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.

Acylperrhenate reagents promote hydroxyl-directed syn-oxidative polycyclizations of primary and secondary hydroxypolyenes, forming bis- and tristetrahydrofuranyl alcohols with excellent trans-stereoselectivity for each tetrahydrofuran ring. The combination of dichloroacetylperrhenate/dichloroacetic anhydride affords stereoselective syn-oxidative bicyclization to bistetrahydrofuranyl alcohol products, whereas trifluoroacetylperrhenate/trifluoroacetic anhydride or trichloroacetylperrhenate/trichloroacetic anhydride are more suitable for stereoselective formation of tristetrahydrofuranyl alcohols from acyclic hydroxytrienes. In the tricyclization reaction chirality induction from a single stereogenic hydroxyl group affords diastereoselective formation of six additional stereocenters in a single step. However, we have found that the growing polytetrahydrofuran chain can exert chelation effects upon the alkoxyrhenium intermediate, thus diminishing the degree of product diastereoselectivity. These syn-oxidative cyclization synthesis strategies mimic a possible pathway for the biosynthesis of many polycyclic ether natural products, including the tristetrahydrofuran acetogenin goniocin (1).

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Despite the growth of photoredox methods in academia, application of photoredox at scale in the pharmaceutical and fine chemical industries has been slow. In this report, a photoredox trifluoromethylation of a thiophenol was modified from the original literature report, and the mechanism was investigated to define the key scale-up parameters. The mechanistic insight was leveraged in the design and execution of two different reactor designs: an LED-based plug flow photoreactor and a laser-based continuous stirred tank photoreactor. In one of the first examples of commercial-scale photoredox chemistry, the process was scaled to provide over 500 kg of the desired intermediate and amended to fully continuous manufacturing.

Glecaprevir was identified as a potent hepatitis C virus (HCV) protease inhibitor, and a large-scale synthesis was required to support the late-stage clinical trials and subsequent commercial launch. The large-scale synthetic route to glecaprevir required the development of completely new synthetic approaches to the two key structural features: the 18-membered macrocycle 3 and the difluoromethyl-substituted cyclopropyl amino acid 4. In this first manuscript, we describe the route development for the macrocycle 3; the second manuscript will describe the development of a new synthetic route to the difluoromethyl-substituted cyclopropyl amino acid 4 and the final assembly of glecaprevir. The large-scale synthetic route to the macrocycle employed a unique intramolecular etherification reaction as the key step in the macrocycle synthesis, avoiding the scalability limitations of the ringclosing metathesis (RCM) reaction of the enabling route. The large-scale synthetic route to the macrocycle was successfully used to produce the amount of glecaprevir required to support the late-stage clinical development.