FLOW CHEMISTRY
The selection of an appropriate synthesis route requires theoretical and practical evaluation of each molecule involved in the process . However , general trends can be identified based on the structural characteristics of the molecules . Case studies on flucytosine synthesis are presented at the end of this article .
When assessing late-stage fluorination strategies , it is essential to consider the economic perspective on both a laboratory and a manufacturing scale . At laboratory scale , specialised agents such as diethylaminosulfur trifluoride ( DAST ) are often preferred , due to their easy handling and reduced reactivity . On the other hand , their high cost makes them impractical for largescale manufacturing processes . Therefore , when considering larger-scale production , selective strategies utilising flow chemistry techniques become more interesting . Flow chemistry enables precise control over reaction conditions , efficient reagent utilisation and enhanced scalability , thereby offering potential cost advantages for the implementation of earlystage and late-stage fluorination in manufacturing processes .
Phases of the process
The development of a continuous fluorination process from initial research to full-scale production involves several distinct phases . In the first phase , known as process research , a comprehensive literature survey is conducted , and initial basic ( batch ) tests are performed to gather fundamental knowledge .
Subsequently , in the process design phase , the process concept is formulated , encompassing the first idea about production or pilot plant design , considering crucial economic factors , such as the estimated costs for the whole development , engineering and equipment . Development then progresses to the chemical feasibility phase , wherein the main process development and relevant parameters are determined , ensuring the feasibility of the proposed approach .
During the technical feasibility phase , trials are carried out using already scalable equipment , demonstrating the process viability on a larger scale . At this point , the concept of the pilot plant , if required , is finalised . Through engineering phases ( basic and detailed ), the plant is designed , and all essential components and process parameters are determined . At the end of the detailed engineering phase , the pilot or production plant can be fully constructed and automated .
Case studies
During our first case study , we took a process from the literature for the synthesis of flucytosine , utilising elemental fluorine , for which the development work-up to chemical feasibility had already been performed and we went further in the realisation pathway . During the technical feasibility , we transitioned to process on scalable equipment .
Due to the larger size of this equipment , a scale-up of one order of magnitude had already been made . Within the larger system , we started facing new effects that were never faced in the small-scale system , such as blocking of the inlets because of back-flow . By slight adaptations of the process , we were able to overcome the issues , transfer the literature process to a scalable system and produce some kilograms of flucytosine .
In a second case study , we started at the very beginning of the development pathway in which we selected potential candidates for fluorination with elemental fluorine on a theoretical basis . The most promising were tested in principle lab trials , and a first optimisation of processing conditions was performed .
We were able to obtain results within our lab system similar to those described in literature . Conditions in this lab system are already similar to those in the scalable system ; hence a direct transfer to the technical feasibility is planned as the next step . ●
Dr Dirk Kuschneck
STRATEGIC DIRECTOR
MICROINNOVA
Fluorination reactor set up at pilot scale
J j dirk . kuschneck @ microinnova . com www . microinnova . com
SEP / OCT 2023 SPECCHEMONLINE . COM
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