Acetyl salicylic acid

Salicylates are esters or salts of salicylic acid. Acetyl salicylic acid (aspirin) is rapidly con-... 

Carbonation Kolbe reaction Treatment of a salt of a phenol with CO2 replaces a ring hydrogen with a carboxyl group. This reaction is applied in the conversion of phenol itself into ort/io-hydroxybenzoic acid, known as salicylic acid. Acetylation of salicylic acid produces acetylsalicylic acid (aspirin), which is the most popular painkiller in use today. 

The first step in the industrial synthesis of aspirin is known as the Kolbe-Schmitt carboxylation reaction. The phenolate ion reacts with carbon dioxide under pressure to form o-hydroxybenzoic acid, also known as salicylic acid. Acetylation of salicylic acid with acetic acid forms acetylsalicylic acid (aspirin). 

When the phenol contains a carboxylic acid group, e.g., m- or p-hydroxy-benzoic acid, the acetylated derivative will of course remain in solution as the sodium salt, but is precipitated when the solution is subsequently acidified. Salicylic acid, however, cannot be acetylated under these conditions. 

Required Salicylic acid, 10 g. pyridine, 7 ml. acetyl chloride. 

Dissolve 10 g. of salicylic acid (o-hydroxybenzoic acid) in 7 ml. of dry pyridine contained in a too ml. conical flask. Then without delay (since this solution if allowed to stand tends to become a semi-solid mass) run in 7 5 ml. (8 3 g.) of acetyl chloride, adding about i ml. of the chloride at a time, and shaking the mixture continuously during the addition. The heat of the reaction causes the temperature of the mixture to rise rapidly ... 

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. 

Acetylation. Boil i g. of salicylic acid with 4 ml. of an acetic anhydride-acetic acid mixture (equal volumes) under reflux for 10 minutes. Pour into water. Filter off the aspirin (p. 111), wash with water and recrystallise from aqueous acetic acid (1 1) m.p. l36 ... 

Salicylic acid, however, cannot be acetylated under these conditions. 

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 ... 

The best known aryl ester is O acetylsalicylic acid better known as aspirin It is pre pared by acetylation of the phenolic hydroxyl group of salicylic acid... 

Coum rinic Acid Compounds. These synthetic phyUoquinone derivatives and congeners have been employed as anticoagulants since the isolation of 3,3 -methylenebis(4-hydroxy-2H-l-benzopyran-2-one) [66-76-2] (bis-4-hydroxycoumarin or dicoumarol) (1) from spoiled sweet clover in 1939. The ingestion of the latter was responsible for widespread and extensive death of bovine animals at that time. The parent compound for the synthesis of many congeners is 4-hydrocoumarin, which is synthesized from methyl salicylate by acetylation and internal cyclization. The basic stmctures of these compounds are shown in Figure 2, and their properties Hsted in Table 6 (see Coumarin). 

SIMULTANEOUS DETERMINATION OF ACETYL SALICYLIC ACID AND ACETAMINOPHEN IN A.C.A TABLETS BY FT-IR/ATR SPECTROMETRY... 

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. 

Acetic anhydride is mainly used to make acetic esters and acetyl salicylic acid (aspirin). 

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. 

Stuer et al. [46] evaluated the presence of the 25 most used pharmaceuticals in the primary health sector in Denmark (e.g., paracetamol, acetyl salicylic acid, diazepam, and ibuprofen). They compared PECs with experimental determinations and they conclude that measured concentrations were in general within a factor of 2-5 of PECs. Carballa et al. [45] also determined PECs for pharmaceuticals (17), musk fragrances (2) and hormones (2) in sewage sludge matrix. For that purpose they used three different approaches (1) extrapolation of the per capita use in Europe to the number of Spanish inhabitants for musk fragrances (2) annual prescription items multiplied by the average daily dose for pharmaceuticals and (3) excretion rates of different groups of population for hormones. They indicated that these PECs fitted with the measured values for half of them (carbamazepine, diazepam, ibuprofen, naproxen, diclofenac, sulfamethoxazole, roxithromycin, erythromycin, and 17a-ethiny I e strad iol). 

The existence of two polymorphs was reported for a NO-releasing derivative of acetyl-salicylic acid [28]. Selection crystallization of one form or the other was achieved from a number of solvent systems (14 solvents and 3 preparative methods), but several systems were identified that yielded mixtures of the two forms. The single-crystal structure of Form I was reported, but the habit of the Form II crystals precluded their characterization. The transition point of the two forms was calculated from intrinsic dissolution data to be higher than the melting points of both polymorphs and thus the two forms bear a monotropic relationship. 

Essentially, all methods of synthesis are variations of the reaction of acetylchloride, acetic anhydride or ketene11 with salicylic acid using a variety of catalysts such as pyridine12 or sulfuric acid13 and reaction conditions (c.f. 14). The preparation of aspirin labeled with a i4c iaj-,eie(j acetyl group has also been reported.15 Efforts to improve the commercial processes continue to the present day. 

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