反应详情

温度

200 °C

Add 4-chloro-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (0.22 g, 1.11 mmol), 4-(1-(2-(pyrrolidin-1-yl)ethyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidine trihydrochloride (0.57 g, 1.2 eq), N-methylpyrrolidinone (10 mL) and diisopropylethylamine (1.16 mL, 6.0 eq) in a microwave tube. Seal the tube and heat in a microwave reactor at 200° C. for 30 minutes. Dilute the reaction mixture with water and extract with ethyl acetate. Wash with saturated aqueous sodium chloride. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify by normal phase chromatography, eluting with a 1-10% methanol/dichloromethane gradient, to give 5-methyl-4-(4-(1-(2-(pyrrolidin-1-yl)ethyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidin-1-yl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one as a racemate (0.19 g, 36%). MS (ES) m/z=478 [M]+. Chiral separation (Chiralpak AD-H, 30% ethanol/70% CO2 w/0.2% isopropylamine) provides enantiomer 1 (>99% ee) and (R)-5-methyl-4-(4-(1-(2-(pyrrolidin-1-yl)ethyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidin-1-yl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one as enantiomer 2 (>99% ee). MS (ES) m/z=478 [M]+ for both compounds.

1. customSeal the tube
2. extractionextract with ethyl acetate
3. washWash with saturated aqueous sodium chloride
4. dry with materialDry the organics over anhydrous sodium sulfate
5. filtrationfilter
6. concentrationconcentrate in vacuo
7. customPurify by normal phase chromatography
8. washeluting with a 1-10% methanol/dichloromethane gradient