1-(2-chloroethyl)azepane;hydrochloride

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

Procedure: A solution of 1-(2-chloroethyl)perhydroazepine hydrochloride (42 mg, 0.21 mmol) in N,N-dimethylformamide (1 mL) was treated with triethylamine (30 μL, 0.22 mmol) then transferred to a flask containing 3,4-dimethyl-4-(3-(1H-1,2,3-triazol-4-yl)phenyl)piperidine (Preparation 44, 45 mg, 0.176 mmol) in N,N-dimethylformamide (2 mL). Sodium iodide (32 mg, 0.21 mmol) and sodium hydrogencarbonate (18 mg, 0.21 mmol) were added and the resultant mixture was heated at 60° C. overnight. The solvent was then removed in vacuo and the residue was partitioned between saturated aqueous sodium hydrogencarbonate solution (5 mL) and dichloromethane (5 mL). The phases were separated and the aqueous layer was further extracted with dichloromethane (2×5 mL). The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by reversed phase preparative HPLC (condition 2) to give the acetate salt of the title compound. The free base was obtained by treating with dilute aqueous ammonia solution (2 mL) and extracting with ether (4×3 mL). Drying over Na2SO4, filtering and evaporation to dryness gave the title compound as a white solid (16 mg, 24%). then transferred to a flask The solvent was then removed in vacuo the residue was partitioned between saturated aqueous sodium hydrogencarbonate solution (5 mL) and dichloromethane (5 mL) The phases were separated the aqueous layer was further extracted with dichloromethane (2×5 mL) The combined extracts were dried over Na2SO4 filtered concentrated in vacuo The residue was purified by reversed phase preparative HPLC (condition 2)

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

Procedure: To a solution of 7.5 g of 1,3-dihydro-5-(2-chlorophenyl)-7-chloro-2H-1,4-benzodiazepine-2-thione in a solvent mixture comprising 30 ml of a 10% aqueous sodium hydroxide solution and 30 ml of methanol is added dropwise under ice cooling with stirring an aqueous solution of 7.0 g of 1-chloro-2-(perhydroazepin-1-yl)ethane hydrochloride over a period of about 10 minutes, and the resulting mixture is stirred at room temperature for 4 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is rinsed with a 5% aqueous sodium hydroxide solution, washed with water and dried. Thereafter the solvent is distilled off to obtain an oily residue of 2-(2-perhydroazepin-1-ylethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine. The oily product thus obtained is treated, according to usual procedure, with 2.74 g of fumaric acid and recrystallized from isopropyl alcohol to obtain 9.9 g of 2-(2-perhydroazepin-1-ylethylthio)-5-(2-chlorophenyl)-7 -chloro-3H-1,4-benzodiazepine fumarate, m.p. 170°-171° C. is added dropwise under ice cooling extracted with ethyl acetate The extract is rinsed with a 5% aqueous sodium hydroxide solution washed with water dried Thereafter the solvent is distilled off

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

Procedure: To a solution of 7.5 g of 1,3-dihydro-5-(2-chlorophenyl)-7-chloro-2H-1,4-benzodiazepine-2-thione in a solvent mixture comprising 30 ml of a 10% aqueous sodium hydroxide solution and 30 ml of methanol is added dropwise under ice cooling with stirring an aqueous solution of 7.0 g of 1-chloro-2-(perhydroazepin-1-yl)ethane hydrochloride over a period of about 10 minutes, and the resulting mixture is stirred at room temperature for 4 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is rinsed with a 5% aqueous sodium hydroxide solution, washed with water and dried. Thereafter the solvent is distilled off to obtain an oily residue of 2-(2-perhydroazepin-1-ylethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine. The oily product thus obtained is treated, according to usual procedure, with 2.74 g of fumaric acid and recrystallized from isopropyl alcohol to obtain 9.9 g of 2-(2-perhydroazepin-1-ylethylthio)-5-(2-chlorophenyl)-7 -chloro-3H-1,4-benzodiazepine fumarate, m.p. 170°-171° C. is added dropwise under ice cooling extracted with ethyl acetate The extract is rinsed with a 5% aqueous sodium hydroxide solution washed with water dried Thereafter the solvent is distilled off

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

Procedure: A solution of 1-(2-chloroethyl)perhydroazepine hydrochloride (42 mg, 0.21 mmol) in N,N-dimethylformamide (1 mL) was treated with triethylamine (30 μL, 0.22 mmol) then transferred to a flask containing 3,4-dimethyl-4-(3-(1H-1,2,3-triazol-4-yl)phenyl)piperidine (Preparation 44, 45 mg, 0.176 mmol) in N,N-dimethylformamide (2 mL). Sodium iodide (32 mg, 0.21 mmol) and sodium hydrogencarbonate (18 mg, 0.21 mmol) were added and the resultant mixture was heated at 60° C. overnight. The solvent was then removed in vacuo and the residue was partitioned between saturated aqueous sodium hydrogencarbonate solution (5 mL) and dichloromethane (5 mL). The phases were separated and the aqueous layer was further extracted with dichloromethane (2×5 mL). The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by reversed phase preparative HPLC (condition 2) to give the acetate salt of the title compound. The free base was obtained by treating with dilute aqueous ammonia solution (2 mL) and extracting with ether (4×3 mL). Drying over Na2SO4, filtering and evaporation to dryness gave the title compound as a white solid (16 mg, 24%). then transferred to a flask The solvent was then removed in vacuo the residue was partitioned between saturated aqueous sodium hydrogencarbonate solution (5 mL) and dichloromethane (5 mL) The phases were separated the aqueous layer was further extracted with dichloromethane (2×5 mL) The combined extracts were dried over Na2SO4 filtered concentrated in vacuo The residue was purified by reversed phase preparative HPLC (condition 2)

