Trans-(+/-)-11-Chloro-2,3,3a,12b-tetrahydro-2-meth

Magnesium metal turnings (10 g) were added to a suspension of 11-chloro-2-methyl-2, 3-dihydro-1H-dibenzo[2, 3:6, 7]oxepino[4, 5-c]pyrrol-1-one (7 g) in methanol (50 mL). The reaction mixture was slowly heated to refluxing temperature. Brisk effervescence was observed. The reaction mixture was cooled to control the reaction and again refluxed for about 2 hours. The reaction mass was diluted with methanol (30 mL), further refluxed for about 30 minutes, cooled to ambient temperature, slurried in water (150 mL) and filtered. pH of the filtrate was adjusted to 1-2 by adding concentrated hydrochloric acid. A clear solution was obtained. The solution was extracted with ethyl acetate (3×50mL) followed by washing with water (3×50 mL). Ethyl acetate was recovered to obtain a mixture of diastereomers as brown oil (4.6 g) followed by separation of the two isomers using silica gel column chromatography eluting with ethyl acetate-hexane mixture. cis-isomer: 50percent trans-isomer: 9percent2 g of 1 l-chloro-2-methyl-2, 3-dihydro-lH-dibenzo[2, 3:6, 7]oxepino[4, 5-c]pyrrol- 1-one was dissolved in a mixture of methanol (60 mL) and acetic acid (20 mL). The reaction mixture was heated to about 53°C. Magnesium metal turnings (2.0 g) were added portion-wise. The reaction mixture was stirred for about 1 hour, filtered and washed with methanol (100 mL). Methanol was removed by distillation from the filtrate to obtain a white solid (16 g). The white solid was dissolved in dichloromethane (200 mL) and washed with water (2 x 500 mL). The solid obtained during filtration was also dissolved in water (100 mL) and the aqueous layer was extracted with dichloromethane (50 mL). The two dichloromethane solutions were combined. Dichloromethane was removed by distillation under reduced pressure to obtain a mixture of two isomers as an oily brown compound (2 g). The mixture of isomers was separated into cis- and irans-isomers using silica gel column chromatography eluting with ethyl acetate :hexane (30:70) mixture. irans-isomer: 0.7 gcz2 g of 11-chloro-2-methyl-2, 3-dihydro-1H-dibenzo[2, 3:6, 7]oxepino[4, 5-c]pyrrol-1-one was dissolved in a mixture of methanol (60 mL) and acetic acid (20 mL). The reaction mixture was heated to about 50° C. Magnesium metal turnings (2.38 g) were added portion-wise at about 45° C. to about 65° C. The reaction mixture was stirred at ambient temperature for about 2 hours. Water (80 mL) was added. The pH of the reaction mixture was adjusted to 1 by adding concentrated hydrochloric acid. The reaction mixture was extracted with ethyl acetate (150 mL) and washed with water (3×200 mL). Ethyl acetate was distilled-off to obtain a mixture of two isomers as an oily brown compound (2 g). The mixture of isomers was separated into cis- and trans-isomers using silica gel column chromatography eluting with ethyl acetate:hexane (30:70) mixture. trans-isomer: 0.7 g cis-isomer: 0.8 g.Preparation of Asenapine sulphate salt: Trans-1 l-chloro-2, 3, 3a, 12b-tetrahydro-2-methyl-lH-dibenz[2, 3:6, 7]oxepino[4, 5-c] pyrrole (Asenapine base) (10.0 gm) obtained as above was dissolved in acetone (200 ml) at room temperature. To this solution, sulphuric acid (3.7 gm) was slowly added at room temperature. The reaction mass was stirred for 1 hour. The reaction mass was filtered and washed with acetone (50 ml). The reaction mass was dried under reduced pressure at 45C for 1 hour to obtain 13 gm of Asenapine sulphate