The past and present of the "Angel Pill" Aspirin

Bayer is a global pharmaceutical company. The infamous heroin was once born here. However, aspirin, known as the "angel pill", was also born in the "cradle of the devil". It has been famous in the world for more than a hundred years and is known as one of the "three classic drugs in the history of world medicine" along with penicillin and diazepam.

Behind the seemingly ordinary little pill is a legendary history full of ups and downs. Behind the magical story is the great contribution of chemistry to human transformation and exploration of drugs.

1. Introduction

In August 1863, businessman Friedrich Bayer and pigment master Johann Friedrich Weskott founded a pigment company in Germany, which gradually developed into the pharmaceutical giant Bayer after many years. Bayer is famous for its innovative inventions. Many major inventions, such as aspirin, heroin, methadone, ciprofloxacin, and strychnine, all come from Bayer laboratories. Some of these inventions have made indelible contributions to the development and progress of mankind, while others have also brought great suffering to mankind. Bayer has many inventions and patents, and the birth of aspirin has won it huge profits and a good reputation. The rapid development of Western medicine synthesis and pharmacology has led to the flourishing of new drugs, but aspirin has always stood firm in the great trend of renewal and has opened up new uses, truly becoming an enduring magical molecule.

Figure 1 Bayer founder Friedrich Bayer and company logo

2. The Birth of Aspirin

The story of aspirin dates back more than 3,500 years, when the earliest medical document in ancient Egypt, the Ebers Papyrus, recorded that willow could be used to reduce inflammation and relieve pain. Around 400 BC, Hippocrates, the "Father of Medicine," used willow bark extracts to treat pain, fever, and childbirth. However, as history changed, the use of willow as a medicine seemed to have been lost until 1763, when British priest Edward Stone rediscovered the medicinal value of willow bark, but at that time people had no idea of ​​the active ingredients.

In the early 19th century, chemical technology had developed to the laboratory stage and could already separate and identify the active ingredients of some drugs. In 1828, Johann Buchner, a professor of pharmacy at the University of Munich, laboriously extracted a relatively pure yellow substance from willow bark and named it salicin. Ten years later, Italian chemist Raffaele Piria successfully hydrolyzed salicin to obtain glucose and salicyl alcohol components, and then he successfully oxidized the latter to carboxylic acid, which is the well-known salicylic acid (Salicylic acid), which was a huge breakthrough in aspirin research. In 1852, French chemist Charles Gerhardt introduced an acetyl group to the hydroxyl group of the salicylic acid molecule for the first time, becoming the first person in history to synthesize acetylsalicylic acid (aspirin), but he gave up subsequent research due to the instability of the product.

Figure 2 The discovery process of aspirin

In the long history of the discovery of aspirin, there is also a scientist named Hermann Kolbe who must be mentioned. He was the first to use the word "synthesis" to refer to organic synthesis in the modern sense. In 1859, he proposed the Kolbe-Schmidt reaction for the synthesis of salicylic acid with the help of the carboxylation reaction of sodium phenolate and carbon dioxide under high temperature and pressure conditions, which can be widely used in the production of salicylic acid. Once salicylic acid was born, it did not immediately become a panacea as we imagined, mainly because it had many side effects, such as unpleasant odor, irritation to the digestive mucosa, vomiting, and some patients even had gastrointestinal ulcers. At that time, the young Bayer company tried to modify the structure of salicylic acid in order to reduce the irritation to the body. Although it obtained many related patents, the real breakthrough came in 1897, when Felix Hoffmann, a young organic chemist at the Bayer laboratory, synthesized acetylsalicylic acid and was able to crystallize a pure product for medical use. Hoffmann's modified product solved the irritation of salicylic acid. Two years later, Bayer passed the clinical efficacy test of acetylsalicylic acid on pain, inflammation and fever and registered it as the trade name "aspirin" which is still used today. It soon became a best-selling drug.

