NSAID藥物光反應進行hydroxylactonization之研究，第一部份：美洒辛

1. NSAID藥物光反應進行hydroxylactonization之研究，第一部份：美洒辛NSAID藥物光反應進行hydroxylactonization之研究，第一部份：美洒辛 • 本研究使用具有β,γ-不飽和酸官能基之非固醇類抗炎劑 (non-steroidal • antiinflammatory drugs,NSAID)藥物為美洒辛 (IN,Indomethacin) • ，在Hanovia 200W高壓汞燈之照射下，除了發生氧化及酯化反應外，同時 • 會進行hydroxylactonization (HL)。IN與大氣中之氧氣以環加成反應生 • 成β-hydroxy-γ-lactone (INHL)。本研究重點著重於光化學促進hydroxylactonization反應之細節。 • INHL經單離及再結晶後得到無色針狀結晶後，藉由質譜儀、紅外線光 • 譜、核磁共振光譜進行結構之分析外，為了證實及獲得更確實的分子之三 • 維晶體結構，因而利用X光單晶繞射分析的技術，確定INHL產物之結構為：8-(4-Chloro-benzoyl)-3a-hydroxy-5-methoxy-8a-methyl-2-oxo-2,3,3a,8a-tetrahydro-1H-furo[2,3-b]indole，晶體屬於三斜方晶系 (Triclinic)，空間群為P1，晶格常數為a=7.7511(1),b=9.9278(1), • c=22.5604(2,α=79.462(1),β=89.309(1),γ=89.765(1)；環的氮上 • 所連接的對氯苯甲醯支鏈位於苯環的左下方，呈現出立體效應最紓解的狀 • 態，亦即為最穩定之形式，且反應所形成的內酯環和環並不共面。 • 在甲醇溶液中，以IN為光敏化劑，進行HL反應之動力學研究方面，本 • 研究嘗試以不同之照射波長、不同之濃度、不同之溫度及嗜氧、厭氣狀態 • 等影響因子來探討反應動力學及可能之反應機轉。當HL反應進行時，在波長較短的光線激發下，INHL生成及降解速率非常快速，且INHL的生成量會 • 隨著光線趨向長波的激發而增加。在嗜氧的狀態下，其反應速率及生成量 • 較厭氧的狀態下會有增加的傾向。在增加溫度的影嚮下，提高熱效應對反 • 應速率及生成量有明顯降低的趨勢。 • 綜合X光單晶繞射實驗所獲得的結果及反應動力學的研究，推測美洒 • 辛光敏化進行hydroxylactonization反應機轉為，氧分子與環上 • C2=C3雙鍵進行[2+2]環化加成反應並脫去一分子的水，形成具立體選擇性 • 的β-hydroxy-γ-lactone產物，並會進一步形成具有dihydroxy • indolinyl acetic methyl ester的最終產物。

2. Studies of Photolytic Hydroxylactonization of NSAID, Part one : Indomethacin • 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.