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

Continuous flow production in the final step of vortioxetine synthesis. Piperazine ring formation... Abstract 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Flow Chemistry Springer Journals

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

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Publisher
Springer Journals
Copyright
2019 Akadémiai Kiadó
ISSN
2062-249X
eISSN
2063-0212
DOI
10.1007/s41981-019-00036-x
Publisher site
See Article on Publisher Site

Abstract

Abstract 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.

Journal

Journal of Flow ChemistrySpringer Journals

Published: Jun 1, 2019

References