9-chloro-4-methyl-13-oxa-4-azatetracyclo[12.4.0.02,6.07,12]octadeca-1(18),2(6),7(12),8,10,14,16-heptaen-3-one

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

実験手順: P2O5 (90 grams) was added in portions to H3PO4 (90 grams) while maintaining the temperature below 140° C. The mixture was heated at 115° C. for 1.5 hour, whereupon 3-[2-(4-chloro-phenoxy)-phenyl]-1-methyl-pyrrolidine-2,4-dione (XI) (30 grams; 95 mmol) was added. The resulting mixture was stirred for 4 days at 115° C. to 130° C. with extra P2O5 (in total 5 portions of 5 grams each were added). The mixture was poured into water (200 ml) and the resulting precipitate was stirred overnight. The mixture was extracted with dichloromethane (250 ml) and washed with sat. NaHCO3 (pH=7). After drying on magnesium sulphate the solvent was removed under vacuum. The resulting crude product was dissolved in methanol (520 ml) at 70° C. Following removal of part of the methanol by evaporation the product crystallized. The mixture was stirred overnight at −12° C. The crystals were filtered and dried to provide 5-chloro-2,3-dihydro-2-methyl-1H-dibenz[2,3;6,7]oxepino[4,5-c]pyrrol-1-one (VI) (16.4 grams, 55 mmol; 58%), purity according to GC 92%.1H-NMR (400 MHz, CDCl3): 3.2 (s, 3H), 4.3 (s, 1H), 3.8 (m,1H), 7.2-7.4 (m, 6H), 8.2 (dd,1H). while maintaining the temperature below 140° C was added The mixture was extracted with dichloromethane (250 ml) washed with sat. NaHCO3 (pH=7) After drying on magnesium sulphate the solvent was removed under vacuum The resulting crude product was dissolved in methanol (520 ml) at 70° C removal of part of the methanol by evaporation the product crystallized The mixture was stirred overnight at −12° C The crystals were filtered dried

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

実験手順: P2O5 (90 grams) was added in portions to H3PO4 (90 grams) while maintaining the temperature below 140° C. The mixture was heated at 115° C. for 1.5 hour, whereupon 3-[2-(4-chloro-phenoxy)-phenyl]-1-methyl-pyrrolidine-2,4-dione (XI) (30 grams; 95 mmol) was added. The resulting mixture was stirred for 4 days at 115° C. to 130° C. with extra P2O5 (in total 5 portions of 5 grams each were added). The mixture was poured into water (200 ml) and the resulting precipitate was stirred overnight. The mixture was extracted with dichloromethane (250 ml) and washed with sat. NaHCO3 (pH=7). After drying on magnesium sulphate the solvent was removed under vacuum. The resulting crude product was dissolved in methanol (520 ml) at 70° C. Following removal of part of the methanol by evaporation the product crystallized. The mixture was stirred overnight at −12° C. The crystals were filtered and dried to provide 5-chloro-2,3-dihydro-2-methyl-1H-dibenz[2,3;6,7]oxepino[4,5-c]pyrrol-1-one (VI) (16.4 grams, 55 mmol; 58%), purity according to GC 92%.1H-NMR (400 MHz, CDCl3): 3.2 (s, 3H), 4.3 (s, 1H), 3.8 (m,1H), 7.2-7.4 (m, 6H), 8.2 (dd,1H). while maintaining the temperature below 140° C was added The mixture was extracted with dichloromethane (250 ml) washed with sat. NaHCO3 (pH=7) After drying on magnesium sulphate the solvent was removed under vacuum The resulting crude product was dissolved in methanol (520 ml) at 70° C removal of part of the methanol by evaporation the product crystallized The mixture was stirred overnight at −12° C The crystals were filtered dried

