Since the start of the 20th century, the Grignard reaction has been broadly studied and applied to the synthesis of numerous intermediates in the preparation of food additives, industrial chemicals, and in the preparation of pharmaceutical products. Despite these successes, the Grignard reaction remains one of the more challenging reactions to bring to commercial scale due to acute hazards which include: 1) Strongly exothermic activation an reaction steps; 2) heterogeneous reactions with potential suspension and mixing issues; 3) magnesium handling and waste disposal issues. An inherently safer approach to the Grignard reaction has been developed at Eli Lilly and Company where key Grignard reagents and reactive intermediates are produced in continuous stirred tank reactors (CSTR's) operating under steady state control. Significant process safety benefits are realized by the continuous approach including sequestration of activated magnesium and a single initiation lasting for an entire campaign. In addition, the continuous approach can reduce Process Mass Intensity (PMI) up to 30% and minimize inventory of potentially hazardous materials such as elemental magnesium. Careful selection of renewable solvents such as 2-MeTHF and magnesium sourcing can also have a large positive impact on the environmental footprint for a Grignard process. Eli Lilly and Company has developed several continuous Grignard processes by this strategy and production of two key intermediates for Edivoxetine Hydrochloride by continuous Grignard chemistry will be discussed. Commercial implementation of this technology will result in a top end manufacturing scale of ~60L compared to ~8000L in traditional batch processing.

Grignard reaction past, present, and future: Development of greener more sustainable processes

246th National Meeting (2013)

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