Process Development and Large-Scale Synthesis of MK-6186, a Non-Nucleoside Reverse Transcriptase Inhibitor for the Treatment of HIV

Abstract

A new synthetic route has been developed to drug candidate 1, a second-generation NNRTI being developed as a potential treatment of HIV. Regiocontrol in a key alkylation step was achieved by selective N-alkylation of hydrazone 13. After a deprotection and cyclisation sequence, 1 was isolated in six steps in 35% overall yield from readily available starting materials.

Applications of Palladium-Catalyzed C–N Cross-Coupling Reactions

“…In the pharmaceutical industry, the use of benzophenone hydrazone played a key role in the multikilogram-scale synthesis of HIV inhibitor 529 described by Goodyear and co-workers (Merck) ( Scheme 130 ). 446 In the medicinal chemistry route, the core indazole ring of compound 529 was directly constructed using hydrazine hydrate, an undesirable reagent for large-scale operations due to its toxicity. Moreover, the sequence lacked regioselectivity in the direct N1-alkylation of the indazole.…”

Palladium-Catalyzed Amidation and Amination of (Hetero)aryl Chlorides under Homogeneous Conditions Enabled by a Soluble DBU/NaTFA Dual-Base System

“…While milling of the base can compensate for the lack of beneficial grinding with overhead stirring, , mixing effects may be observed when reactions are performed in vessels with different size or configuration or when different agitation speeds are employed . The combined impact of these complex factors renders the development and scale-up of transformations employing heterogeneous bases a highly challenging and time-consuming process. ,,, …”