N,N-dimethylformamide;dimethyl sulfate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 4 ml of toluene was added 245 mg of (N,N-dimethylformamide-dimethyl sulfate) complex compound, and 66 mg of sodium methoxide was added thereto with ice-cooling after which the resulting mixture was subjected to reaction at room temperature for 30 minutes. Subsequently, 200 mg of ethyl 2-[6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinoyl]acetate was added thereto, and the resulting mixture was subjected to reaction under reflux for 5 hours. To the reaction mixture were added 20 ml of chloroform and 20 ml of water, and the organic layer was separated, washed with 20 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: chloroform-ethanol (50:1 by volume)] to obtain 190 mg (yield 84.9%) of ethyl 2-[6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinoyl]-3 -(N,N-dimethylamino)acrylate having a melting point of 184°-186° C. was added with ice-cooling after which the resulting mixture was subjected to reaction at room temperature for 30 minutes the resulting mixture was subjected to reaction under reflux for 5 hours the organic layer was separated washed with 20 ml of saturated aqueous sodium chloride solution dried over anhydrous magnesium sulfate The solvent was removed by distillation under reduced pressure the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: chloroform-ethanol (50:1 by volume)]

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 4 ml of toluene was added 245 mg of (N,N-dimethylformamide-dimethyl sulfate) complex compound, and 66 mg of sodium methoxide was added thereto with ice-cooling after which the resulting mixture was subjected to reaction at room temperature for 30 minutes. Subsequently, 200 mg of ethyl 2-[6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinoyl]acetate was added thereto, and the resulting mixture was subjected to reaction under reflux for 5 hours. To the reaction mixture were added 20 ml of chloroform and 20 ml of water, and the organic layer was separated, washed with 20 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: chloroform-ethanol (50:1 by volume)] to obtain 190 mg (yield 84.9%) of ethyl 2-[6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinoyl]-3 -(N,N-dimethylamino)acrylate having a melting point of 184°-186° C. was added with ice-cooling after which the resulting mixture was subjected to reaction at room temperature for 30 minutes the resulting mixture was subjected to reaction under reflux for 5 hours the organic layer was separated washed with 20 ml of saturated aqueous sodium chloride solution dried over anhydrous magnesium sulfate The solvent was removed by distillation under reduced pressure the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: chloroform-ethanol (50:1 by volume)]

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 6 ml of methylene chloride was added 335 mg of (N,N-dimethylformamide-dimethyl sulfate) complex compound, and 65 mg of sodium methoxide was added thereto at 0° C., after which the resulting mixture was subjected to reaction at 0° to 10° C. for 1 hour. Subsequently, 300 mg of ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-(2,4,6-trimethylbenzenesulfonyloxy)nicotinoyl]acetate and 115 mg of acetic anhydride were added thereto. The resulting mixture was subjected to reaction at room temperature for 2 hours, and 0.31 ml of 2N hydrochloric acid and 3 ml of ethanol were added to the reaction mixture, after which the resulting mixture was subjected to reaction at room temperature for 1.5 hours. The reaction mixture was added to a mixture of 6 ml of methylene chloride and 6 ml of water, and the organic layer was separated, washed with 6 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the crystalline material thus obtained was added 2 ml of diisopropyl ether, after which crystals were collected by filtration to obtain 245 mg (yield 80.2%) of ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-7-(2,4,6-trimethylbenzenesulfonyloxy)-1,8-naphthyridine-3-carboxylate. The physical properties of this compound were identical with those of the compound obtained in Example 41. was added at 0° C., after which the resulting mixture was subjected to reaction at 0° to 10° C. for 1 hour The resulting mixture was subjected to reaction at room temperature for 2 hours after which the resulting mixture was subjected to reaction at room temperature for 1.5 hours the organic layer was separated washed with 6 ml of saturated aqueous sodium chloride solution dried over anhydrous magnesium sulfate The solvent was removed by distillation under reduced pressure to the crystalline material thus obtained after which crystals were collected by filtration

