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Development of Continuous Technology for the Preparation of Pharmaceuticals
Jaklová, Natalie
The present research focuses on the transition of a batch reaction assisted by phase transfer catalyst (PTC) into continuous process. The first reaction studied was an N-alkylation reaction with methyl ester of the 1-methyl-10α-methoxydihydrolysergic acid (MeLUME) as product. MeLUME is one of the intermediates in synthesis of drug Nicergoline. The N-alkylation occurs in two different immiscible phases and the bridge between these phases is the phase transfer catalyst. The study was performed in several different continuous flow apparatuses. The best results were obtained in a capillary reactor, with assistance of ultrasound.
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Microfluidic reactors for chemical synthesis
Jaklová, Natalie ; Klusoň, Petr (advisor) ; Cvak, Ladislav (referee)
The main topic of the Diploma Thesis is the conversion of the batch N-alkylation reaction into a continuous regime. It is the reaction of 10α-methoxydihydrolysergic acid methyl ester to 1-methyl-10α-methoxydihydrolysergic acid methyl ester. It represents one step in the industrial synthesis of Nicergoline, a pharmaceutical used for senile dementia treatment. This methylation reaction is performed in two immiscible liquid phases. Phase-transfer catalysis is used to increase the efficiency of the reaction, which allows the reaction to proceed in the entire volume of the organic solvent, not only at the phase interface. The reaction is rapid, with an exothermic character. The advantages of continuous arrangement are better control of the reaction, increased operational safety due to handling smaller volumes of reaction components, and more intensive removal of heat of the reaction. The Thesis deals with the influence of reaction conditions on the course of the reaction in a microfluidic reactor. The glass microchip reactor was chosen to perform the reaction in a flow arrangement. This reactor could produce up to grams of the product per hour. Several series of experiments were performed on this apparatus. The conversion of the starting material, and selectivities to the product and the side products...
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Preparation of optically pure compounds by stereoslective hydrogenation in a microreactor
Jaklová, Natalie ; Klusoň, Petr (advisor) ; Paterová, Iva (referee)
This bachelor Thesis is introducing an alternative approach to the synthesis of the pharmaceutically important compound (R)-4-chloro-3-hydroxybutyrate ((R)-CHBE). This compound is used as a precursor in the production of pharmaceutically valuable products, such as L-carnitine, (R)-4-amino-3-hydroxybutyric acid and (R)-4-hydroxy-pyrrolidone. At present time these chemicals are predominantly produced by using biochemical methods largely based on enyzmatic reactions in the presence of stereoselective carbonyl reductases. In this Thesis a new approach is described, which is based on stereoselective hydrogenation of ethyl-4-chloracetoacetate catalyzed by an optically pure ruthenium bis(phosphine) complex. The whole process was carried out in a microfluidic reactor system. This assembly is highly promising for a potential scale-up, studies of reaction kitetics, optimization of reaction and process conditions etc. For the reaction described above the optimal reaction conditions, such as temperature, pressure, solvent phase composition and flow rates of gas and liquid phases, were determined. Furthermore, the use of a suitable ionic liquid preserving the catalyst's chiral selectivity was described. Key words: (R)-4-chloro-3-hydroxybutyrate, L-carnitine, microfluid chip reactor, hydrogenation
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