Aspirin Synthesis - History

History

Plant extracts, including willow bark and spiraea, of which salicylic acid was the active ingredient, had been known to help alleviate headaches, pains, and fevers since antiquity. The father of modern medicine, Hippocrates, who lived sometime between 460 BC and 377 BC, left historical records describing the use of powder made from the bark and leaves of the willow tree to help these symptoms.

A French chemist, Charles Frederic Gerhardt, was the first to prepare acetylsalicylic acid in 1853. In the course of his work on the synthesis and properties of various acid anhydrides, he mixed acetyl chloride with a sodium salt of salicylic acid (sodium salicylate). A vigorous reaction ensued, and the resulting melt soon solidified. Since no structural theory existed at that time, Gerhardt called the compound he obtained "salicylic-acetic anhydride" (wasserfreie Salicylsäure-Essigsäure). This preparation of aspirin ("salicylic-acetic anhydride") was one of the many reactions Gerhardt conducted for his paper on anhydrides and he did not pursue it further.

Six years later, in 1859, von Gilm obtained analytically pure acetylsalicylic acid (which he called acetylierte Salicylsäure, acetylated salicylic acid) by a reaction of salicylic acid and acetyl chloride. In 1869, Schröder, Prinzhorn and Kraut repeated both Gerhardt's (from sodium salicylate) and von Gilm's (from salicylic acid) syntheses and concluded both reactions gave the same compound—acetylsalicylic acid. They were first to assign to it the correct structure with the acetyl group connected to the phenolic oxygen.

In 1897, chemists working at Bayer AG produced a synthetically altered version of salicin, derived from the species Filipendula ulmaria (meadowsweet), which caused less digestive upset than pure salicylic acid. The identity of the lead chemist on this project is a matter of controversy. Bayer states the work was done by Felix Hoffmann, but the Jewish chemist Arthur Eichengrün later claimed he was the lead investigator and records of his contribution were expunged under the Nazi regime. The new drug, formally acetylsalicylic acid, was named Aspirin by Bayer AG after the old botanical name for meadowsweet, Spiraea ulmaria. By 1899, Bayer was selling it around the world. The name Aspirin is derived from "acetyl" and Spirsäure, an old German name for salicylic acid. The popularity of aspirin grew over the first half of the 20th century, spurred by its supposed effectiveness in the wake of the Spanish flu pandemic of 1918. However, recent research suggests the high death toll of the 1918 flu was partly due to aspirin, as the doses used at times can lead to toxicity, fluid in the lungs, and, in some cases, contribute to secondary bacterial infections and mortality. Aspirin's profitability led to fierce competition and the proliferation of aspirin brands and products, especially after the American patent held by Bayer expired in 1917.

The popularity of aspirin declined after the market releases of paracetamol (acetaminophen) in 1956 and ibuprofen in 1969. In the 1960s and 1970s, John Vane and others discovered the basic mechanism of aspirin's effects, while clinical trials and other studies from the 1960s to the 1980s established aspirin's efficacy as an anticlotting agent that reduces the risk of clotting diseases. Aspirin sales revived considerably in the last decades of the 20th century, and remain strong in the 21st century, because of its widespread use as a preventive treatment for heart attacks and strokes.