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Synthesis process of key intermediate of tenofovir alafenamide hemifumarate

A technology of tenofovir alafenamide and synthesis process, which is applied in the field of synthesis process of key intermediate of tenofovir alafenamide hemifumarate, can solve the problem of unsuitable for industrial production, harsh hydrolysis conditions, no Illustrate examples and other issues to achieve the effects of low cost, easy access to raw materials, and mild reaction

Active Publication Date: 2016-11-16
GUANGZHOU TROJAN PHARMATEC LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Route 1 needs to use diethyl ester protection, de-diethyl ester protection and then phenyl ester in the synthesis of key intermediate (3), and the hydrolysis conditions are harsh, the route is long, and the operation is cumbersome, so it is not suitable for industrial production
[0011] Route 2 refers to using diphenyl phosphite as raw material, through condensation with chloromethyl benzyl ether, and then through hydrolysis, chlorination, condensation, resolution, deprotection, and esterification to obtain acyloxymethyl phosphonate , condensed with (R)-9-(2-hydroxypropyl) adenine under alkaline conditions to obtain tenofovir alafenamide, but no specific example

Method used

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  • Synthesis process of key intermediate of tenofovir alafenamide hemifumarate
  • Synthesis process of key intermediate of tenofovir alafenamide hemifumarate
  • Synthesis process of key intermediate of tenofovir alafenamide hemifumarate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] Synthesis of (R)-{[2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}phosphonic acid diphenyl ester

[0060]

[0061] Dissolve (R)-9-(2-hydroxypropyl)adenine (5g, 25.8mmol) in 25ml of N-methylpyrrolidone, add potassium tert-butoxide (2.88g, 25.8mmol) into it at room temperature, and stir After 1 hour, diphenyl p-toluenesulfonyloxyphosphonate (14 g, 33.5 mmol) was added, and the reaction was stirred at 25° C. for 12 hours. Add acetic acid (1.2g, 20.6mmol) dropwise again, and after stirring for 20 minutes, the reaction solution is poured into 100ml water, and off-white solids are precipitated, filtered, the filter cake is washed once with water, once with a small amount of ethanol, and dried to obtain 9.6g of solids. The yield was 85%.

[0062] The NMR data of product are as follows:

[0063] 1 H NMR (400MHz, d-DMSO): δ1.32(d,3H),3.35(dd,1H),3.55(dd,1H),4.5(m,2H),6.80–7.21(m,6H),7.31 –7.42(m,4H),8.26(s,1H),8.35(s,1H). 31 P NMR (162MHz, CDCl 3 ) δ18.6.

[0064] (R)...

Embodiment 2

[0072] Synthesis of (R)-{[2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}phosphonic acid diphenyl ester

[0073] Dissolve (R)-9-(2-hydroxypropyl)adenine (5g, 25.8mmol) in 25ml of N-methylpyrrolidone, add sodium hydrogen (1g, 25.8mmol, 60%) at room temperature, stir for 1 After one hour, diphenyl p-toluenesulfonyloxymethylphosphonate (14 g, 33.5 mmol) was added, and the reaction was stirred at 25° C. for 12 hours. Then add acetic acid (1.2g, 20.6mmol) dropwise, and after stirring for 20 minutes, the reaction solution is poured into 100ml water, and an off-white solid is precipitated, filtered, the filter cake is washed once with water, once with a small amount of ethanol, and dried to obtain 8.1g of solid, producing The rate is 72%.

[0074] Synthesis of (R)-{[2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}phosphonic acid monophenyl ester

[0075] Dissolve (R)-{[2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}phosphonic acid diphenyl ester (8.1g, 18.5mmol) in 30ml Tetrahyd...

Embodiment 3

[0077] Synthesis of (R)-{[2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}phosphonic acid diphenyl ester

[0078] Dissolve (R)-9-(2-hydroxypropyl)adenine (10g, 51.6mmol) in 40ml of N,N-dimethylformamide, and add magnesium tert-butoxide (7g, 41.3mmol) at room temperature After stirring for 1 hour, diphenyl p-toluenesulfonyloxymethylphosphonate (21.6 g, 51.6 mmol) was added, and the mixture was stirred and reacted at 75° C. for 8 hours. Add acetic acid (4.9g, 82.6mmol) dropwise, and after stirring for 20 minutes, pour the reaction solution into 250ml of water and 100ml of dichloromethane, extract and separate the layers, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, and filter , the filtrate was spin-dried under reduced pressure to obtain 17 g of solid, with a yield of 75%.

[0079] Synthesis of (R)-{[2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}phosphonic acid monophenyl ester

[0080] Dissolve (R)-{[2-(6-amino-9H-purin-9-yl)-1-methylethox...

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Abstract

The invention discloses a synthetic process of key intermediate of hemifumarate tenofovir alafenamide. A synthetic route is shown below. The synthetic process has the advantages that the strict conditions of the prior art are avoided, the reaction steps are simplified, the raw materials are easy to obtain, reaction is moderate, the cost is lower and the synthetic process is suitable for industrial production.

Description

technical field [0001] The invention relates to a synthesis process of a drug intermediate, in particular to a synthesis process of a key intermediate of tenofovir alafenamide hemifumarate. Background technique [0002] Tenofovir disoproxil fumarate (TDF) {9-R-[(2-phosphonomethoxy)propyl]adenine} is a potent in vitro and in vivo inhibitor of human immunodeficiency virus type 1 (HIV-1) replication agent, a nucleotide antiviral drug. It can not only inhibit the synthesis of enzymes required for virus replication, but also participate in the competition as a substrate analog, incorporate into the DNA of the virus replication, block the extension of the DNA chain, and thereby inhibit the replication of the virus. Antiviral drugs have become one of the eye-catching drugs in the global pharmaceutical market. [0003] Tenofovir alafenamide hemifumarate (TAF) is a newer generation tenofovir (TFV) prodrug than tenofovir disoproxil fumarate (TDF). Clinical data show that: TAF dose ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/6561
Inventor 郑庆泉黄世福曹徐涛
Owner GUANGZHOU TROJAN PHARMATEC LTD
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