抗球虫药物及抗癌药物中间体的合成与工艺研究
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摘要
球虫病是一类寄生性原虫病，传染性强，危害性大，尤其在养鸡业中，鸡球虫病的发生十分普遍，是集约化养鸡业中最主要的疾病。世界上各个国家都先后报道了鸡球虫病的爆发情况。由于化学药品的预防作用，使得球虫病不至于象四十年代时具有毁灭性，但是感染球虫引起的慢性消耗和生产性能下降正在潜移默化中对养鸡业造成巨大的危害。我国因为管理水平低、用药不合理等问题，球虫病引起的损失比发达国家更大。目前球虫病的防治主要依靠抗球虫药物，其中化学合成药物对球虫的防治具有很有重要的作用。
根据国内市场调研和客户要求，本研究工作选取了磺胺喹噁啉(Sulfaquinoxaline)作为研究内容。研究工作对磺胺喹噁啉的合成工艺进行了改进，针对反应温度、反应时间、通气速度三个单因素，进行了一系列的单因素实验，优化出各个因素的最佳值，提出了稳定的氧化条件，解决了工艺中的高成本、高难度、收率低的问题。
另外本研究工作对部分抗癌药物中间体5-溴吲哚(5-bromoindole)、6-氟吲哚啉(6-fluoroindoline)和4-氨甲基-2-羟基苯甲酸甲酯盐酸盐(4-(aminomethyl)-2-hydroxy-benzoicacid methyl ester hydrochloride)的合成进行了研究，解决了合成过程中的关键技术问题，探索出了适合于工业化生产的成熟工艺。在研究4-氨甲基-2-羟基苯甲酸甲酯盐酸盐中间体的过程中，我们发现酚酸的选择性烷基化具有一定的理论意义，迄今成功的报道并不多见，大都面临着收率低、条件苛刻等问题，鉴于此，我们对酚酸系列化合物进行了选择性烷基化研究，发现了一种高收率、操作简便的合成方法，得出了令人满意的结果。
The coccidiosis is an autoecious disease which is rapid in infection and powerful in harm. The outbreak is widespread. It is a dominating disease in the intensived chicken faming. There are all kinds of reports about Coccidiosis in every country all over the world. Because of the protection of chemical medicaments, the harm caused by the coccidiosis today is not as serious as that 60 years ago. However the chronic consumption of the feed and degressive productivity is causing a tremendous damage to the chicken farming imperceptibly. Due to the low-level management and the immoderate use of medication at home, the loss caused by the coccidiosis in our country is more serious than that in developed countries. At present the prevention and cure of the coccidiosis depends on anti-coccidiosis medicament. The chemical anti-coccidiosis medicament plays an important role in the prevention and cure.
According to the market investigation at home and clients'demands, this thesis selects as its object of investigation an anti-coccidiosis medicament: Sulfaquinoxaline. In the experiment, first the synthesis process of Sulfaquinoxaline is modified. Then, aimed at three single factors of temperature, rate of aeration and time, a series of experiments have been carried out Through the experiments, the values of the factors are optimized respectively and the feasible oxidation is obtained, which solve the problems of high cost, difficulty and low rate of retrieval.
In addition, by investigating the synthesis process of some anti-cancer intermediates such as 5-bromo-indole, 6-fluoro-indoline and 4-(aminomethyl)-2-hydroxy-benzoic acid methyl ester hydrochloride, this thesis attempts to solve the key technical problems in the synthesis process and finds a mature technique applicable for industrialized production. In the investigating process of 4-(aminomethyl)-2-hydroxy-benzoic acid methyl ester hydrochloride, the author finds that the method of the selective esterification of phenolic acid is of theoretical significance, which has few successful reports owing to the low rate of retrieval and the rigorous conditions. In view of this, this thesis has studied the compound series of phenolic acid in terms of selective esterification and obtained a synthesis method with the characteristics of high rate of retrieval and easy operation.
