Sequential α-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 α-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 cost-effective 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 (“synthetic 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% solution NMR yield (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.