An Efficient and Practical Synthesis of the HIV Protease Inhibitor Atazanavir via a Highly Diastereoselective Reduction Approach

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• 作者：Xing Fan ; Yan-Li Song ; Ya-Qiu Long
• 刊名：Organic Process Research & Development
• 出版年：2008
• 出版时间：January 2008
• 年：2008
• 卷：12
• 期：1
• 页码：69 - 75
• 全文大小：185K
• 年卷期：v.12,no.1(January 2008)
• ISSN：1520-586X

文摘

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-tert-butoxyaluminum hydride in diethyl ether to afford the desired syn-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 S_N2 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.