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Toward a Scalable Synthesis and Process for EMA401. Part I: Late Stage Process Development, Route Scouting and ICH M7 Assessment

Hardegger, Leo and Mallet, Franck and Bianchi, Barbara and Cai, Chunlong and Grand-Guillaume-Perrenoud, Alexandre and Humair, Roger and Kaehny, Richard and Lanz, Stephan and Li, Cheng and Li, Eddie and Rampf, Florian and Shi, Lei and Spoendlin, Christoph and Teng, Shangjun and Staeuble, Jeannine and Tian, Xiangguang and Wietfeld, Bernhard and Yang, Yao and Yu, Bo and Zepperitz, Christine and Zhang, Xuesong and Zhang, Yong (2020) Toward a Scalable Synthesis and Process for EMA401. Part I: Late Stage Process Development, Route Scouting and ICH M7 Assessment. Organic Process Research & Development, 24 (9). pp. 1743-1755. ISSN 1083-61601520-586X

Abstract

We present the enantioselective synthesis of sodium (3S)-5-(benzyloxy)-2-(diphenylacetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (EMA401, olodanrigan), an angiotensin II type 2 antagonist. The manuscript features the process optimizations of the end game used for late phase clinical supplies; an overview of synthetic strategies identified in a route scouting exercise to a key intermediate phenylalanine derivative; and the analytical control strategy of the potentially formed highly toxic impurity bis(chloromethyl)ether (BCME). Starting from the phenylalanine derivative, we describe the optimizations of the end game from early phase to late phase processes, with consequent improvements in the PMI factor. This sequence includes a Pictet-Spengler cyclization and an amide coupling as the last bond-forming steps, and the manufacturing process was successfully implemented on a 175 kg scale in a pilot plant setup. The modified process conditions eliminated one step by in situ activation of the carboxylic acid, avoided the REACH listed solvent DMF, and resulted in a PMI improvement by a factor of 3. In the final crystallization, a new, thermodynamically more stable, modification of the drug substance was found in the complex solid-state landscape of EMA401 during an extensive polymorph screening. A process suitable for large-scale production was developed to prepare the new polymorph, avoiding the need of any special equipment such as fluidized-bed drying required in the early phase process. In the second section, some of the synthetic approaches investigated for the route scouting of the phenylalanine derivative key intermediate are presented. To conclude, we discuss the analytical control strategy for BCME, the formation of which, due to the simultaneous presence of HCl and CH2O in the Pictet-Spengler cyclization, could not be ruled out. The BCME purge factor calculations using the tools of ICH M7 control option 4 are compared to actual results from spiking experiments.

Item Type: Article
Keywords: EMA401, olodanrigan, phenylalanine derivatives, scale-up, route scouting, ICH M7 control option 4, BCME, bis(chloromethyl)ether
Date Deposited: 07 Oct 2020 00:45
Last Modified: 07 Oct 2020 00:45
URI: https://oak.novartis.com/id/eprint/42523

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