Old King Coal Part 5: Coal Medicines

In the final part of the series, Martin Pitt reveals how coal-tar chemistry led to the first synthetic medicines, blockbuster painkillers and breakthroughs in infectious disease

SALICYLIC ACID is named from the Latin word for willow, salix, as it can be obtained from its bark and has been known in impure form for its relief of pain and fever for over 2,000 years.

It consists of phenol with a carboxylic group adjacent to the -OH. In 1859, German chemist Hermann Kolbe (1818–1884) proved this by synthesising it from phenol, NaOH and CO2 at 125°C and 125 bar, then acidifying, getting a material identical to the natural product. He also coined the word synthesise. He asked his former student Rudolf Schmitt (1830–1898) to recommend someone to help commercialise it and Schmitt suggested one of his own students who had studied the substance, Friedrich von Heyden (1836–1926).

In 1875 Heyden registered his business (with Kolbe as a silent partner and chemical advisor) as Salicylsäure-Fabrik Dr F v Heyden (Salicylic Acid works of Dr F v Heyden) and it began selling the first artificially synthesised and modern packaged pharmaceutical. In addition to relieving pain and fever, von Heyden’s studies had shown it was an antiseptic and less harsh than phenol for wound treatment. He also marketed it as a food preservative. Kolbe and von Heyden vigorously defended their patents against competitors and licensed some. When Kolbe died, Schmitt took over as partner.

In 1885, von Heyden sold his share to Kolbe’s son Carl, also a chemist, and they took on another of Schmitt’s students, Richard Seifert (1861–1919), who began a remarkably productive and inventive career. He immediately converted the process to a dry one developed by Schmitt, doubling the yield and increasing productivity. In 1886, he introduced a new product: phenyl salicylate, the ester of salicylic acid and phenol. Marketed as Salol, it was used as an oral treatment for urinary infections and as an ingredient in mouthwashes.

His work proved an exemplar for pharmaceutical research, called the Salol principle. He produced bismuth compounds from cresols and naphthols for intestinal infections. Like Salol, they were prodrugs, compounds which break down in the body to release the active molecules where they are needed, in the alkaline intestine, not the acid stomach. His bismuth salts of brominated phenols replaced iodoform and are still in use today for wound dressing and treatment of eye infections.

In 1897, Seifert created acetylsalicylic acid to see if it would be kinder on the stomach and registered the name acetylin. He submitted it to the Medical Institute in Bern, who said it had no advantages, so it was shelved. The same year, German chemist Felix Hoffmann (1868–1946) was at Bayer trying a technique which had worked well for their dye business, namely acetylating a lot of known substances to see if they could produce a new commercial one. He unknowingly produced the same substance as Seifert, hoping for something more powerful or less toxic than salicylic acid. It turned out to be both. The research department at Bayer carried out animal and human tests, culminating in actual patients and decided they had a blockbuster. In 1899 Bayer registered the name aspirin for the same compound and brought it to the market, but was unable to get patent protection in Germany since the substance had been made several times before. However, in 1900 they got a monopoly in the US, which brought huge sales until 1917 when the US joined World War One and confiscated their property. The Heyden company rapidly put acetylin into production in 1899 but Bayer’s huge marketing effort meant that aspirin became the name which was known and associated with the company. It is still one of the most used drugs.

Quinine failures

Many people other than Perkin tried to synthesise quinine (the first successful laboratory total synthesis was in 1944, but none has yet been found which is more economic than the natural product). They generally started with aniline, as did German chemist Ludwig Knorr (1859–1921) who converted it to phenyl hydrazine then performed a condensation with ethyl acetoacetate. It did not cure malaria, but it proved to be a stronger antipyretic (fever reducer) than quinine and also acted as an analgesic (pain reliever). He patented it in 1883 and it was sold as Antipyrine – now known as phenazone – it became the first synthetic drug and remained widely used until aspirin eventually replaced it.
Aniline itself was antipyretic and analgesic but was too toxic. Acetylating it produced acetanilide, discovered by French chemist Charles Gerhardt (1816–1856) in 1843. In 1885 at the university of Strassburg two patients were given naphthalene as an experimental treatment for worms, which was unsuccessful. However, one patient had a notable drop in temperature and it was discovered that the pharmacy had mistakenly supplied acetanilide. In 1887 it was marketed as antifebrin by the German coal tar dye company Kalle which also sold wound disinfectant. Its main advantage was its low cost, which made it popular in proprietary remedies and useful as an extender for more expensive drugs. However, immediately after the publication of its properties in 1886, the company Bayer started an intense research programme to test derivatives of acetanilide and produced a p-ethoxy derivative which was marketed in 1887 as a more powerful analgesic under the name phenacetin. It was synthesised from p-nitrophenol (which they fortunately had as a byproduct of one of their dye processes). Its success established Bayer as a leading pharmaceutical company.

Meanwhile, a related compound, acetaminophen, had been synthesised by American chemist Harmon Northrup Morse (1848–1920). In Germany, physician and researcher Joseph von Mering (1848–1908) evaluated all three compounds in human trials, reporting in 1893 that while phenacetin was relatively safe, both acetanilide and acetaminophen caused concerning blood-related side effects.

This did not stop the continued use of acetanilide as a drug but no company took up acetaminophen.

In the 1940s, it was noticed that patients treated with acetanilide or phenacetin had detectable amounts of acetaminophen in their blood. By 1949, it was confirmed that both drugs were metabolised into acetaminophen – the true active substance – meaning they were simply indirect delivery methods. It was concluded that the pure substance did not produce the blood problems which came from impurities in von Mering’s supplies. Acetanilide hydrolysed to aniline which did cause the blood issue and was taken off the shelves. Phenacetin, linked to kidney damage, remained in use longer but was finally banned in the UK in 1980.

Acetaminophen was first marketed with aspirin and caffeine as Trigesic in 1950, then as a single compound under the name and trademark acetaminophen in 1955, and as paracetamol in 1956. It has become one of the world’s most widely used drugs.

Selective stains

In 1876, Heinrich Caro (1834–1910) at BASF invented methylene blue dye, which became one of the most important blue dyes because of its light fastness on cotton. In the 30 years since mauveine there had been enormous progress in chemical understanding and technology. German physician and medical scientist Paul Ehrlich (1854–1915) was poised to build on this understanding. By applying an understanding of the chemical nature of cells and organisms, he extended Witt’s theory of colour and dyeing (see previous Old King Coal article) into the emerging field of biochemistry.

Biologists were already using dyes to stain tissues on microscope slides. Ehrlich injected living animals then dissected them to view the effect on organs. Methylene blue was interesting because it selectively stained nerve cells, as well as being a good stain for bacteria. He suspected the selectivity was due to the presence of a sulfur atom and asked Caro if something similar could be made with an oxygen instead. The result was rhodamine in 1887, which confirmed Ehrlich’s idea by not binding and was also hugely profitable as a brilliant red dye.

He read that methylene blue stained the malaria parasite, so wondered if it could be used as a treatment, since it appeared to be of low toxicity. In 1891, two patients were cured through oral treatment. With no modern requirement for long-term trials or formal approval, the drug quickly entered use. It was considered less potent than quinine but cheaper and available in far greater quantities. This was the first synthetic drug to cure an infectious disease. It was used up to and including World War Two, despite the fact that it gave patients a temporary bluish colour and made urine green or blue. Because it could stain and inactivate some microbes it acted as precise disinfectant, for example against staphylococcus eye infection. Ehrlich would have liked to carry out more testing in animals but there was no suitable animal model (equivalent infection in convenient animals), so he moved on to other research. This was in serums and antitoxins and immunity against diphtheria, developing a successful side-chain theory and quantitative methods for measuring antitoxin activity. With German physiologist Emil von Behring (1854–1917) he developed effective antitoxins for diphtheria and tetanus, for which von Behring got the Nobel prize for Physiology or Medicine in 1901. However, Ehrlich won the 1908 one for his side-chain theory, the “lock and key” model of antibodies and receptors for antigens in immunology.

In 1898, he moved to head a new institute. By now facilities and methods had been developed for infecting and maintaining animals to test cures. In 1901, his laboratory began testing dyes of fuchsin, benzopurpurine and acridine types with mixed success. For example, Trypan blue killed a cattle parasite but coloured the meat blue. In 1904, he coined the word chemotherapy. By replacing nitrogen with arsenic in an azo dye structure, a drug was produced able to kill the syphilis parasite in both animals and humans. Some early field tests were worrying until he discovered that doctors were diluting the concentrate with non-sterile water, thus giving infections. Marketed as Salversan, it was the most widely prescribed drug in the world until it was replaced by penicillin in the 1940s.

Meanwhile Bayer, a major competitor of BASF, started a long-term research programme to try to get an improved malaria treatment. World War One intervened, but in 1931 they introduced mepacrine, with the trade name Atabrine. It was extensively used in World War Two despite the justified complaint that it stained the soldiers yellow. In 1934, Bayer chemist Hans Anderjag (1902–1955) produced chloroquine which was tested and found effective against the parasite but mistakenly judged to be too toxic. It was revived in the 1950s and is now considered an essential medicine.

So many of our medicines are based on chemicals once extracted from coal tar and techniques that grew up in the dye industry as it became more scientific. As we move away from coal as a simple fuel it is worth appreciating how much it contributed to the organic chemical industry and modern life.

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Martin Pitt CEng FIChemE is a regular contributor. Read other articles in his history series: https://www.thechemicalengineer.com/tags/chemicalengineering-history