Development of the Enabling Route for Glecaprevir via Ring-Closing Metathesis

Abstract

Glecaprevir was identified as a potent HCV NS3/4A protease inhibitor, and an enabling synthesis was required to support the preclinical evaluation and subsequent Phase I clinical trials. The enabling route to glecaprevir was established through further development of the medicinal chemistry route. The key steps in the synthesis involved a ring-closing metathesis (RCM) reaction to form the 18-membered macrocycle and a challenging fluorination step to form a key amino acid. The enabling route was successfully used to produce 41 kg of glecaprevir, sufficient to support the preclinical evaluation and early clinical development.

Polymorphism and surface diversity arising from stress-induced transformations – the case of multicomponent forms of carbamazepine

“…Multicomponent crystal forms of pharmaceuticals, especially hydrates, are frequently observed (Stahly, 2007;Cruz-Cabeza et al, 2015) and are increasingly common in recently approved drugs (Caspi et al, 2019;Cink et al, 2020;Califano et al, 2016;Brackemeyer et al, 2017;Pangan et al, 2018). Hydrates, solvates and cocrystals present challenges during development because of the implications for in vivo solubility, manufacturing and storage (Hilfiker et al, 2006;Pudipeddi & Serajuddin, 2005;Threlfall, 1995).…”

Biocatalytic routes to anti-viral agents and their synthetic intermediates

“…A team at Abbvie developed a synthetic route to glecaprevir in which difluoromethyl-ACCA was derived from vinyl-ACCA via multi-step chemical conversion. 269 As the yield was moderate and the synthesis required a complicated work-up procedure, this process proved not to be viable on large scale. The authors disclosed that alternative synthetic procedures had been developed.…”

“…Additionally, both antiviral agents required incorporation of either (1R,2R)-2-(allyloxy)cyclopentanol (218) or the analogous (1R,2R)-2-(pent-4-ynyl)cyclopropanol (219, Chart 7). 269,279,280 Controlled hydrolytic resolution of cyclopentane-1,2-diyl diacetate (222) with BCL, O-alkylation with allyl bromide and subsequent deprotection afforded 218 in 14% overall yield and 96% ee (Scheme 47A). 279 However, running regioselective lipasecatalysed resolution up to complete mono-deacetylation is challenging, thus often requiring termination of the reaction at a the stage of sub-optimal conversion.…”

“…The same Abbvie team that optimised the synthesis of difluoromethyl-ACCA also managed to improve the synthesis of (1R,2R)-2-(allyloxy)cyclopentanol. 269 Ring-opening of cyclopentene oxide (224) with allyl alcohol, Scheme 45 Concise synthesis of 2-oxonon-8-enoic acid and subsequent reductive amination catalysed by a leucine dehydrogenase (LeuDH). 276 GDH: glucose dehydrogenase and DEO: diethyl oxalate.…”

N-acylation of amides through internal nucleophilic catalysis

“…[11][12][13][14] However, for some acid-or basesensitive or biologically related compounds, metal-free and versatile conditions are in demand. Although there are several examples described using mild conditions with a weak base, [15][16][17][18][19] for instance, the conversion of NHBoc to N(Boc) 2 with 4-dimethylaminopyridine (DMAP), 20 the development of versatile and efficient methods for the preparation of imides is still challenging.…”