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. 2020 Jun 19;24(6):1194-1198.
doi: 10.1021/acs.oprd.0c00083. Epub 2020 Apr 7.

An Economical Route to Lamivudine Featuring a Novel Strategy for Stereospecific Assembly

David R Snead  1 , D Tyler McQuade  1 , Saeed Ahmad  1 , Rudy Krack  1 , Rodger W Stringham  1 , Justina M Burns  1 , Irini Abdiaj  1 , Vijayagopal Gopalsamuthiram  1 , Ryan C Nelson  1 , B Frank Gupton  1
Affiliations

An Economical Route to Lamivudine Featuring a Novel Strategy for Stereospecific Assembly

David R Snead et al. Org Process Res Dev. .

Abstract

An economical synthesis of lamivudine was developed by employing a new method to establish the stereochemistry about the heterocyclic oxathiolane ring. Toward this end, an inexpensive and readily accessible lactic acid derivative served the dual purpose of activating the carbohydrate's anomeric center for N-glycosylation and transferring stereochemical information to the substrate simultaneously. Both enantiomers of the lactic acid derivative are available, and either β-enantiomer in this challenging class of 2'-deoxynucleoside active pharmaceutical ingredients can be formed.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
A successful strategy to control the stereochemistry of challenging 2′-deoxyoxathiolane nucleosides.
Figure 2
Figure 2
Anomeric acylation controls the proximal and remote stereochemistry of the oxathiolane ring system. Either enantiomer can be obtained, and the nucleating ability of the acyl handle enables isolation in high purity.
Figure 3
Figure 3
New route to lamivudine. (a) O3, then 1,4-dithiane-2,5-diol. (b) NaOMe. (c) PivCl and levamisole hydrochloride (1 mol %). (d) Br2 and mesitylene, then cytosine. (e) NaBH4.
Figure 4
Figure 4
Current manufacturing route developed at GSK.
Figure 5
Figure 5
(left) Stereoselective installation of a low-molecular-weight asymmetric glycosylation unit can decrease raw material costs for 3TC. (right) Theoretical cost of 3TC based on 100% yield in reduction and equivalent price of ester starting materials ($60/kg).
See this image and copyright information in PMC

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