica gel (5% CH3CN/95% H20 with 0.1% TFA to 80% CH3CN/10% 95% H20 with 0.1% TFA) to give the title compound as a pale yellow solid. ¹H NMR (CDCl3) No. 0.72 (s, 3H), 1.15 (s, 3H), 1.17-1.31 (m, 3H), 1.40-1.56 (m, 3H), 1.61-1.65 (m, 1H), 1.72-1.86 (m, 3H), 1.92-1.99 (m, 3H), 2.05-2.13 (m, 2H), 2.28 (dd, 1H), 2.40 (dd, 1H), 2.52-2.58 (m, 3H), 3.92 (s, 3H), 7.56 (s, 1H), 7.81 (s, 1H), 7.95 (d, 1H), 8.08 (s, 1H), 8.54 (d, 1H). MS calculated M+H: 533.1969, found 533.1974.
Methyl-2-chloro-4-(methylsulfonamido) benzoate (101).; To a stirred solution of methyl-2-chloro-4-amino benzoate 100 (0.457 g, 2.45 mmol) in DCM cooled to 0 0C was added pyridine (2 mL) followed by dropwise addition of methanesulphonyl choride (0.2 mL, 2.5 mmol). After addition was complete, the reaction was allowed to warm to room temperature and stirred for 2 h. After completion, the reaction mixture was concentrated in vacuo. 1 N HCl (5 mL) was added to the residue and the mixture extracted with EtOAc (10 mL). The organic phase was dried over Na2SO4 and concentrated under high vacuum. The crude compound was purified by column chromatography to afford the title intermediate 101 as a solid (0.54 g, 84% yield).
With pyridine; In dichloromethane; at 0 - 20℃;
1 g of <strong>[46004-37-9]methyl 4-amino-2-chlorobenzoate</strong> was cooled to 0C in DCM with 485 muL of Pyridine before Methanesulfonyl Chloride was added dropwise. The reaction was allowed to warm to room temperature and stir overnight. Solvent was concentrated and the crude material was dissolved in Ethyl Acetate and extracted with saturated bicarbonate solution and then brine. The crude material was dried over Magnesium Sulfate, filtered and concentrated to give 1.54 g of methyl 2-chloro-4-(methylsulfonamido)benzoate.
With pyridine; In dichloromethane; at 0 - 20℃;
To 5 g of methyl 2-chloro-4-nitrobenzoate in 100 mL of EtOH was added 20 g of Tin (II) Chloride in portions. The reaction was heated to 55 C. and monitored by TLC until complete. Solvent was concentrated and extraction was performed in Ethyl Acetate and water with TEA to reduce emulsions. The organic layer was dried over Magnesium Sulfate, filtered and concentrated to give 3.9 g of <strong>[46004-37-9]methyl 4-amino-2-chlorobenzoate</strong>. 1 g of <strong>[46004-37-9]methyl 4-amino-2-chlorobenzoate</strong> was cooled to 0 C. in DCM with 485 muL of Pyridine before Methanesulfonyl Chloride was added dropwise. The reaction was allowed to warm to room temperature and stir overnight. Solvent was concentrated and the crude material was dissolved in Ethyl Acetate and extracted with saturated bicarbonate 10' solution and then brine. The crude material was dried over Magnesium Sulfate, filtered and concentrated to give 1.54 g of methyl 2-chloro-4-(methylsulfonamido)benzoate. 107 muL of 1-bromo-2-methoxyethane and 556 mg of Cesium Carbonate were added to 150 mg of methyl 2-chloro-4-(methylsulfonamido)benzoate in DMF and stirred at room temperature for 16 hours. The reaction mixture was extracted in Ethyl Acetate twice with saturated bicarbonate and once with brine, dried over Magnesium Sulfate, filtered and concentrated to give methyl 2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoate. 182 mg of methyl 2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoate was hydrolyzed via Procedure M to yield 169 mg of crude 2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoic acid. 65 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(2-methoxyethyl)methylsulfonamido)benzamide. MS (Q1) 494 (M)+.
1) Benzoyl thiocyanate was generated by refluxing a solution of benzoyl chloride (0.31 mL) and ammonium thiocyanate (0.20 g) in acetone (15 mL) for 30 min. To this solution was added a solution of <strong>[46004-37-9]4-amino-2-chlorobenzoic acid methyl ester</strong> (0.5 g) in CH3CN (10 mL) and the mixture was refluxed for 5 h. The solvent was removed and the residue was partitioned between CH2Cl2 and water. The organic layer was separated, washed with brine, dried and evaporated. The residue was purified by column chromatography to yield 2-chloro-4-(3-benzoylthioureido)benzoic acid methyl ester (0.71 g). ESMS: 349 (MH+).
