Continuous stirred-tank reactor cascade platform for self-optimization of reactions involving solids

Continuous manufacturing of pharmaceuticals and fine chemicals is attractive due to its small physical footprint, consistent product quality, and demonstrated benefits from safety, economic, and environmental perspectives. However, handling solids in research-scale flow reactors creates hurdles, as the solids often lead to reactor channel clogging. To tackle this problem, we present a continuous stirred-tank reactor (CSTR) cascade that can handle slurries/solids during a chemical transformation in flow. Additionally, the design includes a light emitting photo diode (LED) array with photon flux characterized by chemical actinometry. We employ mixed-integer nonlinear programming (MINLP) and Bayesian optimization algorithms for single and multi-objective optimization, respectively. We demonstrate the autonomous optimization of three multiphase catalytic reactions of synthetic importance involving solid substrates, catalysts, and inorganic bases in an automated flow platform comprising a CSTR cascade, newly developed photoreactor, slurries feeding pumps, and an online process analytical technology (PAT). The two first case studies involve MINLP optimization of yield for a Pd-catalyzed Suzuki-Miyaura cross-coupling reaction involving both solid substrates and catalyst for the synthesis of an advanced intermediate, and a metallaphotoredox-catalyzed sp3-sp3 cross-coupling of carboxylic acids with alkyl halides in the presence of solid inorganic base. The third study presents Bayesian multi-objective optimization of a diastereoselective, metallaphotoredox cross-coupling reaction between trans -4-hydroxy proline and 4-bromoacetophenone for which both yield and amount of the trans isomer were optimized while handling potential formation of a solid product. Research-scale fully automated flow platform for reaction self-optimization with solids handling facilitates identification of optimal conditions for continuous manufacturing of pharmaceuticals while reducing amounts of raw materials consumed.