Sulfanilamide protecting groups

The final step in the synthesis of the target molecule, sulfanilamide, is the conversion of the sulfonyl chloride intermediate to a sulfonamide and the removal of the 2,2,2-trifluoroacetyl protecting group. These transformations are accomplished in one step because both reactions take place upon heating the protected sulfonyl chloride with aqueous ammonia. The reaction sequence is shown here ... 

Sulfisoxazole Sulfisoxazole, ATi-(3,4-dimethyl-5-isoxazolyl)sulfanilamide (33.1.19), is synthesized by reacting 4-acetylaminobenzenesulfonyl chloride with 5-amino-3, 4-dimethylisoxazol (33.1.17), which is in turn synthesized by heterocyclization of 2-methy-lacetylacetonitrile with hydroxylamine, and subsequent acidic hydrolysis (hydrochloric add) of the protective acetyl group in the resulting product (33.1.18) [18,19]. 

There has been much emphasis during the last few decades on bacteriostatic agents, which prevent or slow down the rate of bacterial growth and reproduction, so thal the natural protective mechanisms of the body can overcome the infection. These chemicals include the sulfonamide group, such as sulfathiazole, sulfadiazine, sulfanilamide, sulfasuxidine, and... 

What would happen in the synthesis of sulfanilamide if the amino group were not protected as an amide in the chlorosulfonation step ... 

Domagk s (7) discovery that Prontosil protected mice against lethal infections with streptococci and the findings of Foumeau and his group (8) that sulfanilamide was the chemotherapeutically active moiety of Prontosil initiated a... 

Acetylation of aniline produces acetanilide (2) and protects the amino group from the reagent to be used next. Treatment of 2 with chlorosulfonic acid brings about an electrophilic aromatic substitution reaction and yields/>-acetamidobenzene-sulfonyl chloride (3). Addition of ammonia or a primary amine gives the diamide, 4 (an amide of both a carboxylic acid and a sulfonic acid). Finally, refluxing 4 with dilute hydrochloric acid selectively hydrolyzes the carboxamide linkage and produces a sulfanilamide. (Hydrolysis of carboxamides is much more rapid than that of sulfonamides.)... 

The protecting acetyl group is removed by acid-catalyzed hydrolysis to generate the hydrochloride salt of the product, sulfanilamide. Note that of the two amide linkages present, only the carboxylic acid amide (acetamido group) was cleaved, not the sulfonic acid amide (sulfonamide). The salt of the sulfa drug is converted to sulfanilamide when the base, sodium bicarbonate, is added. 

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