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Match-making reactors to chemistry: a continuous manufacturing-enabled sequence to a key benzoxazole pharmaceutical intermediate

Schenkel, Berthold and Venturoni, Francesco and Aubry, Michel and Sevinc, Serbuelent and Sedelmeier, Joerg Mathias and Martin, Benjamin and Susanne, Flavien and Lima, Fabio and Piccioni, Lorenzo (2017) Match-making reactors to chemistry: a continuous manufacturing-enabled sequence to a key benzoxazole pharmaceutical intermediate. Organic process research & development, 21. pp. 1779-1793.

Abstract

The focus of this study was to develop a chemical reaction sequence towards a key benzoxazole building-block, required for clinical manufacturing of a lead candidate in the respiratory disease area. The chemistry consisted of initial low-temperature reactions with an organometallic reagent to generate the benzoxazole core, and was followed by non-cryogenic transformations towards a sulfonamide substituent. With particular interest in continuous-flow manufacturing we attempted to integrate the entire sequence on lab-scale. Subsequent in-depth process research, supported by PAT and calorimetry studies, revealed the critical parameters of each step, leading to the more rational attribution of mode of operation: batch, flow or semi-batch. Two bench-scale cascades of continuously stirred tank reactors (CSTRs) were constructed to meet the challenge of high exothermicity and solids formation, and were key to smoothly upscaling the chemistry to deliver 17 kg of benzoxazole in superior yield, quality and robustness.

Item Type: Article
Keywords: continuous manufacturing; cascade of stirred-tank reactors; organolithium; aryne; sulfonamide; benzoxazole; process development; modelling and simulation; mini-plant
Date Deposited: 18 Nov 2017 00:45
Last Modified: 18 Nov 2017 00:45
URI: https://oak.novartis.com/id/eprint/33478

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