Novel synthetic method of HIV-1 protease inhibitor atazanavir

Abstract

The invention relates to a new synthetic method of an HIV-1 protease inhibitor, Atazanavir, which adopts a convergent-typed synthetic strategy, introduces a construction unit, methoxycarbonyl-tert-lencyl, as an N atom protecting group in the whole early synthetic stage, and takes the diastereomeric selective reduction of aminoketone as the key and final reaction step of the new process. The method comprises the steps that: the compound of formula V, namely, N-1-[N-(methoxycarbonyl)-L-tert-leucine]-N-2-[4-(2-pyridyl)-phenmethyl]hydrazine, and the compound of formula VI, namely, (S)-1-((S)-4-chlorine-3-carbonyl-1-phenyl butane-2-yl-2-amino)-3, 3-dimethyl-1-carbonyl butane-2-yl-methyl carbamate, are treated with nucleophilic substitution reaction to generate the compound of formula VII, namely, 1-[4-(2-pyridyl)phenyl]-5(S)-2, 5-bis{[N-(methoxycarbonyl)-L-tert-leucineyl] amino}-4-carbonyl-6-phenyl-2-azahexane; and the compound of formula VII is treated with reduction reaction to generate the Atazanavir. The invention has the advantages of less process route steps, easily-controlled reaction conditions, simple and convenient operation, low-price and easily-obtained raw material, high product yield, low cost and being suitable for large-scale production.

Description

Synthetic method of HIV-1 protease inhibitor atazanavir technical field The present invention relates to a new protease inhibitor atazanavir (Atazanavir, 1-[4-(Pyridin-2-yl)phenyl]-5(S)-2,5-bis{[N-(methoxycarbonyl)- The synthetic method of L-tert-leucinyl]amino}-4(S)-hydroxy-6-phenyl-2-azahexane). Background technique Human immunodeficiency virus (HIV) is the pathogen that causes acquired immunodeficiency syndrome (AIDS). During the infection cycle of HIV virions, viral proteases are functional enzymes that cleave polyproteins into structural proteins. Therefore, targeting viral protease inhibitors has become an effective method for the treatment of AIDS. Atazanavir is an open-chain azapeptidomimetic compound and a novel protease inhibitor. Compared with other protease inhibitors, atazanavir has two significant advantages. First, it is the only protease inhibitor that is allowed to be taken once a day, which will greatly simplify the dosage course; second, atazanavir h...

AI Technical Summary

Problems solved by technology

This preparation method is the same as the original route when constructing the basic skeleton of the compound, but the chiral epoxy intermediate is prepared from the more expensive chiral diol through a 4-step reaction through a protecting group strategy. Compared with the original route, this route has improved The optical purity of intermediates, but more synthesis steps and higher production costs

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