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Toward a Scalable Synthesis and Process for EMA401. Part II: Development and Scale-up of a Pyridine- and Piperidine-free Knoevenagel-Doebner Condensation

Sidler, Eric and Humair, Roger and Hardegger, Leo (2020) Toward a Scalable Synthesis and Process for EMA401. Part II: Development and Scale-up of a Pyridine- and Piperidine-free Knoevenagel-Doebner Condensation. Organic Process Research & Development, 24 (9). pp. 1756-1762. ISSN 1083-61601520-586X

Abstract

During the route scouting of EMA401 (1), a angiotensin II type 2 antagonist, we identified the synthesis of key amino acid intermediate 2 via its cinnamic acid derivative 3 as a streamlined option. In general, cinnamic acids can be synthesized from the corresponding aldehyde in a Knoevenagel-Doebner condensation in pyridine with piperidine as an organocatalyst. We aimed at replacing both of these reagents and found novel conditions in toluene as the solvent and morpholine as the organocatalyst. Scale-up of the process allowed production of 25 kg of the cinnamic acid 3, which was of required quality for process development on the subsequent phenylalanine ammonia lyase-catalyzed step. The modified conditions were found to be widely applicable to alternative aldehydes, and so of relevance to practitioners of chemical scale-up.

Item Type: Article
Keywords: Knoevenagel-Doebner, scale-up, cinnamic acid, pyridine-free, piperidine-free
Date Deposited: 07 Oct 2020 00:45
Last Modified: 07 Oct 2020 00:45
URI: https://oak.novartis.com/id/eprint/42353

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