臺灣博碩士論文加值系統

異噁唑 ( Isoxazole )是屬於一種雜環化合物，而且具有相當多的應用價值，例如藥物活性與重要的有機合成中間體。
本論文成功的合成了N-(4-芳香基)-5-甲基異噁唑-4-甲醯胺苯(1)(N-(4-aryl)-5-methylisoxazol-4-carboxamide)及N-(4-芳香基)-3-甲基異噁唑-4-甲醯胺苯(2)(N-(4-aryl)-3-methyl-isoxazol-4-carboxamide)兩系列化合物並探討其光譜性質，其中化合物2系列是新化合物。利用5-甲基異噁唑-4-羧基氯和3-甲基異噁唑-4-羧基氯與苯胺進行取代反應可以得到化合物1及化合物2。
以化合物1的異噁唑環上之C5的SCS值對Hammett常數關係作圖，斜率為+1.3，相關係數為0.94。顯示此一結構中C5的化學位移可受苯環之取代基影響，苯環上取代基影響相距四個原子遠的異噁唑環上之C5的13C NMR 化學位移，此影響稱為長距離Hammett 取代效應(long distance Hammett substituent effect)。
化合物2系列化合物藉由元素分析、紅外線光譜、紫外線光譜、質譜、1H 核磁共振光譜與13C 核磁共振光譜等分析方法加以確定。

Isoxazole is a class of heterocyclic compounds having a remarkable
number of applications and has been demonstrated to be very versatile
building blocks in organic synthesis.

Two series of N-(4-aryl)-5-methylisoxazol-4-carboxamide and
N-(4-aryl)-3-methylisoxazol-4-carboxamide were synthesized and
spectroscopic studied to investigate the variation reaction on the substutents phenyl ring. The isoxazole derivatives were prepared from the reaction 5-methylisoxazole-4-carbonyl chloride or 3-methylisoxazole-4-carbonyl chloride and substituted anilines in good
yields.

The SCS on C-13 NMR studies on the series of N-(4-aryl)-5-methyl-
isoxazol-4-carboxamide showed that the aryl substituent effect on
isoxazole’s C5 via long distance Hammett substituent effect (slope = +1.3, r2 = 0.94).

N-(4-aryl)-3-methylisoxazol-4-carboxamide was first synthesized and
characterized by means of melting point, elemental analysis, IR, UV, EI-MS, 1H NMR spectrum and 13C NMR spectrum analysis.

論文目錄

中文摘要………………………………………………………..…i
英文摘要…………………………………………………….……iii
圖目錄……………………………………………………….……iv
表目錄………………………………………………………….…viii
第一章 緒論…………………………………………………….…1
1-1、前言………………………………………………….….……1
1-2、質譜法(Mass Spectrometry, MS)……………………….……5
1-3、核磁共振光譜術(Nuclear Magnetic Resonance, NMR)……..6
1-4、Hammett方程式……………………………………….……..7
1-5、研究動機……………………………………………….……..8
1-6、芳香基醯胺異噁唑命名……………………………………..10
1-7、芳香基醯胺異噁唑逆合成分析……………………………..11
1-8、芳香基醯胺異噁唑其合成途徑…………………………..…12
第二章 結果與討論…………………………………………....…15
2-1、2-乙醯-3-乙基丙烯酸乙酯(5)的製備…………………....…..15
2-2、5-甲基異噁唑-4-羧酸乙酯(6a)和3-甲基異噁唑-4-羧酸
乙酯(6b)的製備……………………...……………………….16
2-3、5-甲基異噁唑-4-羧酸(7a)和3-甲基異噁唑-4-羧酸(7b)的
製備………………………………………………………….....19
2-4、5-甲基異噁唑-4-羧基氯(8a)和3-甲基異噁唑-4-羧基氯(8b)
的製備…………………………………………………….……22
2-5、N-(4-芳香基)-5-甲基異噁唑-4-甲醯胺苯(1)和N-(4-芳香基)
-3-甲基異噁唑-4-甲醯胺苯(2)的製備……...………………..23
2-6、N-(4-芳香基)-3-甲基異噁唑-4-甲醯胺苯(2)的分離…………24
2-7、N-(4-芳香基)-5-甲基異噁唑-4-甲醯胺苯(1)的光譜探討…....26
2-8、N-(4-芳香基)-3-甲基異噁唑-4-甲醯胺苯(2)的光譜探討……41
2-9、N-(4-芳香基)-5-甲基噁唑-4-甲醯胺苯(1)和N-(4-芳香基)-3-
甲基噁唑-4-甲醯胺苯(2)系列的紅外光(IR)吸收光譜探討…56
2-10、N-(4-芳香基)-5-甲基異噁唑-4-甲醯胺苯(1)和N-(4-芳香基)
-3-甲基異噁唑-4-甲醯胺苯(2)系列的紫外光(UV)吸收光譜
探討…………………………………………………………..59
第三章 結論………………………………………………….….…65
第四章 實驗設備與藥品…………………………………..………66
4-1 儀器………………………………………………...……………66
4-2藥品………………………………………………………………67


