加米霉素及中间体的合成与抑菌活性研究
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摘要
加米霉素(Gamitromycin)是一种新型大环内酯类(Marolides)兽用抗生素。制备加米霉素的关键中间体是红霉素A肟的转型产物和贝克曼重排反应得到的中间体9-去氧-8a-氮杂-8a-同型红霉素A,而要控制9-去氧-8a-氮杂-8a-同型红霉素A的含量,就必须考察其被还原前的中间体9-去氧-12-去氧-9,12-亚胺基醚-(8a-氮杂-8a)-红霉素A,以及最后一步溴代正丙烷与9-去氧-8a-氮杂-8a-同型红霉素A的SN2取代反应。
本文主要研究了(9Z)-9-去氧-9-羟基亚胺基红霉素A的合成以及几种合成9-去氧-12-去氧-9,12-亚胺基醚-(8a-氮杂-8a)-红霉素A的方法,利用一步法合成了加米霉素的前体中间体9-去氧-8a-氮杂-8a-同型红霉素A。创新性的利用溴代正丙烷和9-去氧-8a-氮杂-8a-同型红霉素A发生SN2取代反应,最终得到加米霉素,含量高于文献方法。
研究了绝对无水乙醇和水两种反应溶剂中的(9Z)-9-去氧-9-羟基亚胺基红霉素A转型反应。实验结果表明:以水为转型反应的溶剂,其产物收率和含量高于以绝对无水乙醇为反应溶剂的收率和含量。
分别研究了以吡啶、丙酮/水、二氯甲烷/水、甲醇/水等不同体系下制备9-脱氧-12-脱氧-9,12-亚胺醚-(8a-氮杂-8a)-红霉素A的方法。实验证明甲醇/水体系制备的9-脱氧-12-脱氧-9,12-亚胺醚-(8a-氮杂-8a)-红霉素A含量高、收率高,而且低毒,反应条件比较容易控制。
创新性的使用离子液体作为溶剂,对甲苯磺酰氯催化(9Z)-9-去氧-9-羟基亚胺基红霉素A的贝克曼重排反应重排产物含量达到了90%以上。
本文还使用一步法合成9-去氧-8a-氮杂-8a-同型红霉素A,使用一步合成法使得(9Z)-9-去氧-9-羟基亚胺基红霉素A的贝克曼重排反应和还原反应制备9-去氧-8a-氮杂-8a-同型红霉素A这两步反应合并成一步,这样减少了产物在分离过程中的损失,大大提高了反应效率,而且降低了生产成本。
最后,采用了K-B纸片法测定了中间体及加米霉素等对于四种不同的细菌的抑菌效果,通过抑菌圈的直径为指标来衡量药物的抑菌活差异性。
Gamithromycin is a new kind of marolides as a veterinary medicine. The preparation of Gamitromycin is based on the synthesis of (9Z)-Erythromycin A oxime and the Beckmann rearrangement of (9Z)-Erythromycin A oxime. 9-deoxo-8a-Aza-8a-homoErythromycin was an important intermediat to study and the SN2 substitution reaction between 1-Bromopropane and 9-deoxo-8a-Aza-8a-homoErythromycin A was studied in this paper.
The synthesis of (9Z)-9-deoxo-Erythromycin A and kinds of method to synthesize the 9-deoxo-12-deozy-9,12-epoxy-8a,9-didehydro-8a-Aza-8a-homoErythromycin A as well as 9-deoxo-8a-Aza-8a-homoErythromycin A by using the one-step synthesis were studied in this paper. A novel process to prepare Gamithromycin by using 1-Bromopropane in the SN2 substitution reaction got the better yield than the method which was described in literature.
(9Z)-deoxo-Erythromycin A was prepared in both absolute ethanol and water.The yield of (9Z)-deoxo-Erythromycin A which the water as the solvent was better than the absolute ethanol as the solvent.
9-deoxo-12-deozy-9, 12-epoxy-8a,9-didehydro-8a-Aza-8a-homoErythromycin A was prepared in pyridine, acetone/wate, dichlormethane/wate, methanol/water. Methanol/water as the solvent was better than the others.
A novel process for Beckmann's rearrangement by using the ionic liquid as the solvent, (9Z)-deoxo-Erythromycin A as the material,ρ-toluene sulfonyl chloride as the catalyst to synthesize 9-deoxo-12-deozy-9, 12-epoxy-8a, 9-didehydro-8a-Aza-8a-homo Erythromycin A was studied in this paper. The yield was more than 90%
The synthesis of 9-deoxo-8a-Aza-8a-homoErythromycin A by process of the one-step synthesis method to incorporate two steps in to one, which minimized losses in the synthesis process.
