Synthesis of Aspirin: Production & Historical Background of an Analgesic, Lecture notes of History

Download Synthesis of Aspirin: Production & Historical Background of an Analgesic and more Lecture notes History in PDF only on Docsity! Experiment 30 – Synthesis of an Analgesic: Aspirin Page 1 of 4 30. Synthesis of an Analgesic: Aspirin A. Background Aspirin (acetylsalicylic acid) belongs to a class of drugs known as nonsteroidal anti-inflammatory drugs (NSAIDs), which work by blocking the synthesis of prostaglandins in the body. Before exploring the chemistry of aspirin, one should understand the biological process of inflammation. Inflammation in the body occurs in response to the presence of harmful stimuli including: the presence of a foreign organism, nerve damage, and tissue irritation. Symptoms of inflammation include: redness, swelling, pain, and loss of mobility at the affected site. The experience of pain in the body begins with some stimulus that invokes an immune response. To combat the stimulus, the brain signals the body to begin a number of biological cascade reactions that include the synthesis of histamine, bradykinin, and prostaglandins, all of which contribute to the experience of inflammation and pain. During an inflammation response, prostaglandins are synthesized from the ω-6 fatty acid, arachidonic acid, which comes from our diet and can be synthesized in the body from linoleic acid. An important enzyme in the conversion of arachidonic acid to prostaglandins is cyclooxygenase-1 (COX-1) which abstracts a hydrogen atom from arachidonic acid to produce a radical intermediate. This reactive intermediate then undergoes a number of subsequent steps, eventually leading to the production of prostaglandins (PGE2 is shown). Most anti- inflammatory drugs work by inhibiting the prostaglandin synthesis pathway in some manner. In the case of Aspirin, the COX-1 enzyme is deactivated by transfer of the aspirin acetyl group to an important –OH moiety of the COX enzyme. Once the COX enzyme is deactivated, prostaglandin synthesis is inhibited and the pain signal is suppressed. The Discovery of Aspirin The history of aspirin dates back to 1500 B.C. when salicylic acid, the precursor to aspirin, was used medicinally. Salicylic acid is present in the bark of the willow tree and there is evidence that Hippocrates suggested chewing the tree bark to treat fever and as a pain reliever. In slightly O OH arachidonic acid Cyclooxygenase-1 (COX-1) O OH Steps OH O HO OH O Prostaglandin PGE2 Figure 1. Synthesis of a Prostaglandin from Arachidonic Acid Experiment 30 – Synthesis of an Analgesic: Aspirin Page 2 of 4 more recent history (1753), Reverend Edward Stone of England used the willow tree bark for the successful treatment of malaria. Stone later reported his findings to the Royal Society. The modern synthesis and application of aspirin came in the late 1800s at the Bayer laboratory in Germany. Bayer’s pharmaceutical division at the time was under the direction of Arthur Eichengrün. Working in Eichengrün’s lab was a chemist named Felix Hoffmann. Hoffmann’s father suffered from arthritis and took salicylic acid to relieve his symptoms. Unfortunately, the salicylic acid upset his stomach to such a degree that he had to discontinue using it. Hoffmann set out to find an alternative and began preparing salicylic acid derivatives in his laboratory. One such derivative that he crafted was acetylsalicylic acid (aspirin). Hoffmann gave the aspirin to his father who found the medication to successfully treat his arthritis without the negative effects on his stomach. Interestingly, the head of Bayer at that time was reluctant to pursue aspirin for fear that it caused heart problems. After continued persistence by Eichengrün, Bayer began to market aspirin, which yielded the company phenomenon success. Following World War I, Bayer lost their trademark of the aspirin name as part of the terms imposed in the 1919 Treaty of Versailles. Acetylation of Salicylic Acid One method for the preparation of acetylsalicylic acid involves the acylation of salicylic acid as shown in figure 2. The acylating agent is acetic anhydride, which in the presence of an acid catalyst reacts with salicylic acid to provide acetylsalicylic acid in an excellent yield. First, acetic anhydride is protonated by the acid to form an activated carbonyl species. Next, a lone pair from the salicylic acid OH attacks the carbonyl carbon of the activated electrophile. A proton is then transferred from the aromatic oxygen to the ester oxygen. Next, acetic acid (CH3COOH) is dispelled. The resulting protonated ester loses its proton upon reaction with a weak base to provide acetylsalicylic acid. Figure 2. Mechanism for the Acylation of Salicylic Acid OH OHO salicylic acid O O O+ O OHO O + O OH O O O H H O OHO OH O O H O OHO OH O O H Proton Transfer HBO OHO O acetylsalicyclic acid (aspirin) +B H acetic anhydride regenerated acid catalyst