salt. Total yield: 97.0% Impurity VII: 0.09%, Impurity VIII: not detected; Impurity X:not detected; Impurity IXa and IXb: 0.1%; Impurity 'Mu' RRT-3.1: 0.20% HPLC Purity: 99.26%a) Preparation of trans-ll-chloro-2, 3, 3a, 12b-tetrahydro-2-methyl-lH-dibenzo[2, 3:6, 7] oxepino[4, 5-c]pyrrole (Asenapine base): Aluminum chloride (13.87 gm) was added in portions to tetrahydrofuran (600 ml) at -20 to - 25C. Under stirring lithium aluminum hydride (14.92 gm) was added in portions to the reaction mixture while keeping the temperature between -20 C to -25 C. The mixture was stirred for 20 minutes. Trans-l l-chloro-2, 3, 3a, 12b-tetrahydro-2-methyl-lH-dibenz[2, 3:6, 7] oxepino [4, 5-c]pyrrol-l-one (40.0 gm) was dissolved in tetrahydrofuran (400 ml) and was then slowly added to the reaction mixture while keeping the temperature between -20 C to - 25 C. Stirring was continued for 1 hour at temperature between -20 C to -25 C. 0.6 N sodium hydroxide solution (400 ml) was slowly added without controlling the temperature. The reaction mass was diluted with toluene (800 ml) and water (800 ml) and stirred for 30 minutes and the reaction mixture was filtered. The filtrate was separated. The aqueous layer was extracted twice with toluene (2 X 800 ml). The toluene layers were combined and washed with water (800 ml). The toluene layer was distilled out under reduce pressure at 50 C to obtain (38.13 gm) of trans-l l-chloro-2, 3, 3a, 12b-tetrahydro-2-methyl-lH-dibenz [2, 3:6, 7] oxepino [4, 5-c]pyrrole (Asenapihe base). Total yield: 100.0% Impurity VII: 0.14%; Impurity VIII: not detected; Impurity X : not detected; Impurity IXa and IXb : 0.1%; Impurity *M' RRT-3.1: 0.43% HPLC Purity: 98.59Synthesis of asenapine maleate form M 7.12 g (53.4 mmol) of aluminum trichloride and 3.55 g (93.5 mmol) of lithium aluminum hydride were suspended in 200 mL of anhydrous tetrahydrofuran below 10 C. The resulting suspension was stirred at 0C for 15 minutes. A solution of 10.0 g (33.4 mmol) of frans-11-chloro-2, 3, 3a, 12b-tetrahydro-2-methyl-1 /-/-dibenz[2, 3:6, 7]oxepino[4, 5-c] pyrrol-1-one in 100 mL of anhydrous tetrahydrofuran was added dropwise while keeping the temperature below 15 C. The resulting mixture was stirred at 10 C for 1 hour, and the consumption of trans- 1-chloro-2, 3, 3a, 12b-tetrahydro-2-methyl-1 /-/- dibenz[2, 3:6, 7]oxepino[4, 5-c]pyrrol-1-one was checked by TLC. 1 10 mL of a 0.6M aqueous solution of sodium hydroxide was added dropwise while keeping the temperature below 10 C. The resulting mixture was stirred at 20 C for 20 minutes. 150 mL of toluene and 100 mL of water were added, and the resulting mixture was stirred for 20 minutes. Phases were separated and the aqueous phase was washed with 2 x 100 mL of toluene. The combined organic phases were washed with 2 x 300 mL of brine, and dried with anhydrous sodium sulfate. Asenapine base was isolated after removing the solvent under reduced pressure. Then, asenapine base was dissolved in 66 mL of isopropanol. The resulting solution was filtered and heated to 30 C. At this temperature, 4.26 g (36.7 mmol) of maleic acid were added. The resulting mixture was heated to 46 C and stirred at 45-50 C for 1 hour. After cooling to room temperature, the suspension was filtered and the cake was washed with 50 mL of cooled isopropanol. The filtered solid was dried under reduced pressure to obtain 6.5 g of asenapine maleate (yield: 48.4 %).The above obtained asenapine maleate was dissolved in 38 mL of acetone at reflux temperature. 