Sulfonamides acetylation

Hydroamination of Allenes Different related amines can also be cyclized. The use of free amino groups led to long reaction times (several days), but sulfonamides, acetyl or BOc as protecting group led to fast conversion (in the latter case, problems of diastereoselectivity were observed). Optimization studies showed that, although cationic gold (I) complexes were not effective for these conversions, AuCI was a very good catalyst for these reactions. 

Sulfonamides Acetylated metabolites Devoid of antibacterial activity, but elevated concentrations are associated with increased toxicity... 

The sulfonamides are metabolized in the liver. The major derivative is the N4-acetylated sulfonamide. Acetylation, which occurs to a varying extent with each agent, is disadvantageous because the resulting products have no antibacterial activity yet retain the toxic potential of the parent substance. Sulfonamides are eliminated partly as the unchanged drug and partly as metabolic products. The largest fraction is excreted in the urine, and the tj of sulfonamides in the body thus... 

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

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. 

The resulting acetyl compound is usually hydrolyzed with aqueous alkaU to give the free amine. Other A/-acyl derivatives may be used, particularly for the less soluble succinyl and phthaloyl products. The use of -nitrobenzenesulfonyl chloride, followed by reduction of the nitro to an amino function, is much more expensive and is rarely used. A/-Acetylsulfanilyl chloride [121 -60-8] is obtained by the chlorosulfonation of acetanilide [103-84-4] which is the basic material for most of the sulfonamides. 

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). 

Acylation of a sulfonamide on the amide nitrogen serves to remove the sometimes objectionable taste of these drugs. Reac-I ion of intermediate, 154, with acetic anhydride followed by reduction of the nitro group affords acetyl methoxyprazine (156). The last, which has much the same biologic action as Mie parent compound, is used for oral administration in syrups. 

Inclusion of a para acetyl group requires a somewhat different approach to the preparation of these compounds. Reaction of the diazonium salt from p-aminoacetophenone with sulfur dioxide affords the sulfonyl chloride, 203 this is then converted to the sulfonamide, 204, Elaboration via the carbamate with cyclohexyl-amine affords acetohexamide (205). ... 

By heating the diacetyl compound with sodium hydroxide solution partial saponification of the acetyl groups takes place. 25.6 grams of diacetyl compound are heated to boiling for some hours with 100 cc of 2 N sodium hydroxide solution. The precipitate produced by acidification of the solution with acetic acid is filtered off and treated with dilute sodium carbonate solution. The 4-aminobenzene-sulfonacetylamide passes into solution while the simultaneously formed 4-acetylaminobenzene-sulfonamide remains undissolved. It is filtered with suction and the filtrate again acidified with acetic acid. The 4-aminobenzene-sulfon-acetamide separates out and is recrystallized from water. It forms colorless lustrous rhombic crystals Of MP 1B1°C. 

Acetyltransferases catalyze the acetylation of amino, hydroxyl, and thiol functional groups. Acetylation of hydroxy and thiol groups is comparatively rare and of much less importance in alkaloid metabolism than reactions with amino functional groups. The types of amines that are acetylated include arylamines (the major route of metabolism in many species), aliphatic amines, hydrazines, sulfonamides, and the a-amino group of cysteine conjugates. The purification, physical properties, and specificity of the N-acetyltransfereases have been reviewed (116-118). 

Antibacterial sulfonamides contain two N-atoms, the sulfonamido (N1) and the para primary amino (N4). The sulfonamido group, in contrast to a carboxamido group, is chemically and metabolically stable. In other words, hydrolytic cleavage of sulfonamides to produce a sulfonic acid and an amine has never been observed. We, therefore, focus our discussion on the primary amino group, acetylation of which is one of the major metabolic pathways for some sulfonamides. Hydrolysis of the N4-acety luted metabolites back to the parent sulfonamide can occur in the liver, kidney, and intestinal tract. The reaction is strongly influenced by the structure of the parent amine e.g., N4-acetylsulfisoxazole (4.121) was deacetylated by intestinal bacteria whereas /V4-acctyIsulI anilamide (4.122) under identical conditions was not [78][79],... 

Recently the hydroxy metabolites of various sulfonamides could be Isolated and purified, so that specific HPLC techniques could be developed (22,23). As shown in Figure 1, sulfadimidine can be metabolized by hydroxylation at the 5 and 6 position of the pyrimidine ring and by the acetylation- deacetylation pathway (21). After hydroxylation, the metabolites may become glucuronidated and also acetylated (Figure 2). The hydroxy metabolites are microbiologically active and they can be potentiated by trimethoprim (13). 

Newbould and Kilpatrick (N3) found that addition of plasma to the fluid perfusing a rabbit liver preparation reduced the rate of acetylation of two long-acting sulfonamides and that the rate of metabolism was dependent on the concentration of unbound drug. Anton and Boyle (A8) and Wiseman and Nelson (W15) using data from both in vitro and in vivo techniques reported a correlation between the rate of metabolism of a sulfonamide and the extent of protein binding. 

Sulfasalazine is absorbed in the proximal intestine and is then excreted unchanged in the bile. In consequence most of orally administred sulfasalzine reaches the colon as such. It is then split by the intestinal flora into its components sulfapyridine, a sulfonamide antimicrobial agent, and 5-aminosalicylic acid (5-ASA). It has been proven that in inflammatory bowel disease 5-ASA is responsible for the beneficial effects while the sulpha component only contributes to the adverse reaction profile. Although some 5-ASA is absorbed and excreted in urine with a half-life of 0.5-1.5 hours, most is eliminated unchanged in the faeces. Sulfapyridine is to a major extend reabsorbed, metabolized in the liver and excreted in the urine with a half-life, depending on the acetylator phenotype, between 5 and 15 hours. 

Sulfonamides are rather slowly absorbed with peak blood levels 2-6 h after oral intake. Intravenous preparations are sometimes used with comatose patients. Sulfonamides are distributed throughout the body, including the CNS. Binding to serum proteins varies from 20% to 90%. Several sulfonamides are acetylated in the liver followed by excretion in the urine. Soluble sulfonamides are eliminated by glomerular filtration. 

The short-acting sulfonamides include sulfadimidine, sulfamerazine and sulfathiazole. Sulfadimidine, as the most important representative of this group, is relatively soluble and has therefore a lower risk of causing crystalluria while sulfamerazine and sulfathiazole are less soluble sulfonamides. Sulfadimidine has good oral absorption. It has an elimination half-life between 1.5 and 5 hours, depending on acetylator phenotype. 

The sulfonamides are degraded in the liver by acetylation and oxidation metabolites have reduced bacteriological activity. The parent compound and the metabolites are excreted in the urine, primarily by glomerular filtration followed by tubular reabsorption. Some sulfonamides exhibit diurnal variations in excretion, being three times greater at night than during the day. 

Acetylation of sulfonamides is reduced by protein binding, but the formation of glucuronide conjugates is unaffected. 

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