2-amino-4-chloro-N-methylbenzamide

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: Carbonyl-1,1′-diimidazole (1.70 g) was added to 2-amino-4-chlorobenzoic acid (1.50 g) in THF (22.2 mL). After stirring overnight a solution of methylamine in THF (2M, 6.6 mL) was added and the reaction stirred for 3 hours. The reaction was concentrated in vacuo and the residue dissolved in EtOAc (100 mL) and saturated aqueous sodium bicarbonate solution (50 mL). The organics were then washed with saturated aqueous sodium bicarbonate solution (50 mL) and then water (2×100 mL). The organics were extracted with 1 M HCl (4×25 mL, then 2×100 mL then 50 mL), the aqueous phase basified with potassium carbonate (˜50 g) and the organics discarded. The aqueous was then extracted with EtOAc (2×50 mL). The combined organics were dried (MgSO4, 10 g) and concentrated to give 2-amino-4-chloro-N-methylbenzamide (1.2 g, 74%). was added The reaction was concentrated in vacuo the residue dissolved in EtOAc (100 mL) The organics were then washed with saturated aqueous sodium bicarbonate solution (50 mL) The organics were extracted with 1 M HCl (4×25 mL The aqueous was then extracted with EtOAc (2×50 mL) The combined organics were dried (MgSO4, 10 g) concentrated

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

実験手順: Carbonyl-1,1′-diimidazole (1.70 g) was added to 2-amino-4-chlorobenzoic acid (1.50 g) in THF (22.2 mL). After stirring overnight a solution of methylamine in THF (2M, 6.6 mL) was added and the reaction stirred for 3 hours. The reaction was concentrated in vacuo and the residue dissolved in EtOAc (100 mL) and saturated aqueous sodium bicarbonate solution (50 mL). The organics were then washed with saturated aqueous sodium bicarbonate solution (50 mL) and then water (2×100 mL). The organics were extracted with 1 M HCl (4×25 mL, then 2×100 mL then 50 mL), the aqueous phase basified with potassium carbonate (˜50 g) and the organics discarded. The aqueous was then extracted with EtOAc (2×50 mL). The combined organics were dried (MgSO4, 10 g) and concentrated to give 2-amino-4-chloro-N-methylbenzamide (1.2 g, 74%). was added The reaction was concentrated in vacuo the residue dissolved in EtOAc (100 mL) The organics were then washed with saturated aqueous sodium bicarbonate solution (50 mL) The organics were extracted with 1 M HCl (4×25 mL The aqueous was then extracted with EtOAc (2×50 mL) The combined organics were dried (MgSO4, 10 g) concentrated

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

実験手順: 27.2 g of 4-[(diethoxyphosphoryl)methyl]benzoic acid was suspended in a mixture of 60 ml of dichloromethane and 2 ml of DMF. 13.1 g of thionyl chloride was added, and the resulting mixture was refluxed for 1 hour. After completion of reaction, the reaction mixture was allowed to cool and then slowly added dropwise, with ice-cooling and stirring, to a solution of 18.5 g of 2-(N-methylcarbamoyl)-5-chloroaniline in a mixture of 50 ml of pyridine and 30 ml of dichloromethane. After completion of addition, the resulting mixture was stirred at room temperature for 48 hours. Then, 50 ml of water was added to the reaction mixture to precipitate crystals. The crystals were then collected by filtration, fully washed with water and dried, giving 23.6 g of diethyl 4-{[5-chloro-2-(N-methylcarbamoyl)phenyl]carbamoyl}benzylphosphonate. the resulting mixture was refluxed for 1 hour After completion of reaction to cool slowly added dropwise, with ice- cooling After completion of addition to precipitate crystals The crystals were then collected by filtration fully washed with water dried

