2-piperidin-4-yl-3H-isoindol-1-one

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of Part E compound (600 mg, 2.45 mmol) in DMF (20 mL) was added Example 2 Part A compound (2-(4-piperidinyl)-2,3-dihydro-1H-isoindol-1-one) (530 mg, 2.45 mmol) followed by anhydrous potassium carbonate (372 mg, 2.69 mmol). The reaction was stirred at 55° C. overnight. The reaction was cooled to RT. Ethyl ether (200 mL) was added to dilute the reaction, and the organic layer was washed with water (2×50 mL), brine (2×50 mL) and dried over MgSO4. Evaporation gave a crude oil. Purification was performed by flash chromatography on 100 g of silica gel, loaded and eluted with 2% methanol in dichloromethane. Pure fractions were combined and evaporated to give a colorless oil. The resulting oil was dissolved in methanol (2 mL) and HCl in ethyl ether solution (1.0 M, 3.0 mL, 3.0 mmol) was added. The HCl salt precipitated from the solution. The salt was filtered and dried at 60° C. under vacuum to give title compound (490 mg, 80%) as a white solid. The reaction was cooled to RT to dilute the reaction the organic layer was washed with water (2×50 mL), brine (2×50 mL) dried over MgSO4 Evaporation gave a crude oil Purification eluted with 2% methanol in dichloromethane evaporated to give a colorless oil The HCl salt precipitated from the solution The salt was filtered dried at 60° C. under vacuum

反応条件: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of Part E compound (600 mg, 2.45 mmol) in DMF (20 mL) was added Example 2 Part A compound (2-(4-piperidinyl)-2,3-dihydro-1H-isoindol-1-one) (530 mg, 2.45 mmol) followed by anhydrous potassium carbonate (372 mg, 2.69 mmol). The reaction was stirred at 55° C. overnight. The reaction was cooled to RT. Ethyl ether (200 mL) was added to dilute the reaction, and the organic layer was washed with water (2×50 mL), brine (2×50 mL) and dried over MgSO4. Evaporation gave a crude oil. Purification was performed by flash chromatography on 100 g of silica gel, loaded and eluted with 2% methanol in dichloromethane. Pure fractions were combined and evaporated to give a colorless oil. The resulting oil was dissolved in methanol (2 mL) and HCl in ethyl ether solution (1.0 M, 3.0 mL, 3.0 mmol) was added. The HCl salt precipitated from the solution. The salt was filtered and dried at 60° C. under vacuum to give title compound (490 mg, 80%) as a white solid. The reaction was cooled to RT to dilute the reaction the organic layer was washed with water (2×50 mL), brine (2×50 mL) dried over MgSO4 Evaporation gave a crude oil Purification eluted with 2% methanol in dichloromethane evaporated to give a colorless oil The HCl salt precipitated from the solution The salt was filtered dried at 60° C. under vacuum

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

実験手順: By heating in an analogous fashion 2.4 g of 4-amino-2-chloro-6,7-dimethoxyquinazoline, 2.2 g of 2-(4-piperidinyl)-isoindolin-1-one, 2.0 g of anhydrous sodium carbonate and 20 ml of dimethylformamide, the 2-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-piperidinyl]-isoindolin-1-one monohydrochloride is obtained, melting at 288°-289° (dec.).

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

実験手順: The mixture of 5.39 g of 4-amino-2-chloro-6,7,8-trimethoxy-quinazoline, 4.32 g of 2-(4-piperidinyl)-isoindolin-1-one, 4.24 g of anhydrous sodium carbonate and 75 ml of dimethylformamide is stirred under nitrogen at 125°-130° for 16 hours. It is filtered, the filtrate evaporated, the residue dissolved in methylene chloride and the solution washed with aqueous sodium bicarbonate. The organic layer is separated, dried, and evaporated. The residue is suspended in refluxing isopropanol and acidified with hydrogen chloride to pH=1. The precipitate formed is filtered off and triturated with warm ethanol to yield the 2-[1-(4-amino-6,7,8-trimethoxy-2-quinazolinyl)-4-piperidinyl]-isoindolin-1-one monohydrochloride melting at 234° (dec.). It is filtered the filtrate evaporated the residue dissolved in methylene chloride the solution washed with aqueous sodium bicarbonate The organic layer is separated dried evaporated in refluxing isopropanol The precipitate formed is filtered off triturated with warm ethanol

