Synthesis of Captopril starting from an Optically Active β-Hydroxy Acid

A synthesis of N-(3-mercapto-2-D-methylpropanoyl)-L-proline (1, Captopril) is described in which the key intermediate, optically active 3-chloro-2-D-methylpropanoyl chloride (3b), was prepared by treating microbiologically derived optically active 3-hydroxy-2-D-methylpropanoic acid (2) with thionyl chloride. The compound 3b was coupled with L-proline to afford the chloride (4) which was directly converted into Captopril by reaction with hydrosulfide or trithiocarbonate ion in hot water with retention of the stereochemistry. The preparation of another useful intermediate, 3-acetylthio-2-D-methylpropanoic acid (9a), is also described.