反应详情

温度

80 °C

To a solution of (R)-(−)-methanesulfonic acid 3-[3-(isopropylcarbamoylmethyl)-2-(3-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-6-yloxy]-2-methylpropyl ester (1.13 g, 2.18 mmol) in anhydrous acetonitrile (40 mL) was added potassium carbonate (1.51 g, 10.95 mmol) followed by diethyl amine (3.20 g, 4.53 mL, 43.80 mmol) and the reaction mixture was heated at 80° C. in a pressure tube. After 2 days (reaction complete by HPLC), the reaction mixture was concentrated in vacuo to dryness and the residue was partitioned between water (100 mL) and ethyl acetate (150 mL). The aqueous layer was extracted with ethyl acetate (5×150 mL) and with dichloromethane (5×100 mL). The combined organic phase was dried (Na2SO4), solvent evaporated in vacuo, and the resulting residue purified by chromatography on silica gel with a gradient of methanol:dichloromethane (1:19, v/v) to methanol:dichloromethane (1:4, v/v) as eluent. The resultant solid was recrystallised from diethyl ether:hexane to afford (S)-(+)-2-[6-(3-diethylamino-2-methylpropoxy)-2-(3-methoxyphenyl)-4-oxo-4H-quinazolin-3-yl]-N-isopropy-acetamide (EXAMPLE 4a) (0.69 g, 1.40 mmol, 65% from (S)-(+)-2-[6-(3-hydroxy-2-methylpropoxy)-2-(3-methoxyphenyl)-4-oxo-4H-quinazolin-3-yl]-N-isopropylacetamide) as a white solid.

1. customAfter 2 days (reaction complete by HPLC)
2. concentrationthe reaction mixture was concentrated in vacuo to dryness
3. customthe residue was partitioned between water (100 mL) and ethyl acetate (150 mL)
4. extractionThe aqueous layer was extracted with ethyl acetate (5×150 mL) and with dichloromethane (5×100 mL)
5. dry with materialThe combined organic phase was dried (Na2SO4), solvent
6. customevaporated in vacuo
7. customthe resulting residue purified by chromatography on silica gel with a gradient of methanol:dichloromethane (1:19
8. customThe resultant solid was recrystallised from diethyl ether