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).
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.
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