Salicylic acid, synthesis from willow bark

SAM-dependent methylation of salicylic acid. The salicyl alcohol derivative salicin, found in many species of willow (Salix species Salicaceae), is not derived from salicylic acid, but probably via glucosylation of salicylaldehyde and then reduction of the carbonyl (Figure 4.27). Salicin is responsible for the analgesic and antipyretic effects of willow barks, widely used for centuries, and the template for synthesis of acetylsalicylic acid (aspirin) (Figure 4.27) as a more effective analogue. 

From a synthetic standpoint, a historical landmark, after the discovery of electrophilic substitution in the 1860 s, was the synthesis of aspirin, acetylsalicylic acid. The earliest known use of the drug can be traced back to the Greek physician Hippocrates in the 5 century BC. He used powder extracted from the bark of willow trees to treat pain and reduce fever. Sali-cin, the parent of the salicylate drug family that generates salicylic acid in vivo, was isolated... 

Another active principle soon extracted from plants was salicylic acid. Salicin, extracted from the willow tree, has been launched in 1876 by a Scottish physician, Thomas John McLogan It was in extensive competition with Cinchona bark and quinine and never became a very popular treatment for fever or rheumatic symptoms. The Italian chemist Raffaele Piria, after having isolated salicylalde-hyde (1839) in Spireae species, prepared salicylic acid from salicin in Dumas laboratory in the Sorbonne, Paris. This acid was easier to use and was an ideal step before future syntheses. Its structure was closely related to benzoic acid, an effective preservative useful as an intestinal antiseptic for instance in typhoid fever. Acetylsalicylic acid has been first synthesized by Charles Frederic Gerhardt in 1853 and then, in a purer form, by Johann Kraut (1869). Acetylsalicylic acid synthesis with carbolic acid and carbon dioxide was improved by Hermann Kolbe in1874, but in fact nobody noticed its pharmacological interest. 

The simplest aromatic carboxylic acid is benzoic acid. Derivatives are named by using numbers and prefixes to show the presence and location of substituents relative to the carboxyl group. Certain aromatic carboxylic acids have common names by which they are more usually known. For example, 2-hydroxybenzoic acid is more often called salicylic acid, a name derived from the fact that this aromatic carboxylic acid was finst obtained from the bark of the willow, a tree of the genus SaEx. Aromatic dicarboxylic acids are named by adding the words dicarboxylic acid to benzene. Examples are 1,2-benzenedicarboxyhc acid and 1,4-benzenedicar-boxylic acid. Each is more usually known by its common name phthahc acid and terephthalic acid, respectively. Terephthahc acid is one of the two organic components required for the synthesis of the textile fiber known as Dacron polyester (Section 16.4B). 

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