A Scalable Synthesis of Biaryl Unit of the HIV Protease Inhibitor Atazanavir

(E-pub Ahead of Print)

Author(s): C. Vijayalakshmi, M. Giri Prasad, Naresh Kumar Katari*, Pedavenkatagari Narayana Reddy.

Journal Name: Letters in Organic Chemistry

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Atazanavir is one of the most prescribed HIV-1 protease inhibitor approved by the FDA. It was the first protease inhibitor approved for a once-a-day dosing to treat AIDS due to good oral bioavailability and favorable pharmacokinetic profile. This research aims to develop a new synthetic cost effective process for biaryl-hydrazine unit {tert-butyl 2-[4-(2-pyridinyl)benzyl]hydrazinecarboxylate} of atazanavir in large scale. The synthesis involved palladium catalyzed Suzuki-Miyaura coupling of 2-chloropyridine and (4-cyanophenyl)boronic acid followed by DIBAL-H reduction of cyano group to aldehyde which is then treated with tert-butyl carbazate to furnish hydrazone subsequently in situ reduction with NaBH4. A large scale synthesis of biaryl-hydrazine unit of atazanavir was accomplished in three steps and 71% overall yield. We have developed a short and efficient synthesis of atazanavir key intermediate biaryl-hydrazine unit. The process does not require the usage of Grignard reagent, expensive catalyst, protection/deprotection of aldehyde moiety and catalytic hydrogenation.

Keywords: Atazanavir, HIV protease inhibitor, Suzuki-Miyaura coupling, In situ reductioAtazanavir, In situ reduction

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(E-pub Ahead of Print)
DOI: 10.2174/1570178616666190514080155
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