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

実験手順: The mixture of 5.39 g of 4-amino-2-chloro-6,7,8-trimethoxy-quinazoline, 4.32 g of 2-(4-piperidinyl)-isoindolin-1-one, 4.24 g of anhydrous sodium carbonate and 75 ml of dimethylformamide is stirred under nitrogen at 125°-130° for 16 hours. It is filtered, the filtrate evaporated, the residue dissolved in methylene chloride and the solution washed with aqueous sodium bicarbonate. The organic layer is separated, dried, and evaporated. The residue is suspended in refluxing isopropanol and acidified with hydrogen chloride to pH=1. The precipitate formed is filtered off and triturated with warm ethanol to yield the 2-[1-(4-amino-6,7,8-trimethoxy-2-quinazolinyl)-4-piperidinyl]-isoindolin-1-one monohydrochloride melting at 234° (dec.). It is filtered the filtrate evaporated the residue dissolved in methylene chloride the solution washed with aqueous sodium bicarbonate The organic layer is separated dried evaporated in refluxing isopropanol The precipitate formed is filtered off triturated with warm ethanol

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: The mixture of 5.39 g of 4-amino-2-chloro-6,7,8-trimethoxy-quinazoline, 4.32 g of 2-(4-piperidinyl)-isoindolin-1-one, 4.24 g of anhydrous sodium carbonate and 75 ml of dimethylformamide is stirred under nitrogen at 125°-130° for 16 hours. It is filtered, the filtrate evaporated, the residue dissolved in methylene chloride and the solution washed with aqueous sodium bicarbonate. The organic layer is separated, dried, and evaporated. The residue is suspended in refluxing isopropanol and acidified with hydrogen chloride to pH=1. The precipitate formed is filtered off and triturated with warm ethanol to yield the 2-[1-(4-amino-6,7,8-trimethoxy-2-quinazolinyl)-4-piperidinyl]-isoindolin-1-one monohydrochloride melting at 234° (dec.). It is filtered the filtrate evaporated the residue dissolved in methylene chloride the solution washed with aqueous sodium bicarbonate The organic layer is separated dried evaporated in refluxing isopropanol The precipitate formed is filtered off triturated with warm ethanol

反応条件: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of Part E compound (600 mg, 2.45 mmol) in DMF (20 mL) was added Example 2 Part A compound (2-(4-piperidinyl)-2,3-dihydro-1H-isoindol-1-one) (530 mg, 2.45 mmol) followed by anhydrous potassium carbonate (372 mg, 2.69 mmol). The reaction was stirred at 55° C. overnight. The reaction was cooled to RT. Ethyl ether (200 mL) was added to dilute the reaction, and the organic layer was washed with water (2×50 mL), brine (2×50 mL) and dried over MgSO4. Evaporation gave a crude oil. Purification was performed by flash chromatography on 100 g of silica gel, loaded and eluted with 2% methanol in dichloromethane. Pure fractions were combined and evaporated to give a colorless oil. The resulting oil was dissolved in methanol (2 mL) and HCl in ethyl ether solution (1.0M, 3.0 mL, 3.0 mmol) was added. The HCl salt precipitated from the solution. The salt was filtered and dried at 60° C. under vacuum to give title compound (490 mg, 80%) as a white solid. The reaction was cooled to RT to dilute the reaction the organic layer was washed with water (2×50 mL), brine (2×50 mL) dried over MgSO4 Evaporation gave a crude oil Purification eluted with 2% methanol in dichloromethane evaporated to give a colorless oil The HCl salt precipitated from the solution The salt was filtered dried at 60° C. under vacuum

