Continuous flow production in the final step of vortioxetine synthesis. Piperazine ring formation on a flow platform with a focus on productivity and scalability

Autor: Ottó Temesi, Tamás Nagy, Zoltán Iványi, István Ling, Balázs Volk, Márk Oláh, Imre Kőhegyi, György Ruzsics, Katalin Kátai-Fadgyas, László Nagy-Győr, Zoltán Boros
Rok vydání: 2019
Předmět:
Zdroj: Journal of Flow Chemistry. 9:101-113
ISSN: 2063-0212
2062-249X
DOI: 10.1007/s41981-019-00036-x
Popis: In this study, the piperazine formation step of vortioxetine synthesis was investigated under continuous flow conditions. The batch variant of this step could be carried out at laboratory scale at 130–135 °C with a long reaction time (27 h) followed by a laborious optimization process, but the formation of a significant amount of side-products could be detected, thus an efficient purification procedure was necessary. In the attempted scale-up of the batch reaction, a complete conversion could not at all be reached, even after elongated reaction times (36 h). The continuous-flow experiments were carried out in a new, purpose-built flow system. The examinations were extended to a wide range of reaction parameters (ratio of solvents, concentration and molar ratio of reagents, geometry of coiled loop reactor, residence time, temperature) and to the feasibility study of scale-up. In the second part of the experiments, the fine-tuning of scaled-up reaction parameters of continuous flow synthesis was carried out using a systematic design of experiments approach. Finally 190 °C reaction temperature and 30 min of residence time led to the highest efficacy in the production of vortioxetine drug substance with high yield and purity.
Databáze: OpenAIRE
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