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Study on the Synthesis of COX-2 Inhibitor Cimicoxib and Lumiracoxib

Author: DengFaLiang
Tutor: LiuYingXiang
School: Guangdong College of Pharmacy
Course: Medicinal Chemistry
Keywords: cyclooxygenase-2 inhibitor cimicoxib lumiracoxib NSAIDs synthesis
CLC: R914
Type: Master's thesis
Year: 2007
Downloads: 84
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Abstract

Nonsteroidal antiinflammatory drugs (NSAIDs) have become the standard therapy for the inflammation and pain. Because NSAIDs indiscriminately inhibit both isoforms of cyclooxygenase(COX), they are frequently associated with severe adverse effect such as gastric perforation, gastrorrhagia, ulcers, when they are showing therapeutic efficacy. Since the inducible COX-2 playing a role in inflammation is recognized, the development of selective COX-2 inhibitors has become one of the popular domains.This article focuses on the synthesis of cimicoxib and lumiracoxib. cimicoxib(UR-8880), 4-[4-chloro-5-(3-fluro -4-methoxyphenyl)-1H-imidazol-1-yl]benzene Sulfonamide, developed by J. Uriach&Cia. SA, is currently undergoing phase II clinical trials for the oral treatment of acute pain and osterarthritis. Experiments in animals revealed that cimicoxib exhibited a good pharmacokinetic profile and a high safety as regards both the cardiorespiratory and central nervous systems. Clinical trials indicated that cimicoxib appeared to be safe and well tolerated at high doses in humans.Lumiracoxib(COX-189), 2-[2-(2-chloro-6-fluorophenylamino)-5-methylphenyl]acetic acid, developed by Novatis AG, came onto the markets first in Mexico in 2003, now it can be purchased in 55 countries, as the long-term medication of chronic pain associated with osteoarthritis(OA), rheumatoid arthritis(RA) and acute pain, dysmenorrhoea. American food and drug administration licensed lumiracoxib to treat OA, acute pain and dysmenorrhoea, the recommended starting dose is 100 mg once daily or 200 mg once daily. Since lumiracoxib going on the markt, there aren’t any reports for the cases of severe cardiovascular disease. Lumiracoxib isn’t commercial in our country now.This paper synthesied cimicoxib and maked following improvements via repetitive experiments:1. In the reaction of synthesizing N-tert-Butyl-4-acetylaminobenzenesulfonamide, we use mix solvent–dimethoxyethane and heptane to replace single solvent–dimethoxyethane, the both yields are similar, but the mix solvent is cheaper than single solvent.2. Drying N-tert-Butyl-4-aminobenzenesulfonamide in shady place is different from vacuum drying reported in literature. Our strategy makes the procedure easy and doesn’t influence the yield.3. Synthesizing N-tert-Butyl-4-aminobenzenesulfonamide in our strategy, the isolated yield can be improved from 60.5%(from 4-acetylaminobenzenesulfonyl chloride) to 74.4%。4. We found out an effective approach to prepare N-(3-fluoro-4-methoxybenzylidene)- 4-(tert-Butylaminosulfonyl)aniline: the reaction has been aged for 10 hours at reflux in dehydrated alcohol in which the acetic anhydride is added as catalyst.5. 1-(tert-Butylaminosulfonylphenyl)-5-(3-fluoro-4-methoxyphenyl)imidazole and 1-(tert-Butylaminosulfonylphenyl)-4-chloro-5-(3-fluoro-4-methoxyphenyl)imidazole are white solid prepared under optimised condition, which differ from creamy solid reported in literature.6. Sodium hydroxide is avoided in the reaction of synthesizing target compound, making procedure easy. Besides, we replace acetonitrile by 60% ethanol to recrystallize product so as to minish the toxicity and reduce the cost. The chemical structure of the target compound was confirmed by proton magnetic resonance(1H-NMR), carbon-13 nuclear magnetic resonance(13C-NMR), infrared spectra(IR), mass spectrum(MS) and elemental analysis.The overall yield was 42.4%, superior to literature’s report. Because of cheap cost and easy to obtain for raw material, mild reaction condition and simple operation, our strategy may offer reference for industrialized production. This article maked following improvements in synthesizing lumiracoxib:1. An important intermediate N-(2-chloro-6-fluorophenyl)-4-methylanilin was synthesized from 4-methylaniline through amidation, Williamson synthesis and smiles-rearrangement sequence in which the last two reactions are telescoped into a single process using isopropanol as solvent.2. We use CH3ONa to replace CH3ONa/CH3OH, which simplifies the procedure, saves the cost and shortens the reaction time.3. Dehydrated alcohol was taken the place of isopropanol in preparing N-(2-chloro-6-fluorophenyl)-N-chloroacetyl-4-methylanilin. Dehydrated alcohol is cheaper than isopropanol.4. Using reduced iron powder as cocatalyst in preparing N-(2-chloro-6-fluorophenyl)-5 -methyloxindole, the isolated yield can be improved from 80% to 85.1%。5. The method of synthesizing N-(2-chloro-6-fluorophenyl)-5-methyloxindole reported in literature is to extract the mixture by toluene, then recrystallization. Our strategy is to pour the reaction product into the mixed liquid of broken ice and concentrated hydrochloric acid, then stir several minutes to give crude product and recrystallized by 80% methanol. Our procedure is simple.6. The overall yield was 42.4%, superior to literature’s report. The chemical structure of the target compound was confirmed by 1H-NMR, 13C-NMR, IR, UV, MS and elemental analysis.The reseaches in this paper may offer reference for lumiracoxib’s industrialized production.

Study on the Synthesis of COX-2 Inhibitor Cimicoxib and Lumiracoxib

Abstract

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