反应详情

温度

50 °C

Methanesulfonyl chloride (0.145 L, 1865 mmol) was added over 5 minutes to a stirred solution of methyl 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chloro-2′-fluorobiphenyl-4-yl)-3-hydroxypropanoate (Intermediate 31-8; 488 g, 1065 mmol) and triethylamine (0.520 L, 3730 mmol) in tetrahydrofuran (5.0 L) at 10° C. The reaction was heated to 50° C. and left stirring for 2 hours. The reaction was then cooled to 20° C. The mixture was diluted with ethyl acetate (10.0 L), then water (3.0 L) was added. Saturated aqueous ammonium chloride solution (4.1 L) was added. The organic layer was separated and the aqueous layer extracted with ethyl acetate (2.5 L). The organics were combined, washed with 50% brine/water (5.0 L), dried (magnesium sulphate), filtered and the solvent removed in vacuo. The crude product was dissolved in dichloromethane and then chromatographed on silica (5 Kg of Merck lichro prep silica 15-25 μm, 200 mm diameter column), eluting with a solvent gradient of 0-70% ethylacetate/isohexane. Pure fractions were evaporated to dryness to afford methyl 2-[4-[4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorophenyl]-3-chlorophenyl]prop-2-enoate (188 g, 40%) as a white solid.

1. waitleft
2. temperatureThe reaction was then cooled to 20° C
3. customThe organic layer was separated
4. extractionthe aqueous layer extracted with ethyl acetate (2.5 L)
5. washwashed with 50% brine/water (5.0 L)
6. dry with materialdried (magnesium sulphate)
7. filtrationfiltered
8. customthe solvent removed in vacuo
9. dissolutionThe crude product was dissolved in dichloromethane
10. customchromatographed on silica (5 Kg of Merck lichro prep silica 15-25 μm, 200 mm diameter column)
11. washeluting with a solvent gradient of 0-70% ethylacetate/isohexane
12. customPure fractions were evaporated to dryness