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A kind of preparation method of tenofovir disoproxil

A technology for tenofovir and disoproxil, which is applied in the field of preparation of tenofovir disoproxil, can solve the problems of reduced workload, low yield, use of irritating catalysts and the like, and achieves reduced workload , the effect of reducing costs

Active Publication Date: 2018-11-16
浙江永核药业科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The purpose of the present invention is to overcome the problems of using a large number of irritating catalysts, low yield and post-processing difficulties in the existing preparation method of tenofovir disoproxil, and to provide a preparation method of tenofovir disoproxil method
[0010] In the present invention, the inventor adopts ionic liquid as a solvent and applies it to the reaction of tenofovir and halomethyl isopropyl carbonate. The ionic liquid is not only used as a solvent but also as a catalyst for the reaction. Solvent N-methylpyrrolidone and a large number of irritating phase transfer catalysts such as tetrabutylammonium bromide, etc., the workload in the production process is greatly reduced, and it is suitable for industrial production

Method used

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  • A kind of preparation method of tenofovir disoproxil

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preparation example

[0021] [BuPy] BF 4 Synthesis of (1-butylpyridine tetrafluoroborate)

[0022] In a dry three-necked flask, add 31.6g of pyridine, 68.5g of n-bromobutane and 100ml of acetonitrile into 250ml, heat the reaction system to 75°C, keep stirring for 8 hours, monitor the completion of the reaction, and concentrate under reduced pressure to obtain a light yellow solid , and then the solid was washed three times with acetone, and dried under vacuum at 40° C. for 12 hours to obtain 79.6 g of white N-butylpyridine bromide solid, with a yield of 92.2%.

[0023] In another dry three-necked flask, add 0.2mol N-butylpyridine bromide, 0.25mol sodium fluoroborate and 50ml acetone to raise the temperature to 40°C, keep the temperature and stir for 24 hours, monitor the completion of the reaction, filter with suction, and concentrate the filtrate under reduced pressure The crude product of N-butylpyridine tetrafluoroborate was obtained, which was dissolved in dichloromethane, filtered, and the fi...

Embodiment 1

[0026] Preparation of tenofovir disoproxil

[0027] Tenofovir 28.7g (0.1mol), acid-binding agent 40.5g (triethylamine, 0.4mol), chloromethyl isopropyl carbonate 30.5g (0.2mol) and ionic liquid (1-butylpyridine tetra Fluoroborate) 100ml was added to the reaction flask, heated to 40°C and stirred for 1.5 hours. After the reaction, cooled to room temperature, the reaction solution was poured into water, extracted with ethyl acetate, the organic phase was washed three times with water, and dried over anhydrous sodium sulfate. , concentrated under reduced pressure, and the concentrate was recrystallized from petroleum ether to obtain 46.6 g of tenofovir disoproxil, with a yield of 89.7% and an HPLC purity of 99.65%.

Embodiment 2

[0029] Preparation of tenofovir disoproxil

[0030] Tenofovir 28.7g (0.1mol), acid-binding agent 50.6g (triethylamine, 0.5mol), chloromethyl isopropyl carbonate 45.8g (0.3mol) and ionic liquid (1-butylpyridine tetra Fluoroborate) 120ml was added to the reaction flask, heated to 40°C and stirred for 1.5 hours. After the reaction, cooled to room temperature, the reaction solution was poured into water, extracted with ethyl acetate, the organic phase was washed with water, and dried over anhydrous sodium sulfate. Concentrate under reduced pressure, and recrystallize the concentrate from petroleum ether to obtain 47.1 g of tenofovir disoproxil, with a yield of 90.6% and a purity of 99.47% by HPLC.

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Abstract

The invention discloses a tenofovir disoproxil preparation method. The tenofovir disoproxil preparation method includes enabling tenofovir to react with halogenated chloromethyl isopropyl carbonate in ionic liquid in the presence of acid-capturers so as to obtain tenofovir disoproxil. The tenofovir disoproxil preparation method has the advantages that a great quantity of irritant N-methyl pyrrolidone and phase transfer catalysts are avoided, cost and post-treatment workload are both reduced, reaction time is shortened effectively and high yield is achieved.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and relates to a preparation method of tenofovir disoproxil. Background technique [0002] Tenofovir Disoproxil Fumarate (Tenofovir Disoproxil Fumarate) is a new type of nucleotide transcriptase inhibitor developed by Gilead Sciences of the United States, mainly by inhibiting HIV-1 Reverse transcriptase activity inhibits HIV virus replication. Tenofovir disoproxil fumarate is a prodrug of tenofovir, which has good anti-HIV and HBV activity, and was approved by the US FDA in 2001 for the treatment of human immunodeficiency virus infection. At present, it has been listed in many countries and regions such as Canada and Europe. As a first-line drug for the treatment of HIV, it has a good application prospect. The chemical name of tenofovir disoproxil fumarate is (R)-[[2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]phosphonic acid Diisopropoxycarbonyloxymethyl fumarate, the specific ch...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/6561
CPCC07F9/65616
Inventor 隋妍蕾郭其贞王丽华吕燕华
Owner 浙江永核药业科技有限公司