45 mL of hexane (mixture of isomers) were added over the solution at this temperature, and the resulting mixture was stirred at 51 C for 1 hour. After cooling to 10 C and stirring at this temperature for 1 hour, the resulting suspension was filtered and the solid was washed with 6.6 mL of an acetone/hexane 1 :1 mixture (v/v) to obtain 4.8 g of asenapine maleate as a white solid. Following the same procedure, 15.7 g of additional asenapine maleate was obtained. The combined solids (20.5 g of asenapine maleate) were dissolved in 120 mL of acetone at 34 C. After heating to reflux temperature, 40 mL of hexane (mixture of isomers) were added dropwise. Further, additional 100 mL of hexane (mixture of isomers) were added dropwise over 1 hour. Optionally, the resulting mixture can be seeded at this point with asenapine maleate form M. The resulting mixture was cooled and a white solid precipitated off at 35 C. After cooling to 10 C and stirring at this temperature for 1 hour, the resulting suspension was filtered and the solid was washed with 21 mL of an acetone/hexane 1 :1 mixture (v/v) to obtain 17.5 g of asenapine maleate as a white solid after drying under reduced pressure at 40 C for 5 hours. Yield: 85.4 %. Purity (HPLC): 99.5 %. XRPD (step time: 1 second): Form M (see Figure 1).A 2M solution of borane dimethyl sulphide in tetrahydrofuran (128 mL) was added drop-wise to a pre-heated solution (heated to about 64C) of trans-(3a, l2b)-l l-chloro-2- methyl-2, 3, 3a, 12b-tetrahydro-lH-dibenzo[2, 3:6, 7]oxepino[4, 5-c]pyrrol-l-one (30 g) in tetrahydrofuran (300 mL) at about 64C under nitrogen flow. The reaction was allowed to proceed for about 12 hours. Dimethyl sulphide produced during the reaction was slowly removed by distillation from the reaction mixture and fresh tetrahydrofuran was added. Borane dimethylsulphide in tetrahydrofuran 2M solution (24 mL) was added and the reaction mixture was stirred for about 3 hours. Tetrahydrofuran was distilled-off under reduced pressure. Methanol (250 mL) was added to the residue and the reaction mixture was stirred for 15 minutes. A sulphuric acid:water mixture (75 mL:500 mL) was added over about 5 minutes. The reaction mixture was stirred at about 80C for about 7 hours, cooled to about 50C and washed with toluene (2 x 200mL). The layers were separated. The aqueous layer was cooled to about 0C to 5C, and the crystallized salt was filtered, washed with cold water (100 mL) and dried in air at about 45C for about 15 hours.29 g of the air-dried material was suspended in water (150 mL). An ammonia solution was added slowly over about 10 minutes. Asenapine was extracted from the reaction mixture by adding toluene (2 x 100 mL), washing with water (100 mL), then removing toluene by distillation under reduced pressure.Yield: 22.2 gExample 3 Preparation of Asenapine [Formula IV] A 2M solution of borane dimethyl sulphide in tetrahydrofuran (128 mL) was added drop-wise to a pre-heated solution (heated to about 64 C.) of A 2M solution of borane dimethyl sulphide in tetrahydrofuran (128 mL) was added dropwise to a pre-heated solution (heated to about 64 C.) of E. Trans-11-chloro-2, 3, 3a, 12b-tetrahydro-2-methyl-1H-dibenz[2, 3:6, 7]-oxepino[4, 5-c]pyrrol-1-one (IV) and corresponding cis-isomer (V) To a 5 L 3-neck round bottom flask equipped with mechanical stirring was added THF (1.0 L) followed by the hydrogenation product from step D (1.06 moles in about 0.8 L THF). The contents of the vessel were