反应详情

Ethylmagnesium chloride (2.0 M solution in tetrahydrofuran, 0.37 mL, 0.740 mmol) was added dropwise to a stirred suspension of 9-chloro-1-(2-chloro-4,6-dimethylpyrimidin-5-yl)-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (183 mg, 0.369 mmol) and [1,3-bis(diphenylphosphino)propane]dichloronickel (20.0 mg, 0.0369 mmol) in tetrahydrofuran (1.5 mL) at 0° C., and the mixture was stirred at room temperature for 14 hr. The mixture was diluted with aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 70-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was purified by preparative HPLC to give a mixture containing an intermediate of the title compound as the trifluoroacetic acid salt. The mixture was washed with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the solid, which was washed with ethyl acetate/n-hexane to give the title compound as a colorless amorphous (16.5 mg, 0.037 mmol, 9%).

1. extractionextracted with ethyl acetate
2. washThe combined organic layer was washed with brine
3. dry with materialdried over anhydrous magnesium sulfate
4. filtrationfiltered
5. concentrationconcentrated in vacuo
6. customThe residue was purified by flash column chromatography on silica gel eluting with a 70-100% ethyl acetate/n-hexane gradient mixture
7. concentrationThe filtrate was concentrated in vacuo
8. customto give the solid, which
9. customwas purified by preparative HPLC
10. customto give a mixture