Ethyl 2,3-difluorobenzoate

反応条件: temp:50.01; pressure:0.00; stir:

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In a 500 mL round-bottomed flask (t=g) was added crude 4-iodobut-1-ene (11.51 g, 63.2 mmol) in Et2O (100 mL) to give a colorless solution. After cooling to −78° C. under nitrogen, tBuLi (80 mL, 136 mmol) was added dropwise via syringe. The mixture was slowly warmed up to room temperature while stirring for 2 hours. After 20 minutes at room temperature, the mixture was cooled to −78° C. and ethyl 2,3-difluorobenzoate (4.28 mL, 28.7 mmol) was added dropwise via syringe. The mixture was gradually warmed up to room temperature over 30 minutes. The reaction was quenched by water and the volatiles were evaporated. The residue was partitioned between water and EtOAc. The layers were separated and the organic layer was washed with brine, dried with Na2SO4 and concentrated to a light yellow oil. Purification up to 40% Et2O in hexane afforded the desired product as a colorless oil: (1.41 g, 19%). 1H NMR (400 MHz, CDCl3) δ 7.31-7.22 (m, 1H), 7.10-7.03 (m, 2H), 5.82-5.70 (m, 2H), 4.97-4.85 (m, 4H), 2.20-2.00 (m, 4H), 2.00-1.75 (m, 4H). to give a colorless solution The mixture was slowly warmed up to room temperature After 20 minutes at room temperature the mixture was cooled to −78° C. The mixture was gradually warmed up to room temperature over 30 minutes The reaction was quenched by water the volatiles were evaporated The residue was partitioned between water and EtOAc The layers were separated the organic layer was washed with brine dried with Na2SO4 concentrated to a light yellow oil Purification up to 40% Et2O in hexane

