Synthesis Of Important Intermediate Of Brinzolamide And Its Analogues

Brinzolamide, as a new topical carbonic anhydrase inhibitors, is currently the drug of first choice for treatment of glaucoma, and has high selectivity, affinity, and good security. The synthesis of important intermediate of brinzolamide and its analogues was studied in this thesis, and then reactive conditions of some steps were optimized.Starting from thiophene, we compared some factors such as material cost, operational feasibility and industrialization, and prepared (S)-3,4-dihydro-6-chloro-4-hydroxy-4H-thieno-[3,2-e]-1,2-thiazine-1,1-dioxide by 6 steps including chlorination, C-acylation, etherification, sulfamation, carbonyl a-hydrogen bromination and asymmetric reduction-cyclization. The total yield was 21%, ee>97%.The process of bromination of 3-acetyl-5-chloro-2-thiophenesulfonamide was improved, by using 1,3-dibromo-5,5-dimethylhydantoin, copper bromide, N-bromosuccinimide, hydrobromic acid, and liquid bromine as brominating agents instead of pyridinium bromide perbromide. After comparison, it was found that 1,3-dibromo-5,5-dimethylhydantoin has good effect, and the reactive conditions were optimized by orthogonal experiment. The optimium conditions were determined as follows:reactive temperature is 40℃, mole ratio of 3-acetyl-5-chloro-2-thiophenesulfonamide to 1,3-dibromo-5,5-dimet-hylhydantoin is 1:1.4, and time is 5 hours. The novel synthesis increased the yield to 75%, and reduced cost and pollution.Five analogues were synthesized via N-alkylated reaction to (S)-3,4-dihydro-6-chloro-4-hydroxy-4H-thieno-[3,2-e]-1,2-thiazine-1,1-dioxide, and then two kinds of sulfa compounds were prepared by sulfamated reaction to parts of above-mentioned N-alkylated products.