The Synthesis Of COX-2 Inhibitor Valdecoxib

Nonsteroidal anti-inflammatory drugs (NSAIDs) are therapeutic agents widely used in the treatment of pain, fever and inflammation. The mechanism of NSAIDs is mainly inhibiting cyclooxygenase(COX),which is the key enzyme required for the conversion of arachidonic acid into prostagladins(PGs). While PGs have many physiological functions. It can lead to inflammation and pains in the nervous system. Besides, PGs are responsible for nomal renal function, and they are cytoprotective in the gastrointestinal tract. Thus, the therapeutic effects and side effects of this class exist at the same time. As a consequence, NSAIDs users suffer from a high incidence of gastrointestinal irritation, including the development of life-threatening gastrointestinal ulcers. In 1990, Fu et al. discovered the existence of two isoforms of COX: COX-1 and COX-2. COX-1 is constitutively expressed in most tissues and, particularly, in the gastrointestinal tract and kidneys, where it is mainly responsible for the synthesis of cytoprotective PGs. COX-2 is selectively induced by proinflammatory cytokines(IL-1) and growth factors(TNFα) and facilitates the release of PGs involved in the inflammatory process. Therefore, the ideal NSAIDs should selectively inhibit COX-2, the clinicallyuseful NSAIDs inhibit both COX-1 and COX-2, so the therapeutic effects and side effects of this class of drug exist at the same time . Selective inhibition of COX-2 provided a new class of anti-inflammatory, analgesic, and antipyretic drugs with significantly reduced side effects. In the present selective COX-2 inhibitors, Valdecoxib (Bextra),(4-(5-methyl-3-phenyl-isoxazol-4-yl)benzenesulfonamide). It belongs to the second generation of COX-2 inhibitors. It came onto the markets first in America in April,2002. Valdecoxib has been investigated for the treatment of chronic pain associated with osteoarthritis(OA), rheumatoid arthritis(RA) and pain associated with dysmenorrhoea. Its treatment of pain about oral surgery is better than the first generation of COX-2 inhibitors- Rofecoxib (Voixx) and Celecoxib (Celebrex) . A number of studies show that valdecoxib 40mg was significantly more effective than rofecoxib 50mg. Valdecoxib showed a 28000-fold selectively for COX-2 using isolated recombinant human COX-isoenzymes. Under the same experimental conditions the values found for celecoxib, rofecoxib were 375 and 800, respectively. Parecoxib(N-[[4-(5-methyl-3-phenyl-4-isoxazoly)-phenyl]sulfonyl]propanamide) is the water-soluble inactive prodrug of valdecoxib. Intravenous administration of pareco-xib sodium to all animal species resulted in complete and rapid conversion to valdecoxib. Besides, parecoxib canreplace the kind of analgesic drugs such as Morphine and it has no side effects of endurance and so on. Thus , parecoxib and valdecoxib can be widely used in clinical practice. There were no reports on the preperation of valdecoxib in our country. In this paper, we report the synthesis of valdecoxib. Objective:①The aim is to synthesize 4- (5- methyl -3- phenyl- isoxazol- 4- yl) benzenesulfonamide and identify its structure by spectrum.②to improve the synthetic procedures.③to synthesize a good many Valdecoxib in order to synthesize Parecoxib and other compounds.Methods: Valdecoxib is synthesized by six steps. The first step is to synthesize phenylacid chloride. Phenylacetic acid is converted to phenylacid chloride with thionyl chloride. The second step is to synthesize desoxybenzoins. phenylacid chloride in the presence of a Leuis acid such as aluminum chloride to provide the desired compound desoxybenzoins by Friedel-Crafts in high yield. The third step is to synthesize desoxybenzoin keto-oxime. Desoxybenzoins with hydroxylamine hydrochloride by sodium acetate in ethanol, provide the desired compound desoxybenzoin keto-oxime. The forth step is to synthesize 5- hydroxy -5- methyl- 3,4- diphenylisoxazoline. desoxybenzoin keto-oxime is treated with two equivalents of a base such as n-butyllithium in cyclohexane to produce a dianion whic...