Synthesis of acetaminophen Pharmaceutical Chemistry Department-College Of Pharmacy-HMU

Paracetamol or acetaminophen is a very widely used analgesic and antipyretic. It is a relatively safe drug . (toxicity has been observed with very high doses).

Medical uses Fever Pain Osteoarthritis Low back pain Headaches (in combination with Caffeine for migraine headache) Postoperative pain (in combination with NSAID)

The drug phenacetin was formerly used an antipyretic to relieve fever The drug phenacetin was formerly used an antipyretic to relieve fever. But long term use of phenacetin caused kidney damage. In 1893 Joseph von Merking discovered paracetamol which was found to be not only a good antipyretic but also much safer than phenacetin. (unlike phenacetin, and its combinations, paracetamol is not considered carcinogenic at therapeutic doses)

Chemical structure

Synthesis 1. Reduction of para nitro phenol in glacial acetic acid. 2. Acetylation of para amino phenol with ketene. 3.Acetylation of para amino phenol with acetic anhydride.

Acetylation Replacement of active hydrogen present in phenols or amine (primary ,secondary not tertiary) by acetyl group. (preparation of paracetamol. ,preparation of aspirin. ,preparation of acetyl cysteine )

Mechanism

Chemical and Physical properties: White or almost white ,crystalline powder ,sparingly soluble in cold water but in hot water it’s solubility is about 5g/100mL,freely soluble in alcohols, melts at 169○C.

Procedure:- Weigh 1g of para amino phenol and transfer to conical flask. Add 1.1 ml of acetic anhydride. Add 2-3 drops of conc. H2SO4. Heat the mixture at 60◦C for 20 min. Allow the contents of the flask to attain room temperature , after that add 5ml of cold water. Filter the ppt. and calculate the percentage of yield .

Precautions (1) All glass apparatus which are used in the synthesis must be perfectly dry. (2) Concentrated sulphuric acid should always be added with great caution. (3) To complete the reaction mixture it must be warmed at 60°C for 20–25 minutes.