Lamivudine diastereoselective synthesis method

Abstract

A lamivudine diastereoselective synthesis method, which takes chiral auxiliary agent L-menthol as the initial material, synthesizes trans-5-hydroxyl-1, 3-oxygen thiacyclopentane-2-carboxylic acid-(1'R, 2'S, 5'R) menthol ester under the action of concentrated sulfuric acid, choose triethanolamine to obtain trans-isomer trans-5-hydroxyl-1, 3-oxygen thiacyclopentane-2-carboxylic acid-(1'R, 2'S, 5'R) menthol ester, and let the trans-isomer to react with acylating agent to obtain trans-5-acetoxy-1, 3-oxygen thiacyclopentane-2-carboxylic acid-(1'R, 2'S, 5'R) menthol ester, glycosidate with cytosine under the action of alkali to obtain 5S-cytosine-1'-radical-1, 3-oxygen thiacyclopentane-2-carboxylic acid-(1'R, 2'S, 5'R) menthyl ester, and then deoxidize with a deoxidizer, and salifying with aspirin, to ionize and liberate lamivudine. Since triethanolamine is added as in the course of reaction interconverting agent, the yield of lamivudine is increased greatly. Aspirin is added in the course of reaction, so that the lamivudine forms an aspirin salt that has poor water solubility, and therefore can effectively separate and liberate lamivudine from the medium.

Description

Technical field: [0001] The invention relates to a production method of nucleoside analogs, in particular to a diastereoselective synthesis production method of lamivudine. Background technique: [0002] Lamivudine (lamivudine, Zeffix, chemical name: 2,3-dideoxy-3-thiocytosine, referred to as 3TC) is a nucleoside analog and a viral DNA reverse transcriptase inhibitor. For chronic hepatitis B, the treatment of patients with proven decompensated liver disease or histologically confirmed active and (or) fibrosis. Its chemical structure is: [0003] [0004] Lamivudine, a novel deoxynucleoside analog, is (2R-cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl )-2(1H)-Pyrimidinone is one of the four optical isomers of the cis left-handed optical enantiomer, which is a new generation of nucleoside antiviral drugs superior to the anti-HIV drug AZT. It has obvious effects on human immunodeficiency virus HIV and has been approved by dozens of countries to treat AIDS. Since 199...

AI Technical Summary

Problems solved by technology

Then use iodotrimethylsilane as a Lewis acid to couple cytosine through a carbon-nitrogen bond, and use the reducing agent lithium aluminum hydride to reduce the final product lamivudine. The total yield of this method is not high, and the chemical raw materials used more expensive

[0006] Chinese patent CN03135330.4 discloses titled "the diastereoselective preparation method of lamivudine", which introduces the photoactive alcohol ester of glyoxylic acid as the starting material and 2,5-dihydroxy-1,4- Dithiothiane is condensed to obtain trans-5-hydroxyl-1,3-oxathiolane-2-carboxylate, which is condensed with silanized N-acetylcytosine under the action of alkali after halogenation, Then obtain lamivudine by reduction, ammonia solution, etc., the raw materials used are expensive, and lamivudine has high solubility in water, making it difficult to effectively separate them in water

[0010] The patent discloses a diastereoselective synthetic method of nucleoside analogs, but does not directly provide a diastereoselective synthetic method of lamivudine. Those skilled in the art know based on common knowledge that nucleoside analogs include lamivudine. A large class of macromolecular compounds including vudine, on its basis, the main problem to be solved in the industrialized large-scale production of lamivudine production method is how to obtain a single trans left-handed from the mixture of trans and cis isomers Photoisomers, how to increase the yield of cis-left-handed photoantiomer lamivudine, although triethylamine can play this role, but triethylamine has a strong ammonia odor, which is strongly irritating to the human body

Harmful to the health of the operator

[0011] On the other hand, the difficulty of separation and purification of lamivudine in aqueous solution in industrial production is also a problem to be explored. Lamivudine has great solubility in polar media, such as aqueous solvents, making them difficult to Crystallization, the method adopted in the prior art is to make lamivudine form salicylate, so that the solubility of gained lamivudine in water is small and easy to separate, and can be effectively separated and separated from the medium. Salt can be converted into free alkali by conventional methods, but the problem in this method is: it inevitably has salicylic acid residues, and more than 0.02% salicylic acid has serious ototoxicity reactions, and the existing industrial production It is difficult for technology to meet this requirement, and even if this requirement is met, its toxic and side effects still exist

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