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

実験手順: P2O5 (90 grams) was added in portions to H3PO4 (90 grams) while maintaining the temperature below 140° C. The mixture was heated at 115° C. for 1.5 hour, whereupon 3-[2-(4-chloro-phenoxy)-phenyl]-1-methyl-pyrrolidine-2,4-dione (XI) (30 grams; 95 mmol) was added. The resulting mixture was stirred for 4 days at 115° C. to 130° C. with extra P2O5 (in total 5 portions of 5 grams each were added). The mixture was poured into water (200 ml) and the resulting precipitate was stirred overnight. The mixture was extracted with dichloromethane (250 ml) and washed with sat. NaHCO3 (pH=7). After drying on magnesium sulphate the solvent was removed under vacuum. The resulting crude product was dissolved in methanol (520 ml) at 70° C. Following removal of part of the methanol by evaporation the product crystallized. The mixture was stirred overnight at −12° C. The crystals were filtered and dried to provide 5-chloro-2,3-dihydro-2-methyl-1H-dibenz[2,3;6,7]oxepino[4,5-c]pyrrol-1-one (VI) (16.4 grams, 55 mmol; 58%), purity according to GC 92%.1H-NMR (400 MHz, CDCl3): 3.2 (s, 3H), 4.3 (s, 1H), 3.8 (m,1H), 7.2-7.4 (m, 6H), 8.2 (dd,1H). while maintaining the temperature below 140° C was added The mixture was extracted with dichloromethane (250 ml) washed with sat. NaHCO3 (pH=7) After drying on magnesium sulphate the solvent was removed under vacuum The resulting crude product was dissolved in methanol (520 ml) at 70° C removal of part of the methanol by evaporation the product crystallized The mixture was stirred overnight at −12° C The crystals were filtered dried

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

実験手順: P2O5 (90 grams) was added in portions to H3PO4 (90 grams) while maintaining the temperature below 140° C. The mixture was heated at 115° C. for 1.5 hour, whereupon 3-[2-(4-chloro-phenoxy)-phenyl]-1-methyl-pyrrolidine-2,4-dione (XI) (30 grams; 95 mmol) was added. The resulting mixture was stirred for 4 days at 115° C. to 130° C. with extra P2O5 (in total 5 portions of 5 grams each were added). The mixture was poured into water (200 ml) and the resulting precipitate was stirred overnight. The mixture was extracted with dichloromethane (250 ml) and washed with sat. NaHCO3 (pH=7). After drying on magnesium sulphate the solvent was removed under vacuum. The resulting crude product was dissolved in methanol (520 ml) at 70° C. Following removal of part of the methanol by evaporation the product crystallized. The mixture was stirred overnight at −12° C. The crystals were filtered and dried to provide 5-chloro-2,3-dihydro-2-methyl-1H-dibenz[2,3;6,7]oxepino[4,5-c]pyrrol-1-one (VI) (16.4 grams, 55 mmol; 58%), purity according to GC 92%. 1H-NMR (400 MHz, CDCl3): 3.2 (s, 3H), 4.3 (s, 1H), 3.8 (m, 1H), 7.2-7.4 (m, 6H), 8.2 (dd, 1H). while maintaining the temperature below 140° C was added The mixture was extracted with dichloromethane (250 ml) washed with sat. NaHCO3 (pH=7) After drying on magnesium sulphate the solvent was removed under vacuum The resulting crude product was dissolved in methanol (520 ml) at 70° C removal of part of the methanol by evaporation the product crystallized The mixture was stirred overnight at −12° C The crystals were filtered dried

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

実験手順: P2O5 (90 grams) was added in portions to H3PO4 (90 grams) while maintaining the temperature below 140° C. The mixture was heated at 115° C. for 1.5 hour, whereupon 3-[2-(4-chloro-phenoxy)-phenyl]-1-methyl-pyrrolidine-2,4-dione (XI) (30 grams; 95 mmol) was added. The resulting mixture was stirred for 4 days at 115° C. to 130° C. with extra P2O5 (in total 5 portions of 5 grams each were added). The mixture was poured into water (200 ml) and the resulting precipitate was stirred overnight. The mixture was extracted with dichloromethane (250 ml) and washed with sat. NaHCO3 (pH=7). After drying on magnesium sulphate the solvent was removed under vacuum. The resulting crude product was dissolved in methanol (520 ml) at 70° C. Following removal of part of the methanol by evaporation the product crystallized. The mixture was stirred overnight at −12° C. The crystals were filtered and dried to provide 5-chloro-2,3-dihydro-2-methyl-1H-dibenz[2,3;6,7]oxepino[4,5-c]pyrrol-1-one (VI) (16.4 grams, 55 mmol; 58%), purity according to GC 92%. 1H-NMR (400 MHz, CDCl3): 3.2 (s, 3H), 4.3 (s, 1H), 3.8 (m, 1H), 7.2-7.4 (m, 6H), 8.2 (dd, 1H). while maintaining the temperature below 140° C was added The mixture was extracted with dichloromethane (250 ml) washed with sat. NaHCO3 (pH=7) After drying on magnesium sulphate the solvent was removed under vacuum The resulting crude product was dissolved in methanol (520 ml) at 70° C removal of part of the methanol by evaporation the product crystallized The mixture was stirred overnight at −12° C The crystals were filtered dried