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of ethyl-2,3 difluorobenzoate (1.07 g, 5.75 mmol) in DMF (10 mL) was treated with sodium sulfide (896 mg, 11.5 mmol, 2.0 equiv) at 23° C. The mixture was stirred under argon for 10 h. The solution was diluted with ethyl acetate (50 mL) and water (50 mL) and 10% citric acid (5 mL). The organic layer was washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, decanted and concentrated under reduced pressure to give 3-Fluoro-2-mercapto-benzoic acid ethyl ester: 1H NMR (300 MHz, CDCl3) δ 7.71 (t, 1H), 7.38 (m, H), 7.12 (m, 1H), 4.41 (q, 2H), 1.40 (t, 3H); LCMS (100% area) Rt=4.53 min, (pos) [M+H]/z Calc'd 201.0. found 200.9. The organic layer was washed with saturated aqueous sodium bicarbonate dried over sodium sulfate decanted concentrated under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of ethyl-2,3 difluorobenzoate (1.07 g, 5.75 mmol) in DMF (10 mL) was treated with sodium sulfide (896 mg, 11.5 mmol, 2.0 equiv) at 23° C. The mixture was stirred under argon for 10 h. The solution was diluted with ethyl acetate (50 mL) and water (50 mL) and 10% citric acid (5 mL). The organic layer was washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, decanted and concentrated under reduced pressure to give 3-Fluoro-2-mercapto-benzoic acid ethyl ester 1H NMR (300 MHz, CDCl3) δ 7.71 (t, 1H), 7.38 (m, 1H), 7.12 (m, 1H), 4.41 (q, 2H), 1.40 (t, 3H); LCMS (100% area) Rt=4.53 min, (pos) [M+H]/z Calc'd 201.0, found 200.9. The organic layer was washed with saturated aqueous sodium bicarbonate dried over sodium sulfate decanted concentrated under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of ethyl-2,3 difluorobenzoate (1.07 g, 5.75 mmol) in DMF (10 mL) was treated with sodium sulfide (896 mg, 11.5 mmol, 2.0 equiv) at 23° C. The mixture was stirred under argon for 10 h. The solution was diluted with ethyl acetate (50 mL) and water (50 mL) and 10% citric acid (5 mL). The organic layer was washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, decanted and concentrated under reduced pressure to give 3-Fluoro-2-mercapto-benzoic acid ethyl ester: 1H NMR (300 MHz, CDCl3) δ 7.71 (t, 1H), 7.38 (m, H), 7.12 (m, 1H), 4.41 (q, 2H), 1.40 (t, 3H); LCMS (100% area) Rt=4.53 min, (pos) [M+H]/z Calc'd 201.0, found 200.9. The organic layer was washed with saturated aqueous sodium bicarbonate dried over sodium sulfate decanted concentrated under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of ethyl-2,3 difluorobenzoate (1.07 g, 5.75 mmol) in DMF (10 mL) was treated with sodium sulfide (896 mg, 11.5 mmol, 2.0 equiv) at 23° C. The mixture was stirred under argon for 10 h. The solution was diluted with ethyl acetate (50 mL) and water (50 mL) and 10% citric acid (5 mL). The organic layer was washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, decanted and concentrated under reduced pressure to give 3-Fluoro-2-mercapto-benzoic acid ethyl ester: 1H NMR (300 MHz, CDCl3) δ 7.71 (t, 1H), 7.38 (m, H), 7.12 (m, 1H), 4.41 (q, 2H), 1.40 (t, 3H); LCMS (100% area) Rt=4.53 min, (pos) [M+H]/z Calc'd 201.0, found 200.9. The organic layer was washed with saturated aqueous sodium bicarbonate dried over sodium sulfate decanted concentrated under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Example 37(a) was prepared in a similar manner to that described for Example 35(a) except that the starting material described below was employed and that ethoxyamine was used instead of propylamine: 1H NMR (300 MHz, CDCl3) δ 8.59 (m, 1H), 8.08 (d, 1H), 7.88 (d, 1H, J=16.4 Hz), 7.79 (t, 1H), 7.65 (d, 1H), 7.60 (m, 1H), 7.50 (d, 1H, J=16.4 Hz), 7.40 (t, 1H), 7.36 (d, 1H), 7.28 (s, 1H), 7.23 (m, 1H), 7.10 (d, 1H), 3.90 (q, 2H), 1.19 (t, 3H). LCMS (100% area) Rt=4.85 min, (pos) [M+H]/z Calc'd 435.1, found 435.1, (neg) [M−H]/z Calc'd 433.1, found 433.1. Analyzed with 0.35H2O, 0.07 EtOAc Calc'd, C (62.56), H (4.57), N (12.54), S (7.17). Found: C (62.61), H (4.55), N (12.49), S (7.11). Starting material was prepared as follows: A solution of ethyl-2,3 difluorobenzoate (1.07 g, 5.75 mmol) in DMF (10 mL) was treated with sodium sulfide (896 mg, 11.5 mmol, 2.0 equiv) at 23° C. The mixture was stirred under argon for 10 h. The solution was diluted with ethyl acetate (50 mL) and water (50 mL) and 10% citric acid (5 mL). The organic layer was washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, decanted and concentrated under reduced pressure to give 3-Fluoro-2-mercapto-benzoic acid ethyl ester. 1H NMR (300 MHz, CDCl3)57.71 (t, 1H), 7.38 (m, H), 7.12 (m, 1H), 4.41 (q, 2H), 1.40 (t, 3H); LCMS (100% area) Rt=4.53 min, (pos) [M+H]/z Calc'd 201.0, found 200.9. Example 37(a) was prepared in a similar manner to that Starting material was prepared The organic layer was washed with saturated aqueous sodium bicarbonate dried over sodium sulfate decanted concentrated under reduced pressure