1) Pyridine (0.4 mL) was added to a solution of <strong>[46004-37-9]methyl 4-amino-2-chlorobenzoate</strong> (0.3 g) in CH2Cl2 (10 mL) at 0 C. under N2. N,N-Dimethylsulfamoyl chloride (0.21 mL) was added and the mixture was stirred at room temperature for 16 hours and refluxed for 5 hours. DMAP (0.4 g) was added and the mixture was stirred for 3 hours. The mixture was diluted with CH2Cl2 (100 mL), washed successively with 1N HCl, brine, satd. NaHCO3 and brine, dried and evaporated. The residue was purified by flash column chromatography (silica gel; eluent: EtOAc/hexane 1:3) to give 0.31 g of methyl 4-(N,N-dimethylsulfamoyl)amino-2-chlorobenzoate. ESMS: m/z 293 (MH+)
1) A mixture of <strong>[46004-37-9]4-amino-2-chlorobenzoic acid methyl ester</strong> (0.46 g) and 2,5-dimethoxytetrahydrofuran (0.33 mL) in AcOH (16 mL) was heated under reflux for 2 h. The mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The extract was washed with satd. NaHCO3 and brine, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (silica gel; eluent: hexane/EtOAc 5/1) to yield 0.48 g of 2-chloro-4-1-pyrrolyl)benzoic acid methyl ester. ESMS: m/z 236 (MH-). 2)The product obtained above was hydrolyzed with LiOH to give the title compound. ESMS: m/z 220 (M-H)-.
1) A mixture of <strong>[46004-37-9]4-amino-2-chlorobenzoic acid methyl ester</strong> (0.5 g) and 2-chloroethylisothiocyanate (0.26 mL) in THF (20 mL) was refluxed for 24 h. THF was distilled and the residue was purified by column chromatography (silica gel: eluent: hexane/EtOAc 3:1-1:1) to yield 2-chloro-4-(2-thiazolinylamino)benzoic acid methyl ester (74 mg). ESMS: m/z 271 (MH+).
methyl 4-[([1,1'-biphenyl]-2-carbonyl)amino]-2-chlorobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In hexane; dichloromethane;
REFERENCE EXAMPLE 230 Methyl 4-[(1,1'-Biphenyl]-2-carbonyl)amino]-2-chlorobenzoate A solution of 2.37 g of [1,1'-biphenyl]-2-carbonyl chloride in 10 ml of methylene chloride is added dropwise to an ice cold solution of 1.84 g of <strong>[46004-37-9]methyl 4-amino-2-chlorobenzoate</strong> and 1.49 g of N,N-diisopropylethylamine in 50 ml of methylene chloride. The reaction mixture is stirred at room temperature for 18 hours and washed with water, saturated aqueous NaHCO3 and the organic layer dried(Na2 SO4). The organic layer is passed through a pad of hydrous magnesium silicate and hexane added at the boil to give 1.1 g of the desired product as a crystalline solid, m.p. 132-134 C. M+ H=365.
With N-ethyl-N,N-diisopropylamine; In hexane; dichloromethane;
Reference Example 172 Methyl 4-[([1,1'-Biphenyl]-2-carbonyl)amino]-2-chlorobenzoate A solution of 2.37 g of [1,1'-biphenyl]-2-carbonyl chloride in 10 ml of methylene chloride is added dropwise to an ice cold solution of 1.84 g of <strong>[46004-37-9]methyl 4-amino-2-chlorobenzoate</strong> and 1.49 g of N,N-diisopropylethylamine in 50 ml of methylene chloride. The reaction mixture is stirred at room temperature for 18 hours and washed with water, saturated aqueous NaHCO3 and the organic layer dried(Na2 SO4). The organic layer is passed through a pad of hydrous magnesium silicate and hexane added at the boil to give 1.1 g of the desired product as a crystalline solid, m.p. 132-134 C. M+ H=365
With N-ethyl-N,N-diisopropylamine; In hexane; dichloromethane;
REFERENCE EXAMPLE 172 Methyl 4-[([1,1'-Biphenyl]-2-carbonyl)amino]-2-chlorobenzoate A solution of 2.37 g of [1,1'-biphenyl]-2-carbonyl chloride in 10 ml of methylene chloride is added dropwise to an ice cold solution of 1.84 g of <strong>[46004-37-9]methyl 4-amino-2-chlorobenzoate</strong> and 1.49 g of N,N-diisopropylethylamine in 50 ml of methylene chloride. The reaction mixture is stirred at room temperature for 18 hours and washed with water, saturated aqueous NaHCO3 and the organic layer dried(Na2 SO4). The organic layer is passed through a pad of hydrous magnesium silicate and hexane added at the boil to give 1.1 g of the desired product as a crystalline solid, m.p. 132-134 C. M+ H=365
With N-ethyl-N,N-diisopropylamine; In hexane; dichloromethane;
Reference Example 230 Methyl 4-[([1,1'-Biphenyl]-2-carbonyl)amino]-2-chlorobenzoate A solution of 2.37 g of [1,1'-biphenyl]-2-carbonyl chloride in 10 ml of methylene chloride is added dropwise to an ice cold solution of 1.84 g of <strong>[46004-37-9]methyl 4-amino-2-chlorobenzoate</strong> and 1.49 g of N,N-diisopropylethylamine in 50 ml of methylene chloride. The reaction mixture is stirred at room temperature for 18 hours and washed with water, saturated aqueous NaHCO3 and the organic layer dried(Na2 SO4). The organic layer is passed through a pad of hydrous magnesium silicate and hexane added at the boil to give 1.1 g of the desired product as a crystalline solid, m.p. 132-134 C. M+ H=365
