An efficient and practical synthesis of the HIV protease inhibitor atazanavir via a highly diastereoselective reduction approach

Abstract

An efficient and practical synthesis of the HIV-1 protease inhibitor Atazanavir was developed by employing the diastereoselective reduction of ketomethylene aza-dipeptide isostere 10 as the key and final step. The high diastereoselectivity of the amino ketone reduction by lithium tri-iert-butoxyaluminum hydride in diethyl ether to afford the desired svn-1,2-amino alcohol structure was achieved by Felkin- Anh control as a result of the bulky and chiral N-(methoxycarbonyl)-L-tert-leucinyl moiety as the nitrogen protecting group. The coupling of the two key intermediates, N-(methoxycarbonyl)-L-tert-leucine acylated benzyl hydrazine 7 and chloromethyl ketone 9, via an SN2 reaction furnished the amino ketone 10 in high yield under our optimized conditions. Our new methodology features the late introduction of the S-hydroxyl group and the early acylation of benzyl hydrazine and chloromethyl ketone with N-(methoxycarbonyl)-L-tert-leucine, respectively, which confers high efficiency and easy purification. © 2008 American Chemical Society.