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

実験手順: P2O5 (90 grams) was added in portions to H3PO4 (90 grams) while maintaining the temperature below 140° C. The mixture was heated at 115° C. for 1.5 hour, whereupon 3-[2-(4-chloro-phenoxy)-phenyl]-1-methyl-pyrrolidine-2,4-dione (XI) (30 grams; 95 mmol) was added. The resulting mixture was stirred for 4 days at 115° C. to 130° C. with extra P2O5 (in total 5 portions of 5 grams each were added). The mixture was poured into water (200 ml) and the resulting precipitate was stirred overnight. The mixture was extracted with dichloromethane (250 ml) and washed with sat. NaHCO3 (pH=7). After drying on magnesium sulphate the solvent was removed under vacuum. The resulting crude product was dissolved in methanol (520 ml) at 70° C. Following removal of part of the methanol by evaporation the product crystallized. The mixture was stirred overnight at −12° C. The crystals were filtered and dried to provide 5-chloro-2,3-dihydro-2-methyl-1H-dibenz [2,3;6,7]oxepino[4,5-c]pyrrol-1-one (VI) (16.4 grams, 55 mmol; 58%), purity according to GC 92%. 1H-NMR (400 MHz, CDCl3): 3.2 (s, 3H), 4.3 (s, 1H), 3.8 (m, 1H), 7.2-7.4 (m, 6H), 8.2 (dd, 1H). while maintaining the temperature below 140° C was added The mixture was extracted with dichloromethane (250 ml) washed with sat. NaHCO3 (pH=7) After drying on magnesium sulphate the solvent was removed under vacuum The resulting crude product was dissolved in methanol (520 ml) at 70° C removal of part of the methanol by evaporation the product crystallized The mixture was stirred overnight at −12° C The crystals were filtered dried

反応条件: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Phosphoric acid (270 g) is charged in to a round bottom flask and phosphorous pentoxide (270 g) is added in portions at below 140° C. The reaction mixture temperature is allowed to 110° C. and maintained for 2 hours. 3-(2-(4-Chlorophenoxy)phenyl)-1-methylpyrrolidine-2,4-dione (90 g) is added at 110° C. and maintained for 24 hours. Additional phosphorous pentoxide (3×15 g) is added to the reaction mixture in three portions at 110° C. at the time interval of 24 hours. Finally, the reaction mixture is maintained for 48 hours. The reaction mixture is cooled to 25-35° C., poured in to water (4500 mL), and stirred for 15 hours. The reaction mass is extracted with dichloromethane (900 mL), the layers are separated, and the aqueous layer is washed with dichloromethane (900 mL). The combined organic layer is washed with water (450 mL), 5% sodium bicarbonate (450 mL), and water (450 mL). The solvent from the organic layer is evaporated at 45° C. Methanol (180 mL) is charged to the reaction mass and again the solvent is evaporated form the reaction mass completely at 45° C. under reduced pressure. Methanol (450 mL) is charged to the reaction mass and heated at reflux for 30 minutes. The solution is cooled to 25-35° C. and further cooled to −8 to −12° C. The reaction mass is maintained at −8 to −12° C. for 3 hours, the obtained solid is collected by filtration, washed with chilled methanol (90 mL), and dried at 50-60° C. to afford 44 g of the title compound. is allowed to 110° C. maintained for 2 hours maintained for 24 hours Finally, the reaction mixture is maintained for 48 hours The reaction mass is extracted with dichloromethane (900 mL) the layers are separated the aqueous layer is washed with dichloromethane (900 mL) The combined organic layer is washed with water (450 mL), 5% sodium bicarbonate (450 mL), and water (450 mL) The solvent from the organic layer is evaporated at 45° C Methanol (180 mL) is charged to the reaction mass again the solvent is evaporated form the reaction mass completely at 45° C. under reduced pressure Methanol (450 mL) is charged to the reaction mass heated at reflux for 30 minutes The solution is cooled to 25-35° C. further cooled to −8 to −12° C The reaction mass is maintained at −8 to −12° C. for 3 hours the obtained solid is collected by filtration washed with chilled methanol (90 mL) dried at 50-60° C.