With N-ethyl-N,N-diisopropylamine; In hexane; dichloromethane;
REFERENCE EXAMPLE 172 Methyl 4-[([1,1'-Biphenyl]-2-carbonyl)amino]-2-chlorobenzoate A solution of 2.37 g of [1,1'-biphenyl]-2-carbonyl chloride in 10 ml of methylene chloride is added dropwise to an ice cold solution of 1.84 g of <strong>[46004-37-9]methyl 4-amino-2-chlorobenzoate</strong> and 1.49 g of N,N-diisopropylethylamine in 50 ml of methylene chloride. The reaction mixture is stirred at room temperature for 18 hours and washed with water, saturated aqueous NaHCO3 and the organic layer dried(Na2 SO4). The organic layer is passed through a pad of hydrous magnesium silicate and hexane added at the boil to give 1.1 g of the desired product as a crystalline solid, m.p. 132-134 C. M+ H=365
With N-ethyl-N,N-diisopropylamine; In hexane; dichloromethane;
Reference Example 196 Methyl 4-[([1,1'-Biphenyl]-2-carbonyl)amino]-2-chlorobenzoate A solution of 2.37 g of [1,1'-biphenyl]-2-carbonyl chloride in 10 ml of methylene chloride is added dropwise to an ice cold solution of 1.84 g of <strong>[46004-37-9]methyl 4-amino-2-chlorobenzoate</strong> and 1.49 g of N,N-diisopropylethylamine in 50 ml of methylene chloride. The reaction mixture is stirred at room temperature for 18 hours and washed with water, saturated aqueous NaHCO3 and the organic layer dried(Na2 SO4). The organic layer is passed through a pad of hydrous magnesium silicate and hexane added at the boil to give 1.1 g of the desired product as a crystalline solid, m.p. 132-134 C. M+ H=365
With N-ethyl-N,N-diisopropylamine; In thionyl chloride; dichloromethane;
REFERENCE EXAMPLE 241 Methyl 4-[[(2-Phenylmethyl)benzoyl]amino]-2-chlorobenzoate A mixture of 5.0 g of 2-(phenylmethyl)benzoic acid in 5.0 ml of thionyl chloride is heated on a steam bath for 1 hour. The volatiles are evaporated in Vacuo to give 5.70 g of an oil. A 2.85 g portion of the above oil in 25 ml of methylene chloride is added to a solution of 50 ml of methylene chloride containing 1.85 g of <strong>[46004-37-9]methyl 4-amino-2-chlorobenzoate</strong> and 1.65 g of N,N-diisopropylethylamine by stirring at room temperature for 18 hours. The reaction mixture is washed with water, saturated aqueous NaHCO3 and the organic layer dried(Na2 SO4). The organic layer is passed through hydrous magnesium silicate two times and hexane added to the filtrate at the boil to give 2.96 g of the desired product as a crystalline solid, m.p. 133-135 C. M+ =380.
With N-ethyl-N,N-diisopropylamine; In thionyl chloride; dichloromethane;
Reference Example 183 Methyl 4-[[(2-phenylmethyl)benzoyl]amino]-2-chlorobenzoate A mixture of 5.0 g of 2-(phenylmethyl)benzoic acid in 5.0 ml of thionyl chloride is heated on a steam bath for 1 hour. The volatiles are evaporated in vacuo to give 5.70 g of an oil. A 2.85 g portion of the above oil in 25 ml of methylene chloride is added to a solution of 50 ml of methylene chloride containing 1.85 g of <strong>[46004-37-9]methyl 4-amino-2-chlorobenzoate</strong> and 1.65 g of N,N-diisopropylethylamine by stirring at room temperature for 18 hours. The reaction mixture is washed with water, saturated aqueous NaHCO3 and the organic layer dried(Na2 SO4). The organic layer is passed through hydrous magnesium silicate two times and hexane added to the filtrate at the boil to give 2.96 g of the desired product as a crystalline solid, m.p. 133-135 C. M+ =380.
With N-ethyl-N,N-diisopropylamine; In thionyl chloride; dichloromethane;
Reference Example 241 Methyl 4-[[(2-Phenylmethyl)benzoyl]amino]-2-chlorobenzoate A mixture of 5.0 g of 2-(phenylmethyl)benzoic acid in 5.0 ml of thionyl chloride is heated on a steam bath for 1 hour. The volatiles are evaporated in vacuo to give 5.70 g of an oil. A 2.85 g portion of the above oil in 25 ml of methylene chloride is added to a solution of 50 ml of methylene chloride containing 1.85 g of <strong>[46004-37-9]methyl 4-amino-2-chlorobenzoate</strong> and 1.65 g of N,N-diisopropylethylamine by stirring at room temperature for 18 hours. The reaction mixture is washed with water, saturated aqueous NaHCO3 and the organic layer dried(Na2 SO4). The organic layer is passed through hydrous magnesium silicate two times and hexane added to the filtrate at the boil to give 2.96 g of the desired product as a crystalline solid, m.p. 133-135 C. M+ =380.
