Ester of aspirin

A reaction with a rate constant that conforms to Eq. (10-21)—particularly to the feature that the catalysts are H+ and OH-, and not weak acids and bases—is said to show specific acid-base catalysis. This phenomenon is illustrated by the kinetic data for the hydrolysis of methyl o-carboxyphenyl acetate16 (the methyl ester of aspirin— compare with Section 6.6) ... 

N. M. Nielsen, H. Bundgaard, Evaluation of Glycolamide Esters and Various Other Esters of Aspirin as True Aspirin Prodrugs , J. Med. Chem. 1989, 32, 727-734. 

NPC is ideally suited for the analysis of compounds prone to hydrolysis because it employs nonaqueous solvents for the modulation of retention. An example of the use of NPC in the analysis of a hydrolysable analyte was demonstrated by Chevalier et al. [28] for quality control of the production of benorylate, an ester of aspirin. A major issue in benorylate production is the potential formation of impurities suspected of causing allergic side effects therefore monitoring of this step is critical to quality control. The presence of acetylsalicylic anhydride prohibited the use of RPLC since it can be easily hydrolyzed in the water-containing mobile phase. However, an analytical method based on the use of normal-phase chromatography with alkylnitrile-bonded silica as the stationary phase provided an ideal solution to the analysis. Optimal selectivity was achieved with a ternary solvent system hexane-dichloromethane-methanol, containing 0.2 v/v% of acetic acid to prevent the ionization of acidic function and to deactivate the residual silanols. The method was validated and determined to be reproducible based on precision, selectivity, and repeatability. 

The pH-rate profile of the methyl ester of aspirin has three regions, with slopes -1, zero and +1, and the molecule does not contain ionisable groups. By analogy with Figure 13.4, the pseudo-first-order rate constant must have the form... 

Zhao, W, Mackenzie, G.G., Murray, O.T., Zhang, Z., and Rigas, B. (2009). Phosphoaspirin (Mdc-43), a novel benzyl ester of aspirin, inhibits the growth of human cancer cell lines more potently than aspirin A redox-dependent effect. Carcinogenesis 30, 512-519. 

In recent years, several organic reagents have been found which rather selectively carry out 0-acylation of arylhydroxylamine compounds (e.g. Fig. 17). This apparent violation of the general rule was first reported for acetyl cyanide (36, 68, 78). Recently, aspirin was reported to facilitate the covalent binding of carcinogenic arylhydroxylamine compounds to DNA, and it was proposed that an intermolecular transfer of the acetyl group from the phenolic ester of aspirin to the -OH of the arylhydroxylamine compound occurred to produce the arylhydroxylamine-O-acetyl ester (75). Unfortunately, the direct detection of this intermediate was not accomplished. Explanations of these unusual and specific 0-acylations are not yet available. 

Esters of the phenohc hydroxyl are obtained easily by the Schotten-Baumaim reaction. The reaction ia many cases iavolves an acid chloride as the acylating agent. However, acylation is achieved more commonly by reaction with an acid anhydride. The single most important commercial reaction of this type is the acetylation of sahcyhc acid with acetic anhydride to produce acetylsahcyhc acid [50-78-2] (aspirin). 

You will see, by examining this structure, that aspirin is an ester of acetic acid. Aspirin is mankind s most widely used drug. Somewhat over 20 million pounds of aspirin are manufactured each year in the United States alone This amounts to something like ISO five-grain tablets for every person in the country ... 

Some of the pancreatic enzymes in the lumen include pancreatic amylase, pancreatic lipase, elastase, trypsin, a-chymotrypsin, and carboxypeptidase A. For example, the aspirin derivatives aspirin phenylalanine ethyl ester, aspirin phenyllactic ethyl ester, and aspirin phenylalanine amide have been studied as substrates for carboxypeptidase A [67,68], with the phenylalanine ethyl ester derivative proving to be the best substrate. This study indicated that the carboxypeptidase A may serve as a reconversion site for many drug derivatives. 

Erdmann and Uhrich (2000 Erdmann et al., 2000) recently synthesized novel poly(anhydride-co-ester)s containing salicylic acid in the backbone, by melt polycondensation of the disalicylic acid ester of sebacic acid, poly[bis(o-carboxyphenoxy)sebacate] (PCPS) and the copolymer P(CPH-CPS). The release of salicylic acid (the active form of aspirin) from the former was studied in vitro and from the latter was studied in vivo (Erdmann and Uhrich, 2000 Erdmann et al., 2000). Similar polymers that release 5-amino salicylic acid, and p-nitro salicylic acid have been prepared... 

Salicylic acid is manufactured on a large scale. In the dye industry it serves for the production of valuable azo-dyes which exhibit great fastness. To some extent these dyes are applied to mordanted fibres. In addition, the acid and its derivatives are widely used in pharmacy. Being a phenolcarboxylic acid it has a powerful disinfecting action (preservative). It has further proved itself an important antirheumatic and an analgetic. The derivative in which the phenolic hydroxyl group is acetylated (aspirin) has become especially popular. The first medicament of the series was the phenyl ester of salicylic acid, salol, which is produced as a by-product in the technical process. The preparation of salicylaldehyde has been described above (p. 235). 