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of (E)-3,4-bis(difluoromethoxy)phenyl-2-propenoic acid (0.10 g, 0.42 mmol) in CH2Cl2 (5 mL) was treated with oxalyl chloride (0.14 mL, 1.7 mmol) and catalytic DMF (1 drop). The solution was stirred at rt for 1 h and the solvent was removed under reduced pressure to give the acid chloride as a yellow solid. A solution of the acid chloride (0.42 mmol) in pyridine (2.0 mL) was added to a cooled solution of 2-amino-4-chloro-N-methylbenzamide (0.12 g, 0.63 mmol) in pyridine (2.0 mL) at 0° C. The suspension was stirred at 0° C. for 1 h, warmed to rt and stirred for 16 h and then acidified with 1 M HCl. The precipitate was collected by filtration and recrystallised from EtOH/water providing (E)-2-[[3,4-bis(difluoromethoxy)phenyl)-1-oxo-2-propenyl]amino]-5-chloro-N-methylbenzamide (95 mg, 51%) as a pale brown crystalline solid; mp 191.5-195.5° C.; δH (500 MHz, DMSO-d6) 2.82 (d, J=4.5 Hz, 3H, NHCH3), 6.94 (d, J=15.6 Hz, 1H, CH═CHCO), 7.27 (t, J=73 Hz, 1H, OCHF2), 7.28 (t, J=73 Hz, 1H, OCHF2), 7.26 (dd, J5,6=8.0, J3,5=1.6 Hz, 1H, H5), 7.39 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.59 (d, J=15.6 Hz, 1H, CH═CHCO), 7.69 (dd, J5′,6′=8.5, J2′,6′=2.5 Hz, 1H, H6′), 7.77 (d, J5,6=2.5 Hz, 1H, H6), 7.80 (d, J2′,6′=2.5 Hz, 1H, H2′), 8.67 (d, J3,5=2.5 Hz, 1H, H3), 8.84 (m, 1H, NHCH3), 11.82 (s, 1H, NH); δC (125 MHz, DMSO-d6) 26.3, 116.3 (t, J=259 Hz), 116.5 (t, J=259 Hz), 119.2, 119.9, 119.9, 120.7, 122.6, 123.4, 126.8, 129.6, 132.7, 136.2, 139.7, 140.2, 141.9, 142.8, 163.5, 167.8; HRMS (ESI+) calculated for C19H15ClF4N2O4 [M+Na]+ 469.0549, found 469.0546; νmax 1038, 1113, 1260, 1505, 1578, 1626, 3025, 3382 cm−1. warmed to rt stirred for 16 h The precipitate was collected by filtration recrystallised from EtOH/water

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of (E)-3,4-bis(difluoromethoxy)phenyl-2-propenoic acid (0.10 g, 0.42 mmol) in CH2Cl2 (5 mL) was treated with oxalyl chloride (0.14 mL, 1.7 mmol) and catalytic DMF (1 drop). The solution was stirred at rt for 1 h and the solvent was removed under reduced pressure to give the acid chloride as a yellow solid. A solution of the acid chloride (0.42 mmol) in pyridine (2.0 mL) was added to a cooled solution of 2-amino-4-chloro-N-methylbenzamide (0.12 g, 0.63 mmol) in pyridine (2.0 mL) at 0° C. The suspension was stirred at 0° C. for 1 h, warmed to rt and stirred for 16 h and then acidified with 1 M HCl. The precipitate was collected by filtration and recrystallised from EtOH/water providing (E)-2-[[3,4-bis(difluoromethoxy)phenyl)-1-oxo-2-propenyl]amino]-5-chloro-N-methylbenzamide (95 mg, 51%) as a pale brown crystalline solid; mp 191.5-195.5° C.; δH (500 MHz, DMSO-d6) 2.82 (d, J=4.5 Hz, 3H, NHCH3), 6.94 (d, J=15.6 Hz, 1H, CH═CHCO), 7.27 (t, J=73 Hz, 1H, OCHF2), 7.28 (t, J=73 Hz, 1H, OCHF2), 7.26 (dd, J5,6=8.0, J3,5=1.6 Hz, 1H, H5), 7.39 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.59 (d, J=15.6 Hz, 1H, CH═CHCO), 7.69 (dd, J5′,6′=8.5, J2′,6′=2.5 Hz, 1H, H6′), 7.77 (d, J5,6=2.5 Hz, 1H, H6), 7.80 (d, J2′,6′=2.5 Hz, 1H, H2′), 8.67 (d, J3,5=2.5 Hz, 1H, H3), 8.84 (m, 1H, NHCH3), 11.82 (s, 1H, NH); δC (125 MHz, DMSO-d6) 26.3, 116.3 (t, J=259 Hz), 116.5 (t, J=259 Hz), 119.2, 119.9, 119.9, 120.7, 122.6, 123.4, 126.8, 129.6, 132.7, 136.2, 139.7, 140.2, 141.9, 142.8, 163.5, 167.8; HRMS (ESI+) calculated for C19H15ClF4N2O4 [M+Na]+ 469.0549, found 469.0546; νmax 1038, 1113, 1260, 1505, 1578, 1626, 3025, 3382 cm−1. warmed to rt stirred for 16 h The precipitate was collected by filtration recrystallised from EtOH/water

