Chemical Synthesis, Chiral Analysis And Structural Modification Of Brinzolamide

Brinzolamide is a topical carbonic anhydrase inhibitor. The well curative effects, tiny toxicity and small side effects of Brinzolamide make it an important medicine for curing open angle glaucoma.In this thesis, the preparative methods of Brinzolamide were briefly reviewed, and then the synthetic route of Brinzolamide was designed. The methods of each step in the synthetic route were summarized and compared. Brinzolamide was synthesized from 3-(2-bromoacetyl)-5-chloro-2-thiophenesulfonamide through seven-step reactions, including asymmetric reduction, cyclization, N-alkylation, sulfitation, sulfamation, amino protection and amination. The reactive conditions were optimized in overall yield of 29%. According to the phenomenon and data,the reasonable mechanism of the reactions was presumed respectively.Brinzolamide (S)-isomer was synthesized in similar methods through seven-step reactions in overall yield of 23%.The mixture of brinzolamide and its (S)-isomer, on the ratio 1/1,was analyzed by HPLC, so that the column with ideal resolution factor was screened out, and the test conditions were optimized. The results showed that the purity and e.e. value of synthesized Brinzolamide were 99.86% and 100% respectively. The purity and e.e.value of product compound 5 were 98.91% and 97.81% through HPLC analysis respectively, which showed the excellent chiral selectivity of (+)-Ipc2BCl in related reaction.Considering the disadvantages of Brinzolamide, such as short effective time, poor water-solubility, and eye irritating reaction, the plan of structural modification was proposed on the basis of successful cases and the theoretics of drug design. Five analogs of Brinzolamide with potential biological activity were synthesized.