An Expedient Synthetic Route to the Long-Acting RSV Inhibitor JNJ-6231 via Stereoselective Enzymatic Amination and Regioselective Alkylation

JNJ-6231 was discovered as a second-generation long-acting
RSV
inhibitor and served as a follow-up candidate to our previous candidate
JNJ-7950. Early development synthetic route investigation identified
a diastereomerically pure spiro-cyclobutyl amine, an alkyl chloride
containing a benzimidazole, and a chiral difluoromethyl-containing
carboxylic acid as the three key building blocks to synthesize JNJ-6231.
The investigation culminated in developing an enzymatic amination
for the stereoselective synthesis of spiro-cyclobutyl amine with high
diastereoselectivity. Subsequently, the amide group present in the
spiro-cyclobutyl amine building block was regioselectively alkylated
with an alkyl chloride in the presence of a free amine by employing
computationally guided catalytic phase-transfer conditions. Diastereomeric
salt resolution was investigated for the synthesis of chiral difluoromethyl-containing
carboxylic acid. Finally, the free amine was coupled to a chiral difluoromethyl-containing
carboxylic acid to give JNJ-6231. The developed synthetic route was
significantly shorter, higher yielding, and employed overall safer
reagents, solvents, and reaction conditions, demonstrating the integration
of certain green chemistry principles in the route investigation.