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

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 fivemembered 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.

Highlights of the Recent Patent Literature: Continuous Chemistry in the Pharmaceutical Industry

“…In the cyclization step, the isolated yield was 61% with a number of byproducts generated that required recrystallization for purification. In a recent patent application, Roche scientists described a flow process for this step, conducted in a series of continuous stirred tank reactors (CSTRs) . As noted in the patent application, advantages of flow versus batch for this reaction included (1) yield improvement of 10–20%, (2) precipitation of a magnesium–imine complex which protects it from decomposition and over-reaction prior to quench, (3) improved process control and robustness, (4) avoidance of a recrystallization step to improve purity, (5) straightforward scaling, (5) shorter processing times, and (6) significant cost savings.…”