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

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

doi:10.1021/acs.oprd.0c00083

David R Snead, Saeed Ahmad + Show 8 more

Open Access

https://doi.org/10.1021/acs.oprd.0c00083

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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.

Highlights

INTRODUCTION THE NEED AND CHALLENGE INDEVELOPING NEW APPROACHES TOWARD 3TCFinding a new route to lamivudine (3TC)Finding a new route to lamivudine (3TC) and emtricitabine (FTC) with less expensive raw materials constitutes an impactful yet difficult goal
In the course of our effort to develop an improved synthesis of 3TC, we discovered a strategy that allowed us to dictate the 2′deoxynucleoside enantiomer of choice
■ ECONOMIC IMPACT AND CONCLUSIONS. This constitutes a new route to 3TC with high economic potential

Summary

■ ECONOMIC IMPACT AND CONCLUSIONS

This constitutes a new route to 3TC with high economic potential. Our calculations estimate a cost of goods of $96−. 112/kg depending on the degree of solvent recycle compared with the sales price of approximately $140/kg based on the current manufacturing route (Figure 4) This investigational route has further cost reduction potential to $73−98/kg depending on the degree of optimization.[8] The synthesis features inexpensive reagents, and all of the steps proceed in high assay yield. Its relatively low price (∼$15/kg), menthol is still a raw material cost driver that adds significant molecular weight to intermediates that are not incorporated into the final API. This is a problem because reduction of menthyl ester 13 causes a large decrease in molecular weight of the product, necessarily reducing the quantity of alcohol 9 generated per kilogram of ester and corresponding to an increase in cost per kilogram of the resultant API.

■ ACKNOWLEDGMENTS

Findings

■ REFERENCES