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A kind of tenofovir disoproxil fumarate and preparation method thereof

A technology of tenofovir fumarate and dipivoxil, which is applied in the field of medicine, can solve the problems of high process cost, high price, and easy explosion, and achieve the avoidance of genotoxic impurities, the production process is simple and easy to operate, and the production cost is reduced Effect

Active Publication Date: 2016-01-20
湖南千金湘江药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] This operational route is a common method for synthesizing tenofovir disoproxil fumarate, but this method has the following disadvantages: the one is to use expensive n-butyllithium and expensive trimethyl bromide which need to be stored at low temperature Silane; second, it will produce genotoxic impurity K; third, the condensation of tenofovir (PMPA) and chloromethyl isopropyl carbonate will produce a large amount of tenofovir monopiproxil (impurity A)
[0016] This process route uses sodium hydride, which is a high-dangerous product and is very easy to explode when it meets water. Among them, trimethylbromosilane is expensive and the process cost is high
In addition, this route is too long, and using a protective agent, the yield is low

Method used

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  • A kind of tenofovir disoproxil fumarate and preparation method thereof
  • A kind of tenofovir disoproxil fumarate and preparation method thereof
  • A kind of tenofovir disoproxil fumarate and preparation method thereof

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Effect test

Embodiment 1

[0047] The preparation of embodiment 1 compound IX

[0048] Add 400g (1.24mol) of p-toluenesulfonyloxymethyl diethyl phosphate (formula VIII) and 100ml of N,N-dimethylformamide into the three-necked flask, stir for several minutes, then add 1250g of hydrobromic acid solution ( 40wt%) (6.20mol), N 2 Under gas protection, heat up to 95-100°C, react for 5 hours, cool down to room temperature, add 100ml of dichloromethane, stir, separate layers, take the water layer, adjust the pH value of the solution to 3.5 with cold saturated sodium hydroxide solution, and store at room temperature Stir for 0.5 hour, continue cooling to 0-5°C, and filter with suction to obtain 214 g of off-white solid with a yield of 65%.

Embodiment 2

[0049] The preparation of embodiment 2 compound IX

[0050] Add 400g (1.24mol) of p-toluenesulfonyloxymethyl diethyl phosphate (formula VIII) and 100ml of N,N-dimethylformamide into the three-necked flask, stir for several minutes, then add 2092g of hydrobromic acid solution ( 48wt%) (12.4mol), N 2 Under gas protection, heat up to 80-85°C, react for 5 hours, cool down to room temperature, add 100ml of dichloromethane, stir, separate layers, take the water layer, adjust the pH value of the solution to 3 with cold saturated sodium hydroxide solution, and keep at room temperature Stir for 0.5 hour, continue to cool to 0-5°C, and filter with suction to obtain 218 g of off-white solid with a yield of 66%.

Embodiment 3

[0051] The preparation of embodiment 3 compound IX

[0052] Add 400g (1.24mol) of p-toluenesulfonyloxymethyl diethyl phosphate (Formula VIII) and 100ml of N,N-dimethylformamide into the three-necked flask, stir for several minutes, then add 759g of bromotrimethylsilane (4.96mol), N 2 Under gas protection, heat up to 60-65°C, react for 5.5 hours, cool down to room temperature, add 120ml of ethyl acetate, stir, separate layers, take the water layer, adjust the pH value of the solution to 3.3 with cold saturated sodium hydroxide solution, and store at room temperature Stir for 0.5 hour, continue to cool to 0-5°C, and filter with suction to obtain 205 g of off-white solid with a yield of 62%.

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Abstract

The invention relates to an antiviral drug tenofovir disoproxil fumarate and a novel preparation method thereof, belonging to the field of medicines. Content of related substances in the tenofovir disoproxil fumarate, especially content of impurity K is effectively lowered by taking toluenesulfonyloxy diethyl methylphosphonate as a starting material through hydrolysis, condensation and salifying. Moreover, the preparation method is gentle in reaction condition, low in production cost, simple and convenient to operate, and suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to an antiviral drug tenofovir disoproxil fumarate and a new preparation method thereof, belonging to the field of medicine. Background technique [0002] Tenofovir disoproxil fumarate (TDF), chemical name (R)-[[2-(6-amino-9H-purin-9-yl)-1-methylethoxy] Methyl]phosphonic acid diisopropoxycarbonyl methyl ester fumarate (formula Ⅹ) is another new ring-opening phosphonic acid nucleoside compound successfully developed by GileadSciences in the United States after adefovir dipivoxil. It is used for HIV and HBV treatment. First launched in the United States in October 2001, it is now available in countries and regions such as Europe, Australia and Canada. [0003] [0004] Tenofovir disoproxil fumarate is a novel nucleoside analogue, which is hydrolyzed in vivo to obtain the medicinal ingredient tenofovir (PMPA), which mimics the natural nucleotide monophosphate, bypassing the intracellular phosphate The key step of conversion is ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/6561
Inventor 袁秀菊姚亮元袁飞鹏库咏峰
Owner 湖南千金湘江药业股份有限公司
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