Acidity sulfonamides

There are several routes to 3,4-dihydro-2/f- 1,2-benzothiazine dioxides (158), including the cyclization of aminosulfonic acids (157) or cyanosulfonamides (159). 3,4-Dihydro-IH-2,1-benzothiazine dioxides (161) are normally prepared by thermolysis of the sodium sulfonates (160) or aminosulfonamides (162) (71CB1880), and l//-3,4-dihydro-2,3-benzothiazine dioxides (164) are available either by a Pictet-Spengler cyclization of sulfonamides (163) with trioxane or of sulfonamide acids (165) with polyphosphoric acid (76CC470). 

Much of the development of the chemistry of sulfanilamidoselenazole derivatives is a result of the important role played by sulfonamides in chemotherapy and more particularly the good activity of sulfathiazoie against bacterial infections. Backer and De Jonge (441 prepared these derivatives by reaction of 2-amino-4-methyl- and 2-aminO-4-phenyl-selenazoles with A -acetylsulfanilic acid chloride in pyridine.. Alkaline... 

The nucleophiles used are OH (32) [the 2-hydroxythiazole can also be obtained by acidic hydrolysis with strong mineral acids (33)], OR" (5, 8, 30, 34), SR" (8, 9, 12), ArSH (35), and amines (4, 7, 14, 33). Benzamide also reacts with 2-bromothiazole, yielding 2-benzamidothiazole (36). Sulfonamide also reacts with 2-halogenothiazoles in presence of a base and copper powder, yielding 2-sulfonamidothiazoles (37, 38). 

ANTIBACTERIALAGENTSSYNTTiETIC - SULFONAMIDES] (Vol2) 3-Acetyl-4-thiazolidinecarboxylic acid [8064-47-9]... 

Aluminum chloride [7446-70-0] is a useful catalyst in the reaction of aromatic amines with ethyleneknine (76). SoHd catalysts promote the reaction of ethyleneknine with ammonia in the gas phase to give ethylenediamine (77). Not only ammonia and amines, but also hydrazine [302-01-2] (78), hydrazoic acid [7782-79-8] (79—82), alkyl azidoformates (83), and acid amides, eg, sulfonamides (84) or 2,4-dioxopyrimidines (85), have been used as ring-opening reagents for ethyleneknine with nitrogen being the nucleophilic center (1). The 2-oxopiperazine skeleton has been synthesized from a-amino acid esters and ethyleneknine (86—89). 

Acetoiicetyliition Reactions. The best known and commercially most important reaction of diketene is the aceto acetylation of nucleophiles to give derivatives of acetoacetic acid (Fig. 2) (1,5,6). A wide variety of substances with acidic hydrogens can be acetoacetylated. This includes alcohols, amines, phenols, thiols, carboxyHc acids, amides, ureas, thioureas, urethanes, and sulfonamides. Where more than one functional group is present, ring closure often follows aceto acetylation, giving access to a variety of heterocycHc compounds. These reactions often require catalysts in the form of tertiary amines, acids, and mercury salts. Acetoacetate esters and acetoacetamides are the most important industrial intermediates prepared from diketene. 

Relatively unambiguous monotonic SARs also occur where activity depends on the ionization of a particular functional group. A classic example (Fig. 5) is that of the antibacterial sulfonamides where activity is exerted by competitive inhibition of the incorporation of j -amin ohenzoic acid into foHc acid (27). The beU-shaped relationship is consistent with the sulfonamide acting as the anion but permeating into the cell as the neutral species. 

Some related antibacteiials are also included with the sulfonamides. The azo dye, Piontosil (3) is metabolized to sulfanilamide in and was the piogenitoi of the sulfa dmgs. Also, the antibacteiial sulfones, eg, dapsone (4), are believed to act in a similai fashion on enzymes involved with synthesis of fohc acid, leading to bacterial growth inhibition. 

In subsequent studies attempting to find a correlation of physicochemical properties and antimicrobial activity, other parameters have been employed, such as Hammett O values, electronic distribution calculated by molecular orbital methods, spectral characteristics, and hydrophobicity constants. No new insight on the role of physiochemical properties of the sulfonamides has resulted. Acid dissociation appears to play a predominant role, since it affects aqueous solubiUty, partition coefficient and transport across membranes, protein binding, tubular secretion, and reabsorption in the kidneys. An exhaustive discussion of these studies has been provided (10). 

The primary mode of action of the sulfonamides is, however, the interference with the uptake of PABA for the formation of foHc acid [59-30-3]. 

