Acetylsalicylic anhydride

Fig. 4 Effect of acetylsalicylic anhydride impurity on the dissolution rate of aspirin tablets. (From Ref. 34.)...

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. 

Bundgaard, H. Influence of an acetylsalicylic anhydride impurity on the rate of dissolution of acetylsalicylic acid. J. Pharm. Pharmacol. 1974, 26, 535-540. Klug, D.L. The influence of impurities and solvents on crystallization. In Handbook of Industrial Crystallization Myerson, A.S. Ed. Butterworth-Heinemann Boston, 1993 65-87. 

Fig. 16. Formation of AT-salicyloyl amines by aminolysis of acetylsalicylic anhydride and acetylsalicylsalicylic acid...

These results strongly suggest that the immunogenic effect of acetylsalicylic acid preparations as observed in experimental animals is due to acetylsalicylic anhydride and/or acetylsalicylsalicylic acid present as impurities in the preparations and not to the acetylsalicylic acid itself. By extrapolation of these findings to clinical acetylsalicylic acid allergy, it may appear that the impurities rather than the drug substance itself are responsible for the appearance of anti-salicyloyl antibodies in patients treated with acetylsalicylic acid. 

Ali SL (1976 a) Gas-chromatographic determination of traces of acetylsalicylic anhydride and acetylsalicylsalicylic acid in acetylsalicylic acid. Z Analyt Chem 278 365-366... 

Ali SL (1976 b) Application of gas-liquid chromatography and high-performance liquid chromatography to the analysis of trace amounts of salicylic acid, acetylsalicylic anhydride and acetylsalicylsalicylic acid in aspirin samples and aspirin formulations. J Chromatogr 126 651-663... 

Igarashi H, Koizumi K, Muranaka M (1978) Eliciting antigenicities of benzylpenicillin, ampicillin and carbenicillin preparations examined with the reagin-mediated passive cutaneous anaphylaxis system. Int Arch Allergy Appl Immunol 57 341-348 Jansson S-0, Andersson I (1977) Determination of salicylic acid, acetylsalicylic anhydride and acetylsalicylsalicylic acid in acetylsalicylic acid by high-performance liquid chromatography. Acta Pharm Suec 14 161-170... 

Reactive chemical impurities as byproducts of synthesis acetylsalicylsalicylic acid and acetylsalicylic anhydride in aspirin... 

Impurities contaminating commercial aspirin preparations could be responsible for appearance of urticaria and angioedema in some patients (de Weck 1971 Bundgaard and de Weck 1975). These contaminants include acetylsalicylic anhydride, acetylsalicylic salicylic acid and cw-disalicylide. A rapid and convenient colorimetric method has been described recently for the quantitative determination of these immunogenic impurities in aspirin (Bundgaard 1976). 

It should be emphasised that salicylic acid can be readily acetylated by Method 1, and that the above preparation of acetylsalicyclic acid is given solely as an illustration of Method 2. To employ Method 1, add 10 g. of salicylic acid to 20 ml. of a mixture of equal volumes of acetic anhydride and acetic acid, and boil gently under reflux for 30 minutes. Then pour into about 200 ml. of cold water in order to precipitate the acetylsalicylic acid (11 g.) and finally recrystallise as above. Method 2, however, gives the purer product. 

Phenols, unlike amines, cannot be acetylated satisfactorily in aqueous solution acetylation proceeds readily with acetic anhydride in the presence of a little concentrated sulphuric acid as catalyst. Salicylic acid (o-hydroxy-benzoic acid) upon acetylation yields acetylsalicylic acid or aspirin ... 

Place 10 g. of dry salicylic acid and 15 g. (14 ml.) of acetic anhydride in a small conical flask, add 5 drops of concentrated sulphuric acid, and rotate the flask in order to secure thorough mixing. Warm on a water bath to about 50-60°, stirring with the thermometer, for about 15 minutes. Allow the mixture to cool and stir occasionally. Add 150 ml. of water, stir well and filter at the pump. ReorystaUise the crude acetylsalicylic acid from a mixture of equal volumes of acetic acid and water. 

The filtrate from this first batch will comprise a solution of 180 to 270 kg of unprecipitated acetylsalicylic acid (1.0 to 1.5 mols), 510 kg of acetic anhydrice (5.0 mols), 600 kg of acetic acid (10.0 mols) (obtained as a by-product in the acetylation step) and 1,200 kg of the diluent toluene. Into this filtrate, at a temperature of 15° to 25°C, ketene gas is now passed through a sparger tube or diffuser plate, with good agitation, until a weight increase of 420.5 kg of ketene (10 mols) occurs. The reaction mixture wiil now contain 180-270 kg of unprecipitated acetylsalicylic acid (1.0-1.5 mols) and 1,532 kg of acetic anhydride (15 mols) in 1,200 kg of toluene. This mother liquor is recycled to the first step of the process for reaction with another batch of 1,382 kg of salicylic acid. On recirculating the mother liquor, the yield of pure acetylsalicylic acid is 1,780 to 1,795 kg per batch. 

