FLOW CHEMISTRY
methods were underestimated. These can deliver significant advantages in terms of capacity, efficiency, product quality and logistics. This area now represents our next phase of development.
While a fully continuous, multi-step process is conceptually attractive, in practice it is often too complex to implement reliably. Our preferred approach is to keep it simple: a singlestep transformation that delivers an isolated( solid) product using a small scale, modular, dedicated set-up. This, in our view, is the most realistic and practical form of flow chemistry for the pharmaceutical environment.
Flow chemistry is here to stay, but it must offer clear, unique solutions to defined challenges in the early life cycle of an API. The main contribution of a CDMO lies in its readiness to offer fit-for-purpose technical solutions, tailored to specific project needs and grounded in a collaborative approach. ●
Dr Franz Amann
SENIOR SCIENTIST- DEVELOPMENT
CARBOGEN AMCIS k + 41 58 909 06 52 J franz. amann @ carbogen-amcis. com j www. carbogen-amcis. com
References: 1: M. D. Johnson et al., Chimia, 2023, 77, 319 – 326. 2: F. Amann et al., Org. Process Res. Dev., 2016, 20, 446 – 451.
CASE STUDY
A flow process for a thermal Overman rearrangement2 was developed as part of a production project at Carbogen Amcis. The conversion was described in the technical information package and existing literature for small-scale: heating at 180 ° C in six volumes of cymene. It could be reproduced successfully in the lab but larger lab runs already showed decreasing yields, darker colouration and increased precipitate formation.
Differential scanning calorimetry( DSC) provided insight into the thermal behaviour of the starting material. A first small exotherm( onset 100 ° C) is followed by the intended reaction at around 180 ° C. In contrast, the DSC profile of the product shows the onset of decomposition at 164 ° C – below the batch reaction temperature – indicating that it would not be safe to scale up the reaction under batch conditions( Figure 2)
The final optimised flow conditions in the lab were 220 ° C, approximately 8 bar pressure, two volumes of toluene and a residence time of two minutes. Although these conditions fall within the decomposition range indicated by DSC, spot-to-spot conversion was achieved without product degradation.
DSC of neat product
The fast flow process was able to override the kinetics of decomposition, which seems to have an autocatalytic component. DSC may include measurements at different heating rates and interpretation must be adapted accordingly.
During scale-up, the residence time of the flow process was increased from two to three minutes to accommodate the use of wider tubing, required to handle the much higher flow rates.
Flow processing provided a viable solution to the safety and yield limitations of the batch process. Thanks to the simplicity of the chemistry, both chemical and technical development efforts were similar to those of a batch process.
The product was an intermediate for an API. The programme was not continued after the initial 30 kg campaign, halting further development despite the successful implementation.
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