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 4 ml of toluene was added 540 mg of (N,N-dimethylformamide-dimethyl sulfate) complex compound, and 85 mg of sodium methoxide was added thereto at 0° C., after which the resulting mixture was subjected to reaction at 0° to 10° C. for 1 hour. Subsequently, 200 mg of ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-methoxynicotinoyl]acetate was further added to the reaction mixture, and the resulting mixture was subjected to reaction under reflux for 1.5 hours. The reaction mixture was added to a mixture of 8 ml of ethyl acetate and 8 ml of water, and the organic layer was separated, washed with 5 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the crystalline material thus obtained was added 1 ml of diethyl ether, after which crystals were collected by filtration to obtain 170 mg (yield 82.8%) of ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-7-methoxy-4-oxo-1,8-naphthyridine-3-carboxylate. The physical properties of this compound were identical with those of the compound obtained in Example 41. was added at 0° C., after which the resulting mixture was subjected to reaction at 0° to 10° C. for 1 hour the resulting mixture was subjected to reaction under reflux for 1.5 hours the organic layer was separated washed with 5 ml of saturated aqueous sodium chloride solution dried over anhydrous magnesium sulfate The solvent was removed by distillation under reduced pressure to the crystalline material thus obtained after which crystals were collected by filtration

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 4 ml of toluene was added 540 mg of (N,N-dimethylformamide-dimethyl sulfate) complex compound, and 85 mg of sodium methoxide was added thereto at 0° C., after which the resulting mixture was subjected to reaction at 0° to 10° C. for 1 hour. Subsequently, 200 mg of ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-methoxynicotinoyl]acetate was further added to the reaction mixture, and the resulting mixture was subjected to reaction under reflux for 1.5 hours. The reaction mixture was added to a mixture of 8 ml of ethyl acetate and 8 ml of water, and the organic layer was separated, washed with 5 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the crystalline material thus obtained was added 1 ml of diethyl ether, after which crystals were collected by filtration to obtain 170 mg (yield 82.8%) of ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-7-methoxy-4-oxo-1,8-naphthyridine-3-carboxylate. The physical properties of this compound were identical with those of the compound obtained in Example 41. was added at 0° C., after which the resulting mixture was subjected to reaction at 0° to 10° C. for 1 hour the resulting mixture was subjected to reaction under reflux for 1.5 hours the organic layer was separated washed with 5 ml of saturated aqueous sodium chloride solution dried over anhydrous magnesium sulfate The solvent was removed by distillation under reduced pressure to the crystalline material thus obtained after which crystals were collected by filtration

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 4 ml of toluene was added 245 mg of (N,N-dimethylformamide-dimethyl sulfate) complex compound, and 66 mg of sodium methoxide was added thereto with ice-cooling after which the resulting mixture was subjected to reaction at room temperature for 30 minutes. Subsequently, 200 mg of ethyl 2-[6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinoyl]acetate was added thereto, and the resulting mixture was subjected to reaction under reflux for 5 hours. To the reaction mixture were added 20 ml of chloroform and 20 ml of water, and the organic layer was separated, washed with 20 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: chloroform-ethanol (50:1 by volume)] to obtain 190 mg (yield 84.9%) of ethyl 2-[6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinoyl]-3 -(N,N-dimethylamino)acrylate having a melting point of 184°-186° C. was added with ice-cooling after which the resulting mixture was subjected to reaction at room temperature for 30 minutes the resulting mixture was subjected to reaction under reflux for 5 hours the organic layer was separated washed with 20 ml of saturated aqueous sodium chloride solution dried over anhydrous magnesium sulfate The solvent was removed by distillation under reduced pressure the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: chloroform-ethanol (50:1 by volume)]

