Synthesis of an Oxathiolane Drug Substance Intermediate Guided by Constraint Driven Innovation

Abstract

A new route was developed for construction of the oxathiolane intermediate used in the synthesis of lamivudine (3TC) and emtricitabine (FTC). We developed the presented route by constraining ourselves to low cost, widely available starting materials – we refer to this as supply centered synthesis. Sulfenyl chloride chemistry was used to construct the framework for the oxathiolane from acyclic precurors. This bond construction choice enabled the use of chloroacetic acid, vinyl acetate, sodium thiosulfate and water to produce the oxathiolane.

A Continuous Flow Sulfuryl Chloride Based Reaction – Synthesis of a Key Intermediate in a New Route Toward Emtricitabine and Lamivudine

“…The process begins with a Fischer esterification between L-menthol (1) and thioglycolic acid (2). 2 The menthyl thioglycolate (3) is then treated with SO2Cl2 to produce a sulfenyl chloride intermediate 4. 3 The reaction between the thioglycolate 3 and SO2Cl2 is exothermic and so is the reaction of 4 with vinyl acetate (5).…”