R S" "SO2NH2
configuration), the alkylation product with the desired stereochemistry, 4.147, was obtained. Cyclization of 4.147 (after hydrolysis of the ester moiety) was achieved in the presence of trifluoroacetic anhydride in toluene, when ketone 4.148 was obtained in good yields. Its reduction with LiAlH4 in 95% yield gave the cis-alcohol 4.149a, which was epimerized to 4.149b in the presence of cold 1 N H2SO4. A mixture of 76:24 trans/cis epimeric alcohols resulted, which was oxidized with H2O2/Na2WO4 to the sulfone 4.150. By a Ritter reaction with acetonitrile, 4.150 was transformed into the acetamido derivative 4.151. An interesting discovery in these syntheses was that the Ritter reaction occured with retention of configuration for the trans alcohol and with considerable inversion for the cis alcohol. However, finally the desired compound 4.151 was formed preferentially. This was converted to the corresponding sulfonyl chloride 4.152 and sulfonamide 4.153, followed by reduction of the acetamide to the ethylamino moiety with borane-dimethylsulfide, to obtain 4.144. The hydrochloride salt of 4.144 is dorzolamide (MK-507).
The second clinically used topical CAI brinzolamide (4.154) was developed by Alcon Laboratories, probably by using dorzolamide (4.144) as lead (Dean et al. 1993). The two compounds are structurally very similar, with brinzolamide possessing a slightly modified ring, i.e., the 2-substituted-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide class. The main difference between the Merck and Alcon work was that Alcon researchers did not generally publish their research in scientific journals but only patented these compounds (Dean et al. 1993). Only recently have some brinzolamide congeners been described in some detail in a published paper (Chen et al. 2000).
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