Preparation of carbonic anhydrase inhibitors

A process for synthesis of compounds of formula ##STR7## wherein:

• R.sub.1 and R.sub.2 are both chosen from H or C.sub.1-4 alkyl;
• R.sub.3 =C.sub.1-6 alkyl or CH.sub.2 (CH.sub.2).sub.n OR.sub.4 where R.sub.4 =CH.sub.3 or (CH.sub.2).sub.n CH.sub.3 and n=1-4;
• or (CH.sub.2).sub.n Ar where Ar=unsubstituted phenyl, 3-methoxyphenyl, or 4methoxyphenyl and n=1 or 2 which comprises:
• a. displacing the C(2)-chloro of 3-acetyl-2,5-dichlorothiophene with benzyl mercaptide to form 3-acetyl-5-chloro-2-(benzylthio)thiophene.
• b. converting the compound formed in Step a to 3-acetyl-5-chloro-2-thiophenesulfonamide by first reacting the compound formed in Step a with chlorine to form 3-acetyl-5-chloro-2-thiophenesulfenyl chloride, followed by reaction with ammonia to form 3-acetyl-5-chloro-2-thiophenesulfenyl and oxidation to 3-acetyl-5-chloro-2-thiophenesulfonamide;
• c. brominating the compound from Step b to provide 3-bromoacetyl-5-chloro-2-thiophenesulfonamide;
• d. reducing the compound of Step c with an asymetric reducing agent and then treating it with aqueous base to form (S)-3,4-dihydro-6-chloro-4-hydroxy-2H-thieno[3,2-e]-1,2-thiazine-1,1-dioxi de;
• e. selectively alkylating the compound of Step d using a metal carbonate in dimethyl sulfoxide to provide (S)-3,4-dihydro-6-chloro-4-hydroxy-2-substituted-2H-thieno[3,2-e]-1,2-thia zine-1,1-dioxide;
• f. forming (S)-3,4-dihydro-4-hydroxy-2-substituted-2H-thieno[3,2-e]-1,2-thiazine-6-su lfonamide-1,1-dioxide from the compound of Step e by first reacting with an alkyl lithium, then reacting the resulting anion with sulfur dioxide to form a lithium sulfinate, and then reacting the lithium sulfinate with hydroxylamine-O-sulfonic acid;
• g. protecting the C(6)-sulfonamide of Step f, with trimethyl orthoacetate, activating the C(4)-hydroxyl and displacing it with an amine.