Synthesis Of The Intermediate Of DZA

Dorzolamide is a very important drug for treating glaucoma.The key intermediate dorzolamide DZA 2-4 was synthesized in an three-step-reaction.In the first step the (S)-methyl 3-(thiophen-2-ylthio)butanoate was used as the substrate, after acylation and cyclization,6(S)-methyl-5,6-dihydrothieno[2,3-b]thiopyran-4-one (DZA 2-2) comes out as a product. The second reaction was an oxidation, hydrogen peroxide was used as the oxidant to form the 6(S)-methyl-5,6-dihydrothieno[2,3-b] thiopyran-4-one-7,7-dioxide (DZA 2-3). I n the following step the sodium borohydride was the reducing agent and the product was the 6(S)-4H-Thieno[2,3-b]-thiopyran-4-ol-5,6-dihydro-6-methyl-7,7-dioxide. The process has a more short step, high yield, and easy to implement. Compared to the previous process,it will save more time in the chiral separation.The products were charcaterized by IR,mass spectrometry, NMR,HPLC.And then designseries of experiments to optimize the experimental conditions, to find probably the best reaction conditions.In the first step,the optimized experimental conditions was that:the raw material molar ratio was n(SnCL4):n((S)-methyl 3-(thiophen-2-ylthio)butanoate)=0.5:1.0, the reaction temperature was 0℃,and the reaction time was 2h. The DZA 2-2 was obtained with the yield 96.7% and purity was 98.7%.In the second step,the optimized experimental conditions was that:the raw material molar ratio was n(hydrogen peroxide):n(DZA 2-2)=7.0:1.0, the reaction temperature was 70℃, and the reaction time was 18h.The DZA 2-3 was obtained with the yield 78.6% and purity was 96.4%.In the following step,the optimized experimental conditions was that:the raw material molar ratio was n(hydrogen peroxide):n(DZA 2-3)=0.3:1.0, the reaction temperature was 5℃, and methanol as solvent. The DZA 2-3 was obtained with the yield 97.1% and purity was 98.6%.