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Continuous Catalytic Transformations: from optimization in MICRO systems to INDustrial production

Final Report Summary - CCT-MICROINDUS (Continuous Catalytic Transformations: from optimization in MICRO systems to INDustrial production)

The main purpose of the project was the study of a key step in the synthesis of an anti-epileptic drug from UCB Pharma. This step was previously studied directly by hydrogenation of an unsaturated lactam amid key intermediate. The study focused on a new chemical route to obtain this key intermediate by hydrolysis of a lactam acid, then hydrogenation and lastly the amidification step.
Global objective of the work considered the following points:
• Measurements of Gas-liquid mass transfer coefficient
• Optimisation of operating conditions in a continuous hydrogenation reactor
• Development of a model concerning the kinetic rate, such as Langmuir-Hinshelwood model
• Measurement of catalyst deactivation
• Understanding of the correlation between the diastereoselectivity increase and the conversion of unsaturated lactam or in the presence of UCB 42145
• Influence of the additives such as Leucine and different salts

A large screening of conditions was performed, including catalysts, solvents and additives which allowed to get a very high diastereoselectivity. These conditions were applied successfully in batch and continuous reactor and constitute a basis for a potential improved process of the drug.

The second part of the work is related to the synthesis of 1,3,4-thiadiazoles. The work aimed at illustrating different approaches to the challenge of preparing these bioactive products and allows the synthesis of many novel chemical derivatives. In general, 1,3,4-thiadiazole derivatives are prepared by appropriate intra- or intermolecular ring closure reactions and the substituents are then modified as required. The area of the synthesis of 1,3,4-thiadiazole rings continues to grow, and the organic chemistry will provide more and better methods for the synthesis of this interesting heterocycle, allowing the discovery of new drug candidates more active, more specific and safer.
Despite multiple trials, no significant progress could be made and the initial synthetic procedure remains the most attrcative in view of scaling-up the process.

Apart from the technical matters described above, the fellow students involved in the project were trained on company code of conduct, health safety and environment, general pharmaceutical development and cGMP practices. They also got detailed training plans similar to the company employees working in a laboratory environment.