Preparation of the HIV Attachment Inhibitor BMS-663068. Part 3. Mechanistic Studies Enable a Scale-Independent Friedel–Crafts Acylation

Abstract

During the development of a Friedel–Crafts acylation for the preparation of a key pyrrole intermediate in the synthesis of the HIV attachment inhibitor, BMS-663068-03, a significant scale dependence was found. A precipitous drop in yield was observed for the acylation of a protected pyrrole with chloroacetyl chloride upon scale-up. Spectroscopic studies to mitigate this scale dependence led to the identification of the complex effect of dissolved hydrogen chloride (HCl) as well as the poor reactivity of the acylating agent, chloroacetyl chloride. At this point, the counterintuitive choice to switch to a longer, but scale-independent, three-step route was made. By changing the acylating agent to acetyl chloride, a more robust process was obtained. Rapid development of a high yielding α-chlorination then provided the common α-chloroketone intermediate required to generate the desired α-amide ketopyrrole. The improved yield and scalability of this three-step process supported the addition of one linear step to the route, and it was demonstrated successfully at scale.

Synthetic Approaches to the New Drugs Approved During 2020

“…Cabotegravir was approved in Canada and Europe for the treatment of HIV-1 infection in adults to replace the current antiretroviral therapy in patients who are virologically stable and suppressed . The initial approval of the drug was for codosing of cabotegravir with rilpivirine, which was approved in 2011 for the treatment of HIV-1 infection in treatment-naïve adult patients as a fixed-dose combination with emtricitabine and tenofovir disoproxil .…”

“…Cabotegravir and rilpivirine are available as a copackaged kit of vials for concurrent dosing by intramuscular injection. This combination is marketed in Canada under the trade name Cabenuva, although in Europe injectable cabotegravir and rilpivirine are marketed under the trade names Vocabria and Rekambys, respectively . Cabotegravir itself functions as a potent HIV integrase inhibitor, hindering the binding of host DNA to metal cofactors in the active catalytic site of the integrase via a metal chelation process. , Cabotegravir, in combination with non-nucleoside transcriptase inhibitor (NNRTI) rilpivirine, provides an alternative to standard daily oral regimens for maintenance treatment of HIV-1. , This monthly dosed intramuscular injection is the first approved long-lasting HIV treatment .…”

“…This combination is marketed in Canada under the trade name Cabenuva, although in Europe injectable cabotegravir and rilpivirine are marketed under the trade names Vocabria and Rekambys, respectively . Cabotegravir itself functions as a potent HIV integrase inhibitor, hindering the binding of host DNA to metal cofactors in the active catalytic site of the integrase via a metal chelation process. , Cabotegravir, in combination with non-nucleoside transcriptase inhibitor (NNRTI) rilpivirine, provides an alternative to standard daily oral regimens for maintenance treatment of HIV-1. , This monthly dosed intramuscular injection is the first approved long-lasting HIV treatment . The extended release injectable regimen helps to decrease treatment fatigue often experienced by HIV patients. , The long-lasting effect of cabotegravir is made possible by the prolonged plasma half-life of the drug.…”

“…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 . Protection of the ketone and hydrolysis of the N -formyl group within 29 were performed using H 2 SO 4 , ethylene glycol, and trimethyl orthoformate, giving rise to ketal 30 in 90% yield.…”

“…19,20 Cabotegravir, in combination with non-nucleoside transcriptase inhibitor (NNRTI) rilpivirine, provides an alternative to standard daily oral regimens for maintenance treatment of HIV-1. 16,21 This monthly dosed intramuscular injection is the first approved long-lasting HIV treatment. 15 The extended release injectable regimen helps to decrease treatment fatigue often experienced by HIV patients.…”