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


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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

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

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Nsaid hydroxylactonization

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。


Studies of photolytic hydroxylactonization of nsaid part one indomethacin

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.


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