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Continuous flow synthesis of the lamivudine precursor L-Menthyl Glyoxylate

Continuous flow synthesis of the lamivudine precursor L-Menthyl Glyoxylate Lamivudine (3TC) is a drug in the antiretroviral class used to treat AIDS / HIV. Featuring two chiral centers, 3TC has two pairs of diastereomers, of which cis - (−) is the first option, as it has biological activity and is not cytotoxic. Due to the great demand for this compound, several synthetic routes were developed for its production. Among them, the enantioselective synthesis of lamivudine from L-menthyl-glyoxylate, which uses L-menthol as a chiral auxiliary, stands out. L-menthyl-glyoxylate is obtained by reacting menthol with some carboxyl derivatives, such as glyoxyl acid, maleic anhydride and fumaric acid. The present work aims to produce this basic component (L-menthyl glyoxylate) using alternative batch and continuous flow methodologies. The synthesis was carried out in two ways: a) from the esterification of menthol with maleic anhydride followed by ozonolysis of dimenthyl maleate and hydration; and b) starting from the esterification of menthol with fumaric acid to synthesize dimenthyl fumarate, followed by ozone and hydration. For all stages, conversions and selectivity above 90% were observed. The ozonolysis of dimenthyl maleate was transposed to continuous flow conditions resulting in conversion and selectivity above 99%. Thus, the work allowed the development of an alternative process to synthesize L-menthyl-glyoxylate, from the use of domestic ozone generator for the reaction of ozonolysis. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Flow Chemistry Springer Journals

Continuous flow synthesis of the lamivudine precursor L-Menthyl Glyoxylate

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Publisher
Springer Journals
Copyright
Copyright © Akadémiai Kiadó 2021
ISSN
2062-249X
eISSN
2063-0212
DOI
10.1007/s41981-021-00189-8
Publisher site
See Article on Publisher Site

Abstract

Lamivudine (3TC) is a drug in the antiretroviral class used to treat AIDS / HIV. Featuring two chiral centers, 3TC has two pairs of diastereomers, of which cis - (−) is the first option, as it has biological activity and is not cytotoxic. Due to the great demand for this compound, several synthetic routes were developed for its production. Among them, the enantioselective synthesis of lamivudine from L-menthyl-glyoxylate, which uses L-menthol as a chiral auxiliary, stands out. L-menthyl-glyoxylate is obtained by reacting menthol with some carboxyl derivatives, such as glyoxyl acid, maleic anhydride and fumaric acid. The present work aims to produce this basic component (L-menthyl glyoxylate) using alternative batch and continuous flow methodologies. The synthesis was carried out in two ways: a) from the esterification of menthol with maleic anhydride followed by ozonolysis of dimenthyl maleate and hydration; and b) starting from the esterification of menthol with fumaric acid to synthesize dimenthyl fumarate, followed by ozone and hydration. For all stages, conversions and selectivity above 90% were observed. The ozonolysis of dimenthyl maleate was transposed to continuous flow conditions resulting in conversion and selectivity above 99%. Thus, the work allowed the development of an alternative process to synthesize L-menthyl-glyoxylate, from the use of domestic ozone generator for the reaction of ozonolysis.

Journal

Journal of Flow ChemistrySpringer Journals

Published: Mar 1, 2022

Keywords: Lamivudine; Antiretrovirals; Continuous flow; Ozonolysis

References