Modelling chemical kinetics of a complex reaction network of active pharmaceutical ingredient (API) synthesis with process optimization for benzazepine heterocyclic compound

Abstract Pharmaceutical process design and engineering increasingly recognizes the role of chemical engineering in optimizing the productivity of active pharmaceutical ingredient (API) as well as their scale-up. In the present study, this concept is outlined through the kinetic model of numerous parallel and serial reactions that proceed via a two-step benzazepine heterocyclic compound synthesis, introducing 1-(2-bromoethyl)-4-chlorobenzene (4CEBr) and allylamine (AA) as first step reactants, N -(4-chlorophenethyl)prop-2-en-1-aminium chloride (4CPAL) as intermediate (second step reactant), and (1 R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzazepine (lorcaserin) as the desired product, with the second step heterogeneously/homogeneously (negligible mass transfer resistance) catalysed by AlCl 3 as Lewis acid. In addition to these, a plethora of by-products, formed through various mechanisms ranging from eliminations, nucleophilic and electrophilic substitutions and additions, Friedel–Crafts reactions and others, was identified and quantified by nuclear magnetic resonance (NMR), high-performance liquid chromatography coupled with mass spectroscopy (HPLC–MS) and gas chromatography. A large set of experiments was executed for both the first and second step, varying temperature (20–60 °C for the first and 100–120 °C for the second step), reactant and catalyst concentrations, as well as the presence of the first-step reactant (4CEBr and AA) in the second, whereas the stepwise multi-regression modelling with consequent sensitivity analysis ensued. Model optimization indicated that conversions as high as 91% may be achieved in the second step; nonetheless, that a trade-off between yield and productivity has to be considered. An efficient optimization of synthesis steps facilitates further downstream separation, as well as streamlines process intensification when proceeding to the crystallization of API polymorph.