Sulfonamides reaction with, phosgene

This reaction is typical for the synthesis of sulfonylureas it is mildly exothermic and proceeds smoothly in a variety of inert aprotic solvents. The product is usually obtained in very high yield, as a fine crystalline precipitate. The sulfonyl isocyanates are readily prepared from the substituted benzene sulfonamides by reaction with phosgene, Fig. 3, in the presence of an alkyl isocyanate, for example, butyl isocyanate in an inert solvent at 120 to 140°C according to the general procedure of H. Ulrich and A. A. R. Sayigh (Ref. 3). 

Acetazolamide Acetazolamide is 5-acetamido-l,3,4-thiadiazole-2-sulfonamide (9.7.5). The synthesis of acetazolamide is based on the production of 2-amino-5-mercapto-l,3, 4-thiadiazole (9.7.2), which is synthesized by the reaction of ammonium thiocyanate and hydrazine, forming hydrazino-N,N -( ji-(thiourea) (9.7.1), which cycles into thiazole (9.7.2) upon reaction with phosgene. Acylation of (9.7.2) with acetic anhydride gives 2-acetylamino-5-mercapto-l,3,4-thiadiazol (9.7.3). The obtained product is chlorinated to give 2-acetylamino-5-mercapto-l,3,4-thiadiazol-5-sulfonylchloride (9.7.4), which is transformed into acetazolamide upon reaction with ammonia (9.7.5) [24,25]. 

Sulfonamides only combine with phosgene with difficulty. Reaction only occurs at temperatures in excess of 200 C, with the result that low yields of the corresponding sulfonyl isocyanates are obtained (because of cleavage of the S-N bond) [2087a] ... 

Coupling Processes. The coupling can be carried out as in Equation 1 by preparing a sulfonylisocyanate by treating the sulfonamide with phosgene in the presence of butyl isocyanate (BuNCO) in xylene at reflux. Frequently 1,4-diazabicyclooctane (DABCO) aids in catalyzing this reaction. The sulfonyl isocyanate which is usually an oil can be added to a solution or sus nsion of the aminoheterocycle in a solvent such as methylene chloride or acetonitrile. The desired sulfonylurea usually precipitates as a white crystalline solid. Dry conditions are essential to avoid hydrolysis of the extremely water sensitive isocyanate. 

Commercially important arenesulfonyl isocyanates are not directly accessible from the corresponding sulfonamides via phosgenation due to lack of reactivity or by-product formation at elevated temperatures. A convenient method for their preparation consists of the reaction of alkyl isocyanates with sulfonamides to produce mixed ureas which, upon phosgenation, yield a mixture of alkyl and arenesulfonyl isocyanates. The desired product can be obtained by simple distillation (16). Optionally, the oxalyl chloride route has been employed for the synthesis of arenesulfonyl isocyanate (87). 

Several methods have been developed which avoid the use of phosgene. One such route is the reaction of methyl N-heterocyclylcarbamates with sulfonamides in the presence of trimethyl aluminum (Equation 2) to yield sulfonylureas according to Petersen (2). 

The methods described in equations 2-5 are useful in situations where the sulfonylisocyanate is not available. All of these require using a carbamate which can be prepared from the sulfonamide or heterocyclic amine with the appropriate chloroformate. In addition to the added step of chlorformate formation from phosgene and an alcohol, special care is required to prepare some of the carbamates. Although the phenyl carbamates of heterocyclic amines react, as desired, with a broad range of sulfonamides the reaction of phenyl carbamates of sulfonamides is restricted due to the failure of these interme tes to react with triazine amines. 

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