With N-ethyl-N,N-diisopropylamine; In thionyl chloride; dichloromethane;
REFERENCE EXAMPLE 183 Methyl 4-[[(2-phenylmethyl)benzoyl]amino]-2-chlorobenzoate A mixture of 5.0 g of 2-(phenylmethyl)benzoic acid in 5.0 ml of thionyl chloride is heated on a steam bath for 1 hour. The volatiles are evaporated in vacuo to give 5.70 g of an oil. A 2.85 g portion of the above oil in 25 ml of methylene chloride is added to a solution of 50 ml of methylene chloride containing 1.85 g of <strong>[46004-37-9]methyl 4-amino-2-chlorobenzoate</strong> and 1.65 g of N,N-diisopropylethylamine by stirring at room temperature for 18 hours. The reaction mixture is washed with water, saturated aqueous NaHCO3 and the organic layer dried(Na2 SO4). The organic layer is passed through hydrous magnesium silicate two times and hexane added to the filtrate at the boil to give 2.96 g of the desired product as a crystalline solid, m.p. 133-135 C. M+ =380.
With N-ethyl-N,N-diisopropylamine; In hexane; dichloromethane;
REFERENCE EXAMPLE 195 Methyl 2-Chloro-4-?([4'-(trifluoromethyl)[1,1'-biphenyl]-2-carbonyl)amino]benzoate A solution of 3.56 g of ?4'-(trifluoromethyl)[1,1'-biphenyl]-2-carbonyl chloride in 10 ml of methylene chloride is added dropwise to an ice cold solution of 1.86 g of <strong>[46004-37-9]methyl 2-chloro-4-aminobenzoate</strong> and 1.6 g of N,N-diisopropylethylamine in 50 ml of methylene chloride. The reaction mixture is stirred at room temperature for 18 hours and washed with water, saturated aqueous NaHCO3 and the organic layer dried(Na2 SO4). The organic layer is passed through a pad of hydrous magnesium silicate(3*) and hexane added to the filtrate at the boil to give 4.0 g of the desired product as a crystalline solid, m.p. 130-132 C.
With N-ethyl-N,N-diisopropylamine; In hexane; dichloromethane;
Reference Example 219 Methyl 2-Chloro-4-?([4'-(trifluoromethyl)[1,1'-biphenyl]-2-carbonyl)amino]benzoate A solution of 3.56 g of ?4'-(trifluoromethyl)[1,1'-biphenyl]-2-carbonyl chloride in 10 ml of methylene chloride is added dropwise to an ice cold solution of 1.86 g of <strong>[46004-37-9]methyl 2-chloro-4-aminobenzoate</strong> and 1.6 g of N,N-diisopropylethylamine in 50 ml of methylene chloride. The reaction mixture is stirred at room temperature for 18 hours and washed with water, saturated aqueous NaHCO3 and the organic layer dried(Na2 SO4). The organic layer is passed through a pad of hydrous magnesium silicate(3*) and hexane added to the filtrate at the boil to give 4.0 g of the desired product as a crystalline solid, m.p. 130-132 C.
methyl 2-chloro-4-[(2,2-dimethyl-4,6-dioxo-[1,3]dioxan-5-ylidenemethyl)-amino]-benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
In isopropyl alcohol; at 100℃; for 15.5h;
4-Amino-2-chloro-benzoic acid (2.50 g) and lithium hydroxide monohydrate (611 mg) were suspended in tetrahydrofuran (20 ml), and the suspension was stirred at room temperature for 20 min. Thereafter, dimethylsulfuric acid (1.38 ml) was added to the reaction mixture, and the mixture was stirred under reflux for 2 hr. The solvent was removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was neutralized with a saturated aqueous sodium hydrogencarbonate solution and was extracted with diethyl ether. The diethyl ether layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure to give <strong>[46004-37-9]methyl 4-amino-2-chloro-benzoate</strong> (1.68 g, yield 62%). Methyl 4-amino-2-chloro-benzoate (1.68 g) and 5-methoxymethylene-2,2-dimethyl-[1,3]dioxan-4,6-dione (1.53 g) were dissolved in 2-propanol (25 ml), and the mixture was stirred at 100C for 15.5 hr. The solvent was removed by distillation under the reduced pressure, and the residue was washed with diethyl ether to give methyl 2-chloro-4-[(2,2-dimethyl-4,6-dioxo-[1,3]dioxan-5-ylidenemeth yl)-amino]-benzoate (1.92 g, yield 63%).
With calcium carbonate; In methanol; dichloromethane; ethyl acetate;
EXAMPLE 58A methyl 4-amino-2-chloro-5-iodo-benzoate A solution of <strong>[46004-37-9]methyl 4-amino-2-chloro-benzoate</strong> (1.14 g, 6.16 mmol) in dichloromethane (30 mL) and methanol (15 mL) was treated sequentially with calcium carbonate (1.85 g, 18.5 mmol) and benzyl trimethylammonium dichloroiodate (3.22 g, 9.24 mmol), stirred for 18 hours, treated with additional benzyl trimethylammonium dichloroiodate (2 g, 5.75 mmol), stirred for 3 days, filtered into a separatory funnel, washed with saturated NaHSO3, dried (MgSO4), filtered, and concentrated. The concentrate was recrystallized from ethyl acetate to provide the majority of the desired product. The filtrate was concentrated, and the concentrate was purified on silica gel with a gradient of from 10% to 20% ethyl acetate/hexanes to provide a total of 1.3 g of the desired product. MS (ESI(-)) m/z 310 (M-H)-; 1H NMR (CDCl3) d 8.25 (d, J=2.0 Hz, 1H), 6.75 (d, J=2.0 Hz, 1H), 4.52 (br s, 2H), 3.87 (s, 3H). Characterization for the minor product: 1H NMR (300 MHz, CDCl3) 7.72 (d, J=8.8 Hz 1H), 6.63 (d, J=8.5 Hz, 1H), 4.71 (br s, 2H), 3.88 (s, 3H).
