Multistep synthesis of a valsartan precursor in continuous flow

Katharina Hiebler, Sebastian Soritz, Kristian Gavric, Sam Birrer, Manuel C. Maier, Bianca Grabner, Heidrun Gruber-Woelfler

Publikation: Beitrag in einer FachzeitschriftArtikelForschungBegutachtung

Abstract

Valsartan is a potent, orally active angiotensin II receptor blocker and is widely used in the treatment of hypertension and chronic heart failure. Herein, we present an approach for the continuous synthesis of a late-stage precursor of valsartan in three steps. The applied synthetic route involves N-acylation, Suzuki-Miyaura cross-coupling and methyl ester hydrolysis. After optimization of the individual steps in batch, they were successfully transferred to continuous flow processes employing different reactor designs. The first step of the synthetic route (N-acylation) as well as the third step (methyl ester hydrolysis) are performed in coil reactor setups. The key step of the reaction cascade (Suzuki-Miyaura cross-coupling) is catalyzed by a heterogeneous palladium-substituted cerium-tin-oxide with the molecular formula Ce0.20Sn0.79Pd0.01O2-δ. The catalyst particles are implemented in an in-house developed packed-bed reactor, which features an HPLC column as fixed-bed. The combination of the individual reaction modules facilitates the consecutive performance of the three reaction steps. Using the developed multistep continuous setup, the targeted valsartan precursor was obtained with up to 96% overall yield. [Figure not available: see fulltext.].

Originalspracheenglisch
Seitenumfang12
FachzeitschriftJournal of Flow Chemistry
DOIs
PublikationsstatusElektronische Veröffentlichung vor Drucklegung. - 1 Jan 2019

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Valsartan
Acylation
Hydrolysis
Esters
Packed beds
Cerium
Tin oxides
Palladium
Angiotensin Receptor Antagonists
Catalysts

Schlagwörter

    ASJC Scopus subject areas

    • !!Chemistry (miscellaneous)
    • !!Fluid Flow and Transfer Processes
    • Organische Chemie

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    Multistep synthesis of a valsartan precursor in continuous flow. / Hiebler, Katharina; Soritz, Sebastian; Gavric, Kristian; Birrer, Sam; Maier, Manuel C.; Grabner, Bianca; Gruber-Woelfler, Heidrun.

    in: Journal of Flow Chemistry, 01.01.2019.

    Publikation: Beitrag in einer FachzeitschriftArtikelForschungBegutachtung

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    AU - Maier, Manuel C.

    AU - Grabner, Bianca

    AU - Gruber-Woelfler, Heidrun

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