RESUMO
A practical synthesis of a D1 potentiator chiral tetrahydroisoquinoline has been accomplished employing diastereoselective Pictet-Spengler methodology to access the required trans-stereochemistry. A dynamic kinetic resolution by crystallization gives high yields of a N-(phenylsulfonyl)alkyloxazolidinone that is converted to an acyl iminium ion when exposed to a variety of Lewis acids resulting in a highly diastereoselective Pictet-Spengler cyclization. An eight-step linear synthesis that starts with commercially available R-2-bromophenylalanine affords the chiral tetrahydroisoquinoline 1 in 54% overall yield.
RESUMO
Advances in drug potency and tailored therapeutics are promoting pharmaceutical manufacturing to transition from a traditional batch paradigm to more flexible continuous processing. Here we report the development of a multistep continuous-flow CGMP (current good manufacturing practices) process that produced 24 kilograms of prexasertib monolactate monohydrate suitable for use in human clinical trials. Eight continuous unit operations were conducted to produce the target at roughly 3 kilograms per day using small continuous reactors, extractors, evaporators, crystallizers, and filters in laboratory fume hoods. Success was enabled by advances in chemistry, engineering, analytical science, process modeling, and equipment design. Substantial technical and business drivers were identified, which merited the continuous process. The continuous process afforded improved performance and safety relative to batch processes and also improved containment of a highly potent compound.