3-氨基-2-氯苯甲酸甲酯

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of methyl 3-amino-2-chlorobenzoate (16.3 g, 88 mmol) in pyridine (150 mL) was added 2,5-difluorobenzenesulfonyl chloride (13.0 ml, 97 mmol) dropwise. The solution was stirred at rt overnight. The crude reaction mixture was concentrated by about half, and ˜200 mL of water was added. A red oil precipitated from the mixture. The oil was separated, and crystallized upon standing. The crystals were collected by vacuum filtration, washed with ether, and dried in vacuo to generate 16.8 g (46.4 mmol, 52.8% yield) as a white powder. LC/MS indicates that the product is a ˜2:1 mixture of the desired product and the bis-sulfonamide. The white powder was dissolved in THF (100 mL), and a 1 M solution of LiHMDS in THF (100 mL, 100 mmol) was added. A solution of 2-chloro-4-methylpyrimidine (8.0 g, 62.2 mmol) in THF (10 mL) was added dropwise over 15 minutes. The solution was stirred at 20° C. for an additional 20 minutes, and then the reaction was quenched with MeOH (5 mL). The solvent was removed with a rotary evaporator, and the residue was partitioned between EtOAc and water. The aqueous layer was acidified to pH<9 with saturated aqueous ammonium chloride, and extracted with EtOAc. The combined organic layers were dried over anhydrous NaSO4, filtered, and concentrated to ˜50 mL. The brown solution was passed through a pad of silica gel (eluting with EtOAc) and concentrated to generate the title compound (6.78 g, 14.8 mmol, 16.8% yield) as a yellow powder. MS (ESI): 458.0 [M+H]+. The crude reaction mixture was concentrated by about half, and ˜200 mL of water was added A red oil precipitated from the mixture The oil was separated crystallized The crystals were collected by vacuum filtration washed with ether dried in vacuo a ˜2:1 mixture of the desired product The white powder was dissolved in THF (100 mL) The solution was stirred at 20° C. for an additional 20 minutes the reaction was quenched with MeOH (5 mL) The solvent was removed with a rotary evaporator the residue was partitioned between EtOAc and water extracted with EtOAc The combined organic layers were dried over anhydrous NaSO4 filtered concentrated to ˜50 mL concentrated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Following a procedure analogous to Intermediate 5, Step A using methyl 3-amino-2-chlorobenzoate (39 g, 211 mmol) in DCM (200 mL) was added pyridine (51 g, 633 mmol) and 2,6-difluorobenzene-1-sulfonyl chloride (49.1 g, 232 mmol) the title compound was obtained (62 g, 81.6% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.87 (dd, J=1.8 Hz, 8.38 Hz, 1H), 7.72-7.79 (br, 1H), 7.56 (dd, J=1.8 Hz, 7.94 Hz, 1H), 7.45-7.53 (m, 1H), 7.28 (dd, J=7.9 Hz, 8.4 Hz, 1H), 6.95-7.01 (m, 2H), 3.89 (s, 3H).

反应条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of methyl 2-chloro-3-nitrobenzoate (25 g, 116 mmol) in MeOH (150 mL) was added Raney Ni (3 g). The mixture was stirred under H2 atmosphere (50 psi at 25° C.) for 3.5 h. The catalyst was filtered, and the filtrate was concentrated under the reduced pressure to dryness to give the crude product, which was purified by recrystallization in EtOAc to afford the title compound (69 g, 83.5% yield, four batches combined). 1H NMR (400 MHz, CDCl3) δ ppm 6.70-7.25 (m, 3H), 4.40-4.50 (br, 2H), 3.87 (s, 3H). The catalyst was filtered the filtrate was concentrated under the reduced pressure to dryness to give the crude product, which was purified by recrystallization in EtOAc

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Oxalyl chloride (889 mg, 7.0 mmol) was dropwise added to a solution of 3-cyano-4-isobutyloxybenzoic acid (767 mg, 3.5 mmol) in dichloromethane (10 mL) under cooling with ice. Subsequently, a catalytic amount of DMF was added. The mixture was then stirred for one hour at room temperature, heated under reflux for 3 hours, and placed under reduced pressure to distill the solvent off. Toluene was added to the residue and the solvent was distilled off under reduced pressure. THF (10 mL) was added to the residue. Further, a solution of methyl 3 amino-2-chlorobenzoate (497 mg, 2.68 mmol) and triethylamine (1.39 mL, 10 mmol) in THF (10 mL). The resulting mixture was stirred for 14 hours at room temperature, and toluene and aqueous 1M hydrochloric acid were added. The organic portion was taken out, washed with aqueous 1M hydrochloric acid and aqueous saturated sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and placed under reduced pressure to distill the solvent off. under cooling with ice heated under reflux for 3 hours to distill the solvent off Toluene was added to the residue the solvent was distilled off under reduced pressure THF (10 mL) was added to the residue The resulting mixture was stirred for 14 hours at room temperature washed with aqueous 1M hydrochloric acid and aqueous saturated sodium hydrogen carbonate dried over anhydrous magnesium sulfate to distill the solvent off

