(9aS)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (R)-3-cyclohexyl-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazine (100 mg, 0.41 mmol) in 1,1,2,2-tetrachloroethane (2.0 ml), was added oxalyl chloride (58 mg, 0.46 mmol) with stirring under a stream of nitrogen. The mixture was heated at 120° C. for 1.5 h. The mixture was cooled to room temperature and triethylamine (46 mg, 0.46 mmol) and (S)-octahydro-2H-pyrido[1,2-a]pyrazine (70 mg, 0.50 mmol) were added. The mixture was stirred at room temperature for 19 h and then partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane, and the combined organic layers washed with brine, dried over Na2SO4 and concentrated. The resulting brown oil was purified by flash chromatography eluting with 50% (v/v) ethyl acetate in n-heptane, then 0-17% (v/v) methanol in ethyl acetate to afford the title compound as the free base. Hydrochloride salt formation was achieved by the addition of hydrogen chloride (2 M solution in diethyl ether, 1 ml) to a solution of the free base in diethyl ether (2 ml) and ethanol (2 ml). The solvent was removed in vacuo and the precipitate was dried to afford the title compound (1:1 hydrochloride salt) as a solid (78 mg, 0.18 mmol). The mixture was cooled to room temperature The mixture was stirred at room temperature for 19 h partitioned between dichloromethane and water The aqueous layer was extracted with dichloromethane the combined organic layers washed with brine dried over Na2SO4 concentrated The resulting brown oil was purified by flash chromatography eluting with 50% (v/v) ethyl acetate in n-heptane

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (S)-Octahydro-1,4-dioxo-2H-pyrido[1,2-a]pyrazine (0.5 g, 2.98 mmol) was added portionwise to a stirred solution of lithium aluminium hydride (1M in tetrahydrofuran; 11.9 ml, 11.9 mmol). The resulting mixture was heated under reflux for 0.5 h. The solution was then cooled to 0° C. and treated dropwise with water (1.35 ml), 1 M sodium hydroxide solution (0.45 ml), then water (1.35 ml). Tetrahydrofuran (10 ml) was added and the solution stirred for 0.5 h, before filtration. The filter cake was washed with tetrahydrofuran (2×5 ml) and the combined filtrate and washings concentrated to yield (S)-octahydro-2H-pyrido[1,2-a]pyrazine as a yellow oil (0.29 g, 2.07 mmol). The resulting mixture was heated under reflux for 0.5 h The filter cake was washed with tetrahydrofuran (2×5 ml) the combined filtrate and washings concentrated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (S)-Octahydro-1,4-dioxo-2H-pyrido[1,2-a]pyrazine (0.5 g, 2.98 mmol) was added portionwise to a stirred solution of lithium aluminium hydride (1M in tetrahydrofuran; 11.9 ml, 11.9 mmol). The resulting mixture was heated under reflux for 0.5 h. The solution was then cooled to 0° C. and treated dropwise with water (1.35 ml), 1 M sodium hydroxide solution (0.45 ml), then water (1.35 ml). Tetrahydrofuran (10 ml) was added and the solution stirred for 0.5 h, before filtration. The filter cake was washed with tetrahydrofuran (2×5 ml) and the combined filtrate and washings concentrated to yield (S)-octahydro-2H-pyrido[1,2-a]pyrazine as a yellow oil (0.29 g, 2.07 mmol). The resulting mixture was heated under reflux for 0.5 h The filter cake was washed with tetrahydrofuran (2×5 ml) the combined filtrate and washings concentrated

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (R)-3-cyclohexyl-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazine (100 mg, 0.41 mmol) in 1,1,2,2-tetrachloroethane (2.0 ml), was added oxalyl chloride (58 mg, 0.46 mmol) with stirring under a stream of nitrogen. The mixture was heated at 120° C. for 1.5 h. The mixture was cooled to room temperature and triethylamine (46 mg, 0.46 mmol) and (S)-octahydro-2H-pyrido[1,2-a]pyrazine (70 mg, 0.50 mmol) were added. The mixture was stirred at room temperature for 19 h and then partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane, and the combined organic layers washed with brine, dried over Na2SO4 and concentrated. The resulting brown oil was purified by flash chromatography eluting with 50% (v/v) ethyl acetate in n-heptane, then 0-17% (v/v) methanol in ethyl acetate to afford the title compound as the free base. Hydrochloride salt formation was achieved by the addition of hydrogen chloride (2 M solution in diethyl ether, 1 ml) to a solution of the free base in diethyl ether (2 ml) and ethanol (2 ml). The solvent was removed in vacuo and the precipitate was dried to afford the title compound (1:1 hydrochloride salt) as a solid (78 mg, 0.18 mmol). The mixture was cooled to room temperature The mixture was stirred at room temperature for 19 h partitioned between dichloromethane and water The aqueous layer was extracted with dichloromethane the combined organic layers washed with brine dried over Na2SO4 concentrated The resulting brown oil was purified by flash chromatography eluting with 50% (v/v) ethyl acetate in n-heptane

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (S)-Octahydro-1,4-dioxo-2H-pyrido[1,2-a]pyrazine (0.5 g, 2.98 mmol) was added portionwise to a stirred solution of lithium aluminium hydride (1M in tetrahydrofuran; 11.9 ml, 11.9 mmol). The resulting mixture was heated under reflux for 0.5 h. The solution was then cooled to 0° C. and treated dropwise with water (1.35 ml), 1 M sodium hydroxide solution (0.45 ml), then water (1.35 ml). Tetrahydrofuran (10 ml) was added and the solution stirred for 0.5 h, before filtration. The filter cake was washed with tetrahydrofuran (2×5 ml) and the combined filtrate and washings concentrated to yield (S)-octahydro-2H-pyrido[1,2-a]pyrazine as a yellow oil (0.29 g, 2.07 mmol). The resulting mixture was heated under reflux for 0.5 h The filter cake was washed with tetrahydrofuran (2×5 ml) the combined filtrate and washings concentrated