Investigation of Synthesis methods antiepileptic drug pregabalin and optimize the method of choice

Abstract

Pregabalin is one of the chiral compounds used to treat neuralgia and epilepsy. Several methods have been proposed for the synthesis of this drug. In this project, we successfully produced this drug using the classic method of synthesizing the racemic compounds and diastereomer separation. Objective The synthetic method was optimized for localizing the production of this drug in the country, considering the potential of the Iranian pharmaceutical industry. Method and materials For the synthesis of S-pregabalin (1), at first the intermediate of α-β-unsaturated (2) was prepared (Step: I), then this compound was converted to dicarboxylic acid (3) intermediate (Step: II). In the next step, the intermediate (3) was converted to the glutarimide ring (8) (Step: III), then with the hydrolysis of the glutarimide ring (8), the intermediate of glutaric acid monoamide (5) was obtained (Step: IV). Subsequently, the enantiomers of the compound (5) were isolated (Step: V). the desired enantiomer of R-glutaric monoamide acid (6) was converted to S-pregabalin (Step: VI) by Hofmann rearrangement (Step: VI), and by the racemization of the undesired enantiomer of S-glutaric monoamide acid, it was recovered again into glutaric acid monoamide (5) (Step: VII). Moreover, the optically active compound of R-phenyl ethylamine (9) was recovered (Step: VIII).

Findings The FT-IR and 1HNMR spectra of the intermediate which confirm the formation of these compounds. The optical purity R-3- (carbamoylmethyl) -5-methylhexaenoic acid (6) and S-pregabalin was 100% and 90%, respectively. The purity of the S-Pregabalin was 93% compared with similar samples in the Iran market. Total reaction yield was calculated 24.4%. Conclusion Elevated efficiency of the reaction stages, eliminated toxic solvents, and expensive reactants, reducing the production of industrial wastewater, and recycling were the beneficial outcomes of this project. As a result, we achieved the technical knowledge of producing S-Pregabalin, which was an optimized, simple, and cost-effective approach.