Synthesis of aspirin

The key compound m the synthesis of aspirin salicylic acid is prepared from phe nol by a process discovered m the nineteenth century by the German chemist Hermann Kolbe In the Kolbe synthesis also known as the Kolbe—Schmitt reaction, sodium phen oxide IS heated with carbon dioxide under pressure and the reaction mixture is subse quently acidified to yield salicylic acid... 

Kolbe-Schmitt reaction (Section 24.10) The high-pressure reaction of the sodium salt of a phenol with carbon dioxide to give an o-hydroxybenzoic acid. The Kolbe-Schmitt reaction is used to prepare salicylic acid in the synthesis of aspirin. 

Carboxylation of sodium phenoxides with carbon dioxide, to give salicylic acid, the precursor to the synthesis of aspirin. 

Bose et alm have demonstrated the synthesis of aspirin from salicylic acid and acetic anhydride using commercial microwave reactors (Scheme 9.6). Without optimising the conditions, high purity aspirin was obtained in greater than 80% yield (500-800 g scale). 

This is a subcosmopolitan family with concentration in the northern hemisphere. The family of the weeping willow, it has been known since biblical limes and was the source of salicylic acid for the Greek physicians, which led, eventually, to the synthesis of aspirin for the relief of minor pain. Pliable, thin branches are used in basket weaving, and some timber is produced. 

Li etal. discuss the use of on-line Raman spectroscopy to dynamically model the synthesis of aspirin, one of the most documented and well-understood reactions in organic chemistry. That makes it an excellent choice for building confidence in the sampling interface, Raman instrumentation, and analysis procedures. The researchers used wavelets during analysis to remove fluorescent backgrounds in the spectra and modeled the concentrations with multiple linear regression.53... 

Ongoing research led to the development of COX-2 selective inhibitors (e.g., rofecoxib and celecoxib). Celecoxib (Celebrex ) was approved by the FDA in 1998 to treat osteoarthritis and rheumatoid arthritis. Rofecoxib (Vioxx ) was approved in May 1999 to treat osteoarthritis, acute pain, and dysmenorrhea. Sales for the two drugs in 1999 were 1.5 billion and 373 million, respectively. Clinical studies have indicated a significant reduction in GI perforation, ulceration, or bleeding with the COX-2 inhibitors. The recognition of multiple COX isoforms has had one of the greatest impacts on the development of NSAIDs since the original synthesis of aspirin more than a century ago. 

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... 

Acetic Anhydride Acetic anhydride is the most important carboxylic acid anhydride. It is produced at the rate of about 4 billion pounds per year, primarily for synthesis of plastics, fibers, and drags. (See the synthesis of aspirin on p. 1009.) Acetic anhydride consists of two molecules of acetic acid, minus a molecule of water. The most common industrial synthesis begins by dehydrating acetic acid to give ketene. 

The phenol derivatives figure in the structures of a number of important reactions, including the synthesis of aspirin and the manufacture of phenol - formaldehyde plastics and glues. 

The use of acylation in the synthesis of aspirin, acetaminophen (the active ingredient in Tylenol), and heroin (Section 22.9)... 

Integration of green chemistry principles into pre-lab and post-lab questions is another easy and effective inclusion method. The synthesis of aspirin is a common first-year lab procedure. One of the fundamental principles of green chemistry is atom economy. A possible pre-lab question might be to have the students calculate the percent atom economy of the synthesis using the following equation ... 

Propose a synthesis of aspirin (acetylsalicylic acid) starting from benzene. You will need to use an acetylation reaction at some point in your scheme. 

To mention some examples, benzoylation of xylenes was particularly studied because of the use of dimethylbenzophenones as UV-light stabilizers in plastics. Moreover, 2-acetyl-6-methoxynaphthalene represents the precursor to the antirheumatic Naproxen.i ortho- and para-Hydroxy-acetophenones are widely used for the synthesis of aspirin and paracetamol (4-acetamidophenol), respectively. orf/zo-Hydroxyacetophenone is also a key intermediate in the production of 4-hydroxycoumarin and warfarin, both used as anticoagulant drugs in the therapy of thrombotic diseases, and it is also employed in the synthesis of flavonones. ... 

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). 

Reactions 5.14 and 5.15 illustrate two specific examples. In another example, the laboratory synthesis of aspirin (Reaction 5.16), using acetic anhydride, gives excellent yields of the ester. 

In 1834, codeine was isolated from opium by Pierre Jean Robiquet (1780-1840). One year later, Pierre-Joseph Pelletier (1788-1842) and M. Thiboumery discovered thebaine (named after the ancient Egyptian city of Thebes). In 1848, at the University of Giessen, papaverine was extracted from poppy waste by Georg Merck (1825-1873), the son of Heinrich Emanuel Merck. In 1870, Augustus Matthiessen (1831-1870) and Charles R. A. Wright (1844-1894) recognised that codeine is the monomethyl ether of morphine. After the selective methylation of morphine for the preparation of codeine had failed, Felix Hoffmann (1868-1946) tried out in 1897 a selective acetylation, in analogy to the synthesis of aspirin from salicylic acid. [91]... 

Chemists have developed several syntheses for the antiasthmatic drug albuterol (Proventil). One of these syntheses starts with salicylic acid, the same acid that is the starting material for the synthesis of aspirin ... 

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