The sulfonamides impede this synthesis and are therefore toxic to those bacteria that synthesize thek own foHc acid. Mammals cannot synthesize this and related vitamins and depend on food sources for them the sulfas are therefore not toxic to mammals in this regard. 

Subsequent knowledge of the stmcture, function, and biosynthesis of the foHc acid coenzyme gradually allowed a picture to be formed regarding the step in this pathway that is inhibited by sulfonamides. The biosynthetic scheme for foHc acid is shown in Figure 1. Sulfonamides compete in the step where condensation of PABA with pteridine pyrophosphate takes place to form dihydropteroate (32). The amino acids, purines, and pyrimidines that are able to replace or spare PABA are those with a formation that requkes one-carbon transfer catalyzed by foHc acid coenzymes (5). 

Development of Resistance. One of the principal disadvantages of sulfonamide therapy is the emergence of dmg-resistant strains of bacteria. Resistance develops by several mechanisms overproduction of PABA (38) altered permeabiUty of the organisms to sulfonamides (39) and reduced affinity of dihydropteroate synthetase for sulfonamides while the affinity for PABA is retained (40). Sulfonamides also show cross-resistance to other sulfonamides but not to other antibacterials. In plasmodia, resistance may occur by means of a bypass mechanism in which the organisms can use preformed foHc acid (41). 

The most common method for the preparation of sulfonamides is by the action of A/-acetylsulfanilyl chloride with the appropriate amine (1). Excess amine or suitable base is used to neutralize the hydrochloric acid formed. 

In a few cases, A/ -heterocycHc sulfanilamides have been prepared by the condensation of an active heterocycHc haHde with the sulfonamide nitrogen of sulfanilamide or its A/-acetyl derivative in the presence of an acid-binding agent. Sulfapyridine, sulfadiazine, and sulfapyrazine have been made by this method (1), but the most important appHcation is probably for the synthesis of sulfachlorapyridazine (9) and sulfamethoxypyridazine (10) (45). 

A study of the effect of stearic acid and 2iac oxide on a sulfonamide-accelerated, sulfiir-cured natural mbber compound dramatically showed the need for both 2iac and fatty acid activators (Fig. 7) (21). 

General Reaction Chemistry of Sulfonic Acids. Sulfonic acids may be used to produce sulfonic acid esters, which are derived from epoxides, olefins, alkynes, aHenes, and ketenes, as shown in Figure 1 (10). Sulfonic acids may be converted to sulfonamides via reaction with an amine in the presence of phosphoms oxychloride [10025-87-3] POCl (H)- Because sulfonic acids are generally not converted directiy to sulfonamides, the reaction most likely involves a sulfonyl chloride intermediate. Phosphoms pentachlotide [10026-13-8] and phosphoms pentabromide [7789-69-7] can be used to convert sulfonic acids to the corresponding sulfonyl haUdes (12,13). The conversion may also be accompHshed by continuous electrolysis of thiols or disulfides in the presence of aqueous HCl [7647-01-0] (14) or by direct sulfonation with chlorosulfuric acid. Sulfonyl fluorides are typically prepared by direct sulfonation with fluorosulfutic acid [7789-21-17, or by reaction of the sulfonic acid or sulfonate with fluorosulfutic acid. Halogenation of sulfonic acids, which avoids production of a sulfonyl haUde, can be achieved under oxidative halogenation conditions (15). 

The first are competitors of PABA (p-aminobenzoic acid) and thus intermpt host de novo formation of the tetrahydrofoUc acid required for nucleic acid synthesis. Examples of dmgs that fall into this group are the sulfones and sulfonamides. The most weU-known of the sulfones is dapsone (70, 4,4 -diaminodiphenyl sulfone, DDS), whose toxicity has discouraged its use. Production of foHc acid, which consists of PABA, a pteridine unit, and glutamate, is disturbed by the substitution of a sulfonamide (stmcturally similar to PABA). The antimalarial sulfonamides include sulfadoxine (71, Fanasd [2447-57-6]) sulfadiazine (25), and sulfalene (72, sulfamethoxypyrazine [152-47-6] Kelfizina). Compounds of this group are rapidly absorbed but are cleared slowly. 

Of these dyes, Acid Yellow 151 (37) still has the greatest market among the yellows. As reported by USITC, production had increased to 1989 tons in 1985 from 706 tons in 1975. It is produced by coupling diazotized 2-amino-l-phenol-4-sulfonamide to acetoacetanilide followed by metallizing with cobalt to obtain a 1 2 cobalt complex. Acid Orange 24 (38), which is sulfanilic acid coupled to resorcinol to which diazotized mixed xyUdines have been coupled, is an unsymmetrical primary diasazo dye with a bihinctional coupling component. 

---