Preparation method of tenofovir alafenemide fumarate impurities

A technology of acid anhydride and composite catalyst, which is applied in the field of preparation of pharmaceutical impurities, can solve the problems of fewer synthetic routes, low yield, complicated operation, etc., and achieve the effects of less catalyst consumption, high product purity, and simple operation

Pending Publication Date: 2020-09-01
ZHEJIANG CHARIOTEER PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] At present, there are very few synthetic routes for the preparation of PMPA acid anhydride impurities. CN 109081853A discloses that PMPA is used as raw material to prepare PMPA acid anhydride under DMF conditions through DIPEA / DCC, but its yield is very low, only about 40%, and it needs to be prepared in the later stage The column is purified and refined, and the operation is complicated

Method used

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  • Preparation method of tenofovir alafenemide fumarate impurities
  • Preparation method of tenofovir alafenemide fumarate impurities
  • Preparation method of tenofovir alafenemide fumarate impurities

Examples

Experimental program
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Embodiment 1

[0041]At room temperature, add 20g PMPA (1eq) and 250ml acetonitrile into a 500ml three-neck round bottom flask and stir evenly. Add 14.1g triethylamine (2eq) dropwise at room temperature. After the addition is complete, add 8.5g DMAP (1eq), 14.4g DCC (2eq), the temperature was raised to about 50°C, and the reaction was kept for about 24h. Stop the reaction, cool down to room temperature, add 18% HCl aqueous solution dropwise to pH = 3, stir for 30 min, filter, rinse with a small amount of acetonitrile, and discard the filtrate (mainly containing DMAP). Add 200ml of water to the filter cake and stir well, adjust the pH to 10 with 30% NaOH aqueous solution, stir for 30 min, filter, and discard the filter cake (DCU). The filtrate was cooled to about 5°C, 18% HCl aqueous solution was added dropwise to pH = 3, a small amount of seed crystals were added, and the mixture was kept stirring for about 3 hours, and a large amount of white solid was precipitated. Continue to add 18% HCl...

Embodiment 2

[0044] At room temperature, add 20g PMPA (1eq) and 250ml acetonitrile to a 500ml three-necked round-bottomed flask and stir evenly, then add 14.1g triethylamine (2eq) dropwise at room temperature, and then add 17gDMAP (2eq), 14.4g DCC ( 2eq), the temperature was raised to about 50°C, and the reaction was kept for about 24h. Stop the reaction, cool down to room temperature, add 18% HCl aqueous solution dropwise to pH = 3, stir for 30 min, filter, rinse with a small amount of acetonitrile, and discard the filtrate (mainly containing DMAP). Add 200ml of water to the filter cake and stir well, adjust the pH to 10 with 30% NaOH aqueous solution, stir for 30 min, filter, and discard the filter cake (DCU). The filtrate was cooled to about 5°C, 18% HCl aqueous solution was added dropwise to pH = 3, a small amount of seed crystals were added, and the mixture was kept stirring for about 3 hours, and a large amount of white solid was precipitated. Continue to add 18% HCl aqueous solutio...

Embodiment 3

[0046] At room temperature, add 20g PMPA (1eq) and 250ml acetonitrile to a 500ml three-necked round-bottomed flask and stir evenly. Add 10.2g diethylamine (2eq) dropwise at room temperature. After the addition is complete, add 17gDMAP (2eq), 14.4g DCC ( 2eq), the temperature was raised to about 50°C, and the reaction was kept for about 24h. Stop the reaction, cool down to room temperature, add 18% HCl aqueous solution dropwise to pH = 3, stir for 30 min, filter, rinse with a small amount of acetonitrile, and discard the filtrate (mainly containing DMAP). Add 200ml of water to the filter cake and stir well, adjust the pH to 10 with 30% NaOH aqueous solution, stir for 30 min, filter, and discard the filter cake (DCU). The filtrate was cooled to about 5°C, 18% HCl aqueous solution was added dropwise to pH = 3, a small amount of seed crystals were added, and the mixture was kept stirring for about 3 hours, and a large amount of white solid was precipitated. Continue to add 18% HC...

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Abstract

The invention discloses a preparation method of tenofovir alafenemide fumarate impurities. According to the reaction route of the preparation method, a reaction is carried out under the catalysis of acomposite catalyst; the composite catalyst is composed of an organic base A and an organic base B; the organic base A is selected from at least one of triethylamine, N, N-diisopropylethylamine, diethylamine and diisopropylamine; and the organic base B is selected from at least one of 4-dimethylaminopyridine, imidazole, pyridine and 4-dimethylpyridine. The method has the advantages of high reaction conversion rate and high purity of the obtained product.

Description

technical field [0001] The present invention relates to a kind of preparation method of drug impurity, particularly PMPA acid anhydride impurity (chemical name: (R)-[[2-(6-amino-9H-purin-9-yl) in fosprotenofovir crude drug The preparation method of propoxy] methyl] phosphoric anhydride, CAS: 1607007-18-0) belongs to the technical field of medicine and intermediates thereof. Background technique [0002] Tenofovir fosproxil (TAF) is a new generation of nucleoside reverse transcriptase inhibitors developed by Gilead in the United States on the basis of tenofovir disoproxil fumarate (TDF, Tenofovir Disoproxil Fumarate). Different from the chain phosphate structure in TDF, TAF contains phosphophenolate and phosphoalanine isopropyl ester fragments, so it has outstanding plasma stability and can maintain structural integrity to a large extent after entering infected cells. It can effectively avoid metabolic instability and the resulting renal and bone toxicity. Since 2016, the E...

Claims

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Application Information

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IPC IPC(8): C07F9/6561
CPCC07F9/65616
Inventor冉艳蒲通陈恬王乃星李建学朱燕萍钟惺泮育平
OwnerZHEJIANG CHARIOTEER PHARMA