- Paracetamol was first synthesised by Morse in 1878 by the reduction of p-nitrophenol with tin in glacial acetic acid. The p-aminophenol produced by the reducing action of the tin was acetylated in situ by the acetic acid.
- Vignolo simplified the synthesis by using p-aminophenol as the starting material which he acetylated with acetic acid.
- Friedlander modified this process slightly by acetylating the p-aminophenol (from p-nitrophenol) with acetic anhydride in place of acetic acid.
- Many preparative methods have since been described, mostly employing the acetylation of p-aminophenol with acetic anhydride, but other routes have also been discovered and used commercially.
- A number of commercial methods of manufacture are currently in use around the world.
- The early commercial production of paracetamol relied on the nitration of phenol to p-nitrophenol with a reduction step to produce p-aminophenol followed by acetylation with acetic anhydride.
- In a similar process phenol is converted to p-nitrosophenol and then reduced and acetylated as above.
- In the late sixties efforts were made to simplify the process and a single step synthesis from nitrobenzene to p-aminophenol was patented.
- The late seventies saw a new entrant to the field using a process starting from monochlorobenzene followed by nitration, hydrolysis and subsequent acetylation.
- In the mid-eighties a new process was announced involving some interesting chemistry. The route started from phenol but used innovative technology via 4-hydroxyacetophenone followed by a rearrangement to paracetamol. Although at the time great claims were made for the advantages of this process, as yet they remain to be commercially proven.