Synthesis Of Rofecoxib And Its Derivatives

Rofecoxib is a new non-steroid anti-inflammatory drug(NSAID),which has a good curative effect in osteoarthritis and pain. Since Rofecoxib was gone on the market in America in 1999,it had been paid wide interests because there was no adverse effects of NSAID.The mechanism of NSAID is relation to inhibiting cyclooxygenase(COX).COX has two isoenzymes:COX-1 and COX-2. The anti-inflammatory effects of NSAID are mediated by inhibiting COX-2,while the side effects seem to be caused by COX-1. Rofecoxib is a selective COX-2 inhibitor which can provide the desired therapeutic profile of anti-inflammation without the adverse effects. So the development of selective COX-2 inhibitors will have significant positive impacts on the treatment of arthritis,pain,pyrexia and other diseases associate with inflammation. Objecttive:To develop a modification of the general route of the synthesis of rofecoxib(Ⅰ)and its derivatives which are 3-phenyl-4(4-sulfanilamido)phenyl-2 (5H)furanone(Ⅱ),3-(4-chloro)phenyl-4(4-sulfanilamido) phenyl-2(5H)furanone(Ⅲ)and 3-(4-methoxyl)phenyl-4(4-sulfanilamido)phenyl-2(5H)furanone(Ⅳ). The three derivatives were tested for their pharmacological activities.Design:Because of the remarkable efficacy and safety of rofecoxib,we partly changed its chemical structure according to the principle of developing"me-too drug"and expected to obtain new drugs whose effects would be similar to rofecoxib .We analyzed the reason why rofecoxib selectively inhibited COX-2. The difference of structure between COX-1 and COX-2 and the characters of the molecule structure of inhibitors caused the selectivity to COX's isoenzymes. The difference between COX-1 and COX-2 had been attributed to the presence of isoleucine (Ile523) in COX-1 relative to the smaller valine (Val523) in COX-2. The selective COX-2 inhibitors mostly had a side chain whose terminal was methylsulfone (SO2CH3) and sulfanilamido (SO2NH2) including a benzene. Because of its rigid structure the larger COX-2 inhibitors were not accessible to the smaller COX-1 passageway,then did not inhibit COX-1.The -SO2CH3 and -SO2NH2 were considered as the pharmacophores of selective COX-2 inhibitors. Replacement of -SO2CH3 of 4-phenyl of rofecoxib by -SO2NH2 would obtain compoundⅡwhich,we thought,should selectively inhibit COX-2 and have the similar effect. Furthermore, -NH2 and -CH3 were a common seriesof isosterisms which had similar physical and chemical properties. So the derivative(Ⅱ)should have the similar activity to its mother compound.There were different substituent groups in 3-phenyl of rofecoxib such as halogen, C1-6 alkoxyl, CF3, CN, C1-6 alkylthio. We used -Cl and -OCH3 to design the derivatives Ⅲ and Ⅳ. The synthesis of the three compounds Ⅱ,Ⅲ,Ⅳ had not been reported after our consulting internal and external literature.Methods:Compound (Ⅰ) was synthesized by using thioanisole and acetylchloride as raw materials. The reaction of thioansole with acetylchloride through Fiedel-Crafts acylation, oxidation, bromination affored α-bromine-p-methylsulfonyl acetophenone that was cyclodehydrated with sodium phenylacetic acid in the catalysis of diisopropylamine to obtain rofecoxib.Replacement of the solvent o-dichlorobenzene of Fiedel-Crafts acylation by chloroform synthesized the intermediate 4-acetylthioanisole.The common intermediate C of derivatives, α-bromine-p-acetylbenzenesulfonamide,was synthesized by using p-aminoacetophenone as raw material through dizaotization with sulfur dioxide cupric chloride dihydrate to obtain p-acetylbenzenesulfonyl chloride,which was aminolysized and brominated to obtain objective compound C.Compound Ⅱ,Ⅲ,Ⅳ were respectively synthesized by the reaction of sodium phenylacetic acid,sodium p- chlorophenylacetic acid,sodium p-methoxylphenylacetic acid with intermediate C in the catalysis of diisopropylamine.The tests of pharmacology : The four compounds were respectively tested their anti-inflammatory and analgesic...