Grignard reactions are widely used in organic synthesis to form carbon-carbon bonds in the pharmaceutical industry; however, Grignard reactions are considered very hazardous due to the significant exotherm associated with generation of the Grignard reagent along with the unpredictability of the initiation event.  There was a need to run the reaction at scale to meet drug substance demand of a key oncology assets at Amgen. A thermal hazard evaluation of the reaction using calorimetry confirmed the highly exothermic nature of the reaction, which had an adiabatic temperature rise of 133 °C. On a scale from 1 to 5, using Stoessel’s criteria, used in the industry to classify the risk of a reaction, the Grignard reaction was rated a 5.  Therefore, engineering controls were required to reduce the hazard as class 5 reaction are not permitted in our facilities. For the first scale up operations, the charge of starting reagent was separated into 10–15% portions to eliminate the risk of an accidental over-charge, thereby reducing the hazard to Stoessel criticality class 3. Furthermore, due to lack of understanding of the initiation, the reaction mixture was sampled after each charge to ensure reagent consumption and to mitigate the potential for accumulation of heat inside the reactor. Process analytical technology (PAT) in the form of in-situ IR was deployed at scale for qualitative analysis. A total of 1.54 Kg (81 % yield) was generated using this approach. The long-term manufacturing strategy leverages the use of CSTRs (continuously-stirred tank reactors) to perform this hazardous reaction with improved process control. The use of continuous operations allowed maintaining a low inventory of these hazardous reagents and enables improved heat transfer by virtue of the smaller reaction vessel (i.e., increased surface to volume ratio). We successfully demonstrated this process to generate 3.64 kg after continuous operation for 25.5 hours. The process is currently being tech transferred to a CMO which will utilize the same platform used in development.

Safe scale-up of an exothermic grignard reaction based on thermal hazard understanding and engineering control

2019 Fall National Meeting

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