First Generation Process for the Preparation of the DPP-IV Inhibitor Sitagliptin

Abstract

A new synthesis of sitagliptin (MK-0431), a DPP-IV inhibitor and potential new treatment for type II diabetes, suitable for the preparation of multi-kilogram quantities is presented. The triazolopyrazine fragment of sitagliptin was prepared in 26% yield over four chemical steps using a synthetic strategy similar to the medicinal chemistry synthesis. Key process developments were made in the first step of this sequence, the addition of hydrazine to chloropyrazine, to ensure its safe operation on a large scale. The beta-amino acid fragment of sitagliptin was prepared by asymmetric reduction of the corresponding beta-ketoester followed by a two-step elaboration to an N-benzyloxy beta-lactam. Hydrolysis of the lactam followed by direct coupling to the triazolopiperazine afforded sitagliptin after cleavage of the N-benzyloxy group and salt formation. The overall yield was 52% over eight steps.

Asymmetric Catalytic Borylation of α,β-Unsaturated Acceptors

“…A β-borylcarbonyl precursor to the antidiabetic drug sitagliptin [52] was synthesized in 84% yield and 95% ee using CuCO 3 as a catalyst in combination with chiral bisphosphine L23 at room temperature. Oxidation afforded the corresponding β-alcohol product (Scheme 26).…”

Green Chemistry and Associated Metrics

“…Sitagliptin is the active ingredient in Januvia ® , a drug marketed by Merck for the treatment of type II diabetes [42]. Since 2005, the manufacturing process for sitagliptin has undergone three stages of development [43][44][45]. With each new stage, the process has become increasingly more efficient in the context of global waste reduction.…”

Synthesis, biological assay in vitro and molecular docking studies of new imidazopyrazinone derivatives as potential dipeptidyl peptidase IV inhibitors

“…The Merck researchers provided two excellent routes to synthesis b-amino acid 7 [7,8], in this report, another flexible route without crystallization was described, which could conveniently apply to lab investigation. Our initial synthetic efforts were focused on producing the b-amino acids (Scheme 1).…”