引朵美洒辛於醇類溶液的光解反應與動力研究

Studies of Photolysis and Kinetics of Indomethacin in Alcoholic Solvents

彭玉堂(Peng Yung-Town)

指導教授 ： 吳安邦 ； 陳朝洋

臺北醫學大學/藥學院/藥學研究所/碩士(1998年)

摘要

??美洒辛(Indomethacin, IDM)為一非固醇類藥品，具有光敏感性及光毒性， 本研究係將IDM置於極性較高之甲醇溶媒中，於日光下曝曬二個月( 60天)後， 以製備型高壓液相層析儀將光解產物分離，共得四種主要的光解產物IDMP-1、 IDMP-2、IDMP-3及IDMP-4。藉由質譜、紅外線光譜、核磁共振氫譜及碳譜 IDMP-1初步判斷為9-(4-Chlorobenzoyl)-6-methoxy-9a-methyl-4,4a,- dihydro-1,2-dioxa-9-aza-fluoren-3-one。而IDMP-2之結構可確定為1- (4-chloro-benzoyl)-5-methoxy-2,3-dimethyl-indole、IDMP-3為1-( 4-chloro-benzoyl)-5-methoxy-2-methyl-indole-3-carbaldehyde、IDMP-4 為[1-(4-chloro-benzoyl)-5-methoxy-2-methyl-indol-3-yl]-acteic acid methyl ester。 為確定IDMP-1之結構另以X光單晶繞射法鑑定出其構造為8-(4-chloro-benzoyl) -3a-hydroxy-5-methoxy-8a-methyl-3,3a,8,8a-tetra-hydro-furo[2,3-b] indol-2-one。 在乙醇溶液中發現有相同的IDMP-1、IDMP-2、IDMP-3光解產物生成， 而IDMP-5為乙基酯，係類似IDMP-4同為酯化反應之衍生物。在異丙醇中 亦觀測到相同結果，惟不見有異丙基酯之生成。 在醇性溶媒中的光解動力學研究方面：IDM於醇性溶媒中各種不同濃度的 光分解反應呈現出一階次之反應。而IDM在三種不同醇性溶媒的降解速率 則與醇性溶媒之極性呈一正比之關係。在三種不同的溫度之測定，IDM在 甲醇溶液中之降解速率取對數與1/T作圖，可計算出其活化能(Ea)為3.5 kcal/mol。在嗜氧狀態下，IDM的降解反應有增加的傾向，故反應為需氧 反應。 藉由光解產物之鑑定、動力學的研究推測IDM光解反應途徑為：IDM與O2進 行光化學的環加成反應 [(2+2)-Cycloaddition]，先形成一1,2-Diol中間 產物，最後脫水形成光解產物IDMP-1。IDMP-2的形成係經由IDM脫羧基反 應，先脫去C-3的醋酸基(-COOH)形成(-CH2．)中間產物，於溶液中獲得H+ 形成甲基。IDMP-3則由相同之中間產物經氧化反應而生成。IDMP-4及 IDMP-5於不同醇類溶媒中分別進行C-3醋酸基支鏈之酯化反應。

關鍵字

引朵美洒辛 ； 光解反應 ； 氧化反應 ； 酯化反應 ； 光化學環加成反應 ； X光單晶繞射法

並列摘要

Indomethacin (IDM), a well-known anti-inflammatory drug, is a photosensitive and phototoxic agent. This study attempted to separate the photodegradation products when IDM was placed in a polar solvent, such as methanol and exposed to sunlight for 60d. Four photolytic products, IDMP-1, IDMP-2, IDMP-3 and IDMP-4, were isolated by the preparative HPLC. By way of analyzing MS, NMR and IR spectra, their structures were characterized. The structure of IDMP-1 is found to be 9-(4-Chlorobenzoyl)-6-methoxy-9a-methyl- 4,4a,-dihydro-1,2-dioxa-9-aza-fluoren-3-one. While the structure of IDMP-2 is identified as 1-(4-chloro-benzoyl)-5-methoxy-2,3- dimethyl-indole; IDMP-3, 1-(4-chloro-benzoyl)-5-methoxy-2-methyl- indole-3-carbaldehyde; IDMP-4, [1-(4-chloro-benzoyl)-5-methoxy-2- methyl-indol-3-yl]-acteic acid methyl ester. When the single crystal X-ray differaction method was used to determine the structure of IDMP-1, it was elucidated as 8-(4- chloro-benzoyl)-3a-hydroxy-5-methoxy-8a-methyl-3,3a,8,8a- tetrahydro-furo[2,3-b]-indol-2-one. Similar photolytic products including IDMP-1, IDMP-2, IDMP-3 were found in ethanol. Instead of the formation of a methyl ester product, IDMP-4, an ethyl ester IDMP-5 was found in ethanol. The photodegradation in propan-2-ol had also formed the same products : IDMP-1, IDMP-2 and IDMP-3, but no ester ever found in propan-2-ol. The kinetics of IDM in alcoholic solvents were studied. The photodegradation of IDM in alcoholic solvents with different concentration suggest that IDM follows a pseudo first-order kinetic reaction. The polarity constants of the alcoholic solvent were direct proportional to the photodegradation rates of IDM. IDM photodegradation rate at three different temperatures were measured according to Arrhenius equation and Ea=3.5 kcal/mol. At aerobic conditions, the photodegradation rate of IDM was accelerated. Based on the above results, it is concluded that the photodegradation of IDM mainly occurs at the acetic acid group. The product of IDMP-1 was believed to react with O2 via a photochemical [2+2] cycloaddition pathway at C-2 and C-3 of the indole ring. Decarboxylation progresses rapidly and produces IDMP-2. The oxidation goes on to generate the aldehyde derivatives, IDMP-3. IDMP-4 was obtained via the esterfication on the carboxyl group of the acetic acid side chain.

並列關鍵字

Indomethacin ； photolysis ； oxidation ； esterification ； cyclo-addition ； X-ray diffraction