piperidin-4-one;hydrate

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

実験手順: A solution of 5-(2-methyltetrazol-5-yl)-1H-indole (2b) (40 g), piperidin-4-one, hydrate, hydrochloride (80 g) and potassium hydroxide (48 g) in ethanol (1000 mL) was boiled at reflux for 16 hours. After cooling to room temperature, precipitated material was filtered off and carefully washed with water. The remaining crystalline product was dried in vacuo at 80° C. leaving 41 g of crude title compound 3a which was used without further purification. at reflux for 16 hours precipitated material was filtered off carefully washed with water The remaining crystalline product was dried in vacuo at 80° C.

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

実験手順: A mixture of 5-chloro-1H-indole (25 g), piperidin-4-one, hydrate, hydrochloride (71 g), and potassium hydroxide (38 g) in ethanol (450 ml) was refluxed for 6 hours. After cooling inorganic salts were filtered off and ethanol evaporated in vacuo. To the remaining oil was added brine (500 ml) and ethyl acetate (2×200 ml). The organic phase was separated and worked-up as above. Yield of crude title product: 45 g (semicrystalline). was refluxed for 6 hours After cooling inorganic salts were filtered off ethanol evaporated in vacuo To the remaining oil was added brine (500 ml) and ethyl acetate (2×200 ml) The organic phase was separated

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

実験手順: The title compound was prepared analogously to intermediate 15 from 5-cyclopropyl-3-methyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carboxylic acid and 4-piperidone hydrate. MS: 392.2 (MH+).

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

実験手順: The title compound was prepared analogously to intermediate 15 from 5-cyclopropyl-3-methyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carboxylic acid and 4-piperidone hydrate. MS: 392.2 (MH+).

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

実験手順: To a solution of 4-piperidone monohydrate, hydrochloride (30.7 g; 0.2 mol), sodium carbonate (42 g; 0.4 mol) in water (160 mL) was added dichloromethane (500 mL). The mixture was stirred at room temperature and a solution of methyl malonylchloride (26 ml; 1.2 eq) in dichloromethane (100 mL) was added dropwise at room temperature, keeping the temperature of the reaction mixture below 30° C. The pH was maintained at 8 at the end of the addition. The mixture was stirred 4 hours at room temperature. The residue was extracted twice with dichloromethane, dried over magnesium sulfate and evaporate to yield the title compound (37.4 g). the temperature of the reaction mixture below 30° C The pH was maintained at 8 at the end of the addition The mixture was stirred 4 hours at room temperature The residue was extracted twice with dichloromethane dried over magnesium sulfate evaporate

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

実験手順: To a solution of 4-piperidone monohydrate, hydrochloride (30.7 g; 0.2 mol), sodium carbonate (42 g; 0.4 mol) in water (160 mL) was added dichloromethane (500 mL). The mixture was stirred at room temperature and a solution of methyl malonylchloride (26 ml; 1.2 eq) in dichloromethane (100 mL) was added dropwise at room temperature, keeping the temperature of the reaction mixture below 30° C. The pH was maintained at 8 at the end of the addition. The mixture was stirred 4 hours at room temperature. The residue was extracted twice with dichloromethane, dried over magnesium sulfate and evaporate to yield the title compound (37.4 g). the temperature of the reaction mixture below 30° C The pH was maintained at 8 at the end of the addition The mixture was stirred 4 hours at room temperature The residue was extracted twice with dichloromethane dried over magnesium sulfate evaporate

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

実験手順: 4-Piperidone monohydrate (2.0 mmol) and 2-[(5-chloro-1H-indole-2-carbonyl)-amino]-3-phenyl-propionic acid (1.0 mmol) were coupled according to procedure A (0-25° C. reaction temperature) substituting the following workup: the reaction mixture was diluted with ethyl acetate, the resulting solution washed with 2 N NaOH and 2 N HCl, the suspension filtered and the solids dried: Yield 111 mg, 26%; HPLC (60/40) 8.88 minutes (92%); PBMS 424/426 (MH+, 100%); mp 258-261° C.; PBMS 424/426 (MH+, 100%); the resulting solution washed with 2 N NaOH and 2 N HCl the suspension filtered the solids dried HPLC (60/40) 8.88 minutes (92%)

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

実験手順: Powdered potassium hydroxide (144.4 g) was added carefully to a mechanically stirred mixture of 6-fluoroindole (49.23 g, 0.364 mol) and 4-piperidone monohydrate (111.93 g, 0.728 mol) in methanol (1500 ml). The mixture was then heated under reflux under nitrogen for 18 hours and then more potassium hydroxide (40 g) was added and the reaction mixture heated under reflux for a further 4 hours. The reaction mixture was allowed to cool to room temperature and poured onto ice-water (3000 ml) and stirred for 1 hour and the precipitated solid isolated by filtration and dried at 50° C. in vacuo to give a solid. The mixture was then heated under reflux under nitrogen for 18 hours the reaction mixture heated under reflux for a further 4 hours poured onto ice-water (3000 ml) the precipitated solid isolated by filtration dried at 50° C. in vacuo to give a solid

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

実験手順: A solution of 5-(2-methyltetrazol-5-yl)-1H-indole (2b) (40 g), piperidin-4-one, hydrate, hydrochloride (80 g) and potassium hydroxide (48 g) in ethanol (1000 mL) was boiled at reflux for 16 hours. After cooling to room temperature, precipitated material was filtered off and carefully washed with water. The remaining crystalline product was dried in vacuo at 80° C. leaving 41 g of crude title compound 3a which was used without further purification. at reflux for 16 hours precipitated material was filtered off carefully washed with water The remaining crystalline product was dried in vacuo at 80° C.

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

実験手順: A solution of 5-(2-methyltetrazol-5-yl)-1H-indole (2b) (40 g), piperidin-4-one, hydrate, hydrochloride (80 g) and potassium hydroxide (48 g) in ethanol (1000 mL) was boiled at reflux for 16 hours. After cooling to room temperature, precipitated material was filtered off and carefully washed with water. The remaining crystalline product was dried in vacuo at 80° C. leaving 41 g of crude title compound 3a which was used without further purification. at reflux for 16 hours precipitated material was filtered off carefully washed with water The remaining crystalline product was dried in vacuo at 80° C.

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

実験手順: A mixture of 5-chloro-1H-indole (25 g), piperidin-4-one, hydrate, hydrochloride (71 g), and potassium hydroxide (38 g) in ethanol (450 ml) was refluxed for 6 hours. After cooling inorganic salts were filtered off and ethanol evaporated in vacuo. To the remaining oil was added brine (500 ml) and ethyl acetate (2×200 ml). The organic phase was separated and worked-up as above. Yield of crude title product: 45 g (semicrystalline). was refluxed for 6 hours After cooling inorganic salts were filtered off ethanol evaporated in vacuo To the remaining oil was added brine (500 ml) and ethyl acetate (2×200 ml) The organic phase was separated

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

実験手順: A mixture of 5-chloro-1H-indole (25 g), piperidin-4-one, hydrate, hydrochloride (71 g), and potassium hydroxide (38 g) in ethanol (450 ml) was refluxed for 6 hours. After cooling inorganic salts were filtered off and ethanol evaporated in vacuo. To the remaining oil was added brine (500 ml) and ethyl acetate (2×200 ml). The organic phase was separated and worked-up as above. Yield of crude title product: 45 g (semicrystalline). was refluxed for 6 hours After cooling inorganic salts were filtered off ethanol evaporated in vacuo To the remaining oil was added brine (500 ml) and ethyl acetate (2×200 ml) The organic phase was separated