Preparation method of tenofovir disoproxil fumarate hemifumarate

A technology of tenofovir disoproxil and hemifumarate, which is applied in the field of preparation of tenofovir disoproxil hemifumarate, can solve the problems of time-consuming and labor-consuming, difficult industrial preparation, etc., and achieve convenient and reliable process operation control, simple and economical preparation method, high yield effect

Inactive Publication Date: 2014-09-17
SHANGHAI SCIENCHEM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But there is deficiency in the preparation method of tenofovir disoproxil hemifumarate in this patent, it is raw material with tenofovir disoproxil fumarate (molar ratio 1: 1), obtains tenofovir...

Method used

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  • Preparation method of tenofovir disoproxil fumarate hemifumarate
  • Preparation method of tenofovir disoproxil fumarate hemifumarate
  • Preparation method of tenofovir disoproxil fumarate hemifumarate

Examples

Experimental program
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Embodiment 1

[0017] Embodiment 1, the preparation of (R)-(+)-9-[2-(diethoxyphosphorylmethoxy)propyl]adenine

[0018] Add 40g DMF to a 250ml three-necked flask, add 12g (R)-(+)-9-(2-hydroxypropyl)adenine, add 11.3g magnesium tert-butoxide under stirring, stir, and heat up. The internal temperature was 70°C, and 31 g of diethyl p-toluenesulfonyloxyphosphonate was added dropwise to keep the internal temperature at 70°C. After the dropwise addition, stir for 5.0 to 6.0 hours, take samples and control in HPLC until the conversion of raw materials is complete. Cool down to 30-40°C, add 10g of acetic acid dropwise, keep the internal temperature at 30-40°C, and stir for 0.5-1.0h after the addition is complete. Concentrate the solvent under reduced pressure at 70-75°C until there is no distillation, and lower the temperature to 20-30°C. Add 150ml of dichloromethane, add 13g of water, and stir for 1.0-2.0h. Filtrate to obtain filtrate 1. The filter cake was beaten and washed with 60 ml of dichlo...

Embodiment 2

[0019] Example 2, Preparation of (R)-(+)-9-[2-(dihydroxyphosphorylmethoxy)propyl]adenine

[0020] Add the crude (R)-(+)-9-[2-(diethoxyphosphorylmethoxy)propyl]adenine from the previous step into a 250ml three-necked flask, add 30ml of acetonitrile, stir, and cool down. When the inner temperature is lower than 30°C, 37g of TMSBr is added dropwise to keep the inner temperature lower than 30°C. After the dropwise addition, raise the temperature, keep the internal temperature at 60-65°C, stir for 3.0-4.0 hours, take a sample by HPLC and control until the conversion of raw materials is complete, lower the temperature to 40-45°C, and concentrate the solvent under reduced pressure until there is no distillation. Cool down to 0-5°C, add 100g of purified water dropwise, keep at 0-5°C, stir for 1.0-3.0h, then extract twice with 50ml of ethyl acetate. Separate the water layer, control the internal temperature at 0-5°C, add dropwise 50% sodium hydroxide solution, adjust the pH value of t...

Embodiment 3

[0022] Embodiment three, the preparation of free tenofovir disoproxil

[0023] Add 50ml NMP in a 200ml nitrogen-protected three-necked flask, add 12.5g triethylamine, add 12.5g (R)-(+)-9-[2-(dihydroxyphosphorylmethoxy)propyl]adenine, Stir for 0.5~1.0h. Add 31.3g of chloromethyl isopropyl carbonate, raise the temperature to an internal temperature of 55-65°C, and stir for 5.0-6.0 hours to terminate the reaction. Cool down to 20-30°C, add 100ml cyclohexane and extract twice to obtain the lower layer. 60 ml of purified water was added to the lower layer mixture, 100 ml of ethyl acetate was added for extraction three times, and the organic phases were combined. Add water to the above organic phase and wash three times to obtain the organic phase, dry it with anhydrous sodium sulfate, filter, and concentrate to dryness under reduced pressure at 35-40° C. to obtain 20 g of free tenofovir disoproxil.

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Abstract

The invention relates to the field of pharmaceutical chemistry and provides a preparation method of tenofovir disoproxil fumarate hemifumarate. The tenofovir disoproxil fumarate hemifumarate is a eutectic composed of tenofovir disoproxil fumarate and fumaric acid with the ratio of tenofovir disoproxil fumarate to fumaric acid being 2:1. According to the preparation method, (R)-9-(2-hydroxy propyl) adenine is used as a starting material, and condensation, hydrolysis and esterification are carried out to prepare free tenofovir disoproxil fumarate; and the free tenofovir disoproxil fumarate and fumaric acid in a solvent undergo salt formation and crystallization to prepare the tenofovir disoproxil fumarate hemifumarate.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to a preparation method of tenofovir disoproxil hemifumarate. Specifically, the present invention relates to a method for preparing tenofovir disoproxil hemifumarate by salting free tenofovir disoproxil and fumaric acid. Background technique [0002] Tenofovir disoproxil fumarate (TDF), a nucleotide reverse transcriptase inhibitor, is currently approved in the United States for the treatment of HIV-1 alone or in combination with other antiretroviral drugs Infect. The drug was approved in Europe for the treatment of HIV infection. As a treatment drug for HIV infection, it was approved for marketing in the United States in October 2001, in Europe in February 2002, and in Japan in March 2004. It was approved for the treatment of HIV infection. At the same time, the drug can be effectively applied to HIV and HBV infected patients who have been treated with lamivudine, and can be appli...

Claims

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Application Information

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IPC IPC(8): C07F9/6561C07C57/15C07C51/41
Inventor 陈力姜春阳李惠谢军廖文胜
Owner SHANGHAI SCIENCHEM CO LTD
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