A batch-flow hybrid approach for the synthesis of the Schistosomiasis treatment praziquantel

Abstract

The synthesis and development of active pharmaceutical ingredients (APIs) within the pharmaceutical industry has been achieved using traditional batch production methods for more than a century now. Batch production chemistry on a small scale, within the laboratory, is the use of glassware and manually adding reagents together in order to obtain a final product. However, in the last 20 years, the gradual introduction of continuous flow chemistry has had positive impacts on many fields of synthesis. Continuous flow chemistry uses pressure regulated tubing and pumps to pass reagents at a continuous flow rate through micro-reactors and mixing plates, chips, or coils where the chemical reaction can take place and the resultant product is pumped out of the reactor and obtained for further processing. The use of flow chemistry within the manufacturing of APIs over the last two decades has already shown to be highly productive, at lowered expenses, with reduced waste, all resulting in smaller production footprints. Multiple micro-reactors can be coupled to one another in order to achieve multi-step syntheses. With a rapid increase in publications, the use of flow chemistry is being extensively studied in order to determine where this field of study can be implemented and used to improve the efficiency of medicinal drug synthesis. Neglected Tropical Diseases (NTDs) are a major concern for many countries throughout the southern hemisphere, and unfortunately are disregarded by the global North as it is not prevalent within majority of these regions. As a result, this means research and development (R&D) into the disease as well as the push to manufacture and supply is not actively pursued and attractive to big pharmaceutical establishments who are more concerned with diseases of the global North like cardiovascular disease and cancer. Schistosomiasis is the focal NTD of this research study with the approved treatment, praziquantel being the API of interest for flow translation. Here within, we have reported a batch-flow hybrid synthetic procedure for the preparation of praziquantel. This approach consists of three steps whereby the first two steps are flow based and the final step for the conversion to praziquantel is a batch based synthetic step. The first step for the preparation of praziquantel consists of a modified Hofmann procedure for the preparation of the noxious 2-isocyanoethylbenzene from the starting material, 2-phenethylamine. Although we initially faced precipitate issues, leading to fouling of the micro-reactors, we were finally successful in translating this step into flow conditions with an optimised yield of 78% with a residence time of 195 min. Critically, when compared with our in-house batch approach for the preparation of this material, we were able to achieve a slight increase in yield of ~ 6% (72% for batch procedure) with a decrease in the reaction time of 45 min (240 min batch procedure). The second step for the preparation of N-(2,2-dimethoxyethyl)-N-(2-oxo-2-(2-phenethylamino)ethyl)cyclohexanecarboxamide consists of an Ugi four-component reaction whereby 2-isocyanoethylbenzene is condensed with formaldehyde, aminoacetaldehyde dimethyl acetal and cyclohexanecarboxylic acid, all in the polar protic solvent, methanol. Again, we were successful in translating this synthetic step under flow conditions with a good yield of 87% with a residence time of only 60 min. Notably, when compared with our in-house batch procedure, we were able to achieve a comparable yield (89% batch), however, with an appreciable reduction in the reaction time of 47 h (48 h batch). Furthermore, we were able to provide a proof of concept for a telescoped step 1 and 2 for the preparation of N-(2,2-dimethoxyethyl)-N-(2-oxo-2-(2-phenethylamino)ethyl)cyclohexanecarboxamide in an overall yield of 55%. Critically, this was achieved with an off-line separation of the noxious 2-isocyanoethylbenzene from the first step, however, this opens the potential to an integrated in-line separation of 2-isocyanoethylbenzene for the synthesis and consumption of this noxious material on-the-fly. The final step for the conversion of N-(2,2-dimethoxyethyl)-N-(2-oxo-2-(2-phenethylamino)ethyl)cyclohexanecarboxamide to praziquantel involves an intramolecular Pictet-Spengler type reaction which was performed using traditional batch-based chemistry controls. Unfortunately, we were unsuccessful in translating this step under flow conditions, due to challenges faced with the sodium sulfate additive, however, it exhibits green chemistry techniques being performed solventless with the use of the green, methanesulfonic acid (MSA). We were able to prepare praziquantel in a moderate yield of 61% (81% purity) for this stand-alone step with a reaction time of 6 h. Overall, this entire developed procedure allowed for an overall yield of 41% in 10.25 h, which amounts to a space-time productivity of 0.93 g.L-1.h-1 for the preparation of praziquantel.