根据国内市场调研和客户要求，本研究工作选取了磺胺喹噁啉(Sulfaquinoxaline)作为研究内容。研究工作对磺胺喹噁啉的合成工艺进行了改进，针对反应温度、反应时间、通气速度三个单因素，进行了一系列的单因素实验，优化出各个因素的最佳值，提出了稳定的氧化条件，解决了工艺中的高成本、高难度、收率低的问题。
另外本研究工作对部分抗癌药物中间体5-溴吲哚(5-bromoindole)、6-氟吲哚啉(6-fluoroindoline)和4-氨甲基-2-羟基苯甲酸甲酯盐酸盐(4-(aminomethyl)-2-hydroxy-benzoicacid methyl ester hydrochloride)的合成进行了研究，解决了合成过程中的关键技术问题，探索出了适合于工业化生产的成熟工艺。在研究4-氨甲基-2-羟基苯甲酸甲酯盐酸盐中间体的过程中，我们发现酚酸的选择性烷基化具有一定的理论意义，迄今成功的报道并不多见，大都面临着收率低、条件苛刻等问题，鉴于此，我们对酚酸系列化合物进行了选择性烷基化研究，发现了一种高收率、操作简便的合成方法，得出了令人满意的结果。
The coccidiosis is an autoecious disease which is rapid in infection and powerful in harm. The outbreak is widespread. It is a dominating disease in the intensived chicken faming. There are all kinds of reports about Coccidiosis in every country all over the world. Because of the protection of chemical medicaments, the harm caused by the coccidiosis today is not as serious as that 60 years ago. However the chronic consumption of the feed and degressive productivity is causing a tremendous damage to the chicken farming imperceptibly. Due to the low-level management and the immoderate use of medication at home, the loss caused by the coccidiosis in our country is more serious than that in developed countries. At present the prevention and cure of the coccidiosis depends on anti-coccidiosis medicament. The chemical anti-coccidiosis medicament plays an important role in the prevention and cure.
According to the market investigation at home and clients'demands, this thesis selects as its object of investigation an anti-coccidiosis medicament: Sulfaquinoxaline. In the experiment, first the synthesis process of Sulfaquinoxaline is modified. Then, aimed at three single factors of temperature, rate of aeration and time, a series of experiments have been carried out Through the experiments, the values of the factors are optimized respectively and the feasible oxidation is obtained, which solve the problems of high cost, difficulty and low rate of retrieval.
In addition, by investigating the synthesis process of some anti-cancer intermediates such as 5-bromo-indole, 6-fluoro-indoline and 4-(aminomethyl)-2-hydroxy-benzoic acid methyl ester hydrochloride, this thesis attempts to solve the key technical problems in the synthesis process and finds a mature technique applicable for industrialized production. In the investigating process of 4-(aminomethyl)-2-hydroxy-benzoic acid methyl ester hydrochloride, the author finds that the method of the selective esterification of phenolic acid is of theoretical significance, which has few successful reports owing to the low rate of retrieval and the rigorous conditions. In view of this, this thesis has studied the compound series of phenolic acid in terms of selective esterification and obtained a synthesis method with the characteristics of high rate of retrieval and easy operation.
引文
[1] 武书庚，齐广海，郑君杰 球虫病及其控制(J)，饲料广角，2002，6
[2] 张毅强 高淑兰常用抗球虫药及其使用方法，广西西畜牧兽医(J)，1993，19(2)
[3] 聂奎，何大文，武秀琼．畜禽抗球虫药物，四川畜牧兽医学院学报(J)，1999，13(3-4)
[4] 王祖兵，竺光良，汪序中．球虫药的归类和应用，兽药和饲料添加剂(J)，2000，7
[5] 倪风娥，林敏．鸡球虫病的综合防治，畜牧兽医(J)，2002，(97)，7
[6] 邓雯，王天奇等．鸡球虫的发育及侵入机理，洛阳农业高等专科学校学报(J)，2002，22(2)
[7] 姚建聪，谢红涛．鸡球虫病预防与控制的研究概况，当代畜禽养殖业(J)，2002，4
[8] 索勋．食品安全背景下的鸡球虫病控制，中国家禽(J)，2002，24(3)
[9] 张建东，詹勇等．球虫病防治措施研究进展，中国兽药杂志，2002，36(4)
[10] 董研，高大彬．磺胺喹噁啉的合成工艺研究，化工生产与技术(J)，1997，3：10-12．
[11] 彭柱伦，杨侃，陈玉林等．磺胺喹沙啉合成工艺改进，中国医药工业杂志(J)，2000，31(3)：97-98．
[12] 朱惠祥，袁国淦，朱春生．磺胺喹噁啉的合成，化学世界(J)，1988，7，303-304．
[13] 施炜等，农药(J)，1988，27(2)，11
[14] RUHLLAND, Thomas[DE/DK]; KROG-JENSEN, Christian[SE/DK]. Novel indole derivatives. WO01/49680 12.07.2003
[15] Nagasaka T., Yuge T., Onki S., Heterocycles[J], 1977, 8 371-376
[16] Uhle EC.. J. Am. Chem. Soc.[J], 1949, 71: 761-766
[17] Uhle F. C., MeEwen C. M., Schroter H.. J. Am. Chem. Soc.[J], 1960, 82: 1200-1207
[18] Batcho Andrew D., Leimgruber Willy.. Intermediates for Indoles[P], US 3, 976, 639 1976
[19] Batcho Andrew D., Leimgruber Willy.. Indole Derivatives and Their Intermediates[P], Ger. Offen. 2,057,840, 1971
[20] Michael E. Krolski, Alfred F. Renaldo, Duane E. Rudisill.. J. Org. CHem [J], 53: 1170-1176
[21] Henry F. Russell, Brenda J. Harris. Organic Preparations andd procedures INT[J], 1985, 17(6): 391-199
[22] Macor; John Eugene(Penfield, NY). 5-arylindole derivatives. U. S. Appl.