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Oxalyl chloride (889 mg, 7.0 mmol) was dropwise added to a solution of 3-cyano-4-isobutyloxybenzoic acid (767 mg, 3.5 mmol) in dichloromethane (10 mL) under cooling with ice. Subsequently, a catalytic amount of DMF was added. The mixture was then stirred for one hour at room temperature, heated under reflux for 3 hours, and placed under reduced pressure to distill the solvent off. Toluene was added to the residue and the solvent was distilled off under reduced pressure. THF (10 mL) was added to the residue. Further, a solution of methyl 3 amino-2-chlorobenzoate (497 mg, 2.68 mmol) and triethylamine (1.39 mL, 10 mmol) in THF (10 mL). The resulting mixture was stirred for 14 hours at room temperature, and toluene and aqueous 1M hydrochloric acid were added. The organic portion was taken out, washed with aqueous 1M hydrochloric acid and aqueous saturated sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and placed under reduced pressure to distill the solvent off. under cooling with ice heated under reflux for 3 hours to distill the solvent off Toluene was added to the residue the solvent was distilled off under reduced pressure THF (10 mL) was added to the residue The resulting mixture was stirred for 14 hours at room temperature washed with aqueous 1M hydrochloric acid and aqueous saturated sodium hydrogen carbonate dried over anhydrous magnesium sulfate to distill the solvent off

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 3-amino-2-chlorobenzoic acid (500 mg, 2.91 mmol), conc. sulfuric acid (6 mL), and methanol (150 mL) was heated under reflux for 24 hours, and placed under reduced pressure to distill the solvent off. The residue was neutralized by addition of aqueous saturated sodium hydrogen carbonate. The neutralized mixture was extracted with toluene, dried over anhydrous magnesium sulfate, and placed under reduced pressure to distill the solvent off. There was obtained 497 mg (yield 92%) of the desired compound in the form of pale brown oil. was heated under reflux for 24 hours to distill the solvent off The residue was neutralized by addition of aqueous saturated sodium hydrogen carbonate The neutralized mixture was extracted with toluene dried over anhydrous magnesium sulfate to distill the solvent off

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of methyl 3-amino-2-chlorobenzoate (16.3 g, 88 mmol) in pyridine (150 mL) was added 2,5-difluorobenzenesulfonyl chloride (13.0 ml, 97 mmol) dropwise. The solution was stirred at rt overnight. The crude reaction mixture was concentrated by about half, and ˜200 mL of water was added. A red oil precipitated from the mixture. The oil was separated, and crystallized upon standing. The crystals were collected by vacuum filtration, washed with ether, and dried in vacuo to generate 16.8 g (46.4 mmol, 52.8% yield) as a white powder. LC/MS indicates that the product is a ˜2:1 mixture of the desired product and the bis-sulfonamide. The white powder was dissolved in THF (100 mL), and a 1M solution of LiHMDS in THF (100 mL, 100 mmol) was added. A solution of 2-chloro-4-methylpyrimidine (8.0 g, 62.2 mmol) in THF (10 mL) was added dropwise over 15 minutes. The solution was stirred at 20° C. for an additional 20 minutes, and then the reaction was quenched with MeOH (5 mL). The solvent was removed with a rotary evaporator, and the residue was partitioned between EtOAc and water. The aqueous layer was acidified to pH<9 with saturated aqueous ammonium chloride, and extracted with EtOAc. The combined organic layers were dried over anhydrous NaSO4, filtered, and concentrated to ˜50 mL. The brown solution was passed through a pad of silica gel (eluting with EtOAc) and concentrated to generate the title compound (6.78 g, 14.8 mmol, 16.8% yield) as a yellow powder. MS (ESI): 458.0 [M+H]+. The crude reaction mixture was concentrated by about half, and ˜200 mL of water was added A red oil precipitated from the mixture The oil was separated crystallized The crystals were collected by vacuum filtration washed with ether dried in vacuo a ˜2:1 mixture of the desired product The white powder was dissolved in THF (100 mL) The solution was stirred at 20° C. for an additional 20 minutes the reaction was quenched with MeOH (5 mL) The solvent was removed with a rotary evaporator the residue was partitioned between EtOAc and water extracted with EtOAc The combined organic layers were dried over anhydrous NaSO4 filtered concentrated to ˜50 mL concentrated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Following a procedure analogous to Intermediate 5, Step A using methyl 3-amino-2-chlorobenzoate (39 g, 211 mmol) in DCM (200 mL) was added pyridine (51 g, 633 mmol) and 2,6-difluorobenzene-1-sulfonyl chloride (49.1 g, 232 mmol) the title compound was obtained (62 g, 81.6% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.87 (dd, J=1.8 Hz, 8.38 Hz, 1H), 7.72-7.79 (br, 1H), 7.56 (dd, J=1.8 Hz, 7.94 Hz, 1H), 7.45-7.53 (m, 1H), 7.28 (dd, J=7.9 Hz, 8.4 Hz, 1H), 6.95-7.01 (m, 2H), 3.89 (s, 3H).

