Fiduxosin (1) has been under development at Abbott Laboratories for the treatment of benign prostatic hyperplasia. A
convergent strategy required methodologies for preparation of
an enantiomerically pure 3,4-cis-disubstituted pyrrolidine and
a 2,3,5-trisubstituted thienopyrazine in a regiospecific manner.
A [3+2] cycloaddition of an enantiopure azomethine ylide
followed by a diastereoselective crystallization was employed
to prepare the benzopyranopyrrolidine in high diastereomeric
and enantiomeric purity. Conditions for reduction of an O-aryl
lactone susceptible to epimerization were developed, and cyclization of the alcohol/phenol to the ether was accomplished
in high yield. The thienopyrazine was prepared by condensation
of methyl thioglycolate and a regiospecifically prepared 2-bromo-3-cyano-5-phenylpyrazine. Conditions for effective halogen
substitutive deamination to prepare regiospecific trisubstituted
pyrazines will be described.
Dasabuvir
(1) is an HCV polymerase inhibitor which
has been developed as a part of a three-component direct-acting antiviral
combination therapy. During the course of the development of the synthetic
route, two novel coupling reactions were developed. First, the copper-catalyzed
coupling of uracil with aryl iodides, employing picolinamide 16 as the ligand, was discovered. Later, the palladium-catalyzed
sulfonamidation of aryl nonaflate 33 was developed, promoted
by electron-rich palladium complexes, including the novel phosphine
ligand, VincePhos (50). This made possible a convergent,
highly efficient synthesis of dasabuvir that significantly reduced
the mutagenic impurity burden of the process.
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