| 摘要 |
Preparation of Carbonic Anhydrase Inhibitors Carbonic anhydrase inhibitors, useful in the control of ocular hypertension, and having the formula: wherein: Rl and R2 are both chosen from H or <IMG> C1-4 alkyl; R3 = C1-6 alkyl or CH2(CH2)nOR4 where R4=CH3 or (CH2)nCH3 and n = 1-4; or (CH2)nAr where Ar = unsubstituted phenyl, 3I methoxyphenyl, or 4-methoxyphenyl and n = 1 or 2. are prepared by displacing the C(2)-chloro of 3-acetyl-2,5-dichlorothiophene with benzyl mercaptide to form the thioether of structure, which is then converted to 3acetyl-5-chloro-2-thiophenesulfonamide by reaction with chlorine to form 3-acetyl-5-chloro-2-thiophenesulfenyl chloride, followed by reaction with ammonia to fonn 3acetyl-5-chloro-2-thiophenesulfenamide, and finally oxidation. Bromination provides 3-bromoacetyl-5-chloro-2-thiophenesulfonamide which is converted to (S)-3,4-dihydro-6-chloro-4-hydroxy-2H-thieno¢3,2-e!-1,2-thiazine-1,1-dioxide by reduction with (+)-.beta.-chlorodisopinocampheylborane followed by treatment with aqueous base. Alkylation at N(2) provides the (S)-3,4-dihydro-6-chloro-4-hydroxy-2-substituted-2H-thieno¢3,2-e!-1,2 thiazine-1, 1-dioxide. Formation of the C(6) anion is accomplished by halogen-metal exchange, and the anion is reacted with sulfur dioxide to form a lithium sulfinate, which upon reaction with hydroxylamine-O-sulfonic acid provides the (S)-3,4-dihydro-4-hydroxy-2-substituted-2H-thieno¢3,2-e!-1,2-thiazine-6-sulfonamide-1, 1-dioxide. Protection of the C(6)-sulfonamide functionality, followed by acti-ration of the C(4)hydroxyl and displacement with an appropriate amine provides the (R)-3,4-dihydro-4-alkylamino-2-substituted-2H-thienoC3,2 e!-1,2-thiazine-6-sulfonamide-1,1-dioxide.
|
