Continuous Manufacturing as an Enabling Technology for Low‐Temperature Organometallic Chemistry

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

“…Organometallic chemistry is an exemplar for CM and has found many applications in the pharmaceutical industry. ,− Within our product pipeline, we identified a Grignard reaction within the synthetic route toward ipatasertib ( 4 ) − as a candidate for flow chemistry because the Grignard step proved troublesome to scale up. Ipatasertib is a potent small-molecule Akt kinase inhibitor currently being tested in Phase III clinical trials for the treatment of metastatic castration-resistant prostate cancer and triple-negative metastatic breast cancer .…”

Use of Lithium Diisopropylamide in Flow: Operability and Safety Challenges Encountered on a Multigram Scale

“…Continuous technologies enable numerous advantages over batch processing, rapid scale-up and improved temperature control being among them. , Consequently, due to the greater temperature control because of the lower thermal mass of the reaction volume, and enhanced heat transfer in a flow reactor compared to a batch vessel, the use of organometallics in flow is widely known in the literature. ,− Returning to the LDA methodology, with the batch issues that we faced, i.e., poor temperature control and instability of the lithiated intermediate, our workflow for organometallic process development was engaged (Figure ) to determine the feasibility of transferring the synthesis of 1 into flow.…”

“…The custom reactor design allowed precise control of the reaction time by matching the reactor volume to the flow rate (Table ), so that the residence time from lithiation to acetone quench was on the order of 20 s, and the residence time after mixing with acetone was approximately 17 s. These residence times were in line with those used in the small-scale flow run shown above (Figure ). The batch process at 25 g scale (1 L volume) required > 2 h for the LDA addition step, and scaling further in-batch would result in even longer addition times, to control the exotherm and avoid significant decomposition of thermally sensitive species and the promotion of undesired thermal side product 3 …”

Continuous Flow as Enabling Technology: Synthesis of Heteroaromatic Sulfinates as Bench Stable Cross-Coupling Partners

“…Various methodologies for the preparation of aryl (and some heteraryl) sulfinate salts have been described as outlined in Scheme . , Aryl and heteroaryl sulfinates are accessible via redox or other reactions of prefunctionalized organosulfur compounds ( A ). Sulfinative approaches ( B ) occur either via palladium-catalyzed sulfination of aryl halides ,− or by reaction of an organometallic species with electrophilic SO 2 or its surrogate DABSO. ,− Of note, aryl sulfinates are rarely described as isolated compounds and are typically used in situ for consecutive reactions …”

“…From an atom economy perspective, the reaction of an (hetero)­aryllithium species with SO 2 appears the most appealing, however the limited half-life of certain heteroaryl aryllithium intermediates render this approach challenging in conventional batch mode. We therefore hypothesized that a continuous flow “make and consume” approach would allow for rapid generation and electrophilic quench of an unstable aryllithium intermediate and thereby extend the scope of this methodology to access a wide range of advanced heteroaryl sulfinate species. − …”