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In a 500 mL round-bottomed flask (t=g) was added crude 4-iodobut-1-ene (11.51 g, 63.2 mmol) in Et2O (100 mL) to give a colorless solution. After cooling to −78° C. under nitrogen, tBuLi (80 mL, 136 mmol) was added dropwise via syringe. The mixture was slowly warmed up to room temperature while stirring for 2 hours. After 20 minutes at room temperature, the mixture was cooled to −78° C. and ethyl 2,3-difluorobenzoate (4.28 mL, 28.7 mmol) was added dropwise via syringe. The mixture was gradually warmed up to room temperature over 30 minutes. The reaction was quenched by water and the volatiles were evaporated. The residue was partitioned between water and EtOAc. The layers were separated and the organic layer was washed with brine, dried with Na2SO4 and concentrated to a light yellow oil. Purification up to 40% Et2O in hexane afforded the desired product as a colorless oil: (1.41 g, 19%). 1H NMR (400 MHz, CDCl3) δ 7.31-7.22 (m, 1H), 7.10-7.03 (m, 2H), 5.82-5.70 (m, 2H), 4.97-4.85 (m, 4H), 2.20-2.00 (m, 4H), 2.00-1.75 (m, 4H). to give a colorless solution The mixture was slowly warmed up to room temperature After 20 minutes at room temperature the mixture was cooled to −78° C. The mixture was gradually warmed up to room temperature over 30 minutes The reaction was quenched by water the volatiles were evaporated The residue was partitioned between water and EtOAc The layers were separated the organic layer was washed with brine dried with Na2SO4 concentrated to a light yellow oil Purification up to 40% Et2O in hexane

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In a 500 mL round-bottomed flask (t=g) was added crude 4-iodobut-1-ene (11.51 g, 63.2 mmol) in Et2O (100 mL) to give a colorless solution. After cooling to −78° C. under nitrogen, tBuLi (80 mL, 136 mmol) was added dropwise via syringe. The mixture was slowly warmed up to room temperature while stirring for 2 hours. After 20 minutes at room temperature, the mixture was cooled to −78° C. and ethyl 2,3-difluorobenzoate (4.28 mL, 28.7 mmol) was added dropwise via syringe. The mixture was gradually warmed up to room temperature over 30 minutes. The reaction was quenched by water and the volatiles were evaporated. The residue was partitioned between water and EtOAc. The layers were separated and the organic layer was washed with brine, dried with Na2SO4 and concentrated to a light yellow oil. Purification up to 40% Et2O in hexane afforded the desired product as a colorless oil: (1.41 g, 19%). 1H NMR (400 MHz, CDCl3) δ 7.31-7.22 (m, 1H), 7.10-7.03 (m, 2H), 5.82-5.70 (m, 2H), 4.97-4.85 (m, 4H), 2.20-2.00 (m, 4H), 2.00-1.75 (m, 4H). to give a colorless solution The mixture was slowly warmed up to room temperature After 20 minutes at room temperature the mixture was cooled to −78° C. The mixture was gradually warmed up to room temperature over 30 minutes The reaction was quenched by water the volatiles were evaporated The residue was partitioned between water and EtOAc The layers were separated the organic layer was washed with brine dried with Na2SO4 concentrated to a light yellow oil Purification up to 40% Et2O in hexane

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of ethyl-2,3 difluorobenzoate (1.07 g, 5.75 mmol) in DMF (10 mL) was treated with sodium sulfide (896 mg, 11.5 mmol, 2.0 equiv) at 23° C. The mixture was stirred under argon for 10 h. The solution was diluted with ethyl acetate (50 mL) and water (50 mL) and 10% citric acid (5 mL). The organic layer was washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, decanted and concentrated under reduced pressure to give 3-Fluoro-2-mercapto-benzoic acid ethyl ester: 1H NMR (300 MHz, CDCl3) δ 7.71 (t, 1H), 7.38 (m, H), 7.12 (m, 1H), 4.41 (q, 2H), 1.40 (t, 3H); LCMS (100% area) Rt=4.53 min, (pos) [M+H]/z Calc'd 201.0. found 200.9. The organic layer was washed with saturated aqueous sodium bicarbonate dried over sodium sulfate decanted concentrated under reduced pressure