Synthesis of Tenidap: An Improved Process for the Preparation of 5-Chloro-2-oxindole-1-carboxamide

Abstract

An industrially viable, robust, and economic process is developed for Tenidap sodium and its important intermediate 5-chloro-2-oxindole-1-carboxamide. Use of inorganic cyanates, in place of organic isocyanates, makes the process simple and commercially viable. The advantage of using acetic anhydride and sodium acetate over reported reagents such as trifluoroacetic acid and its anhydride on industrial scale is described. Drastic reduction of DMAP in the final step and overall improvement of yields makes the process economical. sodium (1) (Figure 1), are for the treatment of rheumatoid arthritis 1 and osteoarthritis 2 . Tenidap is an inhibitor of prostaglandin 3 and interleukin-1 4 production in the body. It inhibits both the enzymes cycloxygenase and 5-lypoxygenase, 5 which convert arachidonic acid into prostaglandin and leukotrienes 3 , and exhibits superior activity compared to other nonsteroidal antiinflammatory drugs (NSAIDs) such as naproxen, 6 piroxicam, 7 diclofenac sodium, 8 indomethacin, 9 and so forth, currently available in the market. Tenidap sodium has not been launched in the market because of toxic effects found in clinical trials. † DRF publication No. 99.

Practical Syntheses of Oxindole Derivatives: Chemical Development towards 2-(5-Chloro-2-oxo-2,3-dihydroindol-1-yl)acetamide and (S)-2-(5-Chloro-2-oxo-2,3-dihydroindol-1-yl)propionamide

“…A paper in the literature reporting the preparation of tenidap (structure based on the 5-chlorooxindole moiety) mentions the possibility of carrying out the ring opening of the oxindole 34 with aqueous sodium hydroxide and then further functionalizing the resulting aniline with an electrophile. This prompted us to explore the possibility of incorporating the amino acid residue via a reductive amination protocol after the ring opening of oxindole 34 (Scheme ).…”

3‐Alkenyl‐oxindoles: Natural Products, Pharmaceuticals, and Recent Synthetic Advances in Tandem/Telescoped Approaches

“…Ind. Co. reported the signal inhibitory properties of substituted 3-alkenyl-oxindoles such as ST280 (36) and ST458 (37). [35] Finally, mention must be made of tenidap (38), a potent cyclooxygenase inhibitor, developed by Pfizer for the treatment of rheumatoid arthritis and osteo-arthritis.…”

“…[35] Finally, mention must be made of tenidap (38), a potent cyclooxygenase inhibitor, developed by Pfizer for the treatment of rheumatoid arthritis and osteo-arthritis. [36][37][38] Despite the high expectations, it was not launched because of concerns about reduced bone mineral density. [38] …”