The aim of our work was elaboratating an analytical method to control the last step of the synthesis of trans 4-cyclohexyl-S-proline, which is semi-product in the synthesis of fosinopril.

Fosinopril is an antihypertensive medicine which belongs to the group of ACE inhibitors. It posses a long-acting formulation (for 24 h) and a high degree of assimilation.

ACE inhibitors block the conversion of angiotensin I to angiotensin II. They, therefore, decrease the arterial resistance and increase the venous capacity.

The most often applicable drugs of these group are: enalapril, lisinopril and captopril.

This synthesis is based on simple, well-known reactions like aldol condensation, Michael addition and hydrogen reduction. The last step of this work is the hydrolysis of ethyl ester of trans 4-cyclohexyl-S-proline.

The analytical control of this process is difficult because of nonvolatile  product and lack of chromophore group in a molecule enabling detection. The product of reduction with using a UV detector in background impurities present in the mixture is practically invisible.  

The crude product of reduction, having of small amounts of substrate and other compounds with high absorbance in the UV wavelength range, was hydrolysed. The analytical control of hydrolysis of ethyl trans-4-cyclohexyl-S-proline to the corresponding acid is possible by using the Corona CAD detector. Detector operating principle is based on corona discharges and the signal does not depend on the structure of the analyzed compound.

Corona CAD detector allows work in gradient, which we cannot be used in work with RI detector. In our case it is necessary due to the presence of compounds with very different polarity. Conditions of the control of hydrolysis of the ethyl ester of trans 4-cyclohexyl-S-proline were developed. Indications were performed using standard HPLC systems.

This work was financially supported by Ministry of Science and Higher Education grant No N N209 237336.

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