Conversion of Acid Anhydrides into Esters Acetic anhydride is often used to prepare acetate esters from alcohols. For example, aspirin (acetylsalicylic acid) is prepared commercially by the acetylation of o-hydroxybenzoic acid (salicylic acid) with acetic anhydride. 

Aspirin (shown here as acetylsalicylic acid, Ka = 3.2 X 10 4) is a product of the reaction of salicylic acid with acetic anhydride. Calculate the ratio of the concentrations... 

The mixed carbonic anhydride procedure8-7 has been useful in the preparation of amide linkages and thiol esters. Mixed carbonic anhydrides have successfully acylated, under very mild conditions, the carb-anions derived from diethyl ethylmalonate and diethylcadmium.8 The latter gives as a product the corresponding ketone. Mixed anhydrides derived from acetic and acetylsalicylic acids give results similar to those described here.8... 

Acetylium tetrailuoroborate, 4 144t N-Acetyl-p-aminophenol (acetaminophen), acetic anhydride used in production of, 1 158. See also Acetaminophen Acetyl perchlorate, 1 157 Acetylsalicylic acid (aspirin), 22 17-21 acetic anhydride used in production of, 1 158... 

Take aspirin, for example. It has its origins in salicin, the active ingredient in willow bark. When salicin is hydrolysed it produces glucose and salicyl alcohol the latter can be oxidised to salicylic acid. Salicylic acid was also used as a medicine, but it caused irritation and bleeding in the stomach and intestines. However, when salicylic acid is treated with ethanoic anhydride, acetylsalicylic acid (aspirin) is produced. 

The analgesic aspirin, acetylsalicylic acid, is an ester, hi this compound, the alcohol part is actually a phenol, salicylic acid. Aspirin is synthesized from salicylic acid by treatment with acetic anhydride. 

Aspirin Aspirin, acetylsalicylic acid (3.2.2), is synthesized by the acetylation of salicylic acid (3.2.1) nsing acetic anhydride or acetyl chloride [60-63]. 

Esters of the phenolic hydroxyl are obtained easily by the Schotten-Baumann reaction. The reaction in many cases involves 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 salicylic acid with acetic anhydride to produce acetylsalicylic acid [50-78-2] (aspirin). 

Ligusticum chuanziang Hort. Chuan Xiang (rhizome) Tetramethylpyrazine, perlolyrine, leucylphenylalanine anhydride, cnidilide, neocnidilide, ligustilide, acetylsalicylic acid, phthalide, benzoquinone.33-226-419-420 Promote blood flow, remove blood stasis and relieve pain. 

A number of 2,3-fused chromones have been prepared from ethyl chloroformate and acetylsalicylic acid, a source of the mixed anhydride of formic and salicylic acids, and piperidinocycloalkenes (69JCS(C)935). A plausible mechanism is outlined in Scheme 165. It has not proved possible to isolate the chromanone (460) but the formation of 3-acetyl-2-methylchromone from 2-pyrrolidinopropene lends support to the intermediacy of the chromanone. The migration of the acyl group from oxygen to carbon is supported by the synthesis of 3-benzoyl-2-methylchromone rather than 3-acetylflavone from benzoylsalicylic acid and the pyrrolidinopropene. 

Salicylic acid Acetic anhydride O-Acetylsalicylic Acetic acid... 

However, this method is applied only when esterification cannot be effected by the usual acid—alcohol reaction because of the higher cost of the anhydrides. The production of cellulose acetate (see Fibers, CELLULOSE esters), phenyl acetate (used in acetaminophen production), and aspirin (acetylsalicylic acid) (see Salicylic acid) are examples of the large-scale use of acetic anhydride. The speed of acylation is gready increased by the use of catalysts (68) such as sulfuric acid, perchloric acid, trifluoroacetic acid, phosphorus pentoxide, zinc chloride, ferric chloride, sodium acetate, and tertiary amines, eg, 4- dimethylaminopyridine. 

To form aspirin, the salicylic acid is refluxed with acetic anhydride in toluene at 88 to 92°C for 20 hours. The reaction mixture is then cooled in aluminum cooling tanks, and the acetylsalicylic acid precipitates as large crystals that are separated by filtration or by centrifugation, washed, and dried. 

The synthesis of acetylsalicylic acid (aspirin) from the reaction of salicylic acid with acetic anhydride... 

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