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

[ Vol. 17 , Issue. 1 ]

Author(s):

Chapala Vijayalakshmi, Malavattu G. Prasad, Naresh K. Katari* and Pedavenkatagari N. Reddy*   Pages 68 - 72 ( 5 )

Abstract:


Atazanavir is one of the most prescribed HIV-1 protease inhibitors approved by the FDA. It was the first protease inhibitor approved for 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 on a 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 with 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 reduction, grignard reagent, catalytic hydrogenation.

Affiliation:

Department of Chemistry, School of Technology, Gitam University, Hyderabad (T.S) 502329, Department of Chemistry, School of Technology, Gitam University, Hyderabad (T.S) 502329, Department of Chemistry, School of Technology, Gitam University, Hyderabad (T.S) 502329, Department of Chemistry, School of Technology, Gitam University, Hyderabad (T.S) 502329

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