Studies of Photolytic Hydroxylactonization of NSAID, Part one : Indomethacin

• Main Authors: Chien-Liang Lin, 林建良
• Other Authors: An-Bang Wu
• Format: Others
• Language: zh-TW
• Published: 2001
• Online Access: http://ndltd.ncl.edu.tw/handle/87031165594917772610

碩士 === 台北醫學院 === 藥學研究所 === 89 === This research took a nonsteroidal antiinflammatory drug with β,γ-unsaturated carboxylic acid group, Indomethacin (IN) as a model reactant. Under irradiation by a Hanovia 200W high pressure mercury-vapor lamp, IN could be oxidized, esterified and proceeded via hydroxylactonization simultaneously. IN was observed to convert into the corresponding β-hydroxy-γ-lactone (INHL) when reacted with molecular oxygen in the air by a cycloaddition. In the this part, we concentrated on the details of photolytic hydroxylactonization. The structure of INHL formed by hydroxylactonization was determined by UV, IR and NMR spectroscopies. In addition, the molecular structure of INHL had been confirmed as 8-(4-chloro-benzoyl)-3a-hydroxy-5-methoxy-8a-methyl-2-oxo-2,3,3a,8a-tetrahydro-1H-furo[2,3-b]indole by single crystal X-ray diffraction method. The space group for crystals of INHL was P1 in triclinic system. Unit cell dimensions are as follows: a=7.7511(1)Å,b=9.9278(1)Å,c=22.5604(2)Å,α=79.462(1),β=89.309(1) ,γ=89.765(1). The relative orientation of p-chlorobenzoyl in INHL is below the lactone group, and the steric effect is the most relaxed and stable. Lactone ring is also in non-coplanar state with the indole ring. The primary kinetic behavior of photolytic hydroxylactonization of IN in methanol was studied. Hydroxylactonization with various irradiation wavelengths, substrate concentrations, temperature effect and aerobic or anaerobic condition was thoroughly studied and discussed. The rate and yield of hydroxylactonization would be promoted under aerobic condition with increase temperature. In summary, based on the results of X-ray single crystal diffraction method and reaction kinetics, we postulate that the mechanism of the photolytic hydroxylactonization is a typical symmetry-controlled cycloaddition. The double bond (C2=C3) of the 5-membered heterocyclic ring of the indole system of IN reacts via [2+2] Diels-Alder type cycloaddition from the side attack of singlet oxygen. A dioxetane could be a possible intermediate. INHL forms on losing a mole of H2O. When INHL in methanol is further irradiated, a dihydroxy indolinyl acetic methyl ester is generated as a final product.