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 6 ml of methylene chloride was added 335 mg of (N,N-dimethylformamide-dimethyl sulfate) complex compound, and 65 mg of sodium methoxide was added thereto at 0° C., after which the resulting mixture was subjected to reaction at 0° to 10° C. for 1 hour. Subsequently, 300 mg of ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-(2,4,6-trimethylbenzenesulfonyloxy)nicotinoyl]acetate and 115 mg of acetic anhydride were added thereto. The resulting mixture was subjected to reaction at room temperature for 2 hours, and 0.31 ml of 2N hydrochloric acid and 3 ml of ethanol were added to the reaction mixture, after which the resulting mixture was subjected to reaction at room temperature for 1.5 hours. The reaction mixture was added to a mixture of 6 ml of methylene chloride and 6 ml of water, and the organic layer was separated, washed with 6 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the crystalline material thus obtained was added 2 ml of diisopropyl ether, after which crystals were collected by filtration to obtain 245 mg (yield 80.2%) of ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-7-(2,4,6-trimethylbenzenesulfonyloxy)-1,8-naphthyridine-3-carboxylate. The physical properties of this compound were identical with those of the compound obtained in Example 41. was added at 0° C., after which the resulting mixture was subjected to reaction at 0° to 10° C. for 1 hour The resulting mixture was subjected to reaction at room temperature for 2 hours after which the resulting mixture was subjected to reaction at room temperature for 1.5 hours the organic layer was separated washed with 6 ml of saturated aqueous sodium chloride solution dried over anhydrous magnesium sulfate The solvent was removed by distillation under reduced pressure to the crystalline material thus obtained after which crystals were collected by filtration

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 4 ml of toluene was added 540 mg of (N,N-dimethylformamide-dimethyl sulfate) complex compound, and 85 mg of sodium methoxide was added thereto at 0° C., after which the resulting mixture was subjected to reaction at 0° to 10° C. for 1 hour. Subsequently, 200 mg of ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-methoxynicotinoyl]acetate was further added to the reaction mixture, and the resulting mixture was subjected to reaction under reflux for 1.5 hours. The reaction mixture was added to a mixture of 8 ml of ethyl acetate and 8 ml of water, and the organic layer was separated, washed with 5 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the crystalline material thus obtained was added 1 ml of diethyl ether, after which crystals were collected by filtration to obtain 170 mg (yield 82.8%) of ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-7-methoxy-4-oxo-1,8-naphthyridine-3-carboxylate. The physical properties of this compound were identical with those of the compound obtained in Example 41. was added at 0° C., after which the resulting mixture was subjected to reaction at 0° to 10° C. for 1 hour the resulting mixture was subjected to reaction under reflux for 1.5 hours the organic layer was separated washed with 5 ml of saturated aqueous sodium chloride solution dried over anhydrous magnesium sulfate The solvent was removed by distillation under reduced pressure to the crystalline material thus obtained after which crystals were collected by filtration

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 4 ml of toluene was added 245 mg of (N,N-dimethylformamide-dimethyl sulfate) complex compound, and 66 mg of sodium methoxide was added thereto with ice-cooling after which the resulting mixture was subjected to reaction at room temperature for 30 minutes. Subsequently, 200 mg of ethyl 2-[6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinoyl]acetate was added thereto, and the resulting mixture was subjected to reaction under reflux for 5 hours. To the reaction mixture were added 20 ml of chloroform and 20 ml of water, and the organic layer was separated, washed with 20 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: chloroform-ethanol (50:1 by volume)] to obtain 190 mg (yield 84.9%) of ethyl 2-[6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinoyl]-3 -(N,N-dimethylamino)acrylate having a melting point of 184°-186° C. was added with ice-cooling after which the resulting mixture was subjected to reaction at room temperature for 30 minutes the resulting mixture was subjected to reaction under reflux for 5 hours the organic layer was separated washed with 20 ml of saturated aqueous sodium chloride solution dried over anhydrous magnesium sulfate The solvent was removed by distillation under reduced pressure the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: chloroform-ethanol (50:1 by volume)]

