Preparation method of high-purity fumaric acid tenofovir disoproxil fumarate

Abstract

The invention discloses a preparation method of high-purity fumaric acid tenofovir disoproxil fumarate. The method comprises the following steps: (1) preparing tenofovir; (2) preparing tenofovir disoproxil fumarate, carrying out condensation reaction between tenofovir and chloromethyl isopropyl carbonate in an organic solvent under the action of a catalyst, purifying the product to obtain the tenofovir disoproxil fumarate, wherein the catalyst is a mixture of triethylamine and tetrabutylammonium bromide which are in the molar ratio of (22-30) to (1.5-3.0); the ratio of the triethylamine to the organic solvent is (22-30mol) to (150L-200L); and (3) preparing fumaric acid tenofovir disoproxil fumarate, salifying tenofovir disoproxil fumarate and fumaric acid which are obtained in the step (2), carrying out suction filtration, and drying to obtain the fumaric acid tenofovir disoproxil fumarate. According to the preparation method, dual catalysts are adopted in the process of preparing the tenofovir disoproxil fumarate, so that the yield and the efficiency of the tenofovir disoproxil fumarate are effectively increased, and the reaction process of the whole reaction is greatly shortened.

Description

technical field [0001] The invention relates to a preparation method of high-purity tenofovir disoproxil fumarate, which belongs to the technical field of preparation methods of pharmaceutical compounds. Background technique [0002] Tenofovir disoproxil fumarate (I) (Tenofovir disoproxil fumarate, TDF), chemical name: 9-[(R)-2-[[bis[[(isopropoxycarbonyl)oxy]methoxy]phosphorus Acyl] methoxy] propyl] adenine fumarate was developed by Glead Sciences of the United States and was first launched in the United States in October 2001. It is an acyclic nucleoside phosphate compound with anti-HIV and anti-HBV activity, which is tenofovir (II) (chemical name: (R)-9-(2-phosphorylmethoxypropyl) adenine) After entering the human body, it will be hydrolyzed to release tenofovir and produce antiviral effect. [0003] The chemical structures of tenofovir disoproxil fumarate and tenofovir are shown below: [0004] [0005] [0006] Compound U.S. Patent US5922695 discloses the prepar...

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Problems solved by technology

[0010] This technique adopts first the tenofovir disoproxil free base is separated out solid, removes the purification method of salt again, certainly can obtain the slightly higher tenofovir disoproxil fumarate of purity, but the processing method to the organic layer of subsequent treatment is still Too simple, with 10% sodium bicarbonate aqueous solution and washing organic layer, although a small part of acidic impurities can be removed, it is still quite difficult to remove impurities like tenofovir monoxate, and this impurity will interact with Tenofovir dipivoxil is precipitated together and brought into the final product

This process also has a defect, in the process of crystallization with ethyl acetate, a part of tenofovir dipivoxil will be lost, and the product yield will be greatly reduced

[0011] The above two methods for preparing tenofovir disoproxil fumarate all have the disadvantages of large number of impurities and relatively large residues of impurities, low quality, and low yield, which limits further industrialized scale-up production

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