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

Procedure: A solution of 1-(2-chloroethyl)perhydroazepine hydrochloride (42 mg, 0.21 mmol) in N,N-dimethylformamide (1 mL) was treated with triethylamine (30 μL, 0.22 mmol) then transferred to a flask containing 3,4-dimethyl-4-(3-(1H-1,2,3-triazol-4-yl)phenyl)piperidine (Preparation 44, 45 mg, 0.176 mmol) in N,N-dimethylformamide (2 mL). Sodium iodide (32 mg, 0.21 mmol) and sodium hydrogencarbonate (18 mg, 0.21 mmol) were added and the resultant mixture was heated at 60° C. overnight. The solvent was then removed in vacuo and the residue was partitioned between saturated aqueous sodium hydrogencarbonate solution (5 mL) and dichloromethane (5 mL). The phases were separated and the aqueous layer was further extracted with dichloromethane (2×5 mL). The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by reversed phase preparative HPLC (condition 2) to give the acetate salt of the title compound. The free base was obtained by treating with dilute aqueous ammonia solution (2 mL) and extracting with ether (4×3 mL). Drying over Na2SO4, filtering and evaporation to dryness gave the title compound as a white solid (16 mg, 24%). then transferred to a flask The solvent was then removed in vacuo the residue was partitioned between saturated aqueous sodium hydrogencarbonate solution (5 mL) and dichloromethane (5 mL) The phases were separated the aqueous layer was further extracted with dichloromethane (2×5 mL) The combined extracts were dried over Na2SO4 filtered concentrated in vacuo The residue was purified by reversed phase preparative HPLC (condition 2)

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

Procedure: Synthesized from 4-[3-methoxy-7-(4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-1-yloxy]phenol and 1-(2-chloroethyl)azepane hydrochloride according to an analogous synthetic method to Preparation Example 40, 1-{2-{4-[3-methoxy-7-(4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-1-yloxy]phenoxy}ethyl}azepane (345 mg) was used according to an analogous synthetic method to Example 779 described below to provide the title compound (116 mg).

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

Procedure: Synthesized from 4-[3-methoxy-7-(4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-1-yloxy]phenol and 1-(2-chloroethyl)azepane hydrochloride according to an analogous synthetic method to Preparation Example 40, 1-{2-{4-[3-methoxy-7-(4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-1-yloxy]phenoxy}ethyl}azepane (345 mg) was used according to an analogous synthetic method to Example 779 described below to provide the title compound (116 mg).

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

Procedure: Synthesized from 4-[3-methoxy-7-(4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-1-yloxy]phenol and 1-(2-chloroethyl)azepane hydrochloride according to an analogous synthetic method to Preparation Example 40, 1-{2-{4-[3-methoxy-7-(4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-1-yloxy]phenoxy}ethyl}azepane (345 mg) was used according to an analogous synthetic method to Example 779 described below to provide the title compound (116 mg).

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

Procedure: Synthesized from 4-{2-{ethyl[2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amino}ethyl}phenol and 1-(2-chloroethyl)azepane hydrochloride according to an analogous synthetic method to Preparation Example 40, {2-[4-(2-azepan-1-ylethoxy)phenyl]ethyl}ethyl[2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (298 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (255 mg).

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

Procedure: Synthesized from 4-{2-{ethyl[2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amino}ethyl}phenol and 1-(2-chloroethyl)azepane hydrochloride according to an analogous synthetic method to Preparation Example 40, {2-[4-(2-azepan-1-ylethoxy)phenyl]ethyl}ethyl[2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (298 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (255 mg).

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

Procedure: Synthesized from 4-{2-{cyclopropylmethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amino}ethyl}phenol and 1-(2-chloroethyl)azepane hydrochloride according to an analogous synthetic method to Preparation Example 40, {2-[4-(2-azepan-1-ylethoxy)phenyl]ethyl}cyclopropylmethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (392 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (188 mg).

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

Procedure: Synthesized from 4-{2-{cyclopropylmethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amino}ethyl}phenol and 1-(2-chloroethyl)azepane hydrochloride according to an analogous synthetic method to Preparation Example 40, {2-[4-(2-azepan-1-ylethoxy)phenyl]ethyl}cyclopropylmethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (392 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (188 mg).