Sequencing synthesis and crystallization to improve product yield
March 5-10, 2017
Separation and purification processes are created to recover specific compounds from mixtures found in nature or those resulting from chemical transformations. In some cases, integration of reaction and separation can be effective in meeting unique challenges presented by the product of interest. Here, for example, we will use two specific challenges to illustrate our subject: (1) overcoming limitations associated with solid-liquid equilibrium in recovering an enantiomerically pure compound and (2) enhancing the yield of an intermediate in a complex reaction network. In both of these instances, we show how crystallization and tailored reaction conditions can be coupled to achieve enhanced purity and greater yield. Moreover, since such attributes may be achieved using a single stage, the reactive separations can offer operational advantages such as reducing the cost, time, and energy consumption of the process.
Separation of enantiomerically pure compounds is challenging because such compounds have nearly identical chemical and physical properties; their chemical structures differ only in their spatial orientation. Several techniques have been developed to separate stereoisomers that form conglomerate mixtures. However, the situation is considerably more challenging when stereoisomers form racemic compounds: i.e. compounds with a fixed stoichiometric ratio of stereoisomers. We have investigated both conglomerate and racemic-compound systems and will describe our work with both. The advantages of using membrane barriers and crystallization will be summarized, but our primary coverage will go towards our more recent work on resolving enantiomers that form racemic compounds. Specifically, we will show how we exploit reactive crystallization to recover enantiomerically pure amino acids from racemic systems by using enzymatic catalysis to overcome thermodynamic limitations characteristic of racemic-compound forming systems.
Beta-lactam antibiotics can be produced by means of an enzymatically catalyzed reaction, but the catalyst also hydrolyzes the antibiotics into undesired by-products. This challenge corresponds to a classic kinetically controlled system where the desired product is an intermediate of the overall reaction network. We show how a reactive crystallization scheme that selectively removes the desired product from solution, before it is consumed by undesired reactions, can significantly enhance the yield of the product. Specifically, we consider the synthesis of ampicillin by using penicillin G acylase (PGA) to catalyze the reaction of 6-aminopenicillanic acid (6-APA) with D-phenylglycine methyl ester (D-PGME).
Ronald Rousseau, Andreas Bommarius, Matthew McDonald, and Luis Encarnacion-Gomez, "Sequencing synthesis and crystallization to improve product yield" in "Separations Technology IX: New Frontiers in Media, Techniques, and Technologies", Kamalesh K. Sirkar, New Jersey Institute of Technology, USA Steven M. Crame, Rensselaer Polytechnic Institute, USA João G. Crespo, LAQV-Requimte, FCT-Universidade Nova de Lisboa, Caparica, Portugal Marco Mazzotti, ETH Zurich, Switzerland Eds, ECI Symposium Series, (2017). https://dc.engconfintl.org/separations_technology_ix/20