Acetic Anhydride → N-(1-(5-Fluoropyridin-2-yl)vinyl)acetamide

Participants

Reaction Conditions

Reaction Steps

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.

Provenance & Evidence