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.
The reaction of o-fluorobenzaldehydes and their O-methyloximes with hydrazine has been developed as a new practical synthesis of indazoles. Utilization of the methyloxime derivatives of benzaldehydes (in the form of the major E-isomers) in this condensation effectively eliminated a competitive Wolf-Kishner reduction to fluorotoluenes, which was observed in the direct preparations of indazoles from aldehydes. Reaction of Z-isomers of methyloximes with hydrazine resulted in the formation of 3-aminoindazoles via a benzonitrile intermediate.
Nitro groups on alternate corners of cubane enhance the
acidity of cubyl hydrogen (pK
a ∼21) and
provide
sufficient activation for ready anion formation. The sodium salt
of 1,3,5,7-tetranitrocubane reacts easily with
electrophiles and leads thereby to yet more highly substituted cubanes,
like carbomethoxy- and (trimethylsilyl)tetranitrocubane. Anions from these species are also easily formed and
are useful for further substitution on the cubane
nucleus. Dinitrogen tetraoxide reacts with the anion of
tetranitrocubane to give 1,2,3,5,7-pentanitrocubane, the
first
cubane to contain vicinal nitro groups. The reaction probably
involves oxidation of the anion to the corresponding
radical. Similarly, the anion of pentanitrocubane is used to
prepare 1,2,3,4,5,7-hexanitrocubane, the most highly
nitrated cubane made to date. Single-crystal X-ray structural
information is given for both penta- and hexanitrocubane.
A general and practical method for the preparation of unsymmetrically substituted ureas has been developed utilizing palladium-catalyzed amidation. Both aryl bromides and chlorides, as well as heteroaryl chlorides, have been coupled to aryl, benzyl, and aliphatic ureas by using a novel nonproprietary bipyrazole ligand (bippyphos).
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