Development of a Practical Synthesis of an Aminoindanol-Derived M1 Agonist†

An efficient and scalable synthesis of the clinical candidate 1 is described. The first-generation synthesis built the enantioenriched nitro-aminoindanol core from 6-nitroindanone using a five-step literature route. The second-generation route used a safe aromatic nitration protocol in the presence of the unprotected alcohol to afford the requisite nitro-aminoindanol in one step. Challenges addressed in the remainder of the synthesis include a nitro group reduction to afford ppm levels of unreacted Ar-NO2 (a mutagen) and a novel amidine formation under mild conditions via DMAP/K2CO3-promoted reaction with a thioimidate-activated amide. A convenient protocol for freebasing the API was provided by stirring with solid K2CO3 and monitoring disappearance of HI by reverse-phase HPLC.