反应条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of methyl 2-chloro-3-nitrobenzoate (25 g, 116 mmol) in MeOH (150 mL) was added Raney Ni (3 g). The mixture was stirred under H2 atmosphere (50 psi at 25° C.) for 3.5 h. The catalyst was filtered, and the filtrate was concentrated under the reduced pressure to dryness to give the crude product, which was purified by recrystallization in EtOAc to afford the title compound (69 g, 83.5% yield, four batches combined). 1H NMR (400 MHz, CDCl3) δ ppm 6.70-7.25 (m, 3H), 4.40-4.50 (br, 2H), 3.87 (s, 3H). The catalyst was filtered the filtrate was concentrated under the reduced pressure to dryness to give the crude product, which was purified by recrystallization in EtOAc

反应条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of methyl 2-chloro-3-nitrobenzoate (25 g, 116 mmol) in MeOH (150 mL) was added Raney Ni (3 g). The mixture was stirred under H2 atmosphere (50 psi at 25° C.) for 3.5 h. The catalyst was filtered, and the filtrate was concentrated under the reduced pressure to dryness to give the crude product, which was purified by recrystallization in EtOAc to afford the title compound (69 g, 83.5% yield, four batches combined). 1H NMR (400 MHz, CDCl3) δ ppm 6.70-7.25 (m, 3H), 4.40-4.50 (br, 2H), 3.87 (s, 3H). The catalyst was filtered the filtrate was concentrated under the reduced pressure to dryness to give the crude product, which was purified by recrystallization in EtOAc

反应条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of methyl 2-chloro-3-aminobenzoate (11.11 g, 59.86 mM) and 1,3-cyclohexanedione (9.05 g, 80.8 mM) was heated at 120° C. under a stream of nitrogen for 4 hours. The resultant solid was triturated with hot ethyl acetate, then dried in vacuo to afford 14.05 g (84%) of 3-(3-carbomethoxy-2-chloroanilino)cyclohex-2-en-1-one as a yellow orange solid. 1H NMR (CDCl3) δ 7.6 (dt, 1H, J=1 and 8 Hz), 7.3 (t, 1H, J=8 Hz), 6.6 (br s, 1H), 5.62 (s, 1H), 3.95 (s, 3H), 2.6 (t, 2H, J=6 Hz), 2.4 (t, 2H, J=6 Hz), and 2.1 (m, 2H). IR (CHCl3, cm−1) 3050, 2950, 1729, 1536, 1351, 1299, 1290, 1267, and 1135. MS (ES) m/e 278, 280, 282. The resultant solid was triturated with hot ethyl acetate dried in vacuo

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of sodium dithionite (14.0 g, 20.0 mM) and sodium carbonate (6.7 g) in 200 mL of water was slowly added to a solution of methyl 2-chloro-3-nitrobenzoate (6.0 g, 27.9 mM) in 40 mL methanol and 40 mL of tetrahydrofuran at 25° C. over 30 minutes. The mixture was stirred at room temperature for an additional 30 minutes, then extracted with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to afford 1.2 g (33%) of methyl 2-chloro-3-aminobenzoate as a yellow oil, identical in all respects to the material derived via catalytic hydrogenation described above. extracted with ethyl acetate The extracts were washed with brine dried over sodium sulfate filtered concentrated