反応条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Phosphorus pentoxide (270 g) is added in portions to H3PO4 (270 g) and the mixture is maintained for 1-2 hours at 100-120° C. 3-(2-(4-chlorophenoxy)phenyl)-1-methyl-pyrrolidine-2,4-dione (90 g) is added and the mixture is maintained for three days at 100-110° C. Additional P2O5 (30 g) is added in two portions and the mass is maintained for one day at 100-120° C. The mass is poured into water (900 mL) and the mass is stirred overnight at 25-35° C. The mass is extracted with dichloromethane (1000 mL), the layers are separated, and the aqueous layer is washed with dichloromethane (400 mL). The combined organic layer is washed with water (900 mL), 5% sodium bicarbonate (300 mL), and saturated brine solution (500 mL). After drying over anhydrous sodium sulfate, the solvent is removed under vacuum. The residue is dissolved in methanol (400 ml) and heated at reflux for 30-60 minutes. The solution is cooled to −10 to −15° C. and a solid forms. The solid is collected by filtration, washed with chilled methanol (50 mL), and dried to afford the title compound. Yield: 37.5 g. Purity by HPLC: 89.47%. the mixture is maintained for three days at 100-110° C the mass is maintained for one day at 100-120° C The mass is extracted with dichloromethane (1000 mL) the layers are separated the aqueous layer is washed with dichloromethane (400 mL) The combined organic layer is washed with water (900 mL), 5% sodium bicarbonate (300 mL), and saturated brine solution (500 mL) After drying over anhydrous sodium sulfate the solvent is removed under vacuum The residue is dissolved in methanol (400 ml) heated at reflux for 30-60 minutes The solution is cooled to −10 to −15° C. The solid is collected by filtration washed with chilled methanol (50 mL) dried

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

実験手順: P2O5 (90 grams) was added in portions to H3PO4 (90 grams) while maintaining the temperature below 140° C. The mixture was heated at 115° C. for 1.5 hour, whereupon 3-[2-(4-chloro-phenoxy)-phenyl]-1-methyl-pyrrolidine-2,4-dione (XI) (30 grams; 95 mmol) was added. The resulting mixture was stirred for 4 days at 115° C. to 130° C. with extra P2O5 (in total 5 portions of 5 grams each were added). The mixture was poured into water (200 ml) and the resulting precipitate was stirred overnight. The mixture was extracted with dichloromethane (250 ml) and washed with sat. NaHCO3 (pH=7). After drying on magnesium sulphate the solvent was removed under vacuum. The resulting crude product was dissolved in methanol (520 ml) at 70° C. Following removal of part of the methanol by evaporation the product crystallized. The mixture was stirred overnight at −12° C. The crystals were filtered and dried to provide 5-chloro-2,3-dihydro-2-methyl-1H-dibenz[2,3;6,7]oxepino[4,5-c]pyrrol-1-one (VI) (16.4 grams, 55 mmol; 58%), purity according to GC 92%.1H-NMR (400 MHz, CDCl3): 3.2 (s, 3H), 4.3 (s, 1H), 3.8 (m,1H), 7.2-7.4 (m, 6H), 8.2 (dd,1H). while maintaining the temperature below 140° C was added The mixture was extracted with dichloromethane (250 ml) washed with sat. NaHCO3 (pH=7) After drying on magnesium sulphate the solvent was removed under vacuum The resulting crude product was dissolved in methanol (520 ml) at 70° C removal of part of the methanol by evaporation the product crystallized The mixture was stirred overnight at −12° C The crystals were filtered dried