反应详情

Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (68.2 g, 83.5 mmol) was added in one go to a stirred mixture, which had been degassed for 30 minutes with nitrogen, of 4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorophenyl trifluoromethanesulfonate (Intermediate 31-6; 730 g, 1856 mmol), methyl 2-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (Intermediate 31-3; 1164 g, 1948 mmol) (52% strength by proton NMR), tripotassium phosphate (690 g, 3248 mmol) and lithium chloride (138 g, 3248 mmol) in DME (5 L), methanol (2.5 L) and water (2.5 L) at 20° C. The reaction was heated to reflux and stirred under a nitrogen atmosphere overnight. The reaction was cooled to room temperature. The organic layer was filtered through a glass sinter. Ethyl acetate (10.0 L) and 30% brine/water (5.0 L) were added. The aqueous layer was separated and extracted with ethyl acetate (5.0 L), the organic layers were combined, washed with 50% brine/water (10.0 L), dried (magnesium sulphate), filtered and the solvents 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]acetate (389 g, 49%) as a white solid.

1. temperatureThe reaction was heated
2. temperatureto reflux
3. filtrationThe organic layer was filtered through a glass sinter
4. additionEthyl acetate (10.0 L) and 30% brine/water (5.0 L) were added
5. customThe aqueous layer was separated
6. extractionextracted with ethyl acetate (5.0 L)
7. washwashed with 50% brine/water (10.0 L)
8. dry with materialdried (magnesium sulphate)
9. filtrationfiltered
10. customthe solvents removed in vacuo
11. dissolutionThe crude product was dissolved in dichloromethane
12. customchromatographed on silica (5 Kg of Merck lichro prep silica 15-25 μm, 200 mm diameter column)
13. washeluting with a solvent gradient of 0-70% ethylacetate/isohexane
14. customPure fractions were evaporated to dryness