反应详情

温度

0 °C

A solution of 5-fluoropicolinonitrile (Method 35; 1875 g 1 equivalent) in THF (3.7 volumes) was added to methyl magnesium chloride (3N in THF, 1.2 equivalents) maintaining the temperature at 0° C. The reaction mixture was stirred for 30 minutes at 0° C. and then diluted with DCM (3.2 volumes) at 0° C. Acetic anhydride (2.0 equivalents) in DCM (1.6 volumes.) was added at a rate to maintain the temperature at 0° C. The batch was allowed to warm to room temperature and stirred overnight. Saturated, aqueous sodium hydrogen carbonate (13.9 volumes) was added and the product was extracted into EtOAc (1×0.53 volumes, 1×0.26 volumes). The combined extracts were dried, filtered and evaporated in vacuo and purification carried out by chromatography (5 w/w silica; 20-100% DCM in hexane). The mixture of N-mono and N,N-di-acetylated compounds was treated with potassium carbonate (0.1 w/w on mixture) in methanol (5 volumes) for 30 minutes. The inorganic solids were filtered and washed with methanol. Silica was added to the methanol solution to remove residual potassium carbonate prior to evaporation. The product, pre-adsorbed on silica, was eluted through a silica pad (2 w/w silica; 90-100% DCM in hexane) and evaporated to give an orange solid. Mp 61.0-62.2° C., 636 g, 23.0% theory.

1. temperatureto maintain the temperature at 0° C
2. temperatureto warm to room temperature
3. stirringstirred overnight
4. extractionthe product was extracted into EtOAc (1×0.53 volumes, 1×0.26 volumes)
5. customThe combined extracts were dried
6. filtrationfiltered
7. customevaporated in vacuo and purification
8. additionThe mixture of N-mono and N,N-di-acetylated compounds
9. additionwas treated with potassium carbonate (0.1 w/w on mixture) in methanol (5 volumes) for 30 minutes
10. filtrationThe inorganic solids were filtered
11. washwashed with methanol
12. additionSilica was added to the methanol solution
13. customto remove residual potassium carbonate
14. customto evaporation
15. washThe product, pre-adsorbed on silica, was eluted through a silica pad (2 w/w silica; 90-100% DCM in hexane)
16. customevaporated
17. customto give an orange solid