Figure 3 Hermann Kolbe (left) and Felix Hoffmann (right)

3. The complicated dispute over ownership

There is also a touching story about Hoffman's invention of aspirin. It is said that Hoffman's father suffered from rheumatoid arthritis and needed to take salicylic acid for long-term anti-inflammatory and analgesic treatment. However, long-term medication caused his father severe gastrointestinal discomfort. Hoffman, who was full of filial piety, decided to modify the structure of salicylic acid and "cover" the acidic part of the molecule, thus synthesizing aspirin. However, the truth does not seem to be as simple as the circulated story. At the end of 2000, British physician and historian Walter Sneader proposed that Arthur Eichengrün, the head of Bayer's pharmaceutical group at the time, was the main inventor of aspirin.

Figure 4 Arthur Eichengreen

After many twists and turns, Walter Snyder obtained the license of Bayer Company, consulted all the files of the laboratory, and finally determined that Hoffman's synthesis of aspirin was completed under the guidance of Jewish scientist Arthur Eichengreen. More precisely, he succeeded by completely adopting the route proposed by Eichengreen. When the legend that Hoffman invented aspirin to relieve his father's pain became popular, the Nazis had already come to power in Germany. The extreme Nazi Party was unwilling to admit the fact that aspirin was invented by the Jews, so they put the crown on Hoffman's head. Around 1949, Eichengreen died soon after writing his memories of aspirin, and the dispute over the ownership of aspirin was more or less branded with the Nazis and racial discrimination. But whether this is really the case, I am afraid we cannot give a definite conclusion yet.

4. Synthesis of Aspirin

The synthetic route of aspirin is not complicated and can be classified as an esterification reaction, that is, the phenolic hydroxyl group of salicylic acid and acetic anhydride lose a molecule of acetic acid to form a product ester. The reaction usually requires a small amount of acid as a catalyst, such as sulfuric acid and phosphoric acid. The reaction mechanism can be roughly described as follows: first, the phenolic hydroxyl group of salicylic acid attacks the acid-activated acetic anhydride, then removes the proton under the action of the acid radical ion to form a hemiketal structure, and finally removes a molecule of byproduct acetic acid with the help of an acid catalyst and completes the proton transfer process to obtain acetylated salicylic acid. It is worth mentioning that preparations containing high concentrations of aspirin often have a strong vinegar smell. This is because aspirin will hydrolyze in a humid environment and decompose into salicylic acid and acetic acid.

Figure 5 Synthesis and reaction mechanism of aspirin

5. “New branches grow on old trees”

Aspirin quickly became popular around the world after its birth. However, by 1971, when new antipyretic and analgesic drugs emerged one after another, aspirin was no longer the only one. At this time, people discovered its new role, and aspirin ushered in a new "spring". With the in-depth study of aspirin, people have discovered some new applications of it in recent years, such as cancer prevention, diabetes prevention and treatment, inhibition of platelet aggregation, and relief of cataracts. However, these new applications still need further clinical research before they can be truly promoted.

According to statistics, more than 70% of the world's population has taken aspirin. However, "all medicines are poisonous", and there are still many things to pay attention to in the actual use of aspirin. For people with allergic constitutions, taking aspirin may cause rashes, angioedema, asthma or other allergic reactions; although aspirin is much less irritating to the gastrointestinal tract than salicylic acid, long-term use may still cause gastric mucosal erosion, bleeding and ulcers, so aspirin is best taken after meals or at the same time as antacids, and patients with ulcers should use it with caution or not at all.

VI. Conclusion

As Academician Ding Kuiling of the Shanghai Institute of Organic Chemistry said, synthetic chemistry is the main driving force for new drug discovery and the source of technological progress in the drug manufacturing industry. For a long time in the future, chemical synthetic drugs will continue to be the theme of new drug research by major pharmaceutical companies in the world. From the initial treatment of headaches and fever to the current development of aspirin with a variety of attractive potential medical values, the research will continue. It seems that this small "legendary" molecule has not yet "revealed" all its secrets. Will it bring us new surprises in the future? I believe that everyone is looking forward to it as much as I am.

References

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[3] Desborough, Michael JR, and David M. Keeling. "The aspirin story–from willow to wonder drug." British Journal of Haematology, 2017, 177(5): 674-683.

[4] Song Zuyi. New effects and side effects of aspirin discovered in recent years. Chinese Practical Medicine, 2013, 30: 161-162.

[5] Wang Fang. Overview of the development history of aspirin. Chinese General Practice, 2016, 19(26): 3129-3135.