Advancing Flow Chemistry in API Manufacturing - Pharmaceutical Technology

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Advancing Flow Chemistry in API Manufacturing
Continuous flow chemistry offers potential for greater control, improved safety and environmental profiles, and efficient chemical transformations.


Pharmaceutical Technology
Volume 37, Issue 4, pp. 78-82

Other developments

Scientists at LyraChem, based in Newcastle-upon-Tyne, United Kingdom, and Newcastle University reported on intensified azeotropic distillation as an approach for optimizing direct amidation (10). The direct synthesis of amides from the corresponding carboxylic acids and amines was shown to operate under varying degrees of mixed kinetic and mass-transfer rate control when water was removed by azeotropic distillation (10). A systematic approach was developed to quantify the contribution of boil-up rate to conversion rate and decouple the physical rates from the chemistry. Intensive boiling was used to improve the removal of water during azeotropic distillation and enhance conversion. The researchers reported that some acylations previously thought to be difficult or impossible could be achieved in the absence of coupling agents under green conditions. A cascade of continuous stirred-tank flow reactors operating under intensified conditions was assessed for scale-up of direct amidation reactions and compared to a production-scale batch reactor. The researchers reported that the use of the continuous stirred-tank flow reactors operating under intensified conditions could provide the necessary high rates of heat transfer and, therefore, offer advantages over a conventional batch reactor system (10).

Asymmetric synthesis is an important area of research for producing single enantiomer drugs. Researchers in the Department of Chemistry, School of Science at the University of Tokyo, recently reported on the use of continuous-flow chemistry with chiral heterogeneous catalysts in asymmetric carbon–carbon bond formation (11). They developed and applied a chiral calcium catalyst based on calcium chloride with a chiral ligand to the asymmetric 1,4-addition of 1,3-dicarbonyl compounds to nitroalkenes as a model system (11). The researchers sought to improve the low catalyst turnover number (TON) of asymmetric carbon–carbon bond-forming issues (12). To address product inhibition, the calcium catalyst was applied to continuous flow with a chiral heterogeneous catalyst. The continuous-flow system, using a newly synthesised, polymer-supported Pybox, was successfully used, and the catalyst TON was improved 25-fold compared with those of the previous Ca(OR)2 catalysts (11).

Researchers at the Department of Synthetic and Biological Chemistry in the Graduate School of Engineering, Kyoto University Nishikyo-ku, in Kyoto, Japan applied a flash-chemistry approach using flow microreactors to produce a highly reactive palladium catalyst with a tri-tert-butylphosphine (tBu3P) ligand for a Suzuki–Miyaura coupling (12, 13). The flash chemistry enabled the use of highly reactive unstable species as a catalysts for chemical synthesis. Fast micromixing of a solution of [Pd(OAc)2] and that of tBu3P in an 1:1 mole ratio gave a solution of a highly reactive unstable species, which was transferred to a vessel by using a flow microreactor, in which Suzuki–Miyaura coupling was conducted (13). The coupling reactions were completed in 5 minutes at room temperature, thereby preventing deboronation of the used aryl and heteroarylboronic acids (12).

In another study, researchers from the Institute of Science and Technology in Ikoma, Japan, and the School of Pharmacy and Molecular Sciences at James Cook University in Townsville, Australia reported on the diastereoselective [2+2] photocycloaddition of a chiral cyclohexenone with ethylene in a continuous flow microcapillary reactor (14). The researchers reported that the microcapillary reactors have higher conversions and selectivity than the batch system even after shorter irradiation times due to better temperature control, light penetration and generation of gas–liquid slug flow with improved mass transfer in the microreactor (14).

In another development, researchers at the Institute of Organic Chemistry at Aachen University in Germany reported on the asymmetric organocatalytic hydrogenation of benzoxazines, quinolines, quinoxalines and 3H-indoles in continuous-flow microreactors using Fourier transform infrared (FTIR) spectroscopy in-line analysis (15). Reaction monitoring was achieved by using an in-line ReactIR flow cell, which allowed for optimization of the reaction parameters. The researchers reported that the reductions proceeded well, and the desired products were isolated in high yields and with good enantioselectivities (15).


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