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: Carbonyl-1,1′-diimidazole (1.70 g) was added to 2-amino-4-chlorobenzoic acid (1.50 g) in THF (22.2 mL). After stirring overnight a solution of methylamine in THF (2M, 6.6 mL) was added and the reaction stirred for 3 hours. The reaction was concentrated in vacuo and the residue dissolved in EtOAc (100 mL) and saturated aqueous sodium bicarbonate solution (50 mL). The organics were then washed with saturated aqueous sodium bicarbonate solution (50 mL) and then water (2×100 mL). The organics were extracted with 1 M HCl (4×25 mL, then 2×100 mL then 50 mL), the aqueous phase basified with potassium carbonate (˜50 g) and the organics discarded. The aqueous was then extracted with EtOAc (2×50 mL). The combined organics were dried (MgSO4, 10 g) and concentrated to give 2-amino-4-chloro-N-methylbenzamide (1.2 g, 74%). was added The reaction was concentrated in vacuo the residue dissolved in EtOAc (100 mL) The organics were then washed with saturated aqueous sodium bicarbonate solution (50 mL) The organics were extracted with 1 M HCl (4×25 mL The aqueous was then extracted with EtOAc (2×50 mL) The combined organics were dried (MgSO4, 10 g) concentrated

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

実験手順: 27.2 g of 4-[(diethoxyphosphoryl)methyl]benzoic acid was suspended in a mixture of 60 ml of dichloromethane and 2 ml of DMF. 13.1 g of thionyl chloride was added, and the resulting mixture was refluxed for 1 hour. After completion of reaction, the reaction mixture was allowed to cool and then slowly added dropwise, with ice-cooling and stirring, to a solution of 18.5 g of 2-(N-methylcarbamoyl)-5-chloroaniline in a mixture of 50 ml of pyridine and 30 ml of dichloromethane. After completion of addition, the resulting mixture was stirred at room temperature for 48 hours. Then, 50 ml of water was added to the reaction mixture to precipitate crystals. The crystals were then collected by filtration, fully washed with water and dried, giving 23.6 g of diethyl 4-{[5-chloro-2-(N-methylcarbamoyl)phenyl]carbamoyl}benzylphosphonate. the resulting mixture was refluxed for 1 hour After completion of reaction to cool slowly added dropwise, with ice- cooling After completion of addition to precipitate crystals The crystals were then collected by filtration fully washed with water dried

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of (E)-3,4-bis(difluoromethoxy)phenyl-2-propenoic acid (0.10 g, 0.42 mmol) in CH2Cl2 (5 mL) was treated with oxalyl chloride (0.14 mL, 1.7 mmol) and catalytic DMF (1 drop). The solution was stirred at rt for 1 h and the solvent was removed under reduced pressure to give the acid chloride as a yellow solid. A solution of the acid chloride (0.42 mmol) in pyridine (2.0 mL) was added to a cooled solution of 2-amino-4-chloro-N-methylbenzamide (0.12 g, 0.63 mmol) in pyridine (2.0 mL) at 0° C. The suspension was stirred at 0° C. for 1 h, warmed to rt and stirred for 16 h and then acidified with 1 M HCl. The precipitate was collected by filtration and recrystallised from EtOH/water providing (E)-2-[[3,4-bis(difluoromethoxy)phenyl)-1-oxo-2-propenyl]amino]-5-chloro-N-methylbenzamide (95 mg, 51%) as a pale brown crystalline solid; mp 191.5-195.5° C.; δH (500 MHz, DMSO-d6) 2.82 (d, J=4.5 Hz, 3H, NHCH3), 6.94 (d, J=15.6 Hz, 1H, CH═CHCO), 7.27 (t, J=73 Hz, 1H, OCHF2), 7.28 (t, J=73 Hz, 1H, OCHF2), 7.26 (dd, J5,6=8.0, J3,5=1.6 Hz, 1H, H5), 7.39 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.59 (d, J=15.6 Hz, 1H, CH═CHCO), 7.69 (dd, J5′,6′=8.5, J2′,6′=2.5 Hz, 1H, H6′), 7.77 (d, J5,6=2.5 Hz, 1H, H6), 7.80 (d, J2′,6′=2.5 Hz, 1H, H2′), 8.67 (d, J3,5=2.5 Hz, 1H, H3), 8.84 (m, 1H, NHCH3), 11.82 (s, 1H, NH); δC (125 MHz, DMSO-d6) 26.3, 116.3 (t, J=259 Hz), 116.5 (t, J=259 Hz), 119.2, 119.9, 119.9, 120.7, 122.6, 123.4, 126.8, 129.6, 132.7, 136.2, 139.7, 140.2, 141.9, 142.8, 163.5, 167.8; HRMS (ESI+) calculated for C19H15ClF4N2O4 [M+Na]+ 469.0549, found 469.0546; νmax 1038, 1113, 1260, 1505, 1578, 1626, 3025, 3382 cm−1. warmed to rt stirred for 16 h The precipitate was collected by filtration recrystallised from EtOH/water