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Continuous Flow-Facilitated CB2 Agonist Synthesis, Part 2: Cyclization, Chlorination, and Amination

  • Michael Prieschl
    Michael Prieschl
    Center for Continuous Flow Synthesis and Processing (CCFLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria
    Institute of Chemistry, NAWI Graz, University of Graz, Heinrichstrasse 28, 8010 Graz, Austria
  • Peter Sagmeister
    Peter Sagmeister
    Center for Continuous Flow Synthesis and Processing (CCFLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria
    Institute of Chemistry, NAWI Graz, University of Graz, Heinrichstrasse 28, 8010 Graz, Austria
  • Christian Moessner
    Christian Moessner
    Department of Process Chemistry & Catalysis, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland
  • Joerg Sedelmeier*
    Joerg Sedelmeier
    Department of Process Chemistry & Catalysis, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland
    *Email: [email protected]
  • Jason D. Williams*
    Jason D. Williams
    Center for Continuous Flow Synthesis and Processing (CCFLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria
    Institute of Chemistry, NAWI Graz, University of Graz, Heinrichstrasse 28, 8010 Graz, Austria
    *Email: [email protected]
  • , and 
  • C. Oliver Kappe*
    C. Oliver Kappe
    Center for Continuous Flow Synthesis and Processing (CCFLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria
    Institute of Chemistry, NAWI Graz, University of Graz, Heinrichstrasse 28, 8010 Graz, Austria
    *Email: [email protected]
Cite this: Org. Process Res. Dev. 2023, 27, 4, 601–609
Publication Date (Web):March 29, 2023
https://doi.org/10.1021/acs.oprd.3c00036
Copyright © 2023 American Chemical Society

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    Abstract

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    A new route to the cannabinoid receptor type 2 agonist, RG7774, has been developed circumventing an alkylation with poor regioselectivity as the final step. In the new synthetic route, this side chain is incorporated from the beginning. In this article, the development of the final four transformations is detailed, using a combination of batch and flow processing. Due to poor solubility, an N-pivaloylation was performed in batch, followed by cyclization at up to 200 °C, enabled by flow processing. The following chlorination and SNAr steps were examined in both batch and flow for improved handling of hazardous reagents and intermediates, as well as enhanced heat transfer. A workup between these two steps was found to be vital in preventing side product formation from residual dimethylamine. To achieve this on a laboratory scale, a continuous solid phase treatment was developed, whereby two cation exchange columns (containing SCX-2 silica) were cycled, with monitoring by UV/vis analysis. These four steps were demonstrated with a combined yield of 72%, which serves as a significant positive contribution to the new route’s high overall yield of 53%.

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    Cited By

    This article is cited by 1 publications.

    1. Peter Sagmeister, Michael Prieschl, Dainis Kaldre, Chethana Gadiyar, Christian Moessner, Joerg Sedelmeier, Jason D. Williams, C. Oliver Kappe. Continuous Flow-Facilitated CB2 Agonist Synthesis, Part 1: Azidation and [3 + 2] Cycloaddition. Organic Process Research & Development 2023, 27 (4) , 592-600. https://doi.org/10.1021/acs.oprd.3c00035