Sequential -lithiation and aerobic oxidation of an arylacetic acid - continuous-flow synthesis of cyclopentyl mandelic acid

The development of a multistep continuous- flow process, consisting of a direct a- lithiation stage and subsequent hydroxylation by aerobic oxidation, is reported. The protocol is applied to the synthesis of cyclopentylmandelic acid ( CPMA), the main building block for the anticholinergic glycopyrronium bromide ( glycopyrrolate). We demonstrate the safe utilization of organolithium reagents and molecular oxygen in combination by using a continuous- flow protocol. The first stage involves the formation of a di- lithium enolate intermediate, which was either pre- formed in batch or formed in flow by using n- hexyllithium as a costeffective and industrially safe base. The subsequent hydroxylation stage utilized molecular oxygen under homogeneous and mild conditions ( atmospheric pressure and room temperature) to give the desired product. A diluted form of oxygen gas, consisting of less than 10% O2 in N2 ( Bsynthetic air<^>), is used in pharmaceutical batch manufacturing to effectively address safety concerns when handling molecular oxygen. The telescoped flow process afforded the target intermediate in 65% solutionNMRyield ( 50% isolated yield after re- crystallization). The continuous- flow process opens up new opportunities for the manufacture of CPMA, with a protocol which can safely handle pure O2, and compares favorably with existing Grignard- based batch processes.