引朵美洒辛於醇類溶液的光解反應與動力研究

1. 引朵美洒辛於醇類溶液的光解反應與動力研究 • 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。

2. Studies of Photolysis and Kinetics of Indomethacin in Alcoholic Solvents • 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.