Merck Eprova AG

Folic acid was converted to the corresponding dimethyl ester benzenesulfonate and stereoselectively hydrogenated in organic solvents. An extended screening with rhodium‐ and iridium‐diphosphine catalysts was performed. Under optimized conditions the asymmetric hydrogenation provided a solution of tetrahydrofolic acid dimethyl ester with up to 44% de. The de could be increased to 98% by fractional crystallization of L‐tetrahydrofolic acid dimethyl ester benzenesulfonate from the hydrogenation mixture. Hydrolysis of the ester afforded optically pure L‐tetrahydrofolic acid, which can be isolated or converted into its 5‐ or 10‐ or 5,10‐substituted derivatives.