Preparation of the HIV Attachment Inhibitor BMS-663068. Part 5. Selective C-7 Bromination of the 6-Azaindole Core

Abstract

We report research focused on the preparation of an advanced intermediate in the synthesis of a novel antiretroviral. This manuscript describes the development of an efficient oxidation of a 6-azaindole derivative, the bromination of the resulting N-oxide using PyBroP, the removal of the protecting group, and the isolation of the brominated azaindole product. The work reported herein has been successfully implemented in the multikilogram scale to fund development and clinical activities of BMS-663068.

Nucleophilic Halogenation of HeterocyclicN‐Oxides: Recent Progress and a Practical Guide

“…Researchers from Bristol‐Myers Squibb reported an impressively selective and mild nucleophilic bromination of azaindole N ‐oxide 18 with PyBroP in the C7 position (product 19 , Scheme 7). [13,47] In contrast to PyBroP, POBr 3 gave a complex mixture of decomposition products, while with PPh 3 /Br 2 , PPh 3 /NBS, AcBr and PhSO 2 Br mostly the deoxygenation of N ‐oxide without incorporation of the bromide was observed (azaindole 20 ).…”

“…Azaindole 19 was prepared on a multi‐grams scale and further used as key intermediate in the synthesis of HIV‐1 attachment inhibitor pro‐drug BMS‐663068 (product 21 , Scheme 7). [47] Unfortunately, the substrate scope of nucleophilic bromination with PyBroP remains uninvestigated to date.…”

Preparation of the HIV Attachment Inhibitor BMS-663068. Part 7. Development of a Regioselective Ullmann–Goldberg–Buchwald Reaction

“…Despite many attempts, the C7-chloride azaindole coupling partner was resistant to the application of metal mediated processes, leaving thermal S N Ar as the only viable option. Prior to the invention of the α-bromination process, the corresponding bromide 1 had been difficult to prepare, inhibiting its exploration as a coupling partner . For some time, the formation of the bromide had been seen as a critical objective for the development of an alternate strategy for triazole incorporation; the intrinsically higher reactivity of bromides was anticipated to provide access to a broader array of metal mediated coupling processes .…”

Synthetic Approaches to the New Drugs Approved During 2020

“…Fostemsavir was synthesized in a linear sequence as described in Schemes and . The evolution of the synthetic approach to this molecule from the initial medicinal chemistry route to commercial routes (scaled to >1000 kg) has been described in a series of literature reports from Bristol-Myers Squibb. ,,− Sulfonyl pyrrole 27 underwent a three-step sequence involving a Friedel–Crafts acylation using acetyl chloride and AlCl 3 , an α-chlorination of the resulting ketone using N -chlorosuccinimide (NCS) and MsOH, and a displacement of the resulting chloroketone with sodium tosylamide 28 . This three-step, telescoped sequence rapidly resulted in the delivery of ketopyrrole 29 in 62–75% yield .…”