Stereoselective and Enantioselective Strategies for the Commercial-Scale Synthesis of Dorzolamide Hydrochloride

Dorzolamide hydrochloride is a topical carbonic anhydrase (CA) inhibitor that controls elevated intraocular pressure (IOP) associated with open-angle glaucoma and ocular hypertension. An improved commercial-scale synthesis of dorzolamide was developed to overcome the limitations of previously reported methods in terms of yield, cost, and scalability. A key step in this scheme is the highly stereoselective early-stage epimerization followed by recrystallization-based purification of the key intermediate by using a unique solvent system. The optimized synthetic process exhibited robustness in the batch manufacturing of dorzolamide, consistently delivering a 70% overall yield and meeting quality specifications in line with the ICH guidelines. Alternatively, a new synthetic route for dorzolamide hydrochloride has been developed, employing trimethyl orthoacetate and benzylsulfonyl chloride, which features an enantioselective reaction that results in improved yield and purity.