Bálint Pethő*, Gábor B. Szilágyi, Béla Mengyel, Tamás Nagy, Ferenc Farkas, Katalin Kátai-Fadgyas and Balázs Volk*,
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Development and Process Intensification of an Efficient Flow–Cascade Reaction Sequence in the Synthesis of Afizagabar
Aromatic nitration and catalytic hydrogenation are among the most dangerous reactions in the chemical industry. The traditional, batchwise pilot plant manufacturing process of a key intermediate of our drug candidate afizagabar (S44819) involved these kinds of transformations (besides a Dakin–West-type reaction, a ring closure, and a keto reduction step). To mitigate some of the hazards associated with this sequence, a flow chemical approach was developed. First, a flow–cascade process was elaborated, which furnished the product with a throughput of 1.52 g/h with an HPLC purity of 95.6%. The bottleneck of the procedure in terms of output was the heterogeneous catalytic hydrogenation; therefore, our subsequent process intensification efforts primarily concentrated on this step. Finally, application of higher concentrations and an upscaled hydrogenation reactor combined with the corresponding adjustment of parameters of further reaction steps resulted in an efficient process with an effective product yield of 11.95 g/h and an increased HPLC purity (97.1%). The 4-step uninterrupted process described here is based on a newly developed heterogeneous flow reactor system and a custom-made liquid–liquid extractor, providing an instructive case study on handling hazardous processes in a safe and efficient way.
期刊介绍:
The journal Organic Process Research & Development serves as a communication tool between industrial chemists and chemists working in universities and research institutes. As such, it reports original work from the broad field of industrial process chemistry but also presents academic results that are relevant, or potentially relevant, to industrial applications. Process chemistry is the science that enables the safe, environmentally benign and ultimately economical manufacturing of organic compounds that are required in larger amounts to help address the needs of society. Consequently, the Journal encompasses every aspect of organic chemistry, including all aspects of catalysis, synthetic methodology development and synthetic strategy exploration, but also includes aspects from analytical and solid-state chemistry and chemical engineering, such as work-up tools,process safety, or flow-chemistry. The goal of development and optimization of chemical reactions and processes is their transfer to a larger scale; original work describing such studies and the actual implementation on scale is highly relevant to the journal. However, studies on new developments from either industry, research institutes or academia that have not yet been demonstrated on scale, but where an industrial utility can be expected and where the study has addressed important prerequisites for a scale-up and has given confidence into the reliability and practicality of the chemistry, also serve the mission of OPR&D as a communication tool between the different contributors to the field.