2-Chloro-4-cyanobenzoic acid methyl ester 4-Amino-2-chlorobenzoic acid methyl ester (4.7g, 25mmol) was taken up in water (12ml) and concentrated hydrochloric acid (12ml) was added. The mixture was sonicated to form a fine suspension and then cooled to 0C. A solution of sodium nitrite (1.91g, 27.7mmol) in water (15ml) was then added dropwise so as to maintain the temperature of the reaction between 0-5C. The mixture was stirred at 0-5C for 15 minutes and then neutralised by addition of solid sodium bicarbonate. The resulting solution was then added to a solution of copper cyanide (2.79g, 31mmol) and potassium cyanide (4.0g, 61mmol) in water (25ml) at 75C. The mixture was stirred at 75C for 45 minutes, allowed to cool and then extracted with toluene (2 times). The combined extracts were washed with brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant 20% ethyl acetate/ 80% pet. ether) to give a pale orange solid identified as 2-chloro-4-cyanobenzoic acid methyl ester, yield 2.61g, 53%.
Example 215 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxy-2- methylpropylsulfonyl)-benzamide 8 g of <strong>[46004-37-9]methyl 4-amino-2-chlorobenzoate</strong> was dissolved in 16 mL of MeOH, 8 mL of H2O and 8 mL of concentrated hydrochloric acid and was then cooled to 0 C A solution of 3.9 g of sodium nitrite in 15 mL Of H2O was added dropwise over 30 min. The reaction was stirred at 0 0C for an additional Ih. The cold diazonating mixture was added to a solution of 13.8 g of potassium ethyl xanthate in 10 mL Of H2O at 50-60 0C. The reaction was heated to 65 0C for 2h and monitored by TLC until complete. The mixture was cooled to 25 0C and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO/i), and concentrated. Purified by silica gel chromatography (0-10% ethyl acetate/hexane) to afford methyl 2-chloro-4- (ethoxycarbonothioylthio)benzoate.
Example 211 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-sulfamoylbenzamide A solution of 818 mg of Sodium Nitrite in 13 mL of water was added dropwise to a solution of 2g of <strong>[46004-37-9]methyl 4-amino-2-chlorobenzoate</strong> in 5 mL of HCl and 15 mL of AcOH at 0C. The reaction was removed from the ice bath and stirred at room temperature for 15 minutes. Simultaneously a solution of 460 mg of Copper II Chloride Dihydrate in 1 mL of water was added to a saturated solution of sulfur dioxide gas in 10 mL of AcOH at 0C. The cooled solution containing Copper IIChloride and sulfur dioxide gas was slowly added to the re -cooled initial solution containing Sodium Nitrite. The reaction was warmed to room temperature and stirred until gas no longer evolved. The reaction was filtered through celite and poured into a beaker of stirred icewater until a yellow-orange solid crashed out. The icewater solution was filtered thru a Buchner funnel to collect the methyl 2-chloro-4-(chlorosulfonyl)benzoate precipitate and was dried for 24 hours under vacuum.
With dmap; triethylamine; In acetonitrile; at -40 - 20℃;
To a -4O0C solution of methyl-2-chloro-4-amino-benzoate (0.6 g, 3.23 mmol), BoC2O (2.12 g, 9.6 mmol) and TEA (1.8 ml, 6.6 mmol) in MeCN (8 mL) was added and DMAP (47 mg, 6.1 mmol). The reaction mixture was allowed to warm gradually to room temperature and stirred for 48h and volatiles removed. The residue was purified by column chromatography using 0-50% EtO Ac/Hex anes to provide compound methyl-2-chloro-4- (delta-Boc-amino)-benzoate as a clear syrup (830 mg).
REFERENCE EXAMPLE 75 2-Chloro-4-cyanobenzoic acid, methyl ester 2-chloro-4-aminobenzoic acid, methyl ester (13.95 g) was suspended in a mixture of water (65 ml) and concentrated hydrochloric acid (15.7 MI).. After stirring at room temperature for 10 minutes, the suspension was cooled to 0 C. A solution of sodium nitrite (5.71 g) in water (37 ml) was gradually added over 20 minutes, maintaining a reaction temperature of 0 C. After stirring at 0 C for 35 minutes, the reaction mixture was partially neutralized by the addition of solid sodium carbonate (3.16 g) to afford a cold solution of the diazonium salt. To a pre-cooled solution of copper(I) cyanide (8.4 g) and sodium cyanide (9.19 g) in water (112 ml) was gradually added the above solution of diazonium salt over a 45-50 minute period.. The diazonium salt solution was maintained at 0 C during the addition.. The resulting mixture was stirred for 18 hours at room temperature.. A precipitate was filtered, air-dried, dissolved in ethyl acetate (250 ml), and filtered to remove insoluble matter.. The organic phase was dried over anhydrous magnesium sulfate, and the solvent removed invacuo to afford a crude product as a brown solid (13.2 g).. The crude product was purified by column chromatography on silica gel (250 g), eluding with 5-10% ethyl acetate/hexane to yield the title compound (10.9 g) as a solid, m.p. 90-92 C; MS (EI), m/z: 195 (M)+.