6, 093, 822, July 25, 2000.
[23] Takeshiba; Hideo(Kusatsu, JP); Imai; Chiaki(Shiga-ken, JP). Tricyclic compounds having fungicidal activity, their preparation and their use. U. S. Appl. 5, 981, 752, November 9, 1999
[24] Peglion; Jean-Louis (Le Vesinet, FR); Poitevin; Christophe (Paris, FR); Vilaine; Jean-Paul(Chatenay-Malabry, FR); Villeneuve; Nicole(Rueil-Malmaison, FR); Bourguignon; Marie-Pierre(Chatou, FR); Thollon; Catherine (Paris, FR). Linear or cyclic ureas. U. S. Appl. 6, 566, 364, May 20, 2003
[25] Takeshiba; Hideo (Kusatsu, JP); Imai; Chiaki(Shiga-ken, JP); Ohta; Hiroshi (Shiga-ken, JP); Kato; Shigehiro(Ohmihachiman, JP); Itoh; Hiroyuki (Moriyama, JP). Tricyclic compounds having fungicidal activity, their preparation and their use. U. S. Appl. 5, 773, 618, June30, 1998
[26] Amold; Lee D. (Westborough, MA). -heterocyclyl-substituted quinazline derivatives, processes for their preparation and their use as anti-cancer agents. U. S. Appl. 5, 736, 534. April 7, 1998
[27] Natarajan, K.; Singh, S.; Burke, T. R, Jr.; Grunberger, D.; Aggarwal, B. B. Proc. Natl. Acad Sci. USA. 1996, 93, 9090-9095.
[38] Stwe, H. -T.; Bruhn, G; Knig, W. A.; Hausen, B. M. Naturwissenshaften 1989, 76, 1989-1990.
[29] Tillekeratne, L. M. V.; Sherette, A.; Grossman, P.; Hupe, L.; Hupe, D.; Hudson, R. A. Bioorg. Med Chem. Lett. 2001, 11, 2763-2767.
[30] (a) Rotella, D. P.; Sun, Z.; Zhu, Y.; Krupinski, J.; Pongrac, P.; Seliger, L.; Normandin, D.; Macor, J. E. J Med Chem. 2000, 43, 5037-5043. (b) Xu, G; Hartman, T. L.; Wargo, H.; Turpin, J. A.; Buckhert Jr, R. W.; Cushman, M. Bioorg. Med Chem. 2002, 10, 283-290.
[31] Burke, T. R., Jr.; Fesen, M. R; Mazumder, A.; Wang, J.; Carothers, A. M.; Grunberger, D.; Driscoll, J.; Kohn, K.; Pommier, Y. J. Med Chem. 1995, 38, 4171-4178.
[32] Appendino, G; Minassi, A.; Daddario, N.; Bianchi, F.; Tron, G. C. Org. Lett. 2002, 4, 3839-3841.