第五章 實驗步驟與光譜數據………………………………………68
5-1、2-乙醯-3-乙基丙烯酸乙酯(5)的製備…………………..…..…70
5-2、5-甲基異噁唑-4-羧酸乙酯(6a)和3-甲基異噁唑-4-羧酸乙酯
(6b)的製備…………………………………………………….71
5-3、5-甲基異噁唑-4-羧酸(7a)和3-甲基異噁唑-4-羧酸(7b)的製
備………………………………………………………………72
5-4、5-甲基異噁唑-4-羧基氯(8a)和3-甲基異噁唑-4-羧基氯(8b)
的製備……………………………………………….…………73
5-5、N-(4-芳香基)-5-甲基異噁唑-4-甲醯胺苯(1)和N-(4-芳香基)-
3-甲基異噁唑-4-甲醯胺苯(2)的製備………………………....74
5-6、N-(4-芳香基)-3-甲基異噁唑-4-甲醯胺苯(2)的分離……...…..75
5-7、5-甲基異噁唑-4-羧酸(7a)和3-甲基異噁唑-4-羧酸(7b)混合物
的光譜數據………………………………….….……………....76
5-8、N-(4-芳香基)-5-甲基異噁唑-4-甲醯胺苯(1)的光譜數據….....76
5-9、N-(4-芳香基)-3-甲基異噁唑-4-甲醯胺苯(2)的光譜數據….....79
第六章 參考文獻…………………………………………………....83
附圖…………………………………………………..………………85

第六章 參考文獻

1.Pinho e Melo, T. M. V. D. “Recent Advances on the Synthesis and
Reactivity of Isoxazoles” Current Organic Chemistry., 2005, 9,
925-958.
2.Claisen, L.; Lowman, O. Chem. Ber.,1888, 1149-1157.
3. Lang, S. A.; Lin, Y.-I. In “Comprehensive Heterocyclic Chemistry”,
Katristzky, A. R.; Rees, C. W.; Potts, K. T. Ed., Pergamon Press,
Oxford, 1984, 6, 1-130.
4.Baraldi, P. G.; Barco, A.; Benetti, S.; Pollini, G. P.; Simon, D.
Synthesis, 1987, 857-869.
5.Waldo, J. P.; Larock, R. C. J. Org. Chem., 2007, 72, 9643-9647.
6.Willy, B.; Rominger, F.; Müller, T. J. J. Synthesis, 2008, 293-303.
7.Shen, D. M.; Shu, M.; Chapman, K. T. Org. Lett.,2000, 2, 2789-2792.
8.Lin, S. T.; Kuo, S. H,; Yang, F. M. J. Org. Chem. 1997, 62, 5229-5231.
9.Skoog, D. A.; Holler, F. J.; Nieman, T. A. in Principles of Instrumental
Analysis, 5th Ed., The Thomson Corporation Publishing, USA, 1998.
10.Datta, S.; De, A.; Bhattacharyya, S. P.; Medhi, C.; Brunskill, J. S. A.;
Fadoujou, S.; Fish, S. J. Chem. Soc., Perkin Trans. 1988, 2, 1599.
11.Godfrey, G. F.; Godfrey, M. J. Chem. Soc., Perkin Trans. 1988, 2, 133.
12.Hammett, L. P. J. Am. Chem. Soc. 1937, 59, 96-103.
13.Mao, J.; Yuan, H.; Wang, Y.; Wan, B.; Pieroni, M.; Huang, Q.; van
Breemen, R.; Kozikowski, A.P. ;Franzblau, S.G. J. Med. Chem. 2009,
52, 6966-6978
14.Huang, W. H.; Yang, C. L.; Lee, A, R,; Chiu, H, F, Chem. Pharm.
Bull. 2003, 51(3), 313-314.

15.Huang, C. M.; Hsieh, Y. H.; Huang, W. H.; Lee, A, R, Taiwan Pharm.
J .2007 ,59, 105-112.
16.Rozman, B., Clin. Pharmacokinet., “Clinical pharmacokinetics
of leflunomide” 2002, 41, 421-430.
17. Doleschall, G.; Seres, P.; “Isoxazole–oxazole conversion by
Beckmann rearrangement” J. Chem. Soc., Perkin Trans. 1,
1988, 1875-1879.
18. Fossa, P.; Menozzi, G.; Schenone, P.; Filippelli, W.; Russo, S.;
Farmaco; 1991;46; 789-802.
19. Dains, F.B.; Griffin, E.L. “On the reactions of the formamidines. iii. on
the synthesis of isoxazolone, isoxazole, cyanoacetic and benzoylacetic
acid derivatives” J. Am. Chem. Soc. 1913, 35 (8), 959-970.
20.Patent; Hoechst; CH 603608; 1978; DE 2823938; Chem.Abstr.; 92;
128900.
21.Patent; Hoechst; DE 2524959; 1976; Chem.Abstr.; 86; 72626.
22.Lin, S. T.; Lee, C. C.; Wu, E. C.“Preparation and 13C NMR study on
1-aryl-3,3-difluoro-2-(phenylethynyl)- cyclopropenes: long distance
Hammett substituent effect” Tetrahedron., 2008, 64, 5103-5106.
23. Staack, R. F.; Fritschi, G.; Maurer, H. H.“New designer drug 1-(3-
trifluoromethylphenyl) piperazine (TFMPP): gas chromatography/mass
spectrometry and liquid chromatography/mass spectrometry studies on
its phase I and II metabolism and on its toxicological detection in rat
urine” J. Mass Spectrom. 2003; 38: 971–981.