Efficient Synthesis of a Key Intermediate for Moxifloxacin Via Intramolecular Double Stereodifferentiation

An intramolecular double stereodifferentiation methodology was developed during the synthetic process development of (S,S)-2,8-diazobicylo[4.3.0] nonane (1), the key intermediate of the fourth-generation fluoroquinolone Moxifloxacin. The dual chiral-auxiliary strategy employed in this process guaranteed high stereoselectivity of the hydrogenation reaction to build the cis-[5,6] bicyclic system with desired stereochemistry. 1,6-Bis((R)-1-phenylethyl)-3,4,6,7-tetrahydro-1H-pyrrolo[3,4-b]pyridine-2,5-dione (11f), the precursor of the hydrogenation reaction, was prepared from commercially available and affordable chemicals ethyl acetoacetate, (R)-(+)-1-methylbenzylamine, and acryloyl chloride, and the process was further facilitated by telescoping the first three steps into one pot. Moreover, this process has been proven robust at a hectogram scale, providing 450 g of intermediate 1 with a total yield of 56.2% over seven steps and enantiomeric excess of more than 99%, demonstrating the potential for commercial-scale applicability.