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 6 ml of methylene chloride was added 335 mg of (N,N-dimethylformamide-dimethyl sulfate) complex compound, and 65 mg of sodium methoxide was added thereto at 0° C., after which the resulting mixture was subjected to reaction at 0° to 10° C. for 1 hour. Subsequently, 300 mg of ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-(2,4,6-trimethylbenzenesulfonyloxy)nicotinoyl]acetate and 115 mg of acetic anhydride were added thereto. The resulting mixture was subjected to reaction at room temperature for 2 hours, and 0.31 ml of 2N hydrochloric acid and 3 ml of ethanol were added to the reaction mixture, after which the resulting mixture was subjected to reaction at room temperature for 1.5 hours. The reaction mixture was added to a mixture of 6 ml of methylene chloride and 6 ml of water, and the organic layer was separated, washed with 6 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the crystalline material thus obtained was added 2 ml of diisopropyl ether, after which crystals were collected by filtration to obtain 245 mg (yield 80.2%) of ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-7-(2,4,6-trimethylbenzenesulfonyloxy)-1,8-naphthyridine-3-carboxylate. The physical properties of this compound were identical with those of the compound obtained in Example 41. was added at 0° C., after which the resulting mixture was subjected to reaction at 0° to 10° C. for 1 hour The resulting mixture was subjected to reaction at room temperature for 2 hours after which the resulting mixture was subjected to reaction at room temperature for 1.5 hours the organic layer was separated washed with 6 ml of saturated aqueous sodium chloride solution dried over anhydrous magnesium sulfate The solvent was removed by distillation under reduced pressure to the crystalline material thus obtained after which crystals were collected by filtration

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 4 ml of toluene was added 540 mg of (N,N-dimethylformamide-dimethyl sulfate) complex compound, and 85 mg of sodium methoxide was added thereto at 0° C., after which the resulting mixture was subjected to reaction at 0° to 10° C. for 1 hour. Subsequently, 200 mg of ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-methoxynicotinoyl]acetate was further added to the reaction mixture, and the resulting mixture was subjected to reaction under reflux for 1.5 hours. The reaction mixture was added to a mixture of 8 ml of ethyl acetate and 8 ml of water, and the organic layer was separated, washed with 5 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the crystalline material thus obtained was added 1 ml of diethyl ether, after which crystals were collected by filtration to obtain 170 mg (yield 82.8%) of ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-7-methoxy-4-oxo-1,8-naphthyridine-3-carboxylate. The physical properties of this compound were identical with those of the compound obtained in Example 41. was added at 0° C., after which the resulting mixture was subjected to reaction at 0° to 10° C. for 1 hour the resulting mixture was subjected to reaction under reflux for 1.5 hours the organic layer was separated washed with 5 ml of saturated aqueous sodium chloride solution dried over anhydrous magnesium sulfate The solvent was removed by distillation under reduced pressure to the crystalline material thus obtained after which crystals were collected by filtration

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 4 ml of toluene was added 245 mg of (N,N-dimethylformamide-dimethyl sulfate) complex compound, and 66 mg of sodium methoxide was added thereto with ice-cooling after which the resulting mixture was subjected to reaction at room temperature for 30 minutes. Subsequently, 200 mg of ethyl 2-[6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinoyl]acetate was added thereto, and the resulting mixture was subjected to reaction under reflux for 5 hours. To the reaction mixture were added 20 ml of chloroform and 20 ml of water, and the organic layer was separated, washed with 20 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: chloroform-ethanol (50:1 by volume)] to obtain 190 mg (yield 84.9%) of ethyl 2-[6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinoyl]-3 -(N,N-dimethylamino)acrylate having a melting point of 184°-186° C. was added with ice-cooling after which the resulting mixture was subjected to reaction at room temperature for 30 minutes the resulting mixture was subjected to reaction under reflux for 5 hours the organic layer was separated washed with 20 ml of saturated aqueous sodium chloride solution dried over anhydrous magnesium sulfate The solvent was removed by distillation under reduced pressure the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: chloroform-ethanol (50:1 by volume)]