(613f) Continuous Cryogenic Flow Amination and Centrifugal Extraction - Scale-up and Processing Strategy in Multi-Kilo Scale.

Herein, we report the scale-up and kilo-scale demonstration of a continuous flow amination process utilizing diphenyl phosphoryl azide (DPPA). The flow process is carried out through initial formation of the enolate in batch using lithium diisopropylamine (LDA), followed by three distinct reactions in three cascading continuous stirred tank reactors (CSTR) to allow precise temperature control. The first reaction requires cryogenic temperatures (< -45 °C) to prevent the formation of a diazo byproduct during the DPPA addition. The subsequent protection step occurs at cryogenic temperatures (< -45 °C), followed by hydrolysis at elevated temperatures (+40 °C). The aqueous workup is conducted using three continuous centrifugal extractors in series, followed by reactive crystallization. The evaluation of reaction kinetics in the CSTRs and the control of key process parameters through online process analytical technology (PAT) tools, including mass flow controllers, oxygen sensors, pH probes, and two automated online HPLCs, is reported. The demonstration of the continuous process, featuring six continuous unit operations at multi kg scale in a GMP facility is discussed, showcasing strategies for efficient continuous processing, and minimizing start-up costs.