Development of a Kilogram-Scale Synthesis of <i>cis</i>-LC15-0133 Tartrate, a Potent Dipeptidyl Peptidase IV Inhibitor

Abstract

(4 S )- N -Boc-4-fluoro- l -proline methyl ester ( 4 ) was prepared from the following sequence of reactions: esterification of trans -4-hydroxy- l -proline ( 2 ), Boc protection, and fluorination by DAST. Reaction of 4 with lithiated oxadiazole provided oxadiazolyl ketone 7 . Deprotection of the Boc group of 7 and subsequent coupling with bromoacetyl bromide gave bromide 9 . Coupling reaction of 9 with excess oxazolidine 16 provided coupled product 17 . Unexpectedly, the stereogenic center of 17 was completely epimerized to a virtually 1:1 mixture of cis - and trans - 17 at this stage. After the deprotection of the N,O -methylene acetal group of 17 using aqueous ammonium chloride, crystallization induced dynamic resolution (CIDR) of cis - and trans -mixture of LC15-0133 ( 1 ) in the course of tartrate salt formation provided cis -LC15-0133 ( 1a ) tartrate salt in 83% yield (>98% de).