A kind of preparation method of tenofovir alafenamide intermediate

Abstract

The invention belongs to the technical field of medicinal chemistry, and provides a method for preparing a tenofovir alafenamide intermediate. Tenofovir is used as a raw material and reacted with an alkali metal base or salt to generate a tenofovir alkali metal monosalt , and then react with triphenyl phosphite to generate the target intermediate; the method has simple reaction conditions, high raw material availability, high yield and high purity, reduces the use of a large amount of organic bases, produces less waste liquid, and causes little environmental pollution. Suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, in particular to a preparation method of a tenofovir alafenamide intermediate. Background technique [0002] Tenofovir alafenamide fumarate, chemical name 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl) Ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine fumarate, is a new type of nucleotide reverse transcriptase inhibitor, its chemical structure is as follows: [0003] [0004] The compound was developed by Gilead Sciences in the United States and was approved by the U.S. FDA in November 2016 under the trade name Vem1idy. As an oral nucleotide reverse transcriptase inhibitor, it is another prodrug of tenofovir disoproxil fumarate (TDF) for hepatitis B virus infection (HBV) and acquired immune syndrome ( HIV). This product is rapidly converted into tenofovir after oral administration, and is phosphorylated to tenofovir diphosphate under the action of cellular kinases, which inhibit...

AI Technical Summary

Problems solved by technology

[0024] (1) The use of materials such as DCC and DMAP produces a large amount of waste, which is easy to remain in the product and difficult to remove;

[0025] (2) Use a large amount of organic bases such as triethylamine and pyridine, which are highly toxic, difficult to reprocess, and unfriendly to the environment;

[0026] (3) The raw material of large batches is difficult to obtain in the hydrolysis method, and synthetic route is longer;

[0027] (4) If the feeding ratio is too large or the amount of solvent is too much, post-processing will produce a large amount of waste liquid, which is difficult to handle and will cause great environmental pollution.

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