"Greening" of the industrial technology of enoxaparin sodium synthesis

The aim: carrying out stages of synthesis of intermediates of Enoxaparin sodium, considering the variation of synthesis parameters. Correlation analysis between the technological parameters of the synthesis and the quality of the obtained samples. Evaluation of the influence of the quality of semi-finished products on the quality of the final substance. Implementation of the principles of green chemistry in the synthesis of Enoxaparin sodium by reducing the production cycle and using the most environmentally friendly solvents and reagents. Materials and methods: samples of intermediates of the substance Enoxaparin sodium were synthesized according to the method described in the patent, as well as with a variation of the selected critical technological parameters. The obtained samples of intermediate products were analyzed according to the internal specification. In addition, an NMR-spectroscopy analysis was carried out for detailed structural characterization of Enoxaparin sodium intermediate molecules. Results: the method of synthesis of intermediates of the Enoxaparin substance proposed in the patent was evaluated and the critical parameter for the formation of the final molecule was selected, namely the reaction mass holding time. The intermediate of Enoxaparin sodium - benzethonium salt of heparin and benzyl ester of heparin were developed according to the selected parameters and the analysis of the obtained samples was carried out according to the internal ND. Taking into account the principles of green chemistry, the method of synthesis of the intermediate product - benzyl ester of heparin was optimized by solvent regeneration. Conclusions: As a result of the research, the methods of synthesis of intermediates of Enoxaparin were evaluated and the technological parameters of the synthesis of intermediates were determined, allowing to obtain a substance equivalent to the original Clexane® and Lovenox®. Evaluation of the method of synthesis of intermediate products according to the principles of green chemistry was carried out. The possibilities of greening the synthesis were analyzed. The holding time of the reaction mass of the benzethonium salt of heparin was reduced from 6 to 4 hours, and the benzyl ester of heparin from 25 to 22 hours. The E-factor indicator was reduced by regeneration of the solvent at the stage of synthesis of heparin benzyl ester