Intramolecular general base catalysed reactions (Section II, Tables E-G) present less difficulty. A classification similar to that of Table I is used, but since the electrophilic centre of interest is always a proton substantial differences between different general bases are not expected. This section (unlike Section I, which contains exclusively unimolecular reactions) contains mostly bimolecular reactions (e.g. the hydrolysis of aspirin [4]). Where these are hydrolysis reactions, calculation of the EM still involves comparison of a first order with a second order rate constant, because the order with respect to solvent is not measurable. The intermolecular processes involved are in fact termolecular reactions (e.g. [5]), and in those cases where solvent is not involved directly in the reaction, as in the general base catalysed aminolysis of esters, the calculation of the EM requires the comparison of second and third order rate constants. 

Acetylsalicylate deacetylase Aspirin esterase, aspirin hydrolase Acetyl esters of aryl alcohols, negatively charged esters... 

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... 

H. Bundgaard, N. M. Nielsen, A. Buur, Aspirin Prodrugs Synthesis and Hydrolysis of 2-Acetoxybenzoate Esters of Various V-(Hydroxyalkyl)amides , Int. J. Pharm. 1988, 44, 151-158. 

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. 

Half-life in water 52 h at pH 7.0 and 25°C ca 40 days at pH 2.5 and 25°C. Additional information The rate of HO catalysed hydrolysis of esters is > the rate of H hydrolysis of esters. Solid aspirin absorbs water from the atmosphere and then hydrolyses (Fig. 2.13). 

Many of the fragrances and tastes from plants are due to esters. The smells we perceive are generally due to a combination of esters, but often one ester fragrance will dominant. By mimicking these natural esters, the food industry has synthesized hundreds of different flavoring agents. Three of these are shown in Figure 15.14. Many pheromones are esters. Pheromones are chemical compounds used by animals for communication. Many medications are also esters. Aspirin is an ester of salicylic acid (see Chapter 13). 

A typical example of an intramolecularly catalyzed reaction is the hydrolysis of aspirin (equation 2.15).12 The hydrolysis of the ester bond is achieved by intramolecular general-base catalysis. Comparison with the uncatalyzed hydrolysis rate of similar compounds gives a rate enhancement of some 100-fold from the catalysis.13 This may be extrapolated to a figure of 5000-fold if the pKa of the base is 7 rather than the value of 3.7 in aspirin. 

Despite the presence of water throughout the body, hydrolysis reactions of esters and amides require enzymes to proceed at an appreciable rate. Numerous enzymes throughout the body carry out hydrolysis reactions. The enzymes, both esterases and amidases, are found in the digestive system, individual cells, and plasma. The exact site of hydrolysis of a specific drug depends on the drug s structure and functionality. The ester in aspirin... 

It is interesting to take notice of the effect of an aromatic carboxylic acid group on hydrolysis. The effects of pH on the hydrolysis of aspirin and aspirin methyl ester have been investigated. 

FIGURE 5.31 pH-rate constant profiles for the hydrolysis of aspirin (dotted line) and aspirin methyl ester (solid line). [Graph reconstructed from data by G. M. Loudon, J. Chem. Ed., 68, 973 (1991).]... 

The pH-rate constant profiles of aspirin and aspirin methyl ester are shown in Figure 5.31. The profiles for aspirin methyl ester and aspirin are partitioned into three and four zones, respectively. Distinctively, the aspirin methyl ester profile is expressed by Equation (5.158b). The aspirin profile has similar hydrolysis rates in the zones of very low and very high pH to the aspirin methyl ester profile. However, in the range of pH 3 to 7, aspirin shows one upward bend at a pH close to 3.5, which is about the pKa (=3.4) of aspirin. At pH 4 to 5, the hydrolysis rate of aspirin is... 

Lipoic acid uses its S-S bond in redox reactions (Chapter 50), while shikimic acid is an intermediate in the formation of compounds with benzene rings, such as phenylalanine, in living things (Chapter 49). Salicylic acid s ethyl ester is aspirin, which is, of course, like the last example ibuprofen, a painkiller. 

Salbutamol is made from aspirin, itself simply the acetate ester of the natural product salicylic acid, by a series of substitution reactions. The first is a Friedel-Crafts acylation (an electrophilic substitution) in which aspirin itself is the acylating agent it is an isomerization in which the acetyl group gets transferred from O to C. Acylation occurs para to the electron-donating alkoxy substituent, and gives this ketone. 

Acetic anhydride is used to make acetic acid esters. It is especially effective in difficult acetylations, such as in the manufacture of aspirin and cellulose acetate. 

Aspirin is an ester of salicylic acid and ethanoic acid. Paracetamol and ibuprofen are also compounds containing C=0 bonds (Figure 4.8). 

Aspirin (= Acetylsalicylic Synthetic acetate ester of Salicylic COX (PGH, synthase)... 

Non-cytochrome P450 enzymes may also be involved in oxidative reactions. One such enzyme is alcohol dehydrogenase whose substrates include vitamin A, ethanol, and ethylene glycol. Aldehyde dehydrogenase is another enzyme. Most reduction reactions also involve microsomal enzymes, with the exception of ketone reduction. Nitro compounds are reduced to amines and volatile anesthetics undergo dehalo-genation by microsomal enzymes. Hydrolysis reactions are involved in metabolism of compounds with amide bonds or ester linkages, as in the conversion of aspirin to salicylate (Brown, 2001). 

Salol and Aspirin.— The sodium salt and several derivatives possess medicinal properties as internal antiseptics as antipyretics or temperature reducers, and to lessen the pain of rheumatism. The most common of these are salol, which is the phenyl ester of salicylic acid, as an acid, and aspirin, which is the acetic acid ester of salicylic acid, as a phenol. 

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