Reductive amination scale-up

One-pot reductive aminations are frequently used synthetic methodology to form carbon-nitrogen bonds.  A reductive amination involves the formation of a reactive imine intermediate and subsequent reduction by heterogeneous hydrogenation.  Accurate detection of the hydrogenation endpoint is critical to avoid over hydrogenation and the formation of impurities.

Reaction scheme
Imine intermediates are often unstable ex situ (prone to degradation by hydrolysis) and are therefore challenging to monitor with conventional offline analytical techniques. In addition, multiple grab-sampling of a reactor under hydrogen pressure is time consuming and may significantly increase batch cycle time. Finally, difficulties can be encountered with batch to batch or reactor to reactor variability introduced by mass transfer effects, starting materials and catalyst quality. 

ReactIR^TM application

ReactIR™ technology is used from lab scale to pilot plant scale to ensure optimum performance of the reductive amination process.

The monitoring strategy demonstrated at lab scale shows that it is easily possible to track in situ and in real time the appearance and disappearance of the reactive imine intermediate during both steps.

The hydrogenation step takes ten hours to reach completion in a one liter reactor and determination of the endpoint in real time allows avoiding the formation of the major impurities encountered in this chemistry. ReactIR™ monitoring is preferred to the conventional hydrogen uptake monitoring technique since it provides component-specific information and is more sensitive to detect the onset of product degradation upon over-hydrogenation.The subsequent pilot plant batch is successfully completed in a 100 liter glass lined reactor. This single batch is performed in support of clinical trials. Having no prior experience of the process behavior at this scale, the ability to get dynamic information on reaction progress is essential to ensure the level of control required to avoid batch failure. The real-time profiles provided by ReactIR™ confirm that the imine intermediate is formed fast and stable during the post-stir period, under the reaction conditions defined during process development. A pressure of hydrogen is applied to the mixture and is post-stirred under these conditions until the imine and amine characteristic peaks followed with ReactIR™ reach a plateau. Based on the ReactIR™ signal, it takes less than two hours for the hydrogenation to reach completion-versus nearly ten hours observed at lab scale.

Seeing is believing

In situ monitoring with information-rich ReactIR ™ technology provides a better understanding of the reductive amination process during development stage since it is possible to get specific information on each reaction components, including the unstable imine intermediate. As the process is scaled-up, the same monitoring technology is used in the plant to control in real time the designed process and ensure optimum performance.

What ReactIR^TM can do for your reductive amination

High product quality is achieved by accurate real-time determination of the hydrogenation endpoint and minimization of impurities formation. Reduced batch cycle time results from the ability to monitor the hydrogenation step in situ. Multiple sampling of the reaction mixture under pressure is avoided and analytical results are obtained with no delay. Successful scale-up results from the dynamic control of reaction progress. Consistent high product quality is achieved at different scales, regardless of mass transfer effects and process variability, ensuring "right first time" development of the desired product.