Method for synthesizing emtricitabine intermediate

Abstract

The invention discloses a synthetic method of emtricitabine intermediates, namely, (2R, 5S)-5-(5'-fluoro-cytimidine-1-group)-1, 3-oxathiolane-2-carboxylic acid-L-menthyl ester having the structural formula of (VI), (2R, 5S)-5-hydroxy-1, 3-oxathiolane-2-carboxylic acid-L-menthyl ester having the structural formula of (III) is taken as raw material to obtain chloro compounds having the structural formula of (IV) by chlorination reaction, then the chloro compounds (IV) are treated with condensation and hydrolyzation reactions with N, O-bis(trimethoxy)5-flurocytosin having the structural formula of (V), thus obtaining the (2R, 5S)-5-(5'-fluoro-cytimidine-1-group)-1, 3-oxathiolane-2-carboxylic acid-L-menthyl ester (VI). The invention uses bis(trichloromethyl) carbonic ester to replace the thionyl chloride in the prior art so as to be taken as a chlorination reagent, thus having the advantages of safe and reliable operation and environmental protection.

Description

(1) Technical field The present invention relates to a synthetic method of an emtricitabine intermediate, in particular to (2R, 5S)-5-(5'-fluoro-cytosine-1-yl)-1,3-oxathiolane- Synthetic method of 2-carboxylate-L-menthyl ester. (2) Background technology Emtricitabine (Compound I) is an anti-AIDS drug developed in recent years. It is a new nucleoside reverse transcriptase inhibitor and is a highly efficient and selective inhibitor of HIV and HBV. There are many reports in the literature on the synthesis of emtricitabine, and the main routes are: (1) using glyoxylic acid as a raw material, reacting with 2,5-dithiane-1,4-diol, and then introducing chiral prosthetic groups, glycosides (Mansour T, et al EP: 515157 (1992)), (2) L-gulose obtained by multi-step reaction (Jeong L, et al. J Med Chem, 36 (2): 181— 195(1993)); (3) using (S)-(+)-mandelic acid as raw material, obtained by multi-step reaction (Keshava M., et al., US: 6380388, (2002)); (4) by Ethylene glycol is used as ...

AI Technical Summary

Problems solved by technology

In this reaction, due to the use of thionyl chloride as the chlorination reagent, the raw materials are highly toxic. At the same time, a large amount of sulfur dioxide waste gas is generated during the reaction process, which seriously corrodes the equipment and seriously pollutes the environment, affecting the health and safety of operators.

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