反应详情

温度

30 °C

A stirred solution of methyl 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chloro-2′-fluorobiphenyl-4-yl)acetate (Intermediate 31-7; 615 g, 1437 mmol) in DMF (2.5 L) was cooled to 15° C., under a nitrogen atmosphere. Potassium carbonate (214 g, 1545 mmol) was then added followed by paraformaldehyde (47.5 g, 1581 mmol). The reaction was stirred for 5 hours at 30° C. The reaction was then added to stirred water (25.0 L) and ethyl acetate (10.0 L). Concentrated hydrochloric acid (430 ml) was then added slowly with stirring. The aqueous layer was separated and extracted with ethyl acetate (7.5 L). The organics were combined and washed with, 50% brine/water (10.0 L), dried (magnesium sulphate), filtered and the solvent was removed in vacuo. Gave methyl 2-[4-[4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorophenyl]-3-chlorophenyl]-3-hydroxypropanoate (762 g) as a yellow gum, 64% by LCMS (therefore 488 g, 74% yield). The material was used crude in the next stage.

1. additionThe reaction was then added
2. stirringwith stirring
3. customThe aqueous layer was separated
4. extractionextracted with ethyl acetate (7.5 L)
5. washwashed with, 50% brine/water (10.0 L)
6. dry with materialdried (magnesium sulphate)
7. filtrationfiltered
8. customthe solvent was removed in vacuo