2-chloro-4-[6-(2-methoxy-phenyl)-pyrimidin-4-ylamino]-benzoic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
4, 6-Dichloropyrimidine (0. 72mmol), 2-METHOXYPHENYLBORONIC acid (0. 66 mmol), sodium carbonate (1. 97 mmol), and Pd (PPh3) 2CI2 (3 mol%) were suspended in a mixture of DME/ETOH/WATER (2. 5 ML/0. 38 ML/0. 38 ML). The mixture was heated in a Personal Chemistry Optimizer microwave system at 130C for 900 s. 'PrOH (5 ml) and the corresponding aniline derivative (0. 66 MMOL) were added, and the mixture was treated with conc. HCI under stirring to reach a pH value of 1- 2. The mixture was then heated in the microwave at 150C for 900 s. The solvent was evaporated under reduced pressure and the residue suspended in H20 (10 mL). With sat. NAHC03 solution the mixture was set to pH = 6-7 and extracted with EtOAc (3x 20 ML). The combined organics were washed with brine and dried over NA2SO4. After evaporation of the solvent the residue was taken up in DMSO and purified via prep.-HPLC (XTerra Prep. MS C18 5 um, 19 x 150 mm, gradient from water to MeCN over 13 min). In the case of products with an acid group in the anilino part, the corresponding methyl esters were prepared via treatment with TMSCHN2 (2-4 eq.) in DCM/MEOH (2 mL/1 mL) at room temperature.
racemic (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxylic acid trifluoroacetic acid salt[ No CAS ]
[ 1229704-05-5 ]
Yield
Reaction Conditions
Operation in experiment
33%
With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 2h;
Example 370 Preparation of 2-Chloro-4-[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid methyl ester To a stirred solution of (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid, TFA salt (200 mg, 0.34mmol) in methylene chloride (3 mL), HATU (Aldrich, 235 mg, 0.62 mmol) was added followed by the addition of DIPEA(0.3 mL, 1.72 mmol) and 4-Amino-2-chloro-benzoic acid methyl ester (Example 296, 128 mg, 0.69 mmol). The mixture was stirred at RT for 2 h. The reaction was quenched with water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with sodium sulfate. The solvent was removed and the residue was purified by flash chromatography (0-25% EtOAc/Hexanes) to give the title compound as a white solid (72 mg, 33% yield).MS (ES+) m/z Calcd: [(M+H)+]: 634, found: 634
(1) Methyl 2-chloro-4-[(5,6,6a,7,8,9-hexahydro-4H-2-phenalenyl)carboxamido]benzoate [Show Image] A suspension of 5,6,6a,7,8,9-hexahydro-4H-2-phenalenecarboxylic acid (0.150 g) in anhydrous benzene (3 ml) was added with thionyl chloride (1 ml), and the mixture was refluxed by heating for 3 hours. The reaction mixture was concentrated under reduced pressure, the resulting residue was dissolved in anhydrous benzene (3 ml) and pyridine (5 ml), the solution was added with <strong>[46004-37-9]methyl 2-chloro-4-aminobenzoate</strong> (0.142 g) and 4-dimethylaminopyridine (one pellet), and the mixture was stirred overnight at room temperature. The reaction mixture was added with 2 N aqueous hydrochloric acid and thereby made acidic, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, 10% aqueous sodium carbonate, and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was recrystallized from chloroform-n-hexane to obtain the title compound (0.236 g, yield: 89%) as colorless needles (melting point: 163.5-165C). 1H-NMR (400MHz, CDCl3): delta 1.27-1.41 (2H, m), 1.73-1.87 (2H, m), 1.89-2.04 (4H, m), 2.54-2.63 (1H, m), 2.83-2.88 (4H, m), 3.92 (3H, s), 7.38 (2H, m), 7.64 (1H, dd, J=8.4, 2.1Hz), 7.84 (1H, d, J=2.1Hz), 7.91 (1H, d, J=8.4Hz), 7.91 (1H, br-s)
With pyridine; dmap; In benzene; at 20℃; for 15h;
General procedure: To a suspension of 5,6,6a,7,8,9-hexahydro-4H-phenalene-2-carboxylic acid (0.338 g, 1.56 mmol) in benzene (7.5 ml) was added SOCl2 (2.5 ml). The reaction mixture was refluxed for 4 h, then evaporated, and the residue was dissolved in benzene (3 ml) and pyridine (10 ml). Methyl 4-aminobenzoate (0.259 g, 1.71 mmol) and 4-DMAP (0.020 g, 0.164 mmol) were added to the resulting solution. The reaction mixture was stirred at rt for 15 h, then poured into 2 M aqueous HCl and extracted with AcOEt. The organic phase was washed with 10% aqueous Na2CO3. Usual work-up gave a residue, which was purified by silica gel column chromatography(AcOEt/n-hexane = 1:10) to afford methyl 4-[(5,6,6a,7,8,9-hexahydro-4H-2-phenalenyl)carboxamido]benzoate (0.478 g,88%). To a suspension of the above ester (0.385 g, 1.10 mmol) in EtOH (10 ml) was added 2 M aqueous NaOH (7.5 ml). The reaction mixture was stirred at 60 C for 1 h, then cooled, acidified by adding 2 M aqueous HCl and extracted with CHCl3. Usual work-up gave a residue, which was purified by recrystallization from EtOH to afford 7a (0.348 g, 94%).