反応条件: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of Part E compound (600 mg, 2.45 mmol) in DMF (20 mL) was added Example 2 Part A compound (2-(4-piperidinyl)-2,3-dihydro-1H-isoindol-1-one) (530 mg, 2.45 mmol) followed by anhydrous potassium carbonate (372 mg, 2.69 mmol). The reaction was stirred at 55° C. overnight. The reaction was cooled to RT. Ethyl ether (200 mL) was added to dilute the reaction, and the organic layer was washed with water (2×50 mL), brine (2×50 mL) and dried over MgSO4. Evaporation gave a crude oil. Purification was performed by flash chromatography on 100 g of silica gel, loaded and eluted with 2% methanol in dichloromethane. Pure fractions were combined and evaporated to give a colorless oil. The resulting oil was dissolved in methanol (2 mL) and HCl in ethyl ether solution (1.0 M, 3.0 mL, 3.0 mmol) was added. The HCl salt precipitated from the solution. The salt was filtered and dried at 60° C. under vacuum to give title compound (490 mg, 80%) as a white solid. The reaction was cooled to RT to dilute the reaction the organic layer was washed with water (2×50 mL), brine (2×50 mL) dried over MgSO4 Evaporation gave a crude oil Purification eluted with 2% methanol in dichloromethane evaporated to give a colorless oil The HCl salt precipitated from the solution The salt was filtered dried at 60° C. under vacuum

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

実験手順: (S)-N-[2-(3,4-Dichlorophenyl)-4-oxobutyl]-N-methylbenzamide (270 mg) in methanol (2 mL) was added to a solution of 4-(1-oxoiso-indolin-2-yl)piperidine (200 mg) and acetic acid (0.053 mL) in methanol (3 mL). After 15 minutes, sodium cyanoborohydride (58 mg) in methanol (1 mL) was added in a single portion. After 6 hours, the reaction mixture was diluted with aqueous sodium bicarbonate, stirred for 30 minutes, and extracted with dichloromethane. The organic extracts were dried, evaporated, and chromatographed, with dichloromethane:methanol (gradient 98:2, 95:5) as the eluent. The resulting material was dissolved in dichloromethane, precipitated out as the hydrochloride salt with ethereal hydrogen chloride, evaporated, and placed under high vacuum overnight to give the title compound (390 mg) as a white solid; MS: m/z=550(M+1). Analysis for C31H33Cl2N3O2 ·1.65 HCl·0.40 (CH3CH2O): Calculated: C, 61.14; H, 6.08; N, 6.56; Found: C, 61.09; H, 6.10; N, 6.48. After 6 hours extracted with dichloromethane The organic extracts were dried evaporated chromatographed, with dichloromethane The resulting material was dissolved in dichloromethane precipitated out as the hydrochloride salt with ethereal hydrogen chloride evaporated placed under high vacuum overnight

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

実験手順: (S)-N-[2-(3,4-Dichlorophenyl)-4-oxobutyl]-N-methylbenzamide (270 mg) in methanol (2 mL) was added to a solution of 4-(1-oxoiso-indolin-2-yl) piperidine (200 mg) and acetic acid (0.053 mL) in methanol (3 mL). After 15 minutes, sodium cyanoborohydride (58 mg) in methanol (1 mL) was added in a single portion. After 6 hours, the reaction mixture was diluted with aqueous sodium bicarbonate, stirred for 30 minutes, and extracted with dichloromethane. The organic extracts were dried, evaporated, and chromatographed, with dichloromethane:methanol(gradient 98:2, 95:5) as the eluent. The resulting material was dissolved in dichloromethane, precipitated out as the hydrochloride salt with ethereal hydrogen chloride, evaporated, and placed under high vacuum overnight to give the title compound (390 mg) as a white solid; MS: m/z=550(M+1). Analysis for C31H33Cl2N3O2 ·1.65 HCl·0.40 (CH3CH2)2O: Calculated: C, 61.14; H, 6.08; N, 6.56; Found: C, 61.09; H, 6.10; N, 6.48. After 6 hours extracted with dichloromethane The organic extracts were dried evaporated chromatographed, with dichloromethane The resulting material was dissolved in dichloromethane precipitated out as the hydrochloride salt with ethereal hydrogen chloride evaporated placed under high vacuum overnight