Development of a Large-Scale Synthesis of Sulphostin, a Dipeptidyl Peptidase IV Inhibitor

For the progress of the in vivo study on sulphostin, a dipeptidyl peptidase IV inhibitor, its large-scale synthetic method was investigated. The optical resolution of (3S,RSP)-1-amino(sulfoamino)phosphinyl-3-benzyloxycarbonylamino-2-piperidin-one, which was the most difficult step in the previous method, was simplified by using fractional crystallization. The use of 2 mol equiv of (1S,2R)-(+)-2-amino-1,2-diphenylethanol for optical resolution gave desired diastereomer 15 in good yield as a less soluble salt. In the present synthetic method, there were no requirements for purification using column chromatography, reaction at cryogenic temperature, and treatment using the haloalkane solvents. The total yield of the new method was 4.6%, which was an improvement of approximately 2-fold compared to the method reported previously.