MRT - Three-Stage Lithium-Organic Synthesis

By: Matthias Junkers, Aldrich ChemFiles 2009, 9.4, 17.

Benefit from MRT & Flow Chemistry: cost & time savings, highly reliable synthesis protocol guaranteeing constant quality.

Scheme 11 shows an extension of the concept described in the previous example. For a custom API synthesis project the general reaction sequence from Scheme 10 was prolonged by an additional 3rd microreactor. In the 1st microreactor a substituted heterocyclic bromide is submitted to the metal halide exchange. The 2nd microreactor couples the aryllithium intermediate to a substituted cyclic imine. A protective group reagent intercepts the resulting lithiated amine in the 3rd microreactor leading directly to the final product. Traditional work-up between reaction steps is completely avoided by placing all reactions into one flow sequence.

Scheme 11: Direct conversion of Lithium-organic intermediates in a 2-stage MRT system

Parallel investigation of the same reaction sequence performed as a batch process showed severe variation of yields and product profiles. In contrast the product was synthesized in the microreactors constant quality with an overall yield of 55%, independent from production scale variations. The flow synthesis procedure benefits from all advantages described for the previous example and allows production of 3kg of API within 24 hours. The whole custom synthesis project was finished in less than three months, proving the feasibility of flow chemistry for industrial scale multi-step synthesis of APIs.

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