(241g) Analysis of Continuous Reactive Crystallization Process to Beta-Lactam Antibiotics Via Green Chemistry Criteria

Continuous production of high-volume (on the order of 10,000 tons per year) beta-lactam antibiotics, such as amoxicillin and cephalexin, via enzymatic reactive crystallization stands to remedy key disadvantages of the current processes, such as: recipe complexity due to protection and deprotection steps, low spacetime yield from distinct synthesis and purification steps, and limited conversion owing to enzyme side reactions. While we have found enhanced conversion, yield, productivity, and selectivity for the reactive crystallization process compared to the conventional reaction in a homogenous phase [1,2], no Green Chemistry-based analysis has been performed to-date on enzymatic beta-lactam synthesis for either the reactive crystallization or the homogeneous reaction case.

We analyzed the enzymatic reactive crystallization process to amoxicillin and cephalexin under representative conditions of two reactant concentrations, process pH, reactor residence time, and crystal suspension density. We calculated atom economy, reaction mass efficiency, complete E factor, and process mass intensity. We also determined the E+ factor of the process by tallying electricity use on pilot scale in addition to reactants, catalysts, auxiliaries, buffers, and solvents [3]. Last, we calculated complexity, green aspiration level, and relative process greenness [4]. We found that significant savings are derived from the purification being driven by the reaction.

We show that the Green Chemistry metrics strongly depend on the absolute and relative concentration of reactants and the effective recycle ratio of non-precipitated product. Energy consumption was found to depend on enzyme concentration and suspension density, with wastewater treatment being responsible for a significant portion of the energy requirement.

References

[1] MA McDonald, AS Bommarius, RW Rousseau, Chem. Eng. Sci. 2017, 165, 81-88

[2] MA McDonald, AS Bommarius, RW Rousseau, MA Grover, Comp. Chem. Eng. 2019, 123, 331-343

[3] F Tieves, et al., Tetrahedron 2019, 75, 1311-1314

[4] F. Roschangar et al., Green Chemistry 2017, 19, 281-285