2,3,4,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-6-one

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 8 ml sealed vial was charged with 100 mg (0.161 mmoles) of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide (WO 2005/002577), 67 mg (0.483 mmol) of hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (WO 2003/066635), 44.5 mg (0.322 mmol) of potassium carbonate; the reagents were dissolved in 0.8 ml of DMSO. The reaction mixture was heated at 180° C. for 36-48 hrs and then added to a saturated NH4Cl solution and back extracted with DCM; the crude material was purified on SPE cartridge (Silica) eluting with a gradient from cyclohexane/ethyl acetate 9:1, to ethyl acetate 100% and affording 45 mg of the title compound as pale yellow solid. A 8 ml sealed vial back extracted with DCM the crude material was purified on SPE cartridge (Silica) eluting with a gradient from cyclohexane/ethyl acetate 9:1, to ethyl acetate 100%

反応条件: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 8 ml sealed vial was charged with 100 mg (0.187 mmoles) of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide (WO 2005/002577), 78.6 mg (0.561 mmol) of hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (WO 2003/066635), 52 mg (0.374 mmol) of potassium carbonate; the reagents were dissolved in 0.8 ml of DMSO. The reaction mixture was heated at 180° C. for 36-48 hrs and then added to a saturated NH4Cl solution and back extracted with dichloromethane; the crude material was purified on SPE cartridge (Silica) eluting with a gradient from cyclohexane/ethyl acetate 9:1, to ethyl acetate 100% and affording 71 mg of the title compound as pale yellow solid. A 8 ml sealed vial back extracted with dichloromethane the crude material was purified on SPE cartridge (Silica) eluting with a gradient from cyclohexane/ethyl acetate 9:1, to ethyl acetate 100%

反応条件: temp:82.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Charge a 500 mL three necked round bottomed flask with 2-[6-chloro-8-(2-chlorophenyl)-2-methyl-purin-9-yl]ethanol (13.3 g, 0.0412 mmol) and ethanol (200 mL), followed by 2,3,4,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-6-one (6.365 g, 0.0453 mol) and triethylamine (14.8 mL, 3.5 eq). Heat the mixture to 80-85° C. for 24 h. Cool the reaction to room temperature and concentrate under vacuum to give a yellow solid as the crude product. Purify the crude material by column chromatography, using 400 g of silica gel and eluting with dichloromethane/methanol (50:1), to give the product as a yellow solid (13.3 g). 1H NMR (dmso-d6): δ 7.55-7.41 (m, 4H); 5.72 (bs, 2H); 4.16-3.92 (m, 3H); 3.71 (s, 2H); 3.71-3.68 (m, 1H); 3.02-2.93 (m, 2H); 2.74 (m, 1H); 2.70 (s, 3H); 2.44 (m, 2H); 2.32-2.29 (m, 1H); 1.76-1.69 (m, 1H). Cool the reaction to room temperature concentrate under vacuum to give a yellow solid as the crude product Purify the crude material by column chromatography eluting with dichloromethane/methanol (50:1)

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 8 ml sealed vial was charged with 100 mg (0.161 mmoles) of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide (WO 2005/002577), 67 mg (0.483 mmol) of hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (WO 2003/066635), 44.5 mg (0.322 mmol) of potassium carbonate; the reagents were dissolved in 0.8 ml of DMSO. The reaction mixture was heated at 180° C. for 36-48 hrs and then added to a saturated NH4Cl solution and back extracted with DCM; the crude material was purified on SPE cartridge (Silica) eluting with a gradient from cyclohexane/ethyl acetate 9:1, to ethyl acetate 100% and affording 45 mg of the title compound as pale yellow solid. A 8 ml sealed vial back extracted with DCM the crude material was purified on SPE cartridge (Silica) eluting with a gradient from cyclohexane/ethyl acetate 9:1, to ethyl acetate 100%

反応条件: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 8 ml sealed vial was charged with 100 mg (0.161 mmoles) of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide (WO 2005/002577), 67 mg (0.483 mmol) of hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (WO 2003/066635), 44.5 mg (0.322 mmol) of potassium carbonate; the reagents were dissolved in 0.8 ml of DMSO. The reaction mixture was heated at 180° C. for 36-48 hrs and then added to a saturated NH4Cl solution and back extracted with DCM; the crude material was purified on SPE cartridge (Silica) eluting with a gradient from cyclohexane/ethyl acetate 9:1, to ethyl acetate 100% and affording 45 mg of the title compound as pale yellow solid. A 8 ml sealed vial back extracted with DCM the crude material was purified on SPE cartridge (Silica) eluting with a gradient from cyclohexane/ethyl acetate 9:1, to ethyl acetate 100%

反応条件: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 8 ml sealed vial was charged with 100 mg (0.187 mmoles) of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide (WO 2005/002577), 78.6 mg (0.561 mmol) of hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (WO 2003/066635), 52 mg (0.374 mmol) of potassium carbonate; the reagents were dissolved in 0.8 ml of DMSO. The reaction mixture was heated at 180° C. for 36-48 hrs and then added to a saturated NH4Cl solution and back extracted with dichloromethane; the crude material was purified on SPE cartridge (Silica) eluting with a gradient from cyclohexane/ethyl acetate 9:1, to ethyl acetate 100% and affording 71 mg of the title compound as pale yellow solid. A 8 ml sealed vial back extracted with dichloromethane the crude material was purified on SPE cartridge (Silica) eluting with a gradient from cyclohexane/ethyl acetate 9:1, to ethyl acetate 100%

反応条件: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 8 ml sealed vial was charged with 100 mg (0.187 mmoles) of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide (WO 2005/002577), 78.6 mg (0.561 mmol) of hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (WO 2003/066635), 52 mg (0.374 mmol) of potassium carbonate; the reagents were dissolved in 0.8 ml of DMSO. The reaction mixture was heated at 180° C. for 36-48 hrs and then added to a saturated NH4Cl solution and back extracted with dichloromethane; the crude material was purified on SPE cartridge (Silica) eluting with a gradient from cyclohexane/ethyl acetate 9:1, to ethyl acetate 100% and affording 71 mg of the title compound as pale yellow solid. A 8 ml sealed vial back extracted with dichloromethane the crude material was purified on SPE cartridge (Silica) eluting with a gradient from cyclohexane/ethyl acetate 9:1, to ethyl acetate 100%

反応条件: temp:82.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Charge a 500 mL three necked round bottomed flask with 2-[6-chloro-8-(2-chlorophenyl)-2-methyl-purin-9-yl]ethanol (13.3 g, 0.0412 mmol) and ethanol (200 mL), followed by 2,3,4,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-6-one (6.365 g, 0.0453 mol) and triethylamine (14.8 mL, 3.5 eq). Heat the mixture to 80-85° C. for 24 h. Cool the reaction to room temperature and concentrate under vacuum to give a yellow solid as the crude product. Purify the crude material by column chromatography, using 400 g of silica gel and eluting with dichloromethane/methanol (50:1), to give the product as a yellow solid (13.3 g). 1H NMR (dmso-d6): δ 7.55-7.41 (m, 4H); 5.72 (bs, 2H); 4.16-3.92 (m, 3H); 3.71 (s, 2H); 3.71-3.68 (m, 1H); 3.02-2.93 (m, 2H); 2.74 (m, 1H); 2.70 (s, 3H); 2.44 (m, 2H); 2.32-2.29 (m, 1H); 1.76-1.69 (m, 1H). Cool the reaction to room temperature concentrate under vacuum to give a yellow solid as the crude product Purify the crude material by column chromatography eluting with dichloromethane/methanol (50:1)