4-Acetamidobenzenesulphonyl chloride

The chemistry of sulphonamides has been dealt exhaustively by Lednicer and Mitscher [64] and by Korger [65]. Generally the sulpha drugs are prepared by two alternative routes (Scheme 1). The first method uses acetanilide (39) as the starting material, which is chlorosulphonated to get 4-acetamidobenzenesulphonyl chloride (40). Reaction of the latter with the appropriate arylamine affords the intermediate 41, which is hydrolysed with an acid or base to form the sulphonamides. Alternatively 4-nitrobenzenesulphonyl chloride (43) may be used to synthesize the sulpha drugs (as shown in Scheme 1). One can also use benzenesulphenyl chloride (45) as the starting material to synthesize the desired sulphonamides [65]. 

QHgNiOiS. Colourless crystals, m.p. 164 5-166-5" C. It is usually prepared by treating p-acetamidobenzenesulphonyl chloride with ammonia, and hydrolysing the acetyl derivative to the base. Used for the treatment of streptococcal infections, gonorrhoea, meningococcal meningitis and urinary infections. Liable to cause unpleasant reactions, such as nausea, cyanosis and skin rashes. 

Note that p-acetamidobenzenesulphonyl chloride will similarly react with primary and secondary amines, and the products, after hydrolysis of the acetyl group, may furnish notable drugs e.g., the condensation products with 2-amino-pyridine and 2-aminothiazole, after remo al of the acetyl groups, provide the drugs commonly known as sulphapyridine (M B 693) and sulphathidzole respectively. 

Sulphapyridine. Dissolve 18-8 g. of 2-aminopyridine in 40 ml. of dry pyridine (Section 11,47,22) in a 250 ml. flask and add 48 0 g. of p-acetamidobenzenesulphonyl chloride (4) the temperature rises to about 70°. Cool, add excess of water, filter the precipitated 2-(p-acet-amidobenzonesulphonamido)p3Tidine (s acetyl-sulphapyridine) at the pump and recrystallise it from 50 per cent, acetic acid. The yield of pm product, m.py. 224°, is 46-5 g. 

The p-acetamidobenzenesulphonyl chloride (Section IX,9) must be pure under no circumstances should it contain more than 1-2 per cont. of the corresponding sulphonic acid. This may be ensured by lixiviating the sulphonyl chloride with pure anhydrous acetone and filtering the solution from the acid. 

Sulphapyridine. Dissolve 4.7 g (0.05 mol) of 2-aminopyridine in a mixture of 40 ml of anhydrous acetone and 6 ml of dry pyridine (CAUTION) in a 250-ml flask, and add 11.7 g (0.05 mol) of pure p-acetamidobenzenesulphonyl chloride (4). The reaction mixture is set aside overnight and 5.5 g of the almost pure 2-( p-acetamidobenzenesulphonamido)pyridine (s acetylsulpha-pyridine) is filtered off by diluting the filtrate with water a further crop (4g) is obtained. The total product is recrystallised from acetone to give white needles of pure product, m.p. 224 °C. The yield is 8g (55%). 

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