Syntheses of Carprofen, a Carbazole-based Non-steroidal Anti-inflammatory Agent

Abstract

Syntheses of carprofen (6) have been achieved by two approaches from carbazole (11).In one, 2,9-diacetylcarbazole (12) and 2-acetylcarbazole (13) were chlorinated with trichloroisocyanuric acid (15) to give the 6-chloro derivatives ( 16) and ( 17), respectively.Reduction of 16 with NaBH4, followed by acetylation, cyanide displacement, and hydrolysis afforded 6 in 73% yield from 1 6 .Alternatively, 17 was converted into its trimethylsilyloxy cyanohydrin derivative (27).which was reduced with SnC12 and hydrolysed to give 6 in 75% yield from 17.In the other approach, the ketone (IS), derived by a Friedel-Crafts acylation of 9-acetylcarbazole with 2-chloropropanoyl chloride followed by chlorination with 15, was converted into the hydroxyketal(Z8) with methanolic NaOMe.Mesylation of 28, followed by a modified Favorskii rearrangement and hydrolysis gave 6 in 73% yield from 18.Non-steroidal anti-inflammatory drugs (NSAIDs) are used extensively to ameliorate the symptoms of inflammation and pain, particularly those associated with rheumatoid arthritis.1The primary mode of action of carboxylic acid NSAIDs, of which aspirin is the prototype, is the inhibition of prostaglandin biosynthesis by obsuuctmg the action of cyclooxygenase in the arachidonic acid cascade?However, associated with the chronic use of NSAIDs are several side effects that are related to the inhibition of prostaglandin synthesis, such as gastrointestinal ulceration, bleeding, and renal toxicity.'It should be noted that another group of arachidonic acid metabolites, the leukolrienes, are also known to conuibute to inflammation and NSAIDinduced side cffects.3Among the NSAIDs, those of the 2-arylpropanoic acid class4 are probably the most prominent, and are represented by ibuprofen (I), naproxen (2), flurbiprofen (3), phenoprofen (4).and ketoprofen (5).In these and other 2-arylpropano~c acid NSAIDs studied, the (S)-enantiomer is the biologically active isomer, hut there is good evidence for the in viva conversion of the (R)-enantiomer into the 6% a Dedicated to Professor Arnold Brossi on the occasion of his 70th birthday.