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TAF(tenofovir alafenamide fumarate) preparation method

An adenine and reaction technology, applied in the field of preparation of TAF, can solve the problems of large pollution and post-treatment, affecting industrial production, etc., and achieve the effects of reducing pollution, optimizing reaction conditions, and optimizing reaction solvent.

Inactive Publication Date: 2015-12-09
ZHEJIANG TIANSHUN BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, some highly toxic substances that are not used in industry are used in the existing preparation route, such as DCC, and a large amount of DCU will be produced in the reaction of DCC condensation, which will cause relatively large pollution and post-treatment, which will affect its industrial production.

Method used

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  • TAF(tenofovir alafenamide fumarate) preparation method

Examples

Experimental program
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Effect test

Embodiment 1

[0032] Add adenine to sodium hydroxide solution, then add ethylene carbonate, the molar ratio of adenine to ethylene carbonate is 1:1-1:1.5; the reaction temperature is 150°C, react for 24 hours, and then add ethyl acetate The ester was recrystallized and filtered to give the solid product 9-(2-hydroxyethyl)adenine.

Embodiment 2

[0034] Suspend 9-(2-hydroxyethyl)adenine in dimethylformamide, and add magnesium isopropoxide to it, wherein the amount of magnesium isopropoxide is 9-(2-hydroxyethyl)adenine One-half, then add p-toluenesulfonyloxymethylphosphonic acid diethyl ester, p-toluenesulfonyloxymethylphosphonic acid diethyl ester and 9-(2-hydroxyethyl) adenine The ratio is 1.5-2:1. The reaction temperature is 95° C., and the reaction time is 10 h. After the reaction is completed, 9-[2-(phosphorylmethoxy)ethyl]adenine is extracted and separated by acetone.

Embodiment 3

[0036] Add phenol and mercaptopropionic acid to 9-[2-(phosphorylmethoxy)ethyl]adenine, wherein the molar ratio of phenol to 9-[2-(phosphorylmethoxy)ethyl]adenine is 2-2.5:1, the molar ratio of mercaptopropionic acid to 9-[2-(phosphorylmethoxy)ethyl]adenine is 1.5-2:1. The reaction temperature is 120°C, and the reaction time is 20h. After the reaction was completed, it was extracted and separated with ether to obtain the intermediate shown in formula I.

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Abstract

The invention provides a TAF(tenofovir alafenamide fumarate) preparation method. The method comprises taking adenine as an initial raw material, employing propylene carbonate to add isopropanol at 1 position, then under the effect of magnesium isopropoxide, reacting with diethyl (tosyloxy)methylphosphonate, then removing ether, then reacting with phenol for condensation, and performing chlorination, condensation, resolution and salification, so as to obtain the product. The technology route is subjected to optimization and improvement, and pollution discharge is reduced.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to a preparation method of TAF. Background technique [0002] Tenofovir alafenamide fumarate (tenofoviralafenamide fumarate, TAF) Chinese chemical name, N-[[S(P)]-[2-(adenin-9-yl)-1(R)-methylethoxymethyl Base l] (phenoxy) phosphono] -L-alanine isopropyl ester. [0003] The drug is an experimental novel prodrug of tenofovir used to treat HIV infection. The data showed that the TAF-containing drug group achieved a similar virological response to the Stribild drug group, and the proportion of patients with HIV viral load ≤ 50 copies / ml at 24 weeks of treatment was 87% and 90%, respectively. In addition, the study data also showed that at 24 weeks of treatment, the decrease in lumbar spine and hip bone mineral density from baseline levels, compared with the Stribild group, the TAF drug group achieved a statistically significant smaller reduction (p<0.005 ). [0004] However, some ...

Claims

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Application Information

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IPC IPC(8): C07F9/6561
Inventor 张胜
Owner ZHEJIANG TIANSHUN BIOTECH
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