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Development of a Continuous Flow Grignard Reaction to Manufacture a Key Intermediate of Ipatasertib

By Kaldre, Dainis; Stocker, Severin; Linder, David; Reymond, Helena; Schuster, Andreas; Lamerz, Jens; Hildbrand, Stefan; Püntener, Kurt; Berry, Malcolm; Sedelmeier, Jörg

Published on

Abstract

This article outlines the development of a continuous flow process for the manufacture of a key intermediate of the active pharmaceutical ingredient ipatasertib for the treatment of metastatic castration-resistant prostate cancer and triple-negative metastatic breast cancer. The reaction sequence incorporates multiple telescoped unit continuous operations, including a Br/Mg exchange reaction leading to intramolecular cyclization of the magnesium species onto a neighboring nitrile group to form a five-membered ring in 5-exo-dig fashion. The product from the reaction mixture is obtained after continuous aqueous acidic hydrolysis, neutralization/extraction, water wash, and phase separation. Each of these unit operations took place in a cascade of continuous stirred tank reactors. The control strategy was refined via a series of continuous lab studies at 20 g/h using a Design of Experiments approach to define process parameter ranges and to help identify any criticality therein. The learnings from this laboratory study served as a basis for the construction of a suitable pilot-plant facility, where the control strategy was verified at a representative manufacturing scale of about 1.0 kg/h.

Journal

Organic Process Research & Development. Volume 28, 2024, 1576–1586

DOI

10.1021/acs.oprd.3c00235

Type of publication

Peer-reviewed journal

Affiliations

  • F. Hoffmann-La Roche Ltd.
  • MB Chemistry Consulting Ltd.

Article Classification

Research Article

Classification Areas

  • Intermediate
  • Process Analytical Technologies

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