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Preparation method for tenofovir

A technology of tenofovir and adenine, which is applied in the field of tenofovir preparation, can solve the problems of high cost and price, and achieve the effects of less three wastes, mild reaction conditions and improved product quality

Active Publication Date: 2011-05-18
ZHONGSHAN BAILING BIOTECHNOLOGY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These processes often lead to high cost and price of final products, and bring other uncertain factors in the environmental protection and safety of production

Method used

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  • Preparation method for tenofovir
  • Preparation method for tenofovir
  • Preparation method for tenofovir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] In a 250ml reaction bottle, add adenine 20.0gDMF150ml at room temperature under nitrogen protection, further add (R)-propylene carbonate 18.0g, KOH 0.5g, heat up to 130°C for 8 hours, cool down to 70°C and add 200ml at a constant speed Stir the toluene at a low speed to crystallize, cool to room temperature and continue to cool down to 0-5°C, filter, wash with 50ml of frozen toluene, and dry the filter cake at 60°C to obtain 25.4g of (R)-9-(2-hydroxypropyl)adenine , Molar yield 89%.

[0050] In a 250ml reaction bottle, add 50ml of DMF at room temperature and under the protection of nitrogen, add 25.4g of the product from the previous step, add 22.4g of potassium tert-butoxide at room temperature, and slowly add 45.0g of diethyl p-toluenesulfonyloxyphosphonate dropwise after keeping for one hour React for 3 to 5 hours. After the reaction is complete, add 15.0 g of acetic acid to neutralize excess potassium alkoxide. After distilling DMF under reduced pressure, add 300 ml...

Embodiment 2

[0054] In a 250ml reaction bottle, add adenine 20.0g DMF150mL at room temperature under nitrogen protection, further add (R)-propylene carbonate 20.0g, NaOH 0.5g, heat up to 133°C for 5 hours, cool down to 70°C and add at a constant speed Stir 200ml of toluene at a low speed to crystallize, cool to room temperature and continue cooling to 0-5°C, filter, wash the filter cake with 50ml of frozen toluene, and blow dry at 60°C to obtain (R)-9-(2-hydroxypropyl)adenine 25.8 g, molar yield 90%.

[0055] In a 250ml reaction bottle, add 80ml of DMF at room temperature and under nitrogen protection, add 25.8g of the product from the previous step, add 24.0g of potassium tert-butoxide at room temperature, keep it for one hour, then add p-toluenesulfonyloxyphosphonic acid within 1 to 2 hours 50.0 g of diethyl ester was reacted for 2 to 3 hours. After the reaction was complete, 12.0 g of formic acid was added to neutralize excess potassium alkoxide. After the DMF was distilled under reduc...

Embodiment 3

[0058] In a 250ml reaction bottle, add adenine 20.0g DHF100ml at room temperature and under the protection of nitrogen, further add (R)-propylene carbonate 20.0g, KOH 0.5g, heat up to 136°C for 5 hours, cool down to 80°C and add at a constant speed 200ml of toluene was stirred at a low speed to crystallize, cooled to room temperature and then cooled to 0-5°C, filtered, washed with 50ml of frozen toluene, and the filter cake was blown-dried at 60°C to obtain (R)-9-(2-hydroxypropyl)adenine 24.5 g, molar yield 86%.

[0059] In a 250ml reaction bottle, add 50ml of DHF at room temperature and under the protection of nitrogen, add 24.5g of the product from the previous step, add 22.4g of potassium tert-butoxide at room temperature, keep it for one hour, and slowly add 45.0 g of diethyl p-toluenesulfonyloxyphosphonate g reaction for 3 to 5 hours, after the reaction is complete, add 15.0 g of propionic acid to neutralize excess potassium alkoxide, distill DHF under reduced pressure an...

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Abstract

The invention discloses a preparation method for tenofovir disoproxil fumarate, which comprises the following steps of: A, performing condensation reaction adenine and (R)-propylene carbonate which serve as raw materials to generate (R)-9-(2-hydroxypropyl) adenine; B, performing condensation reaction on the (R)-9-(2-hydroxypropyl) adenine and p-methylphenyl mesyloxy diethyl phosphonate under the catalysis of potassium alcoholate to prepare (R)-9-[2-(diethyl phosphonyl methoxy) propyl] adenine; C, reacting the (R)-9-[2-(diethyl phosphonyl methoxy) propyl] adenine obtained by the step B with para-toluenesulfonate acyl chloride to protect an amino group at bit four to prepare (R)-4-(p-toluenesulfonyl)-9-[2-(diethyl phosphonyl methoxy) propyl] adenine; D, hydrolyzing the (R)-4-(p-toluenesulfonyl)-9-[2-(diethyl phosphonyl methoxy) propyl] adenine obtained by the step C under a strong acid condition to obtain (R)-4-(p-toluenesulfonyl)-9-[2-(dihydroxy phosphonyl methoxy) propyl] adenine; and E, reacting the (R)-4-(p-toluenesulfonyl)-9-[2-(dihydroxy phosphonyl methoxy) propyl] adenine obtained by the step D with mercapto-benzene under a weak alkaline condition to remove a para-toluenesulfonate group to obtain the tenofovir. The invention aims to provide the preparation method for the tenofovir, which is low in cost, safe in process and good in product quality, and is suitable for industrialization.

Description

technical field [0001] The invention relates to a method for preparing tenofovir. Background technique [0002] Tenofovir disoproxil fumarate (fovir disoproxil fumarate, TDF), whose structure is shown in formula (I), was developed by Glead Scierices in the United States, and it is the first drug approved in the United States and Europe for the treatment of HIV infection. Nucleotide reverse transcriptase inhibitors were approved by the FDA for the first time in October 2001. It is now available in countries and regions such as Europe, Australia and Canada. At the 58th American Association for the Study of Liver Diseases Annual Meeting in 2007 and the 43rd European Liver Diseases Annual Meeting in 2008, reports on the treatment of chronic hepatitis B with tenofovir disoproxil attracted widespread attention. [0003] [0004] Tenofovir disoproxil fumarate is a new type of nucleoside (acid) analogue, which obtains the medicinal component tenofovir after hydrolysis in vivo, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561
Inventor 黄凌张和平刘遗松秦和平霍延豪沈惠宾黄文军周海香梁待亮
Owner ZHONGSHAN BAILING BIOTECHNOLOGY CO LTD
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