机械研磨法合成γ-氨基丁酸前体以及在缩合反应中的应用研究
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摘要
本文共分为四章,其中第一章主要讲述了无溶剂反应的种类,并对其中的固相机械研磨法进行了概括,阐述其影响因素,对机械研磨法在有机合成中的应用进行了概述,同时分析了其应用优势及发展前景。
第二章阐述了γ-氨基丁酸(GABA)以及其衍生物的生理功能、药物应用价值以及以5-亚烃基米氏酸与硝基烷烃类化合物在固相机械研磨条件下进行Michael加成合成γ-氨基丁酸衍生物的前体。GABA类化合物对哺乳动物神经中枢具有一定调节作用,在医药方面应用广泛。反应在以CH3ONa作为缚酸剂的条件下,机械研磨合成,反应条件温和,时间短,选择性好,收率高。与传统路线相比,反应过程中不使用溶剂,减少环境污染,降低生产成本,为γ-氨基丁酸衍生物的前体的合成提供了一条绿色高效的工艺路线。
第三章讲述了氨基酸类化合物具有重要的生理功能以及广泛的应用价值。阐述了氨基酸与1,3-二羰基化合物的固相缩合反应,反应生成氨基酸类似化合物。其中温度为反应控制的重要因素,操作简单,时间短,收率高。由上可知,固相机械研磨法高效,绿色,操作简单,对于药物合成工业很有价值。
This dissertation consists of four chapters. The Chapter one is a review of research progress on the solid-state mechanochemistry in organic synthesis. It is reported factors of solid-phase mechanochemistry, reaction mechanism, as well as their applications in pharmaceutical industry. Close attention has also been paid to the prospects of the applications and perspective.
In the Chapter two, we describe the physiological function of GABAs, as well as its value . GABA is nonprotein amino acid which has been identified as the nerve center of a mammalian inhibitory neurotransmitter. It is an important intermediate of drugs. In this paper, a facile Michael addition reaction of 5-alkylidene Meldrum's Acid with nitroalkanes in solid state has been achieved by mechanochemical grinding in the presence of CH3ONa. The reactions proceed smoothly under solvent-free condition and give their corresponding results in high yields. The method is more efficient and green as compared to prior arts.
In the Chapter three, a method of mechanochemical grinding is used in the condensation of amino acids with 1,3-dicarbonyl compounds in the present of KOH. This rout provide a simple manipulation, efficient, time-saving way for synthesizing derivatives of amino acids.
In conclusion, the method of mechanochemical grinding, which might be useful for preparing drugs, has the advantage of efficiency, “green”, simple manipulation, mild conditions. It might be valuable to the pharmaceutical industry.
第二章阐述了γ-氨基丁酸(GABA)以及其衍生物的生理功能、药物应用价值以及以5-亚烃基米氏酸与硝基烷烃类化合物在固相机械研磨条件下进行Michael加成合成γ-氨基丁酸衍生物的前体。GABA类化合物对哺乳动物神经中枢具有一定调节作用,在医药方面应用广泛。反应在以CH3ONa作为缚酸剂的条件下,机械研磨合成,反应条件温和,时间短,选择性好,收率高。与传统路线相比,反应过程中不使用溶剂,减少环境污染,降低生产成本,为γ-氨基丁酸衍生物的前体的合成提供了一条绿色高效的工艺路线。
第三章讲述了氨基酸类化合物具有重要的生理功能以及广泛的应用价值。阐述了氨基酸与1,3-二羰基化合物的固相缩合反应,反应生成氨基酸类似化合物。其中温度为反应控制的重要因素,操作简单,时间短,收率高。由上可知,固相机械研磨法高效,绿色,操作简单,对于药物合成工业很有价值。
This dissertation consists of four chapters. The Chapter one is a review of research progress on the solid-state mechanochemistry in organic synthesis. It is reported factors of solid-phase mechanochemistry, reaction mechanism, as well as their applications in pharmaceutical industry. Close attention has also been paid to the prospects of the applications and perspective.
In the Chapter two, we describe the physiological function of GABAs, as well as its value . GABA is nonprotein amino acid which has been identified as the nerve center of a mammalian inhibitory neurotransmitter. It is an important intermediate of drugs. In this paper, a facile Michael addition reaction of 5-alkylidene Meldrum's Acid with nitroalkanes in solid state has been achieved by mechanochemical grinding in the presence of CH3ONa. The reactions proceed smoothly under solvent-free condition and give their corresponding results in high yields. The method is more efficient and green as compared to prior arts.
