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Chiral resolution method of tenofovir alafenamide

A tenofovir alafenamide, chiral separation technology, applied in the field of medicine, can solve the problem of inability to obtain the purity of tenofovir alafenamide, etc., achieve improved connection, simple reagents, and reduce toxic and side effects Effect

Active Publication Date: 2019-09-27
NANJING GRITPHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Tenofovir alafenamide itself contains 3 chiral centers, and it is extremely important to control its chirality during its preparation. In the preparation methods reported in the existing literature, the chiral resolution, isomer impurity control and Without detailed reports, it is impossible to obtain tenofovir alafenamide in the S configuration with higher purity

Method used

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  • Chiral resolution method of tenofovir alafenamide
  • Chiral resolution method of tenofovir alafenamide
  • Chiral resolution method of tenofovir alafenamide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] The reaction equation is as follows:

[0032]

[0033] step 1)

[0034] Add 10.0 g of TAF-2, 50 mL of acetonitrile, and 6.25 mL of ethanol into a 100 mL three-neck flask, add 1.51 g of D-(-) tartaric acid under stirring, heat up and reflux for 1 h. Stop heating, and stir in an ice-water bath for 30 min after natural cooling. Filter with suction, wash the filter cake with a small amount of cold acetonitrile, and keep the filtrate.

[0035] Step 2)

[0036] Add 50mL saturated NaHCO to the filtrate 3 , and 50mL of dichloromethane, fully stirred for 30min. The liquid was separated, the aqueous phase was extracted with dichloromethane, and the organic phases were combined and dried to obtain 5.3 g of brown-red oil.

[0037] step 3)

[0038] Add 20 mL of acetonitrile to dissolve 5.3 g of red oil, then add 0.43 g of TAF-3 seed crystals (5%) to induce crystallization, stir at room temperature for 1 h, place in -5°C ice-water bath and stir for 3 h, and filter and dry to...

Embodiment 2

[0042] step 1)

[0043] Add 300.g of TAF-2, 1.5L of acetonitrile, and 187.5mL of ethanol into a 2L reaction flask, add 45g of D-(-)tartaric acid under stirring, heat up and reflux for 2h. Stop heating, and stir in an ice-water bath for 1 h after natural cooling. Suction filtration, the filter cake was washed with a small amount of cold acetonitrile, and the filtrate was retained.

[0044] Step 2)

[0045] Add 200mL saturated NaHCO to the filtrate 3 , and 50mL of dichloromethane, fully stirred for 1h. The liquid was separated, and the aqueous phase was extracted with dichloromethane, and the organic phases were combined and dried to obtain 175 g of a brownish-red oil.

[0046] step 3)

[0047] 175 g of the red oil was dissolved in 150 mL of acetonitrile, 14 g (8.0%) TAF-3 seed crystals were added to induce crystallization, stirred at room temperature for 1 h, then placed in an ice-water bath at -5°C and stirred for 3 h, filtered and dried to obtain a yellow solid TAF- 3 1...

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PUM

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Abstract

The invention discloses a chiral resolution method of tenofovir alafenamide, and belongs to the field of drug synthesis. The method comprises the following steps: racemic tenofovir alafenamide (TAF-2) and D-tartaric acid form a salt, the salt is subjected to weak alkaline hydrolysis, and then the hydrolyzed salt is induced by a crystal seed to crystallize in order to obtain (S)-tenofovir alafenamide (TAF-3). The method adopts conventional reagents with low toxicity, so the method is suitable for industrial production, allows the highly pure TAF-3 with a purity of 97% or above to be obtained, and has an excellent resolution effect.

Description

Technical field [0001] The invention belongs to the field of medical technology and relates to drug synthesis technology, specifically a preparation method of tenofovir alafenamide. Background technique [0002] There are approximately 400 million hepatitis B patients worldwide. Hepatitis B is a life-threatening disease that can lead to cirrhosis of the liver and is the direct cause of 80% of primary liver cancers worldwide. Hepatitis B is currently not completely curable and seriously threatens human health. [0003] Hepatitis B treatment drugs on the market mainly include injectable interferon alpha, peginterferon alpha, and oral lamivudine, telbivudine, adefovir dipivoxil, and tenofovir disoproxil esters, entecavir and other common nucleoside analogs. However, interferons have shortcomings such as high price and many adverse reactions, and oral nucleoside drugs have shortcomings such as easy drug resistance and easy relapse after drug withdrawal. [0004] On November 1...

Claims

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Application Information

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IPC IPC(8): C07F9/6561
CPCC07F9/65616C07B2200/07Y02P20/55
Inventor 杨建楠赵海峰陆滢炎吴小涛赵卿霍立茹李战
Owner NANJING GRITPHARMA CO LTD