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.