Preparation of the HIV Attachment Inhibitor BMS-663068. Part 6. Friedel–Crafts Acylation/Hydrolysis and Amidation

Abstract

The development of a process for appending the oxalyl amide side chain to the azaindole core of the HIVattachment inhibitor BMS-663068 is described. A Friedel−Crafts acylation installed the oxalyl ester, which was subsequently hydrolyzed and amidated with a benzoyl piperazine. The development of the commercial route necessitated several key changes to the initial synthesis. For instance, in the original acylation process, nitromethane, a commonly used, but highly energetic cosolvent, was employed which was eventually replaced by catalytic tetra-n-butylammonium bisulfate to overcome gelling issues encountered during the reaction when nitromethane was omitted. It was further demonstrated that the amidation sequence could be relegated to a single-pot, homogeneous transformation through the use of the cost-effective coupling reagent diphenylphosphinic chloride. The above modifications have been utilized in multiple campaigns and reproducibly demonstrated on scales of up to 200 kg input.

Leveraging High-Throughput Experimentation to Drive Pharmaceutical Route Invention: A Four-Step Commercial Synthesis of Branebrutinib (BMS-986195)

“…Of these reagents, none were ideal for commercialization due to sourcing, cost, and greenness concerns. However, a much more desirable reagent with extensive use on a commercial scale, DPPCl (diphenylphosphinic chloride), furnished the product with 74 RAP and a modest <1 RAP of the chloride 1,4-adduct, leaving the remaining mass balance as an unreacted starting material. Therefore, a second HTE array would be pivotal for identifying conditions that afford the product in high yield with minimal 1,4-adduct.…”

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 .…”

“…Amidation of 34 with piperazine 35 was performed using DPPCl in NMP. The addition of water crystallized the coupled product 36 , which was isolated in 94% yield …”

“…The addition of water crystallized the coupled product 36, which was isolated in 94% yield. 43 With aryl bromide 36 in hand (Scheme 7), an Ullman coupling with 3-methyl-1H-1,2,4-triazole using CuI and N,N- 47,48 In a randomized, double-blind Phase 2/3 trial, the alloral combination ravidasvir/danoprevir treatment demonstrated a cure rate of 99% (SVR12) and a good resistance barrier profile in noncirrhotic HCV genotype 1 patients with a 12-week treatment duration. 49 An account of the medicinal chemistry campaign that culminated in ravidasvir has been published.…”