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Industrial production process for tenofovir disoproxil fumarate

A technology of tenofovir disoproxil and production process, applied in the field of industrialized production technology of tenofovir disoproxil, can solve the problems of high cost and price of the final product, and achieve the effects of simple operation of the production process and improved safety.

Inactive Publication Date: 2010-10-27
杭州和素企业管理有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

We have proved through our own experiments that these processes often lead to high cost of final products, and bring a series of other uncertain factors in terms of environmental protection and safety of production

Method used

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  • Industrial production process for tenofovir disoproxil fumarate
  • Industrial production process for tenofovir disoproxil fumarate
  • Industrial production process for tenofovir disoproxil fumarate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] Add adenine 100g (0.74mol) in a 2L three-necked flask, N 2 Protect, then add 500ml of DMF, start stirring, add, add R-propylene carbonate 95g (0.92mol), add NaOH 3g (0.075mol), stir at room temperature for 10 minutes, after the system is uniform, start to heat up to 100-130°C, Insulation reaction, sampling test after 12 hours, (the reaction is clear and transparent); when the content of adenine in the reaction system is below 1%, the reaction can be stopped; slowly lowered to below 90°C, start to add 600ml of toluene, a large amount of white solids are precipitated After cooling down to room temperature, continue to drop to 0-5°C, keep stirring for 2 hours; filter with suction, soak and wash the filter cake with 200ml ice toluene to obtain about 180g of wet filter cake, about 130-140g of dry product, HPLC purity 85%- 90%, melting point 188-192°C;

[0068] Refining: add 130g of the product obtained in the previous step to 600ml of ethanol and 100ml of toluene, heat up t...

Embodiment 2

[0070] Add adenine 100g (0.74mol) in a 2L three-necked flask, N 2 Protect, then add 700ml of DMSO, start stirring, add, add R-propylene carbonate 95g (0.92mol), add KOH 4g (0.071mol), stir at room temperature for 10 minutes, after the system is uniform, start to heat up to 110-125°C, Insulation reaction, sampling test after 8 hours, the reaction is basically clear or with a little floc; when the content of adenine in the reaction system is below 1%, the reaction can be stopped; after slowly cooling to room temperature, continue to drop to 0-5°C , keep stirring for 2 hours; filter with suction, soak and wash the filter cake with 200ml ice toluene to obtain about 170g of wet filter cake, about 125-130g of dry product, HPLC purity of 82%-88%, melting point of 182-188°C;

[0071] Refining: Add 130g of the product obtained in the previous step to 500ml of methanol and 100ml of toluene, heat up to dissolve, add 5g of activated carbon, reflux for half an hour and remove the activated...

Embodiment 3

[0073] In a 1L four-necked flask, add R-9-(2-hydroxypropyl) adenine 100g (0.52mol), N 2 For protection, add 200ml of DMF, start stirring; add 90g (0.53mol) of magnesium tert-butoxide, the whole reaction system is grayish white and turbid, (magnesium tert-butoxide decomposes with water, it is necessary to ensure that the whole system is anhydrous and oxygen-free);

[0074] Slowly raise the temperature to 50-70°C, and keep warm at this temperature for 1 hour; then raise the temperature to 60-80°C, and start to add 250g of DESMP (diethyl p-toluenesulfonyloxyphosphonate) (0.77mol) dropwise;

[0075]With the dropwise addition of DESMP, the reaction solution will release heat, control the rate of addition, about 1.5hrs drop, when DESMP drops about 75%, the reaction solution will become clear gelatinous transparent orange yellow; dropwise 2 Check the HPLC after 1 hour, when the raw material in the HPLC is below 2%, the reaction can be stopped; slowly drop to room temperature, add 75g...

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Abstract

The invention discloses an industrial production process for tenofovir disoproxil fumarate represented by a structural formula (II). The production process comprises the following steps of: (1) preparing R-9-(2-hydroxypropyl)adenine by taking adenine and R-propylene carbonate as initial raw materials; (2) performing a condensation reaction on the obtained R-9-(2-hydroxypropyl)adenine and diethyl(tosyloxy)methylphosphonate under the catalytic action of magnesium alkoxide to prepare R-9[2-(diethyl-phosphonic acid methoxy)propyl]adenine; (3) hydrolyzing R-9[2-(diethyl-phosphonic acid methoxy)propyl]adenine to obtain tenofovir; and (4) performing condensation on the tenofovir and the chloromethyl isopropyl carbonate under the catalytic action of triethylamine to prepare the tenofovir disoproxil fumarate. The process of the invention has the characteristics of low cost, safe process, high product quality and suitability for industrial production.

Description

1. Technical field [0001] The present invention relates to an antiviral drug tenofovir disoproxil fumarate ((R)-[[2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl] An industrial production process of tenofovir disoproxil, an intermediate of phosphonic acid diisopropoxycarbonyloxymethyl fumarate). 2. Background technology [0002] Tenofovir disoproxil fumarate (TDF), chemical name (R)-[[2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl Base] phosphonic acid diisopropoxycarbonyloxy methyl ester fumarate, its structure is as shown in formula (I), is researched and developed by U.S. Glead Sciences company, listed in the U.S. for the first time in October, 2001, now in Europe, Listed in countries and regions such as Australia and Canada. At the 58th American Association for the Study of Liver Diseases Annual Meeting in November 2007 and the 43rd European Liver Diseases Annual Meeting in April 2008, reports on the treatment of CHB with tenofovir disoproxil attracted widespread atte...

Claims

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Application Information

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IPC IPC(8): C07F9/6561
Inventor 姜维斌洪梅林
Owner 杭州和素企业管理有限公司
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