Tetrahydrofuran → 5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole maleate

Participants

Reaction Conditions

Reaction Steps

Tetrahydrofuran (72 mL) and dichloromethane (8 mL) are charged in to a round bottom flask. The mixture is cooled to −10 to 5° C. and aluminum chloride (4.46 g) is charged in to the mixture. A solution of lithium aluminium hydride in tetrahydrofuran (2.4 M; 19 mL) is added to the reaction mixture at −10° C. to 5° C. A solution of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-1-one (10 g) in a mixture of tetrahydrofuran (108 mL) and dichloromethane (12 mL) is added to the above reaction mixture. The reaction mixture is maintained at −10° C. to 5° C. for 1-2 hours. A 3% sodium hydroxide solution (150 mL) is added to the reaction mixture at below 10° C. and stirred for 30 minutes. Water (150 mL) and ethyl acetate (100 m) are charged in to the mixture. The reaction mass is allowed to warm to 25-35° C., filtered, and the unwanted solid is washed with tetrahydrofuran (50 mL). Separated the organic and aqueous layers, the aqueous layer is extracted with ethyl acetate (80 mL), and the combined organic layer is washed with 30% brine solution (100 mL). The solvent from the organic layer is evaporated completely under reduced pressure at below 50° C. Isopropyl alcohol (2×10 mL) is charged and again the solvent form the mixture is evaporated completely at below 50° C. under reduced pressure. Isopropyl alcohol (50 mL) is charged to the reaction mass. Maleic acid (5.04 g) is added to the reaction mass at 25-35° C. The reaction mixture is stirred at 25-35° C. for 15-30 minutes, then seeded with asenapine maleate (0.1 g) and the mixture is stirred for 15-18 hours at 25-35° C. The reaction mixture is cooled to 0-5° C. and maintained for 1-2 hours. The obtained solid is collected by filtration, washed with isopropyl alcohol (10 mL) at 0-5° C., and dried by suction for 15 minutes to form asenapine maleate. The resultant compound is charged in to another round bottom flask containing a mixture of isopropyl alcohol (40 mL) and methanol (10 mL). The reaction mixture is heated to 60-65° C., basic carbon (1 g) is added to the reaction solution at the same temperature and maintained for 10-20 minutes. The reaction mass is filtered and the solid is washed with isopropyl alcohol (10 mL). The resultant filtrate is charged in to another round bottom flask and maintained at 25-35° C. for 2-3 hours. Then the reaction mass is cooled to 0-5° C. and stirred for 30-60 minutes. The obtained solid is collected by filtration, washed with isopropyl alcohol (10 mL) at 0-5° C., and dried at 60-65° C. under reduced pressure to afford 9.05 g of the title compound. Purity by HPLC: 99.8%; deschloro asenapine of formula (XIII): 0.04%; cis asenapine of formula (XIV): 0.01%; tetrahydro asenapine maleate of formula (XV): not detected; amide compound of formula (XVII): not detected; n-oxide: 0.05%.

Provenance & Evidence