Synthesis of celecoxib

With regard to the synthesis of celecoxib (1), several routes were described in the 1995 patent by G. D. Searle As shown in Scheme 1, dione 7 was prepared by the Claisen condensation of 4-methylacetophenone with ethyl trifluoroacetate in the presence of NaOMe in methanol under reflux. Subsequent diarylpyrazole formation from the condensation of dione 7 and 4-sulfonamidophenylhydrazine hydrochloride then delivered... 

Habeeb, A. G., Praveen Rao, P. N., Knaus, E. E. Design and synthesis of celecoxib and rofecoxib analogues as selective cycloox-ygenase-2 (COX-2) inhibitors replacement of sulfonamide and methylsulfonyl pharmacophores by an azido bioisostere. 7. Med. Chem. 2001,44(18), 3039-3042. 

In 2011, Gaulier and coworkers reported the synthesis of celecoxib (Celebrex ) via C-H arylation of pyrazoles at the C2 position (Scheme 16.41) [84]. Pyrazole 183 was coupled with aryl bromide 184 using Fagnou s catalytic system to form... 

Scheme 16.41 Synthesis of celecoxib using a Pd-catalyzed C-H arylation.

Meloxicam is an enolcarboxamide related to piroxicam that preferentially inhibits COX-2 over COX-1, particularly at its lowest therapeutic dose of 7.5 mg/d. It is not as selective as celecoxib and may be considered "preferentially" selective rather than "highly" selective. The drug is popular in Europe and many other countries for the treatment of most rheumatic diseases and approved for treatment of osteoarthritis in the USA. It is associated with fewer clinical gastrointestinal symptoms and complications than piroxicam, diclofenac, and naproxen. Similarly, while meloxicam is known to inhibit synthesis of thromboxane A2, even at supratherapeutic doses its blockade of thromboxane A2 does not reach levels that result in decreased in vivo platelet function (see common adverse effects above). 

Ongoing research led to the development of COX-2 selective inhibitors (e.g., rofecoxib and celecoxib). Celecoxib (Celebrex ) was approved by the FDA in 1998 to treat osteoarthritis and rheumatoid arthritis. Rofecoxib (Vioxx ) was approved in May 1999 to treat osteoarthritis, acute pain, and dysmenorrhea. Sales for the two drugs in 1999 were 1.5 billion and 373 million, respectively. Clinical studies have indicated a significant reduction in GI perforation, ulceration, or bleeding with the COX-2 inhibitors. The recognition of multiple COX isoforms has had one of the greatest impacts on the development of NSAIDs since the original synthesis of aspirin more than a century ago. 

A causal relation between celecoxib and these thrombotic events cannot be established with certainty on the basis of the available evidence. However, the temporal relation between the start of treatment and the thrombotic event was impressive, at least in three patients, and the findings were consistent with the hypothesis that thrombosis is an adverse consequence of reduced production of systemic prostaglandin I2 brought about by COX-2 inhibition. Reduced synthesis of prostaglandin I2 may act in concert with other thrombotic risk factors (such as those occurring in this series of patients) to precipitate acute vascular occlusion. 

Structure-Activity Analysis. As a second approach to further test the h)q)othesis that COX-2 inhibition is not necessary for inducing apoptosis by COX-2 inhibitors, structural modifications of celecoxib were performed to dissociate COX-2 inhibitory and apoptotic activities. Structure-activity analysis was performed by the synthesis of a series of celecoxib derivatives with different substituents at the terminal phenyl ring and evaluation of the apoptosis-inducing potency of each. Figure 9 summarizes the structures, the COX-2 inhibitory activities (ICg(j) and the apoptosis-inducing activities (Tj 2 required for 50% cell death) of celecoxib and seven representative derivatives. 

Synthesis of non-steroidal anti-inflammatory dmg celecoxib and structural analogs 12COC1390. 

Non-selective NSAIDs inhibit both COX isoforms. Celecoxib is an NSAID that exhibits antipyretic, analgesic, and anti-inflammatory activities. The mechanism of action of celecoxib is due to inhibition of prostaglandin synthesis via inhibition of COX-2. At therapeutic concentrations in humans, celecoxib does... 

Palamoor, M., Jablonski, M.M. Synthesis, characterization and in vitro studies of celecoxib-loaded poly(ortho ester) nanoparticles targeted for intraocular drug delivery. CoUoids Surf. B Biointerfaces 112, 474 82 (2013). doi 10.1016/j.colsurfb.2013.07.039... 

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