Preparing method for realizing industrial mass production of tenofovir disoproxil fumarate

A technology for tenofovir fumarate and dipyfurate, applied in the field of medicine, can solve the problems of unsuitable industrialized large-scale production, complex synthesis process, large environmental pollution, etc., and achieves easy purchase, high reaction conversion rate, and reduced The effect of pollution

Inactive Publication Date: 2016-06-01
广东京豪生物制药有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] In the existing patents of tenofovir disoproxil fumarate that have been applied for or published, the synthesis process is relatively complicated, the yield is low, the environmental pollution is large, and it is not suitable for large-scale industrial production

Method used

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  • Preparing method for realizing industrial mass production of tenofovir disoproxil fumarate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0014] Example 1: (1) Preparation of (R)-9-[2-(diethoxyphosphonomethoxy)propyl]adenine

[0015] Add 100g of N,N-dimethylformamide, 30g of (R)-9-2-(hydroxypropyl)adenine, 8g of magnesium tert-butoxide and diethyl p-toluenesulfonyloxymethylphosphonate into the reaction vessel Stir 90g of the ester, heat to 90~95°C, keep warm and stir for 8 hours, terminate the reaction, and obtain the reactant. Cool to room temperature, add glacial acetic acid, adjust the pH to pH 6.5-7.5. Add an appropriate amount of dichloromethane, reflux for 5 hours, separate and extract the dichloromethane layer, filter, wash with dichloromethane, combine the filtrate and wash, and distill under reduced pressure to obtain a thick substance. The molar ratio of (R)-9-2-(hydroxypropyl)adenine to magnesium tert-butoxide is 1:0.6.

Embodiment 2

[0016] Embodiment 2: (2) tenofovir synthesis

[0017] Add (R)-9-[2-(diethoxyphosphonomethoxy)propyl]adenine into the reaction vessel, add 450 g of hydrobromic acid, stir, heat up and reflux for 10 hours, and the reaction ends. Distill under reduced pressure, cool to room temperature, add an appropriate amount of dichloromethane and water, separate and extract the dichloromethane layer, adjust the pH to 3.0 with 20% sodium hydroxide solution, lower the temperature to 10°C, crystallize for 12 hours, filter to obtain substitute Nofovir crude. Add an appropriate amount of water, heat until the solid dissolves, cool down to 10°C, conduct crystallization for 12 hours, filter to obtain tenofovir essence. Dry under reduced pressure at 55°C to obtain a dry product of tenofovir.

Embodiment 3

[0018] Embodiment 3: (3) Synthesis of tenofovir disoproxil

[0019] Add 300g of N-methylpyrrolidone, 90g of triethylamine and 25g of tenofovir into the reaction vessel, stir, heat to 70°C, add 40g of chloromethyl isopropyl carbonate dropwise, keep stirring for 10 hours, and stop the reaction . Add an appropriate amount of ethyl acetate, filter, wash the filter residue with an appropriate amount of ethyl acetate, combine the washed filtrates, add an appropriate amount of water to wash 3 times, add anhydrous sodium sulfate for dehydration, and filter. The filtrate was distilled under reduced pressure at 55°C and evaporated to dryness to obtain tenofovir disoproxil oil. The molar ratio of tenofovir and triethylamine is: 1:10.

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Abstract

The invention relates to a preparing method for realizing industrial mass production of tenofovir disoproxil fumarate.The preparing method includes the following steps of preparing (R)-9-[2-(diethoxyphosphonylmethoxy) propyl] adenine, synthesizing tenofovir, refining tenofovir, dewatering tenofovir, synthesizing tenofovir disoproxil and synthesizing tenofovir disoproxil fumarate.The technical scheme is easy to operate, selected reagents are low in price, the number of side reactions is small, the yield is high, few three wastes are generated in the reaction process, and the preparing method is beneficial for environment protection and suitable for industrial mass production.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a preparation method of tenofovir disoproxil fumarate, a medical raw material used in the field of AIDS and hepatitis B treatment. Background technique [0002] Tenofovir disoproxil fumarate is a new type of oral broad-spectrum antiviral drug. It is an ester prodrug of tenofovir and belongs to a new type of nucleotide reverse transcriptase inhibitor. The chemical name is 5 -(((1R)-2(6-Amino-9H-purin-9-yl)-1-methylethoxy)methyl)-2,4,6,8-tetraoxo-5-phosphanonyl Diisopropyl diacid-5-oxide fumarate, English name tenofovirdisoproxilfumarate. This product is hydrolyzed into tenofovir after oral administration, and then phosphorylated by cellular kinases to generate a pharmacologically active metabolite tenofovir diphosphate, which competes with 5'-deoxyadenosine triphosphate and participates in viral DNA After synthesis, after entering the viral DNA, due to the lack of 3'-OH group, th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561C07C57/15C07C51/41
CPCC07F9/65616C07C51/412
Inventor 卢晓露陈文彪郑辉
Owner 广东京豪生物制药有限公司
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