(1) Methyl 2-chloro-4-[(6a-methyl-5,6,6a,7,8,9-hexahydro-4H-2-phenalenyl)carboxamido]benzoate [Show Image] A suspension of 6a-methyl-5,6,6a,7,8,9-hexahydro-4H-2-phenalenecarboxylic acid (0.150 g) in anhydrous benzene (3 ml) was added with thionyl chloride (1 ml), and the mixture was refluxed by heating for 3 hours. The reaction mixture was concentrated under reduced pressure, the resulting residue was dissolved in anhydrous benzene (2 ml) and pyridine (5 ml), the solution was added with <strong>[46004-37-9]methyl 2-chloro-4-aminobenzoate</strong> (0.1333 g) and 4-dimethylaminopyridine (one pellet), and the mixture was stirred overnight at room temperature. The reaction mixture was added with 2 N aqueous hydrochloric acid and thereby made acidic, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, 10% aqueous sodium carbonate, and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane = 1:15) to obtain the title compound (0.249 g, yield: 96%). The compound was recrystallized from chloroform-n-hexane to obtain colorless needles (melting point: 157-158C). 1H-NMR (400MHz, CDCl3): delta 1.16 (3H, s), 1.51 (2H, td, J=12.9, 4.8Hz), 1.71 (2H, dt, J=12.9, 4.1Hz), 1.78-1.89 (2H, m), 1.99-2.15 (2H, m), 2.82 (2H, dt, J=17.1, 8.6Hz), 2.96 (2H, ddd, J=17.3, 7.8, 3.2Hz), 3.91 (3H, s), 7.36 (2H, s), 7.64 (1H, dd, J=8.7, 2.1Hz), 7.84 (1H, d, J=2.1Hz), 7.89 (1H, d, J=8.7Hz), 7.98 (1H, br-s)
With pyridine; dmap; In benzene; at 20℃; for 15h;
General procedure: To a suspension of 5,6,6a,7,8,9-hexahydro-4H-phenalene-2-carboxylic acid (0.338 g, 1.56 mmol) in benzene (7.5 ml) was added SOCl2 (2.5 ml). The reaction mixture was refluxed for 4 h, then evaporated, and the residue was dissolved in benzene (3 ml) and pyridine (10 ml). Methyl 4-aminobenzoate (0.259 g, 1.71 mmol) and 4-DMAP (0.020 g, 0.164 mmol) were added to the resulting solution. The reaction mixture was stirred at rt for 15 h, then poured into 2 M aqueous HCl and extracted with AcOEt. The organic phase was washed with 10% aqueous Na2CO3. Usual work-up gave a residue, which was purified by silica gel column chromatography(AcOEt/n-hexane = 1:10) to afford methyl 4-[(5,6,6a,7,8,9-hexahydro-4H-2-phenalenyl)carboxamido]benzoate (0.478 g,88%). To a suspension of the above ester (0.385 g, 1.10 mmol) in EtOH (10 ml) was added 2 M aqueous NaOH (7.5 ml). The reaction mixture was stirred at 60 C for 1 h, then cooled, acidified by adding 2 M aqueous HCl and extracted with CHCl3. Usual work-up gave a residue, which was purified by recrystallization from EtOH to afford 7a (0.348 g, 94%).
A suspension of 5,6,7,7a,8,9,10,11-octahydro-4H-2-benzo[ef]heptalenecarboxylic acid (0.090 g) in anhydrous benzene (3 ml) was added with thionyl chloride (1 ml), and the mixture was refluxed by heating for 3 hours. The reaction mixture was concentrated under reduced pressure, the resulting residue was dissolved in anhydrous benzene (2 ml) and pyridine (5 ml), the solution was added with <strong>[46004-37-9]methyl 2-chloro-4-aminobenzoate</strong> (0.082 g) and 4-dimethylaminopyridine (one pellet), and the mixture was stirred overnight. The reaction mixture was added with 2 N aqueous hydrochloric acid and thereby made acidic, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, 10% aqueous sodium carbonate, and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane = 1:10) to obtain methyl 2-chloro-4-[(5,6,7,7a,8,9, 10, 11-octahydro-4H-2-benzo[eflheptalenyl)carboxamido]benzoate (0.080 g, yield: 53%). 1H-NMR (400MHz, CDCl3): delta 1.51-1.71 (6H, m), 1.79-1.98 (6H, m), 2.91 (4H, t, J=5.7 Hz), 3.25-3.32 (1H, m), 3.92 (3H, s), 7.41 (2H, s), 7.65 (1H, dd, J=8.7, 2.1 Hz), 7.84 (1H, d, J=2.1 Hz), 7.91 (1H, d, J=8.7 Hz), 7.93 (1H, br-s)
With pyridine; dmap; In benzene; at 20℃; for 15h;
General procedure: To a suspension of 5,6,6a,7,8,9-hexahydro-4H-phenalene-2-carboxylic acid (0.338 g, 1.56 mmol) in benzene (7.5 ml) was added SOCl2 (2.5 ml). The reaction mixture was refluxed for 4 h, then evaporated, and the residue was dissolved in benzene (3 ml) and pyridine (10 ml). Methyl 4-aminobenzoate (0.259 g, 1.71 mmol) and 4-DMAP (0.020 g, 0.164 mmol) were added to the resulting solution. The reaction mixture was stirred at rt for 15 h, then poured into 2 M aqueous HCl and extracted with AcOEt. The organic phase was washed with 10% aqueous Na2CO3. Usual work-up gave a residue, which was purified by silica gel column chromatography(AcOEt/n-hexane = 1:10) to afford methyl 4-[(5,6,6a,7,8,9-hexahydro-4H-2-phenalenyl)carboxamido]benzoate (0.478 g,88%). To a suspension of the above ester (0.385 g, 1.10 mmol) in EtOH (10 ml) was added 2 M aqueous NaOH (7.5 ml). The reaction mixture was stirred at 60 C for 1 h, then cooled, acidified by adding 2 M aqueous HCl and extracted with CHCl3. Usual work-up gave a residue, which was purified by recrystallization from EtOH to afford 7a (0.348 g, 94%).
