Efficient Syntheses of Pyrofolic Acid and Pteroyl Azide, Reagents for the Production of Carboxyl-Differentiated Derivatives of Folic Acid

Reaction of folic acid ( 1 ) with excess trifluoroacetic anhydride provides access to both the previously unknown N 10 -(trifluoroacetyl)pyrofolic acid ( 8) and pyrofolic acid ( 9 ). Reaction of either of these materials with hydrazine selectively affords pteroyl hydrazide ( 13 ), which may be oxidized to pteroyl azide ( 27) on a large scale (62% overall from 1 without the need for chromatography). Treatment of 27 with differentially protected glutamates provides a convenient and high-yielding synthesis of differentially protected, optically pure folates.