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. 2020 Oct 16;24(10):2266-2270.
doi: 10.1021/acs.oprd.0c00145. Epub 2020 May 13.

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

K Kashinath  1 , David R Snead  1 , Justina M Burns  1 , Rodger W Stringham  1 , B Frank Gupton  1 , D Tyler McQuade  1
Affiliations

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

K Kashinath et al. Org Process Res Dev. .

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 precursors. This bond construction choice enabled the use of chloroacetic acid, vinyl acetate, sodium thiosulfate, and water to produce the oxathiolane.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Commercial retrosynthetic route for lamivudine and emtricitabine.
Figure 2
Figure 2
Supply-centered synthesis: molecular construction from commodity chemical materials.
Figure 3
Figure 3
Proposed route to oxathiolane from vinyl acetate and glycolate ester.
Figure 4
Figure 4
Proposed mechanism for the formation of oxathiolane 4 from 15 commencing with hydrolysis of the acetate.
Figure 5
Figure 5
Esterification of l-menthol.
Figure 6
Figure 6
Synthesis of 4 directly from l-menthol.
Figure 7
Figure 7
One-pot synthesis of 4 from l-menthol and ethyl vinyl ether.
See this image and copyright information in PMC

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