Novel method for preparing tenofovir

A compound and reaction technology, applied in the new field of preparation of tenofovir, can solve problems such as unstable yield of chiral enrichment treatment

Inactive Publication Date: 2012-12-26
INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the literature data show that the yield of chiral enrichment treatment is very unstable

Method used

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  • Novel method for preparing tenofovir
  • Novel method for preparing tenofovir
  • Novel method for preparing tenofovir

Examples

Experimental program
Comparison scheme
Effect test

specific Embodiment approach

[0078] The present invention will be further illustrated by specific intermediates and examples below. However, it should be understood that these intermediates and examples are only used for more detailed and specific explanation, and should not be understood as limiting the present invention in any form. invention.

[0079] The present invention provides a general and / or specific description of the materials and test methods used in the test. Although many materials and operating methods used to achieve the purpose of the present invention are well known in the art, the present invention is still described here in as much detail as possible. It is clear to those skilled in the art that, in the following, unless otherwise specified, the materials and operating methods used in the present invention are well known in the art.

Embodiment 1

[0080] Example 1: (R)-1-Trityloxy-2-propanol (Formula XIV, R 1 ＝R 2 =H) Preparation

[0081] Add (R)-1,2-propanediol (24.0g, 0.315moL), N,N-dimethylaminopyridine (0.25g, 2.00mmoL), dichloromethane (350mL) and TEA (46.0g, 0.45 moL), cooled in an ice water bath, magnetically stirred. Triphenylchloromethane (88.7g, 0.315moL) was added in batches, and the addition was completed in about 1 hour. After 1.5 hours of reaction, the ice-water bath was removed, and then the temperature was raised to room temperature, and then reacted at room temperature for about 15 hours (TLC detection, until triphenylchloromethane disappeared). Add distilled water (100mL) to dissolve the triethylamine hydrochloride generated by the reaction, transfer to a separatory funnel for layering, and wash the oil phase with 5% sodium bicarbonate solution (2×100mL) and distilled water (100mL) in turn, and then use anhydrous After drying over sodium sulfate and filtering, the filtrate was evaporated to remove...

Embodiment 2

[0082] Example 2: (R)-[(2-Trityloxy-1-methylethoxy)methyl]phosphonic acid diisopropyl ester (Formula XV, R 1 ＝R 2 =H) Preparation

[0083] The crude product obtained in Example 1 (96.6 g, about 0.30 moL) and anhydrous THF (500 mL) were added to the flask, stirred magnetically, and cooled in an ice-water bath. Sodium hydride (70% oil powder, 11.3g, 0.33mol) was added in batches, and the addition was completed in about 40 minutes. After 0.5 hours, remove the ice-water bath, then let the temperature rise to room temperature and react for about 2 hours, and then heat and reflux for about 3 hours until the reaction liquid surface is basically free of gas foam. The temperature is lowered to 5℃, and the compound of formula Va (diisopropyl p-toluenesulfonyloxymethylphosphonate, where Y is p-tolyl and R is isopropyl, 106.2g, 0.30moL) is added dropwise through a constant pressure funnel. Anhydrous THF (200 mL) solution was added in about 0.5 hours, the ice-water bath was removed af...

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Abstract

The invention relates to a novel method for preparing tenofovir, in particular to a method for preparing a tenofovir compound, in particular the monohydrate of the tenofovir for resisting hepatitis B viruses and human immunodeficiency viruses. The method comprises the following steps of: using (substituted) triphenylchloromethane XIII to protect hydroxy in the end position of (R)-1,2-propanediol, condensing the obtained product with dialkyl sulfonyloxy methyl phosphonate V to obtain XV, hydrolyzing the XV in the aqueous solution of an organic acid to remove the protective group of the hydroxyl at the end position of XV to obtain an intermediate XI, condensing sulfonate XII of the intermediate XI with adenine to obtain an intermediate VII, transforming the intermediate VII into the corresponding trimethylsilyl phosphonate VIII by trimethylsilyl bromide (TMSBr), and hydrolyzing the VIII to obtain the target product. The method has the advantages of short process route, convenient operation, low cost and easy access of raw materials and favorability for large scale production.

Description

Technical field: [0001] The present invention relates to a preparation method of Tenofovir (PMPA), a compound against hepatitis B virus and AIDS virus. Background technique: [0002] The chemical name of Tenofovir (I) is (R)-{[2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}phosphonic acid or (R) -9-(2-phosphonomethoxypropyl) adenine, its structural formula is: [0003] [0004] Tenofovir belongs to the category of acyclic nucleoside phosphonates. Since its preparation process generally goes through a hydrolysis step, the product is provided in the form of tenofovir monohydrate (II): [0005] [0006] There are three synthetic routes for II that have been reported in the literature, and the details are as follows. [0007] Synthetic Route 1 [0008] This route first protects the hydroxyl group in D-(+)-isobutyl lactate with dihydropyran (DHP), and then reduces the ester to alcohol III with bis(methoxyethoxy) aluminum hydride. After p-toluenesulfonate and adenine are condensed, the p...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/6561A61K31/675A61P31/18A61P31/20
CPCY02P20/55
Inventor 仲伯华朱红元何新华刘河陈兰福
Owner INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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