Recent Advances in Continuous Rhodium-Catalyzed Hydroformylation

Wang, Xiao

doi:10.1556/1846.2015.00003

Cited by 12 publications

(1 citation statement)

References 66 publications

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“…We next investigated the Rh-catalyzed hydroformylation within a continuous-flow environment. The optimization of hydroformylation reactions within continuous-flow environments has been of considerable interest . Ley and co-workers studied the hydroformylation of styrene derivatives within a tube-in-tube reactor .…”

Section: Resultsmentioning

confidence: 99%

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

García-Lacuna

Fleiß

Munday

et al. 2021

Org. Process Res. Dev.

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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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Section: Resultsmentioning

confidence: 99%