1222102-29-5

Developed by Dong-A ST, evogliptin was approved in 2015 in the Republic of Korea for blood glucose control in patients with diabetes mellitus type 2 (type 2 DM). Evogliptin is an orally bioavailable dipeptidyl peptidase IV (DPP-4) inhibitor, which acts to prevent insulin secretion following meals. Dong-A ST arranged licensing agreements with Geropharm and Eurofarma Laboratórios for the sale of evogliptin in various countries in eastern Europe and Brazil, respectively, pending future approvals. While a manufacturing route has not been disclosed to date, the most scalable published route is described below.

The synthesis of piperizone 125 began from commercially available amino acid derivative 127 . The alcohol within 125 was then quantitatively converted to tert-butyl ether 128 by treatment with isobutylene gas in the presence of acid. Subsequent hydrogenation to remove the Cbz protecting group resulted in amine 129, and this was followed by reductive amination to provide ethylene diamine intermediate 130. Hydrogenative carbamate removal facilitated a cyclization reaction, giving rise to piperizone 131 as the free base. Finally, treatment with a tartaric acid derivative delivered the stable piperizone salt 125.
The second key synthon of evogliptin is the β-amino acid fragment 136. Commercially available acid 132 was treated with CDI prior to subjection to Meldrum’s acid to afford ketodiester 133. Subjection of 133 to warm EtOH triggered a decarboxylation event, and this was followed by reductive amination reaction involving ammonium acetate and the remaining ketone functionality to afford racemic amine 134 in 91% over the three steps. Resolution with a tartaric acid derivative followed by free base formation with sodium carbonate gave the enantiopure aminoester 135 in good yield. Finally, a two-step Boc protection followed by ester saponification furnished aminoester 136 in 89% yield over the final two-step sequence, setting the stage for the final assembly of evogliptin.
The final API was assembled in a straightforward manner from intermediates 125 and 136. Acid 136 was first activated as the mixed anhydride, followed by the addition of 125 in the presence of Hünig’s base to give penultimate product 137 in 71% over two steps. Hydrogenolytic removal of the benzyl carbamate afforded evogliptin (XVI), with a longest linear sequence of eight steps from simple amino acid building blocks.