subsequently cooled to 0C. Solid potassium t-butoxide (178 g, 1.59 mol, 1.5 eq) was then added portion-wise while maintaining a temperature of less than 5 C. The resulting dark suspension was stirred at less than 5 C. until complete consumption of the amino ester, as determined by HPLC. Dimethyl sulfate (170 mL, 1.8 mol, 1.7 eq) was then slowly added while maintaining a temperature of less than 5 C., giving an orange suspension. The contents of the vessel were stirred at less than 5 C. until the reaction was complete by HPLC (<5% des-methyl lactam) at which time ammonium hydroxide (0.5 L) in water (1.0 L) was added to decompose any remaining dimethyl sulfate. The mixture was gradually warmed to room temperature and stirred overnight. Ethyl acetate (0.5 L) was added and the layers were separated. The resultant aqueous layer contained product solids that were extracted into ethyl acetate (2.5 L, 0.5 L) at elevated temperature (55 C.).Example 3 Preparation of trans-8-chloro-10, 11-dihydro-11-[(methyl-amino)methyl]-dibenz[b, f]oxepin-10-carboxylic acid hydrochloride (I).HCl; Potassium hydroxide (333.8 g, 6.30 mole) was added to a mixture of cis-11-chloro-2, 3, 3a, 12b-tetrahydro-2-methyl-1H-dibenz[2, 3:6, 7]oxepino[4, 5-c]pyrrol-1-one (V) and B. Chromatographic (Silica) Purification of (IV) 5-Diazabicyclo[4, 3, 0]non-5-ene; (DBN, 1.6 L) is added to toluene (400 L) containing a mixture of cis-isomer (V) and trans-isomer (IV) (10 kg in total) and the reaction mixture is stirred for 1 hour at 20 C. Water (200 L) is added and the pH of the aqueous layer is adjusted to pH 4 with acetic acid (approximately 1.0 L). Stirring is continued for 15 minutes and, if necessary, acetic acid is added to adjust the pH to 4.0 (+/-0.2). The layers are separated. The toluene layer is washed with water (200 L), concentrated to a volume of 25 L and purified by chromatography on silica (100 kg) with toluene (115 L) and toluene:ethyl acetate 95:5 v/v (900 L). The fractions are pooled and fractions containing exclusively compound Method A Trans-8-chloro-10, 11-dihydro-11-[(methylamino)methyl]-dibenz[b, f]-oxepin-10-carboxylic acid hydrochloride (I).HCl (55.5 g) and silica gel (55 g) were suspended in xylene (550 mL). The suspension was heated to reflux for 1 night. The reaction mixture was cooled to 65 C. and ethyl acetate (550 mL) was added. The silica gel was filtered off and washed with ethyl acetate (550 mL). The organic phase was evaporated. The crude product was dissolved in methanol (750 mL). The methanol was partly evaporated upon which crystallization of the product takes place. After cooling to 5 C. for 3 hours, the product was obtained by filtration. This yielded Method B; Trans-8-chloro-10, 11-dihydro-11-[(methylamino)methyl]-dibenz[b, f]-oxepin-10-carboxylic acid hydrochloride (I).HCl (50 g, 142 mmol) was suspended in dichloromethane (1 L) and N, N-dimethylformamide (50 mL). To this suspension was added thionyl chloride (50 mL, 84 mmol). After 30 minutes a clear solution was formed. This solution was added dropwise to a cold mixture of methanol (1 L) and triethylamine (158, 1150 mmol). Additional triethylamine (35 mL) was added to adjust the pH to 8. The organic phase was washed with 1 N hydrochloric acid (1 L) and with brine (2×1 L). The organic phase was subsequently washed with saturated sodium bicarbonate solution (1 L). The organic phase was dried with magnesium sulfate and evaporated. The crude product (40.7 g) was crystallized from methanol (100 mL). This furnished trans-11-chloro-2, 3, 3a, 12b-tetrahydro-2-methyl-1H-dibenz[2, 3:6, 7]oxepino-[4, 5-c]pyrrol-1-one (IV) (32 g, 75%); 1H-NMR (399.87 MHz in CDCl3 relative to TMS) delta 3.03 (d, 3H), 4.03 (m, 1H), 3.53-3.65 (m, 2H), 3.82 (m, 1H), 7.01-7.28 (m, 6H), 7.87 (dd, 1H).Magnesium metal turnings (10 g) were added to a suspension of 11-chloro-2-methyl-2, 3-dihydro-1H-dibenzo[2, 3:6, 7]oxepino[4, 5-c]pyrrol-1-one (7 g) in methanol (50 mL). The reaction mixture was slowly heated to refluxing temperature. Brisk effervescence was observed. The reaction mixture was cooled to control the reaction and again refluxed for about 2 hours. The reaction mass was diluted with methanol (30 mL), further refluxed for about 30 minutes, cooled to ambient temperature, slurried in water (150 mL) and filtered. pH of the filtrate was adjusted to 1-2 by adding concentrated hydrochloric acid. A clear solution was obtained. The solution was extracted with ethyl acetate (3×50mL) followed by washing with water (3×50 mL). Ethyl acetate was recovered to obtain a mixture of diastereomers as brown oil (4.6 g) followed by separation of the two isomers using silica gel column chromatography eluting with ethyl acetate-hexane mixture. cis-isomer: 50% trans-isomer: 9%Preparation of 2 g of 1 l-chloro-2-methyl-2, 3-dihydro-lH-dibenzo[2, 3:6, 7]oxepino[4, 5-c]pyrrol- 1-one was dissolved in a mixture of methanol (60 mL) and acetic acid (20 mL). The reaction mixture was heated to about 53C. Magnesium metal turnings (2.0 g) were added portion-wise. The reaction mixture was stirred for about 1 hour, filtered and washed with methanol (100 mL). Methanol was removed by distillation from the filtrate to obtain a white solid (16 g). The white solid was dissolved in dichloromethane (200 mL) and washed with water (2 x 500 mL). The solid obtained during filtration was also dissolved in water (100 mL) and the aqueous layer was extracted with dichloromethane (50 mL). The two dichloromethane solutions were combined. Dichloromethane was removed by distillation under reduced pressure to obtain a mixture of two isomers as an oily brown compound (2 g). The mixture of isomers was separated into cis- and irans-isomers using silica gel column chromatography eluting with ethyl acetate :hexane (30:70) mixture. irans-isomer: 0.7 gcz's-isomer: 0.7 g2 g of 11-chloro-2-methyl-2, 3-dihydro-1H-dibenzo[2, 3:6, 7]oxepino[4, 5-c]pyrrol-1-one was dissolved in a mixture of methanol (60 mL) and acetic acid (20 mL). The reaction mixture was heated to about 50 C. Magnesium metal turnings (2.38 g) were added portion-wise at about 45 C. to about 65 C. The reaction mixture was stirred at ambient temperature for about 2 hours. Water (80 mL) was added. The pH of the reaction mixture was adjusted to 1 by adding concentrated hydrochloric acid. The reaction mixture was extracted with ethyl acetate (150 mL) and washed with water (3×200 mL). Ethyl acetate was distilled-off to obtain a mixture of two isomers as an oily brown compound (2 g). The mixture of isomers was separated into cis- and trans-isomers using silica gel column chromatography eluting with ethyl acetate:hexane (30:70) mixture. trans-isomer: 0.7 g cis-isomer: 0.8 g.

Molecular Weight:299.7
XLogP3:3.1
Hydrogen Bond Acceptor Count:2
Exact Mass:299.0713064
Monoisotopic Mass:299.0713064
Topological Polar Surface Area:29.5
Heavy Atom Count:21
Complexity:429
Defined Atom Stereocenter Count:2
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes