Paracetamol was first made in 1877…or possibly 1852.

• Mangus BC, Miller MG (2005). Pharmacology application in athletic training. Philadelphia, Pennsylvania: F.A. Davis. p. 39. ISBN 9780803620278. Archived from the original on 8 September 2017. Retrieved 7 September 2017.
• Eyers SJ (April 2012). The effect of regular paracetamol on bronchial responsiveness and asthma control in mild to moderate asthma (Ph.D. thesis). University of Otago). Archived from the original on 24 August 2021. Retrieved 24 August 2021.
• Roy J (2011). “Paracetamol – the best selling antipyretic analgesic in the world”. An introduction to pharmaceutical sciences: production, chemistry, techniques and technology. Oxford: Biohealthcare. p. 270. ISBN 978-1-908818-04-1. Archived from the original on 24 August 2021. Retrieved 24 August 2021.

Some reports state that Cahn & Hepp or a French chemist called Charles Gerhardt first synthesized paracetamol in 1852.

• Eyers SJ (April 2012). The effect of regular paracetamol on bronchial responsiveness and asthma control in mild to moderate asthma (Ph.D. thesis). University of Otago). Archived from the original on 24 August 2021. Retrieved 24 August 2021.
• Roy J (2011). “Paracetamol – the best selling antipyretic analgesic in the world”. An introduction to pharmaceutical sciences: production, chemistry, techniques and technology. Oxford: Biohealthcare. p. 270. ISBN 978-1-908818-04-1. Archived from the original on 24 August 2021. Retrieved 24 August 2021.

Acetanilide was the first aniline derivative serendipitously found to possess analgesic as well as antipyretic properties, and was quickly introduced into medical practice under the name of Antifebrin by Cahn & Hepp in 1886.

• Cahn A, Hepp P (1886). “Das Antifebrin, ein neues Fiebermittel” [Antifebrin, a new antipyretic]. Centralblatt für klinische Medizin (in German). 7: 561–4. Archived from the original on 1 September 2020. Retrieved 21 February 2019.

But its unacceptable toxic effects—liver and kidney damage and cyanosis due to methemoglobinemia, an increase of hemoglobin in its ferric [Fe³⁺] state, called methemoglobin, which cannot bind oxygen, and thus decreases overall carriage of oxygen to tissue—prompted the search for less toxic aniline derivatives such as phenacetin.

• Bertolini A, Ferrari A, Ottani A, Guerzoni S, Tacchi R, Leone S (2006). “Paracetamol: New vistas of an old drug”. CNS Drug Reviews. 12 (3–4): 250–75. doi:10.1111/j.1527-3458.2006.00250.x. PMC 6506194. PMID 17227290.
• Brodie, B. B.; Axelrod, J. (1948), “The estimation of acetanilide and its metabolic products, aniline, N-acetyl p-aminophenol and p-aminophenol (free and total conjugated) in biological fluids and tissues”, J. Pharmacol. Exp. Ther., 94 (1): 22–28, PMID18885610.

Phenacetin (acetophenetidin, N-(4-ethoxyphenyl)acetamide) is a pain-relieving and fever-reducing drug, which was widely used following its introduction in 1887 in Elberfeld, Germany by German company Bayer. It was one of the first synthetic fever reducers to go on the market. It is also known historically to be one of the first non-opioid analgesics without anti-inflammatory properties. Although paracetamol was produced earlier, a historical accident saw it ignored after Joseph von Mering‘s 1893 assessment.

Harmon Northrop Morse synthesized paracetamol at Johns Hopkins University via the reduction of p-nitrophenol with tin in glacial acetic acid in 1877, but it was not until 1887 that clinical pharmacologist von Mering tried paracetamol on humans. In 1893, von Mering published a paper reporting on the clinical results of paracetamol with phenacetin, another aniline derivative. Von Mering claimed that, unlike phenacetin, paracetamol had a slight tendency to produce methemoglobinemia. (An attached note says this could conceivably have been caused by the contamination of his paracetamol with the 4-aminophenol from which it was synthesised.) Paracetamol was then quickly discarded in favor of phenacetin. The sales of phenacetin established Bayer as a leading pharmaceutical company.

• Bertolini A, Ferrari A, Ottani A, Guerzoni S, Tacchi R, Leone S (2006). “Paracetamol: New vistas of an old drug”. CNS Drug Reviews. 12 (3–4): 250–75. doi:10.1111/j.1527-3458.2006.00250.x. PMC 6506194. PMID 17227290.
• Morse HN (1878). “Ueber eine neue Darstellungsmethode der Acetylamidophenole” [On a new method of preparing acetylamidophenol]. Berichte der deutschen chemischen Gesellschaft (in German). 11 (1): 232–233. doi:10.1002/cber.18780110151. Archived from the original on 6 November 2018.
• Silverman M, Lydecker M, Lee PR (1992). Bad Medicine: The Prescription Drug Industry in the Third World. Stanford University Press. pp. 88–90. ISBN 978-0804716697.
• von Mering J (1893). “Beitrage zur Kenntniss der Antipyretica”. Ther Monatsch. 7: 577–587.
• Sneader W (2005). Drug Discovery: A History. Hoboken, NJ: Wiley. p. 439. ISBN 978-0471899808. Archived from the original on 18 August 2016.

Phenacetin was withdrawn from medicinal use as dangerous from the 1970s (e.g., withdrawn in Canada in 1973, and by the U.S. Food and Drug Administration in 1983). Phenacetin has been used as a cutting agent to adulterate cocaine in the UK and Canada, due to the similar physical properties. There, it has been given the nickname “magic”.

• Gralak, Boris; Enoch, Stefan; Tayeb, Gérard (2000). “Anomalous refractive properties of photonic crystals”. Journal of the Optical Society of America A. 17 (6): 1012–20. Bibcode:2000JOSAA..17.1012G. CiteSeerX 10.1.1.462.8012. doi:10.1364/JOSAA.17.001012. PMID 10850471.
• “Phenacetin”. DrugBank. Retrieved 28 April 2020.
• “Drugs withdrawn from the market containing phenacetin” (PDF). Department of Health and Human Services – FDA. 5 October 1983. Archived from the original (PDF) on 30 October 2014.
• Sneader W (2005). Drug Discovery: A History. Hoboken, NJ: Wiley. p. 439. ISBN 978-0471899808. Archived from the original on 18 August 2016. The eminent clinical pharmacologist Joseph von Mering collaborated with the Bayer Company in a trial of paracetamol in 1893. He found it to be an effective antipyretic and analgesic, but claimed it had a slight tendency to produce methaemoglobinaemia. This could conceivably have been caused by the contamination of his paracetamol with the 4-aminophenol from which it was synthesised.
•  “Cancer chemical in street cocaine”. BBC News. 23 November 2006.

Von Mering’s claims remained essentially unchallenged for half a century, until two teams of researchers from the United States analyzed the metabolism of acetanilide and phenacetin. In 1947, David Lester and Leon Greenberg found strong evidence that paracetamol was a major metabolite of acetanilide in human blood, and in a subsequent study they reported that large doses of paracetamol given to albino rats did not cause methemoglobinemia. In 1948, Bernard Brodie, Julius Axelrod and Frederick Flinn confirmed that paracetamol was the major metabolite of acetanilide in humans, and established that it was just as efficacious an analgesic as its precursor.

• Sneader W (2005). Drug Discovery: A History. Hoboken, NJ: Wiley. p. 439. ISBN 978-0471899808. Archived from the original on 18 August 2016.
• Lester D, Greenberg LA, Carroll RP (1947). “The metabolic fate of acetanilid and other aniline derivatives: II. Major metabolites of acetanilid appearing in the blood”. J. Pharmacol. Exp. Ther. 90 (1): 68–75. PMID 20241897. Archived from the original on 2 December 2008.
• Brodie BB, Axelrod J (1948). “The estimation of acetanilide and its metabolic products, aniline, N-acetyl p-aminophenol and p-aminophenol (free and total conjugated) in biological fluids and tissues”. J. Pharmacol. Exp. Ther. 94 (1): 22–28. PMID 18885610.
• Brodie BB, Axelrod J (1948). “The fate of acetanilide in man” (PDF). J. Pharmacol. Exp. Ther. 94 (1): 29–38. PMID 18885611. Archived (PDF) from the original on 7 September 2008.
• Flinn FB, Brodie BB (1948). “The effect on the pain threshold of N-acetyl p-aminophenol, a product derived in the body from acetanilide”. J. Pharmacol. Exp. Ther. 94 (1): 76–77. PMID 18885618.

They also suggested that methemoglobinemia is produced in humans mainly by another metabolite, phenylhydroxylamine. Phenylhydroxylamine is the organic compound with the formula C₆H₅NHOH. It is an intermediate in the redox-related pair C₆H₅NH₂ and C₆H₅NO. Phenylhydroxylamine should not be confused with its isomer α-phenylhydroxylamine or O-phenylhydroxylamine. This compound can be prepared by the reduction of nitrobenzene with zinc in the presence of NH₄Cl. Alternatively, it can be prepared by transfer hydrogenation of nitrobenzene using hydrazine as an H₂ source over a rhodium catalyst. Phenylhydroxylamine is unstable to heating, and in the presence of strong acids easily rearranges to 4-aminophenol via the Bamberger rearrangement. Oxidation of phenylhydroxylamine with dichromate gives nitrosobenzene. The compound condenses with benzaldehyde to form diphenylnitrone, a well-known 1,3-dipole. Phenylhydroxylamine is attacked by NO⁺ sources to give cupferron.

• E. Bamberger “Ueber das Phenylhydroxylamin” Chemische Berichte, volume 27 1548-1557 (1894). E. Bamberger, “Ueber die Reduction der Nitroverbindungen” Chemische Berichte, volume 27 1347-1350 (1894) (first report)
• O. Kamm (1941). “Phenylhydroxylamine”. Organic Syntheses. 4: 57. doi:10.15227/orgsyn.004.0057.
• P. W. Oxley, B. M. Adger, M. J. Sasse, M. A. Forth (1989). “N-Acetyl-N-Phenylhydroxylamine via Catalytic Transfer Hydrogenation of Nitrobenzene using Hydrazine and Rhodium on Carbon”. Organic Syntheses. 67: 187. doi:10.15227/orgsyn.067.0187.
• I. Brüning, R. Grashey, H. Hauck, R. Huisgen, H. Seidl (1966). “2,3,5-Triphenylisoxazolidine”. Organic Syntheses. 46: 127. doi:10.15227/orgsyn.046.0127.
• C. S. Marvel (1925). “Cupferron”. Organic Syntheses. 4: 19. doi:10.15227/orgsyn.004.0019.

A follow-up paper by Brodie and Axelrod in 1949 established that phenacetin was also metabolized to paracetamol. This led to a “rediscovery” of paracetamol.

• Bertolini A, Ferrari A, Ottani A, Guerzoni S, Tacchi R, Leone S (2006). “Paracetamol: New vistas of an old drug”. CNS Drug Reviews. 12 (3–4): 250–75. doi:10.1111/j.1527-3458.2006.00250.x. PMC 6506194. PMID 17227290.
• Brodie BB, Axelrod J (1949). “The fate of acetophenetidin (phenacetin) in man and methods for the estimation of acetophenitidin and its metabolites in biological material”. J Pharmacol Exp Ther. 94 (1): 58–67.