Acetylsalicylic acid synthesis

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. 

Arrhenius, Svante, 86,353 Arsenic, 573-574 Asparagine, 622t Aspartic acid, 622t Aspirin. See Acetylsalicylic acid Astaxanthin, 157 Asymmetric synthesis, 601 Atherosclerosis, 604... 

The widely used platelet inhibitor aspirin or acetylsalicylic acid, by acetylating the enzyme cyclooxygenase, inhibits platelet function by preventing the formation of thromboxane A2 and the synthesis of prostaglandin I2 (PGI2) (68). Aspirin has been used in combination with other antiplatelet agents such as ticlopidine, which inhibits ADP-induced platelet aggregation (69). 

Acetylsalicylic acid and related non-steroidal anti-inflammatory drugs (NSAIDs) selectively inhibit the cyclooxygenase activity of prostaglandin synthase [2] and consequently the synthesis of most eicosanoids. This explains their analgesic, antipyretic, and antirheumatic effects. Frequent side effects of NSAIDs also result from inhibition of eicosanoid synthesis. For example, they impair hemostasis because the synthesis of thromboxanes by thrombocytes is inhibited. In the stomach, NSAIDs increase HCl secretion and at the same time inhibit the formation of protective mucus. Long-term NSAID use can therefore damage the gastric mucosa. 

You find them in citrus fruits (citric acid), vinegar (acetic acid), aspirin (acetylsalicylic acid), and numerous other natural and synthetic compounds, as well on numerous organic exams. In this chapter you explore the structure, synthesis, and reactions of these acids and acids like them. 

Hoffman s acetylsalicylic acid competed with the other salicylate compounds after its initial synthesis. In 1899 Hoffman s employer, the Bayer Company, founded in 1861 by Friedrich Bayer (1825-1880), began to market acetylsalicylic acid under the name Aspirin. The term aspirin was derived by combining the letter a from acetyl and spirin from spiric acid. Spiric acid is another name for salicylic acid found in plants of the genus Spirea. Bayer pro-... 

The active principle was shown to be salicin by Buchner in 1828 but the bitter taste and damage to the gastric mucosa limited its use. Piria isolated salicylic acid from salicin in 1838. In 1859, Kolbe discovered the structure and synthesis of salicylic acid and in 1897 acetylsalicylic acid was synthesized by Hoffmann. Two years later, in 1899, acetylsalecylic acid, the first nonsteroidal antiinflammatory drug was registered under the name Aspirin (Fig. 2). 

Pain research is a traditional and well established field within the pharmaceutical industry. Beginning with the isolation of morphine in a small pharmacy by Adam Serturner (1806), the next major breakthrough in pain treatment was achieved by the synthesis of acetylsalicylic acid by Felix Hoffmann in the Bayer Laboratories in Wuppertal (1897). Further outstanding contributions by the pharmaceutical industry were the first fully synthetic opioids pethidine (1939) and methadone (1946). Continued efforts up to now have resulted in many potent and clinically accepted analgesics with reasonable side effects and covering nearly all facets of pain treatment. However, pain treatment is far from being satisfactory in respect to more complex pain states, e.g. neuropathy, visceral pain or migraine. 

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. 

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. 

Bose and coworkers have performed known chemical processes in various kitchen microwave devices to explore microwave chemistry at a larger scale [33]. Representative examples for multigram-scale synthesis without optimization of reaction conditions have been presented, such as the rapid preparation of 500-800 g of acetylsalicylic acid (Aspirin). Another valuable pharmaceutical compound, Tylenol (acetaminophen, paracetamol), could be... 

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

The drug acetylsalicylic acid (aspirin) irreversibly inhibits the cyclooxygenase activity, while ibuprofen inhibits the reductase activity. Both drugs treat inflammation, pain, and fever because they inhibit prostaglandin synthesis. Prostaglandins are very unstable, so they tend to act locally (otherwise a sprained ankle would cause pain throughout the body). 

Pharmacology studies the effects of drugs and how they exert their effects. For example, penicillin cures certain bacterial infections and acetylsalicylic acid (ASA) can reduce inflammation. How do they accomplish these respective effects Through research we now know that penicillin can disrupt the synthesis of cell walls in susceptible bacterial strains by inhibiting a key enzyme, while ASA can inhibit the action of a human cell membrane enzyme known as cyclooxygenase, which is responsible for the synthesis of a number of inflammatory mediators. 

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... 

Piria, working with Spiraea species, first isolated salicylaldehyde in 1839 while working in Dumas laboratory and then prepared salicylic acid.28 This was followed by the first synthesis of acetylsalicylic acid in 1853 by Gerhardt29... 

The inhibition of cyclooxygenase by acetylsalicylic acid, which results in a decrease in prostaglandin synthesis, with perceived pain relief as the functional readout ... 

Figure 12.10. Role of eicosanoids in thrombocyte (platelet) aggregation, and rationale of low-dose acetylsalicylic acid treatment. a Thrombocyte aggregation is suppressed by the intact vascular endothelium by a constant secretion of PGE and PGI. b Inhibition subsides at lesions. This sets off aggregation, which is sustained and amplified by the secretion of thromboxanes by the platelets themselves. Aggregation will also promote plasmatic coagulation (i.e., fibrin clot formation), b Effects of low dose application of acetylsalicylic acid. Endothelial cells are nucleated covalently inactivated cyclooxygenase molecules will be replaced by newly synthesized ones, so that the activity is not substantially diminished. In contrast, thrombocytes lack protein synthesis, so that the effect of repeated doses will be cumulative.

We will then convert our acetylsalicylic acid to acetic acid with a step-by-step organic synthesis. The equation for the reaction is given below, and figure 2.1.1 shows the stmcture of the molecules in the reaction. The lines between the symbols for the elements represent the bonds. Note that some of these are double bonds. Carbon is a very versatile element. 

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