In the Chapter three, a method of mechanochemical grinding is used in the condensation of amino acids with 1,3-dicarbonyl compounds in the present of KOH. This rout provide a simple manipulation, efficient, time-saving way for synthesizing derivatives of amino acids.
In conclusion, the method of mechanochemical grinding, which might be useful for preparing drugs, has the advantage of efficiency, “green”, simple manipulation, mild conditions. It might be valuable to the pharmaceutical industry.
引文
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[2]王建基,李汝雄.有机固体化合物无溶剂反应[J].化学教育, 2004, (4):4-6.
[3]李焱,尚红卫.固态有机反应研究进展[J].焦作师范高等专科学校学报, 2007, 23(1): 75-76.
[4]野国中,李正名.超临界流体在机合成中的应用[J].化学通报, 2002, (4): 221.
[5] Savage P E. Organic chemical reactions in supercritical water[J]. Chem. Rev, 1999, 99(2): 603.
[6]李颖华.超临界二氧化碳在有机合成中应用[J].化学世界, 2002, (9): 490.
[7]阎立峰,朱清时.离子液体及其在有机合成中应用[J].化学通报, 2001, 11: 673.
[8]杜大明,陈晓,花文廷.离子液体介质中有机合成及催化不对称反应研究新进展[J].有机化学, 2003, (4): 33.
[9]唐林生,冯柏成.无溶剂有机合成的促进方法及其前景[J].精细石油化工进展, 2008, 9(3): 19-22.
[10]李晓陆,王永梅,孟继本.固态有机反应新进展[J].有机化学, 1998, 18: 20-28.
[11]吴方领.固相研磨合成研究[J].商丘师范学院学报, 2005, 21(2): 125-128.
[12] Wang Cai-lan, Wang Yu-lu, Wang Xiao-yang, et al. An efficient oxidation of arylsemicarbazides to the azo ureas[J]. Organic Preparations and Procedures International, 1998, 30(1): 97-99.
[13] Wang Yu-lu, Cheng jie, Li Jian-ping, et al. Two-phase dehydrogenation of aryl substituted carbazide compounds[J]. Synthetic Communications, 1994, 24(12): 1737-42.
[14] Wang Yu-lu, Shi Lei, Jia Xue–shun, et al. An efficient and convenient procedure for preparation of diaryl carbazone from aryl substituted carbazide[J]. Synthetic Communications, 1999, 29(1): 53-56.
[15] Wang Hong, Wang Yu-lu, Zhang Geng, et al. An efficient solid-phase method for the preparation of diarylcarbazones[J]. Synthetic Communications, 2000, 30(8): 1425-1429.
[16] Karaman R, Goldblum A, Breuer Eli, et al. Acylphosphonic acids and methyl hydrogen acylphosphonates: physical and chemical properties and theoretical calculations[J]. Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1989, (4): 765-74.
[17] Liao Yi-hua, Shabany H, Spilling C D. The preparation of acyl phosphonates by the heterogeneous oxidation of 1-hydroxy phosphonates[J]. Tetrahedron Letters, 1998, 39(46): 8389-8392.
[18] Kaboudin B. Surface-mediated solid-phase reactions: the preparation of acyl phosphonates by oxidation of 1-hydroxyphosphonates on the solid surface[J]. Tetrahedron Letters, 2000, 41(17): 3169-3171.
[19] Firouzabadi H, Iranpoor N, Sobhani S, et al. High yield preparation of alpha-ketophosphonates by oxidation of alpha-hydroxyphosphonates with zinc dichromate trihydrate (ZnCr2O73H2O) under solvent-free conditions[J]. Tetrahedron Letters, 2001, 42(26): 4369-4371.
[20] Morey J, Frontera A. Solid-state redox chemistry : preparation of l,4-naphthoquinone, hydroquinone, and the corresponding mixedquin kydrone in the solid state[J]. J. Chem. Ed., 1995, 72: 63.
[21] Morey J, Saa J M. Solid state redox chemistry of hydroquinones and quinohes[J]. Tetrahedron, 1993, 49: 105.
[22] Toda F, Yagi Min, Kiyoshige K. Baeyer-Villiger reaction in the solid state[J]. Journal of the Chemical Society, Chemical Communications, 1988, (14): 958-9.
[23] Toda F, Kiyoshige K, Yagi M. Angew. NaBH4 reduction of ketones in the solid-state[F]. Ange. Chem.-Int. Ed. Engl, 1989, 28: 320.
[24]王春.芳香醛与丙二酸亚异丙酯的固相缩合反应[J].应用化学, 2003, 20(8): 809-810.
[25]李晓陆.含氮杂环化合物固相化学反应研究[J].中国科学(B)辑, 1997, 27(3): 202-207.
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