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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

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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.

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Acknowledgements

The authors thank Ms. Ildikó Pomlényi for the analytical measurements. Thanks are due to Medicinal Chemistry Research Group and Dr. Péter Kovács (Hungarian Academy of Sciences, Budapest, Hungary) for scientific support.

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Authors and Affiliations

  1. H-ION Research, Development and Innovation Ltd, 29−33 Konkoly-Thege Miklós út, Budapest, 1121, Hungary

    Zoltán Boros, László Nagy-Győr & Ottó Temesi

  2. SynBiocat Ltd, 3 Szilasliget utca, Budapest, 1172, Hungary

    Zoltán Boros & György Ruzsics

  3. Egis Pharmaceuticals Plc, 30−38 Keresztúri út, Budapest, 1106, Hungary

    Katalin Kátai-Fadgyas, Imre Kőhegyi, István Ling, Tamás Nagy, Zoltán Iványi, Márk Oláh & Balázs Volk

  4. Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, 3 Műegyetem rkp., Budapest, 1111, Hungary

    Márk Oláh

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  1. Zoltán Boros
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  2. László Nagy-Győr
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Correspondence to Zoltán Boros or Balázs Volk.

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A discussion about efficiency of the heat transfer with varying loop geometries can be found at ???.

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Boros, Z., Nagy-Győr, L., Kátai-Fadgyas, K. et al. Continuous flow production in the final step of vortioxetine synthesis. Piperazine ring formation on a flow platform with a focus on productivity and scalability. J Flow Chem 9, 101–113 (2019). https://doi.org/10.1007/s41981-019-00036-x

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  • DOI: https://doi.org/10.1007/s41981-019-00036-x

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