Manufacturing Process Development for Uprifosbuvir (MK-3682): A Green and Sustainable Process for Preparing Penultimate 2′-Deoxy-α-2′-Chloro-β-2′-Methyluridine

Abstract

A simple and efficient process to prepare Uprifosbuvir intermediate, 2′-deoxy-α-2′-chloro-β-2′-methyluridine (1), from bis-pivaloyl tertiary alcohol 5a is described. The key discoveries are a novel BSA-promoted anhydrouridine formation catalyzed by HCl as an additive and a milder safe Me 2 SiCl 2 -promoted chlorination of anhydrouridine. These discoveries collectively enabled the establishment of a robust process toward compound 1, which was demonstrated successfully at the plant scale.

Advancements in hydrochlorination of alkenes

“…Very recently, a modified procedure was reported by researchers from Merck ( Scheme 27 ) [ 88 – 89 ]. They observed that the reaction of 144 with Me 2 SiCl 2 yielded the desired product 145 along with 5–10% of the undesired elimination byproduct 146 .…”