This document summarizes the synthesis of several common nonsteroidal anti-inflammatory drugs (NSAIDs) including naproxen, ketoprofen, ketorolac, diclofenac, and ibuprofen. It outlines the key reaction steps for producing each compound, starting from various aromatic precursors and involving reactions such as acylation, alkylation, hydrolysis, bromination, reduction, chlorination, and hydrolysis.

1. Md. Saiful Islam
B.Pharm, M.Pharm (PCP)
North South University
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Synthesis of Naproxen, Ketoprofen,
Ketorolac, Diclofenac and Ibuprofen

2. Naproxen: 2-Acetyl-6-methoxy-naphthalene may be prepared by the acylation of 6-
methoxynaphthalene. The resulting product is then subjected to a series of reactions, namely ;
Wilgerodt-Kindler reaction, esterification, alkylation and hydrolysis ultimately yields DL-Naproxen.
Resolution of the resulting racemic mixture is caused through precipitation of the more potent D-
enantiomer as the cinchonidinesalt.
Synthesis of Naproxen,
Ketoprofen, Ketorolac,
Diclofenac andIbuprofen

3. Ketoprofen: Ketoprofen, 2-(3-benzoyl) propionic acid (3.2.37), is synthesized from 3-
methylbenzophenone, which undergoes bromination and forms 3-bromo-methylbenzophenone
(3.2.33). The reduction of the resulting product by sodium cyanide gives 3-
cyanomethylbenzophenone (3.2.34), which is reacted with the diethyl ester of carbonic acid in the
presence of sodium ethoxide. The resulting cyanoacetic ester derivative (3.2.25) is alkylated by
methyl iodide and the resulting product (3.2.36) undergoes acidic hydrolysis, forming ketoprofen
(3.2.37).
Ketorolac:

4. Diclofenac: Diclofenac, 2-[(2,6-dichlorophenyl)-amino]-phenylacetic acid (3.2.42), is synthesized
from 2-chlorobenzoic acid and 2,6-dichloroaniline. The reaction of these in the presence of sodium
hydroxide and copper gives N-(2,6-dichlorophenyl)anthranylic acid (3.2.38), the carboxylic group of
which undergoes reduction by lithium aluminum hydride. The resulting 2-[(2,6-dicholorphenyl)-
amino]-benzyl alcohol (3.2.39) undergoes further chlorination by thionyl chloride into 2-[(2,6-
dichlorophenyl)-amino]-benzylchloride (3.2.40) and further, upon reaction with sodium cyanide
converts into 2-[(2,6-dicholorophenyl)-amino]benzyl cyanide (3.2.41). Hydrolysis of the nitrile
group leads to diclofenac(3.2.42).
Ibuprofen: p-Isobutyl acetophenone is prepared by the acetylation of isobutyl benzene which
upon treatment with hydrocyanic acid yields the corresponding cyanohydrin. This on heating with
hydrogen iodide in the presence of red phosphorous helps to reduce the benzylic hydroxyl moiety
; further hydrolysis of the nitrile groups gives the official compound.