4-Amino-2-chloro-benzoic acid (2.50 g) and lithium hydroxide monohydrate (611 mg) were suspended in tetrahydrofuran (20 ml), and the suspension was stirred at room temperature for 20 min. Thereafter, dimethylsulfuric acid (1.38 ml) was added to the reaction mixture, and the mixture was stirred under reflux for 2 hr. The solvent was removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was neutralized with a saturated aqueous sodium hydrogencarbonate solution and was extracted with diethyl ether. The diethyl ether layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure to give methyl 4-amino-2-chloro-benzoate (1.68 g, yield 62%). Methyl 4-amino-2-chloro-benzoate (1.68 g) and 5-methoxymethylene-2,2-dimethyl-[1,3]dioxan-4,6-dione (1.53 g) were dissolved in 2-propanol (25 ml), and the mixture was stirred at 100C for 15.5 hr. The solvent was removed by distillation under the reduced pressure, and the residue was washed with diethyl ether to give methyl 2-chloro-4-[(2,2-dimethyl-4,6-dioxo-[1,3]dioxan-5-ylidenemeth yl)-amino]-benzoate (1.92 g, yield 63%).
2-chloro-4-[(1H-indole-6-carbonyl)-amino]-benzoic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
26%
Step 2: Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (8.3 g, 17.8 mmol, 1.1 equiv.) and diisopropyl ethyl amine (4.4 ml, 33.9 mmol, 2.1 equiv.) were added to 1H-indole-6-carboxylic acid (2.6 g, 16.2 mmol, 1 equiv.) in tetrahydrofuran (30 mL) and the mixture was shaken for 5 minutes at room temperature. 4-Amino-2-chlorobenzoic acid methyl ester (3.3 g, 17.9 mmol, 1.1 equiv.) was added and the resultant mixture was shaken at room temperature for 16 hours. The solvent was removed under vacuum and the residue triturated with dichloromethane (10 mL). The solid was filtered to afford 2-chloro-4-[(1H-indole-6-carbonyl)-amino]-benzoic acid methyl ester, 1.4 g (26% yield). LC (at)215 nm; Rt 1.36: 90%, m/z (ES+): 329 (M+H+.); deltaH (400 MHz; d6-DMSO) 11.65 (1H, s), 10.59 (1H, s), 8.16 (1H, s), 8.10 (1H, s), 7.93 (2H, m), 7.65 (2H, s), 7.59 (1H, m), 6.62 (1H, s), 3.85 (3H, s).
Step 2: Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (6.03 g, 12.9 mmol, 1.1 equiv.) and diisopropyl ethyl amine (3.19 g, 12.9 mmol, 1.1 equiv.) were added to a solution of quinoline-7-carboxylic acid (2.03 g, 11.75 mmol) in tetrahydrofuran (100 ml) and the resultant mixture stirred for 10 minutes. 4-Amino-2-chlorobenzoic acid methyl ester (2.40 g, 12.9 mmol, 1.1 equiv.) in tetrahydrofuran (20 ml) was added and the mixture refluxed for 16 hours. Additional Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (1.10 g, 2.36 mmol, 0.2 equiv.) and diisopropyl ethyl amine (0.61 g, 4.7 mmol, 0.4 equiv.) were added and the mixture refluxed for a further 16 hours. The mixture was evaporated then dissolved in isopropanol (100 ml). Water (5 ml) and 60% aqueous perchloric acid (0.5 ml) were added and the mixture was refluxed for 24 hours. The mixture was filtered while hot then left to cool to room temperature whereupon a crystalline solid was formed. The solid was filtered and washed with cold isopropanol (20 ml) and dichloromethane (20 ml) to give 2-chloro-4-[(quinoline-7-carbonyl)-amino]-benzoic acid methyl ester, 1.42 g (35% yield), as a tan solid. LC (at)215 nm; Rt 1.11: 100%, m/z (ES+): 341 (M+H+.); deltaH (400 MHz; d6-DMSO) 10.96 (1H, br.s), 9.05 (1H, m), 8.73 (1H, s), 8.49 (1H, d), 8.18-8.10 (3H, m), 7.94 (2H, s), 7.68 (1H, dd), 3.86 (3H, s).
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