[2] 张毅强 高淑兰常用抗球虫药及其使用方法，广西西畜牧兽医(J)，1993，19(2)
[3] 聂奎，何大文，武秀琼．畜禽抗球虫药物，四川畜牧兽医学院学报(J)，1999，13(3-4)
[4] 王祖兵，竺光良，汪序中．球虫药的归类和应用，兽药和饲料添加剂(J)，2000，7
[5] 倪风娥，林敏．鸡球虫病的综合防治，畜牧兽医(J)，2002，(97)，7
[6] 邓雯，王天奇等．鸡球虫的发育及侵入机理，洛阳农业高等专科学校学报(J)，2002，22(2)
[7] 姚建聪，谢红涛．鸡球虫病预防与控制的研究概况，当代畜禽养殖业(J)，2002，4
[8] 索勋．食品安全背景下的鸡球虫病控制，中国家禽(J)，2002，24(3)
[9] 张建东，詹勇等．球虫病防治措施研究进展，中国兽药杂志，2002，36(4)
[10] 董研，高大彬．磺胺喹噁啉的合成工艺研究，化工生产与技术(J)，1997，3：10-12．
[11] 彭柱伦，杨侃，陈玉林等．磺胺喹沙啉合成工艺改进，中国医药工业杂志(J)，2000，31(3)：97-98．
[12] 朱惠祥，袁国淦，朱春生．磺胺喹噁啉的合成，化学世界(J)，1988，7，303-304．
[13] 施炜等，农药(J)，1988，27(2)，11
[14] RUHLLAND, Thomas[DE/DK]; KROG-JENSEN, Christian[SE/DK]. Novel indole derivatives. WO01/49680 12.07.2003
[15] Nagasaka T., Yuge T., Onki S., Heterocycles[J], 1977, 8 371-376
[16] Uhle EC.. J. Am. Chem. Soc.[J], 1949, 71: 761-766
[17] Uhle F. C., MeEwen C. M., Schroter H.. J. Am. Chem. Soc.[J], 1960, 82: 1200-1207
[18] Batcho Andrew D., Leimgruber Willy.. Intermediates for Indoles[P], US 3, 976, 639 1976
[19] Batcho Andrew D., Leimgruber Willy.. Indole Derivatives and Their Intermediates[P], Ger. Offen. 2,057,840, 1971
[20] Michael E. Krolski, Alfred F. Renaldo, Duane E. Rudisill.. J. Org. CHem [J], 53: 1170-1176
[21] Henry F. Russell, Brenda J. Harris. Organic Preparations andd procedures INT[J], 1985, 17(6): 391-199
[22] Macor; John Eugene(Penfield, NY). 5-arylindole derivatives. U. S. Appl.
6, 093, 822, July 25, 2000.
[23] Takeshiba; Hideo(Kusatsu, JP); Imai; Chiaki(Shiga-ken, JP). Tricyclic compounds having fungicidal activity, their preparation and their use. U. S. Appl. 5, 981, 752, November 9, 1999
[24] Peglion; Jean-Louis (Le Vesinet, FR); Poitevin; Christophe (Paris, FR); Vilaine; Jean-Paul(Chatenay-Malabry, FR); Villeneuve; Nicole(Rueil-Malmaison, FR); Bourguignon; Marie-Pierre(Chatou, FR); Thollon; Catherine (Paris, FR). Linear or cyclic ureas. U. S. Appl. 6, 566, 364, May 20, 2003
[25] Takeshiba; Hideo (Kusatsu, JP); Imai; Chiaki(Shiga-ken, JP); Ohta; Hiroshi (Shiga-ken, JP); Kato; Shigehiro(Ohmihachiman, JP); Itoh; Hiroyuki (Moriyama, JP). Tricyclic compounds having fungicidal activity, their preparation and their use. U. S. Appl. 5, 773, 618, June30, 1998
[26] Amold; Lee D. (Westborough, MA). -heterocyclyl-substituted quinazline derivatives, processes for their preparation and their use as anti-cancer agents. U. S. Appl. 5, 736, 534. April 7, 1998
[27] Natarajan, K.; Singh, S.; Burke, T. R, Jr.; Grunberger, D.; Aggarwal, B. B. Proc. Natl. Acad Sci. USA. 1996, 93, 9090-9095.
[38] Stwe, H. -T.; Bruhn, G; Knig, W. A.; Hausen, B. M. Naturwissenshaften 1989, 76, 1989-1990.
[29] Tillekeratne, L. M. V.; Sherette, A.; Grossman, P.; Hupe, L.; Hupe, D.; Hudson, R. A. Bioorg. Med Chem. Lett. 2001, 11, 2763-2767.
[30] (a) Rotella, D. P.; Sun, Z.; Zhu, Y.; Krupinski, J.; Pongrac, P.; Seliger, L.; Normandin, D.; Macor, J. E. J Med Chem. 2000, 43, 5037-5043. (b) Xu, G; Hartman, T. L.; Wargo, H.; Turpin, J. A.; Buckhert Jr, R. W.; Cushman, M. Bioorg. Med Chem. 2002, 10, 283-290.
[31] Burke, T. R., Jr.; Fesen, M. R; Mazumder, A.; Wang, J.; Carothers, A. M.; Grunberger, D.; Driscoll, J.; Kohn, K.; Pommier, Y. J. Med Chem. 1995, 38, 4171-4178.
[32] Appendino, G; Minassi, A.; Daddario, N.; Bianchi, F.; Tron, G. C. Org. Lett. 2002, 4, 3839-3841.