Preparation method of antiviral medicine

Abstract

The invention discloses a preparation method of anantiviral medicine tenofovirdisoproxil fumarate. The preparation method disclosed by the invention comprises the following steps of: performing addition reaction on adenine serving as raw material and (R)-epoxypropane in the presence of alkali; then, performing substitution reaction with (diethyoxyl phosphoracyl) methyl-4-methyl benzenesulfonate; then, hydrolyzing by using a hydrobromic acid solution; crystallizing to obtain tenofovir monohydrate; and reacting the product tenofovir monohydrate with chloromethyl isopropyl carbonate and fumaric acid to obtain tenofovirdisoproxil fumarate. The selected initial raw material is low in cost and easily available, and the synthetic line is simplified and the utilization ratio of the raw material and the total yield are improved. The intermediate obtained in the reaction is purified by the recrystallization method, so that the yield is high, less three-wastes are generated in the reaction process, and the cost is low; therefore, the preparation method is favorable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of an antiviral drug tenofovir disoproxil fumarate. Background technique [0002] The present invention relates to a kind of synthesis of antiviral drug tenofovir disoproxil fumarate (VI), structural formula is as follows: [0003] [0004] Tenofovir disoproxil fumarate (VI) is a nucleotide reverse transcriptase inhibitor (nucleotide reverse transcriptase inhibitors, NtRTIs) developed by U.S. Gilead Sciences, which was approved by the U.S. FDA in 2001 for the treatment of AIDS (HIV infection), and in 2008 it was approved for the treatment of chronic hepatitis B (HBV infection). Tenofovir disoproxil fumarate has the characteristics of good tolerance, low drug resistance rate, low drug withdrawal rebound rate, and low nephrotoxicity, especially for patients with HIV combined with HBV infection. Tenofovir disoproxil fumarate is a prodrug of te...

AI Technical Summary

Problems solved by technology

[0006] (1) In the initial stage of the development of the drug, Gilead sciences of the United States conducted in-depth research on the synthesis process of the drug, and disclosed a synthetic route of tenofovir disoproxil fumarate in the patent US5935946. (S)-glycidol is the starting material, the first step uses catalytic hydrogenation reaction, there are unsafe factors in large-scale production, and moisture-sensitive sodium ethoxide is also used at the same time, the production conditions are harsh, the production process is complex, and the production cost very high

[0007] (2) In Chinese Patent Publication No. CN101279987A, a synthetic route of tenofovir (IV) is disclosed. The starting raw material price of this route is relatively low, but highly toxic triphosgene is used in the synthetic process. There are huge unsafe factors, which are not conducive to industrial production

[0008] (3) In the Chinese Patent Publication No. CN101574356A, a route for the synthesis of tenofovir disoproxil fumarate (VI) with (R)-ethyl lactate as the starting material is disclosed, and the synthetic reaction conditions of the route are Relatively mild, but this route uses the process of protection and deprotection, which increases the steps of the synthetic route and reduces the overall yield. In addition, the silica gel chromatography column is used to purify the intermediate many times during the synthetic process, resulting in a very high production cost of this route. High, difficult to achieve industrial production

[0009] (4) In the Czech Chemical Communication (Collect Czech Chem Commun, 1995, 60: 1196-1212), the author publicly reported a synthesis of tenofovir (IV) using (R)-isobutyl lactate as the starting material. route, the synthesis reaction conditions of this route are also relatively mild, but this route uses the technology of protection and deprotection twice, increases the step of synthetic route, reduces total yield, and this route uses expensive Red-Al (red Aluminum) is used as a reducing agent and a macroporous resin is used to purify the intermediate, which leads to high production costs of this route and is difficult to apply on a large scale

[0010] (5) The above-mentioned route (4) has been improved in the U.S. Patent No. 6,653,296, and a similar route for synthesizing tenofovir (IV) has been disclosed. This route omits the protection and deprotection steps of the amino group, and the remaining steps are the same, However, because there are still protection, deprotection processes and red aluminum reduction steps in the synthesis steps, the production cost is still high, and it is difficult to industrialize production

[0011] (6) Chinese Patent Publication No. CN101648974A draws lessons from the method of introducing chiral structure in route (4) and route (5), and discloses another kind of synthesis of fumarate tenoxate with (R)-methyl lactate as the starting material The synthetic route of fovir dipivoxil (VI), this route is relatively short, and the starting material is also relatively cheap, but the introduction of chiral structure requires three-step reactions, and the production cost is very high. Silica gel chromatographic column purification requires a lot of energy, which is difficult to achieve in large-scale production

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