Synthesis of the Lipophilic Amine Tail of Abediterol Enabled by Multiphase Flow Transformations

    • Jorge García-Lacuna1
    • Tobias Fleiß1,2
    • Rachel Munday3
    • Kevin Leslie3
    • Anne O’Kearney-McMullan3
    • Christopher A. Hone*1,2
    • C. Oliver Kappe*1,2
    • 1Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, A-8010 Graz, Austria
    • 2Center for Continuous Flow Synthesis and Processing (CCFLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria
    • 3Chemical Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, Macclesfield, United Kingdom

    The development of a continuous-flow sequence for the synthesis of an important drug candidate precursor is reported. Abediterol is a β2-adrenoceptor agonist that has undergone phase IIa clinical trials for the treatment of respiratory disease. A flow sequence is developed for the preparation of the lipophilic amine tail portion of abediterol. The sequence comprises of a phase-transfer-catalyzed liquid/liquid O-alkylation, a rhodium-catalyzed hydroformylation, and a ruthenium-catalyzed reductive amination. The reactions were optimized separately within continuous-flow environments to identify important parameter effects. The strongly basic O-alkylation operates with greater than 90% conversion within a 23 min residence time. The hydroformylation uses 1 mol % Rh(acac)(CO)2 (acac = acetylacetone) as a catalyst and 6 mol % Xantphos as a ligand with 1.1 equiv of hydrogen and carbon monoxide. The optimized O-alkylation and hydroformylation telescoped flow process was successfully operated over 6 h. The protocol is shown to be high yielding for the desired linear aldehyde (75% gas chromatography yield, ∼2.5 g/h). The sequence requires a solvent switch prior to the reductive amination. The final step is a high-pressure (40 bar) and high-temperature (150 °C) Ru-catalyzed reductive amination using ammonia and hydrogen to afford the amine tail. The solution yield for the formation of the amine tail was 78%. The yield of the reductive amination with an unoptimized isolation was 50%, resulting in an overall isolated yield for the three-step sequence of 38%. This compares favorably against the batch yield of 26% using a different synthetic route.

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