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研究生:梁進源
研究生(外文):Chin-Yuan Liang
論文名稱:頭孢子菌母體Cephem衍生物的合成與應用
論文名稱(外文):The Synthesis and Application of Cephem Derivatives in Cephalosporin System
指導教授:林振東林振東引用關係
學位類別:碩士
校院名稱:東海大學
系所名稱:化學系
學門:自然科學學門
學類:化學學類
論文種類:學術論文
論文出版年:2007
畢業學年度:95
語文別:中文
論文頁數:88
中文關鍵詞:頭孢子菌
外文關鍵詞:Cephem
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Cephem 9 (或Δ3-Cephems)是頭孢子菌抗生素之母體結構,不論是第一代、第二代、第三代或第四代頭孢子菌抗生素皆是如此。頭孢子菌母體及衍生物之合成,首先以Penicillin G 22為起始物,進行酯化、氧化反應,得到化合物31;化合物31以亞磷酸三烷酯進行還原反應,得到重排化合物32;化合物31在還原反應後,加入三乙基胺反應,得到化合物32的另一個異構物35;化合物32以2,2-Dibenzothiazolyl disulfide在酸性條件下進行開環反應得到化合物33;化合物33使用二甲基甲醯胺為溶劑,於低溫-35℃下,加17﹪氨水反應,即可獲得高產率Cephem衍生物之化合物34,其反應經由丙烯氫進行去質子化,之後環化而獲得Cephem 9之骨架;另外一方面,化合物32利用鋅粉在酸中進行氫解及伴隨之重排反應,可得到化合物36;而異構化後的化合物35在相同條件下,可獲得化合物37;化合物36及化合物37為合成化合物34過程常發現之不純物。
Cephem衍生物(化合物34),主要用於頭孢子菌抗生素之合成。化合物34利用鋅粉在酸中進行氫解、再以PG-Acylase在醯胺基上進行去醯化反應可獲得化合物11。化合物11與p-Hydroxyphenylglycine Dane salt (化合物38)進行取代反應得到化合物30。與Phenylglycine Dane salt (化合物39)進行取代反應得到化合物10。化合物30及化合物10為廣效性抗生素,可抑制葛蘭素陽性菌及葛蘭素陰性菌。
It is no matter whether the first generation or the second, third and fourth generation of cephalosporin antibiotics. Cephem (or Delta 3-Cephems) is a key structure of the cephalosporin antibiotics. The related derivative 34 of Cephem 9 was first prepared from Penicillin G 22 as the start material followed by esterification and oxidizing reaction to obtain compound 31. Reduction of 31 with trialkyl phosphite obtained compound 32. After reduction of 31, the resulting 32 underwent thermal rearrangement in triethylamine solution to give isomer 35. Reaction of 32 was carried out in the presence of 2,2-dibenzothiazolyl disulfide under acidic condition to obtain compound 33. Reaction of 33 with 17% ammonium hydroxide in DMF at -35℃ afforded Cephem derivative 34 in good yield. The reaction proceeded via deprotonation of allylic hydrogen followed by ring cyclization and removal of benzothiazolyl sulfide to produce the cephem skeleton. Hydrogenolysis of 32 with zinc powder in DMF solution and followed by dehydration under acidic condition was able to obtain compound 36. Reaction of 35 under the similar condition could obtain compound 37. Compound 36 and 37 are impurities, generally found in the preparation of the related derivative 34.
The derivatives of Cephem 9 were widely empolyed in the synthesis of antibiotics. Hydrogenolysis of 34 with zinc powder in DMF solution followed by deacylation on amide group with PG-acylase could obtain compound 11. Compound 11 is a key intermediate in the preparation of the cephalosporin antibiotics. A solution of 11 and hexamethyldisilazane in methylene chloride was stirred with a solution of p-hydroxyphenylglycine Dane salt (38) at low temperature producing 30 successfully. Simiarly, compound 10 was prepared from the reaction of 11 and phenylglycine Dane salt (39). Compound 30 and 10 are broad-spectrum antibiotic effective in Gram-positive and Gram-negative bacterial infections.
目錄……………………………………………………………………1
表目錄…………………………………………………………………2
附圖目錄………………………………………………………………3
誌謝辭…………………………………………………………………4
Cephem合成反應流程圖……………………………………………..5
Cephem相關衍生物合成流程圖……………………………………..6
Cephem之應用流程圖……………………………………………….7
中文摘要……………………………………………………………..8
英文摘要……………………………………………………………. 9
化合物總圖………………………………………………………….10
壹、 緒論……………………………………………………………13
貳、 結果與討論……………………………………………………28
參、結論……………………………………………………………..62
肆、實驗部分………………………………………………………..64
一、 一般敘述…………………………………………………64
二、 實驗步驟與光譜資料…………………………………….67
參考文獻………………………………………………………………84
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