Salicylic acid esters, hydrolysis

The effects of [1-CD on the kinetics of hydrolysis of salicylic acid esters (199 R = Me, m-nitrophenyl and p-nitrophenyl) have been examined, as has the Smiles rearrangement of (199 R = Me). The latter was accelerated by [1-CD but its hydrolysis was not affected. Various other effects are reported for the other esters.169... 

Type I reprc.sents those that are formed by modifying the carboxyl group (c.g... salt.s. esters, or amides). Type II (a and h) represents those that are derived by substitution on the hydroxyl group of salicylic acid. Tlte derivatives of salicylic iicid were introduced in an attempt to prevent the ga.stric symptoms and the undesirable taste inherent in the common salts of. salicylic acid. Most hydrolysis of type I takes place in the intestine, and most of the type II compounds arc absorbed unchanged into the bloodstream (see aspirin). 

NSAIDs) has been reported [36]. As shown in Table 8.3, the hydrolysis of the methyl esters in human plasma proceeds far too slowly to be of therapeutic interest, with tm values ranging from ca. 5 to 150 h. In contrast, the carbamoylmethyl benzoates are hydrolyzed very rapidly (perhaps too rapidly ) with tm values in the order of minutes. But Table 8.3 also illustrates another important point, namely the marked influence of the acyl moiety on the rate of hydrolysis, with a more than 500-fold difference between the smallest and the largest acid (salicylic acid and sulindac, respectively). 

The case of aspirin in Table 8.3 is of special interest. Indeed, its acetyl ester group is particularly labile to enzymatic and nonenzymatic hydrolysis (see Sect. 7.4), and the reaction is even faster when the carboxy group is neutralized by esterification. A true ester prodrug of acetylsalicylic acid must fulfill the condition that its hydrolysis liberates aspirin rather than a prodrug of salicylic acid. An investigation of several aspirin prodrugs confirmed the interest of carbamoylmethyl esters and showed the (ATV-diethylcarbamoyl)methyl ester (Table 8.3) to liberate the highest proportion (ca. 60%) of aspirin [37], In... 

Most published examples of prodrugs of relevance in the present context contain an a-amino acyl moiety. A number of reasons may explain this fact, such as the lack of toxicity of these natural compounds, the large differences in lipophilicity and other properties between amino acids, and the variability afforded by A-substituents. Interesting examples are provided by salicylic acid and metronidazole. Thus, the hydrolysis of tyrosine and methionine prodrugs of salicylic acid (8.104 and 8.105, respectively) was examined in rabbits after intraduodenal and intracecal administration [134], The former ester, but not the latter, was hydrolyzed in the mucosa of the small intestine. In addition, both prodrugs underwent marked hydrolysis by intestinal microflora. 

Aspirin is an ester, bnt it still contains a carboxylic acid fnnction (p/Ca 3.5). In aqueous solntion, there will thus be significant ionization. However, this ionization now provides an acid catalyst for ester hydrolysis and initiates autolysis (autohydrolysis). The hydrolysis product salicylic acid (pACa 3.0) is also acidic both aspirin and salicylic acid are aromatic acids and are rather stronger acids than aliphatic compounds such as acetic acid (pACa 4.8) (see Section 4.3.5). An aqueous solution of aspirin has a half-life of about 40 days at room temperature. In other words, after about 40 days, half of the material has been hydrolysed, and the biological activity will have deteriorated similarly. 

Ester hydrolysis does not invariably lead to inactive metabolites, as exemplified by acetylsalicylic acid. The cleavage product, salicylic acid, retains pharmacological activity. In certain cases, drugs are administered in the form of esters in order to facilitate absorption (enalapril enalaprilate testosterone undecanoate testosterone) or to reduce irritation of the gastrointestinal Lullmann, Color Atlas of Pharmacology... 

Sahcylsalicylic acid [532-94-3] (salsalate) is prepared by the action of phosphoms trichloride, phosphoms oxychloride, or thionyl chloride on salicylic acid at low temperatures in an appropriate solvent. The cmde product is recrystallized rapidly from ethyl alcohol to avoid hydrolysis and esterification. It is used as an analgesic and an antipyretic, as well as in the treatment of acute and chronic rheumatism and arthritis. It does not induce gastric disturbances because it is only slowly hydrolyzed in the intestine. Owing to the slowness of its hydrolysis (two molecules of salicylic acid per molecule of the ester), the action of sahcylsalicylic acid is less prompt but more persistent than that of other salicylates. Other salicylates of interest include ethylene glycol mono salicylate [87-28-5], dipropylene glycol monomethylether salicylate, bomyl salicylate [560-88-3], and -acetamidophenyl salicylate [118-57-0]. 

Esters (and certain other compounds) may be susceptible to hydrolysis by low or especially high pH, or in the presence of alkaline metal or alkaline earth salts. In the presence of acid, i.e., anion and hydrogen ion, the reaction is at equilibrium. However, in the presence of base and the associated cations, the reaction is driven to completion (e.g., acetyl salicylic acid and the effect of sodium and magnesium salts on the rate and extent of reaction). 

Although metal-promoted hydrolysis of phosphate esters is a topic of very current interest (Section 61.4.4), little work has been published dealing with the effects of metal ions on the hydrolysis of sulfate esters. The acid-catalyzed hydrolysis of aryl sulfates has been shown to occur by an A-l mechanism (Scheme 34).434 Nucleophilic catalysis by amines has been observed in the hydrolysis of p-nitrophenyl sulfate435 and intramolecular carboxyl group catalysis occurs with salicyl sulfate436 as with salicyl phosphate. 

A classic example of ester hydrolysis is demonstrated with aspirin. Aspirin hydrolyzes under acidic and basic conditions to yield acetic and salicylic acid (Fig. 2) (6). Aspirin easily hydrolyzes because it is an activated ester (i.e., the leaving group, carboxylate anion, can readily stabilize the anionic charge). An additional API example that undergoes ester hydrolysis is cyclandelate (7). 

Hydrolysis is an important route of metabolism for esters, amides, carbamates, and acyl hydrazines. Aspirin is rapidly converted to salicylic acid this may be further metabolised to gentisic acid (5-hydroxysalicylic acid), conjugated with glucuronic acid or glycine, or excreted unchanged. 

Hydrolysis is a major biotransformation pathway for drugs containing an ester functionality. This is because of the relative case of hydrolyzing the ester linkage. A classic example of ester hydrolysis is the metabolic conversion of aspirin (acetylsalicylic acid) to salicylic acid. " Of the two aslcr moieties present in cocaine, it appears that, in general, the methyl group is hydrolyzed preferentially to yield ben-roylecgoninc os the major human urinary metabolite. The... 

Aspirin, the widely used analgesic, is the acetyl ester of salicylic acid and is very susceptible to hydrolysis moisture in the air is sufficient to bring about significant decomposition. A bottle of aspirin tablets smells of vinegar when opened this is due to the reaction shown in Figure 8.20 taking place to liberate salicylic and acetic acids. The rate of decomposition is increased because members of the public often store medicines in a cabinet in the bathroom, the one room in the house that is almost guaranteed to have a hot, steamy atmosphere ideal for hydrolysis reactions. 

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