Vioxx synthesis

Anionic/oxidative reaction sequences have been developed in addition to the domino anionic/reductive processes. For example, with regard to the synthesis of novel diaryl heterocycles as COX-2 inhibitors [500], including rofecoxib (Vioxx) 2-972 [501] (which has recently been withdrawn from the market) or the pyrrolin-2-one derivative 2-973 [494], Pal and coworkers reported on a so-far unique domino aldol condensation/oxidation sequence (Scheme 2.218) [503]. 

Another route to the synthesis of the furanone-containing compounds (e.g., 84, Scheme 18) is via magnesium-mediated carbometallation of propar-gyl alcohols, as described by Forgione et al. [67]. Scheme 20 demonstrates this procedure as a feasible means of producing the Merck anti-inflammatory drug Vioxx, 85. 

Rofecoxib, (MK 0966, Vioxx 4-(4-Methylsulfonylphenyl)-3-Phenyl-2(5H)-Furanone), a Selective and Orally Active Inhibitor of Cycooxygenase-2, Synthesis 2001,1778-1779. 

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. 

NSAIDs that preferentially inhibit COX-2 more than COX-1 (Vioxx and Celebrex) target the pain associated with inflammation such as rheumatoid or osteoarthritis with fewer stomach problems because prostaglandin I2 is synthesized by COX-1 in the stomach. In the heart, continuous muscular movements cause capillary wear. Cytokines induce COX-2 to make prostaglandin I2 which dilates the capillaries and prevents excessive blood clotting by thromboxane A4, a COX-1 enzyme product. A COX-2 inhibitor stops prostaglandin I2 synthesis. The heart capillaries do not dilate and there is a greater risk of coronary artery obstruction (heart attacks). 

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