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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Köhler S, Cierpinsky K, Kronenberg G, Adli M (2016) The serotonergic system in the neurobiology of depression: relevance for novel antidepressants. J Psychopharmacol 30:13–22
D’Agostino A, English CD, Rey JA (2015) Vortioxetine (Brintellix): a new serotonergic antidepressant. Pharmacol Ther 40:36–40
Sanchez C, Asin KE, Artigas F (2015) Vortioxetine, a novel antidepressant with multimodal activity: review of preclinical and clinical data. Pharmacol Ther 145:43–57
Bang-Andersen B, Ruhland T, Jorgensen M, Smith G, Frederiksen K, Jensen KG, Zhong H, Nielsen SM, Hogg S, Mork A, Stensbol TB (2011) Discovery of 1-[2-(2,4-Dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multimodal compound for the treatment of major depressive disorder. J Med Chem 54:3206–3221
Gibb A, Deeks ED (2014) Vortioxetine: first global approval. Drugs 74:135–145
Jas G, Kirschning A (2003) Continuous flow techniques in organic synthesis. Chem Eur J 9:5708–5723
Valera FE, Quaranta M, Moran A, Blacker J, Armstrong A, Cabral JT, Blackmond DG (2010) The Flow’s the thing...Or is it? Assessing the merits of homogeneous reactions in flask and flow. Angew Chem Int Ed 49:2478–2485
Hartman RL, McMullen JP, Jensen KF (2011) Deciding whether to go with the flow: evaluating the merits of flow reactors for synthesis. Angew Chem Int Ed 50:7502–7519
Capretto L, Cheng W, Hill M, Zhang X (2011) Microfluidics: Technologies and Applications; Bingcheng, L., Ed. Springer, Berlin, Germany
Wiles C, Watts P (2012) Continuous flow reactors: a perspective. Green Chem 14:38–54
Webb D, Jamison TF (2010) Continuous flow multi-step organic synthesis. Chem Sci 1:675–680
Wegner J, Ceylan S, Kirschning A (2011) Ten key issues in modern flow chemistry. Chem Commun 47:4583–4592
Darvas F, Dormán G, Hessel V (2014) Flow Chemistry Organic, Vol. 1: Fundamentals. Walter de Gruyter GmbH, Berlin, Germany
Hessel V, Kralisch D, Kockmann N, Noël T, Wang Q (2013) Novel process windows for enabling, accelerating, and uplifting flow chemistry. ChemSusChem 6:746–789
Razzaq T, Kappe CO (2010) Continuous flow organic synthesis under high-temperature/pressure conditions. Chem Asian J 5:1274–1289
Marre S, Adamo A, Basak S, Aymonier C, Jensen KF (2010) Design and packaging of microreactors for high pressure and high temperature applications. Ind Eng Chem Res 49:11310–11320
Gutmann B, Cantillo D, Kappe CO (2015) Continuous-flow technology—a tool for the safe manufacturing of active pharmaceutical ingredients. Angew Chem Int Ed 54:6688–6728
Britton J, Raston CL (2017) Multi-step continuous-flow synthesis. Chem Soc Rev 46:1250–1271
Örkényi R, Éles J, Faigl F, Vincze P, Prechl A, Szakács Z, Kóti J, Greiner I (2017) Continuous synthesis and purification by coupling a multistep flow reaction with centrifugal partition chromatography. Angew Chem Int Ed 56:8742–8745
Adamo A, Beingessner RL, Behnam M, Chen J, Jamison TF, Jensen KF, Monbaliu JC, Myerson AS, Revalor EM, Snead DR, Stelzer T, Weeranoppanant N, Wong SY, Zhang P (2016) On-demand continuous-flow production of Pharmaceuticals in a Compact, reconfigurable system. Science 352:61–67
Mascia S, Heider PL, Zhang H, Lakerveld R, Benyahia B, Barton PI, Braatz RD, Cooney CL, Evans JM, Jamison TF, Jensen KF, Myerson AS, Trout BL (2013) End-to-end continuous manufacturing of pharmaceuticals: integrated synthesis, purification, and final dosage formation. Angew Chem Int Ed 52:12359–12363
Cranwell PB, O’Brien M, Browne DL, Koos P, Polyzos A, Pena-Lopez M, Ley SV (2012) Flow synthesis using gaseous Ammonia in a Teflon AF-2400 tube-in-tube reactor: Paal-Knorr Pyrrole formation and gas concentration measurement by inline flow titration. Org Biomol Chem 10:5774–5779
Noel T, Su Y, Hessel VB (2015) Organometallic flow chemistry: the principles behind the use of continuous-flow reactors for synthesis. J Organomet Chem 57(1):42
Müller STR, Wirth T (2014) Diazo compounds in continuous-flow technology. ChemSusChem 8:245–250
Nagy-Győr L, Abaházi E, Bódai V, Sátorhelyi P, Erdélyi B, Balogh-Weiser D, Paizs C, Hornyánszky G, Poppe L (2018) Co-immobilized whole cells with ω-transaminase and Ketoreductase activities for continuous-flow Cascade reactions. ChemBioChem 19:1845–1848
Liu KG, Robichaud AJ (2005) A general and convenient synthesis of N-aryl Piperazines. Tetrahedron Lett 46:7921–7922
Juvale K, Wiese M (2012) 4-Substituted-2-Phenylquinazolines as Inhibitors of BCRP. Bioorg Med Chem Lett 22:6766–6769
Zupancic, B. New Process for the Synthesis of l-(2-((2,4-Dimethylphenyl)thio)phenyl)piperazine. WO 2014161976 PCT Intern. Pat. Appl
Pennell, A. M. K.; Aggen, J. B.; Wright, J. J. K.; Sen, S.; Mcmaster, B. E.; Dairaghi, D. J.; Chen, W.; Zhang, P. Substituted Piperazines. WO 2005056015 PCT intern. Pat Appl
Sun A, Moore TW, Gunther JR, Kim MS, Rhoden E, Du Y, Fu H, Snyder JP, Katzenellenbogen JA (2011) Discovering small-molecule estrogen receptor α/Coactivator binding inhibitors: high-throughput screening, ligand development, and models for enhanced potency. Chem Med Chem 6:654–666
Mao Y, Jang L, Chen T, He H, Liu G, Wang H (2015) A new and practical synthesis of Vortioxetine Hydrobromide. Synthesis 47:1387–1389
Welthy JR, Wicks CE, Wilson RE, Rorrer GL (2007) Fundamentals of momentum. Heat and mass transfer5th edn. John Wiley and Sons, New York
Novi M, Garbarino G, Petrillo G, Dell’Erba C (1987) Electrochemical reduction of some O-Bis(phenylsulphonyl)benzene derivatives. Effect of the substrate structure and of the addition of bases on the product distribution. J Chem Soc Perkin Trans 2:623–632
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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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