Journal of Pharmaceutical Research

Abstract

(S)-5,6-Dihydro-6-methylthieno [2,3-b] thiopyran-4-one is a valuable intermediate in Dorzolamide HCl production, a medication that is prevalent in the management of glaucoma. Productive manufacturing of the intermediate ensures its production on an industrial scale with high yield and purity. The synthesis of the important intermediate should be optimized through this research to enhance the yield, purity, and production at large scales. The synthesis process involved several steps, beginning with the reaction of methyl (R)-3-hydroxybutyrate with p-toluenesulfonyl chloride, followed by the formation of a lithiated thiophene intermediate, esterification, hydrolysis, and cyclization. The reactions were monitored using Thin-Layer Chromatography (TLC), Infrared (IR) Spectroscopy, Proton Nuclear Magnetic Resonance (1H NMR) Spectroscopy, and Gas Chromatography-Mass Spectrometry (GC-MS) to monitor the reaction progress and establish product purity. The major reagents used were n-butyllithium, oxalyl chloride, and DMF. Reaction conditions such as solvent selection, temperature, and stirring time were also maximized to improve the yield of the end product. Route optimization greatly enhanced the yield of (S)-5,6-dihydro-6-methylthieno[2,3-b]thiopyran-4-one from 40% to 60%. TLC, IR, NMR, and GC-MS characterization established that the purity and structure of the final product were very high. The process was more efficient in every step of the reaction, especially the cyclization and esterification steps, with better yields and lower byproducts. This study optimized the synthesis of (S)-5,6-dihydro-6-methylthieno[2,3-b]thiopyran-4-one, which greatly enhanced the purity and yield and provided a scalable and efficient process for large-scale production of the Dorzolamide HCl intermediate.

Keywords: Synthesis optimization, Dorzolamide, Pharmaceutical intermediates