The Kirby-Bauer method was used to detect bacteriostasis activity for different product. And the diameter of inhibition zone is the reflection for different product's bacteriostasis activity.
本文主要研究了(9Z)-9-去氧-9-羟基亚胺基红霉素A的合成以及几种合成9-去氧-12-去氧-9,12-亚胺基醚-(8a-氮杂-8a)-红霉素A的方法,利用一步法合成了加米霉素的前体中间体9-去氧-8a-氮杂-8a-同型红霉素A。创新性的利用溴代正丙烷和9-去氧-8a-氮杂-8a-同型红霉素A发生SN2取代反应,最终得到加米霉素,含量高于文献方法。
研究了绝对无水乙醇和水两种反应溶剂中的(9Z)-9-去氧-9-羟基亚胺基红霉素A转型反应。实验结果表明:以水为转型反应的溶剂,其产物收率和含量高于以绝对无水乙醇为反应溶剂的收率和含量。
分别研究了以吡啶、丙酮/水、二氯甲烷/水、甲醇/水等不同体系下制备9-脱氧-12-脱氧-9,12-亚胺醚-(8a-氮杂-8a)-红霉素A的方法。实验证明甲醇/水体系制备的9-脱氧-12-脱氧-9,12-亚胺醚-(8a-氮杂-8a)-红霉素A含量高、收率高,而且低毒,反应条件比较容易控制。
创新性的使用离子液体作为溶剂,对甲苯磺酰氯催化(9Z)-9-去氧-9-羟基亚胺基红霉素A的贝克曼重排反应重排产物含量达到了90%以上。
本文还使用一步法合成9-去氧-8a-氮杂-8a-同型红霉素A,使用一步合成法使得(9Z)-9-去氧-9-羟基亚胺基红霉素A的贝克曼重排反应和还原反应制备9-去氧-8a-氮杂-8a-同型红霉素A这两步反应合并成一步,这样减少了产物在分离过程中的损失,大大提高了反应效率,而且降低了生产成本。
最后,采用了K-B纸片法测定了中间体及加米霉素等对于四种不同的细菌的抑菌效果,通过抑菌圈的直径为指标来衡量药物的抑菌活差异性。
Gamithromycin is a new kind of marolides as a veterinary medicine. The preparation of Gamitromycin is based on the synthesis of (9Z)-Erythromycin A oxime and the Beckmann rearrangement of (9Z)-Erythromycin A oxime. 9-deoxo-8a-Aza-8a-homoErythromycin was an important intermediat to study and the SN2 substitution reaction between 1-Bromopropane and 9-deoxo-8a-Aza-8a-homoErythromycin A was studied in this paper.
The synthesis of (9Z)-9-deoxo-Erythromycin A and kinds of method to synthesize the 9-deoxo-12-deozy-9,12-epoxy-8a,9-didehydro-8a-Aza-8a-homoErythromycin A as well as 9-deoxo-8a-Aza-8a-homoErythromycin A by using the one-step synthesis were studied in this paper. A novel process to prepare Gamithromycin by using 1-Bromopropane in the SN2 substitution reaction got the better yield than the method which was described in literature.
(9Z)-deoxo-Erythromycin A was prepared in both absolute ethanol and water.The yield of (9Z)-deoxo-Erythromycin A which the water as the solvent was better than the absolute ethanol as the solvent.
9-deoxo-12-deozy-9, 12-epoxy-8a,9-didehydro-8a-Aza-8a-homoErythromycin A was prepared in pyridine, acetone/wate, dichlormethane/wate, methanol/water. Methanol/water as the solvent was better than the others.
A novel process for Beckmann's rearrangement by using the ionic liquid as the solvent, (9Z)-deoxo-Erythromycin A as the material,ρ-toluene sulfonyl chloride as the catalyst to synthesize 9-deoxo-12-deozy-9, 12-epoxy-8a, 9-didehydro-8a-Aza-8a-homo Erythromycin A was studied in this paper. The yield was more than 90%
The synthesis of 9-deoxo-8a-Aza-8a-homoErythromycin A by process of the one-step synthesis method to incorporate two steps in to one, which minimized losses in the synthesis process.
The Kirby-Bauer method was used to detect bacteriostasis activity for different product. And the diameter of inhibition zone is the reflection for different product's bacteriostasis activity.
引文
[1] Doem G V.,Jones R N.,Pfaller M A. et al..Haemophilusn influenaze and moraxella catarrhalis from patients with Community- Acquired Respiratory Tracts Infections: antimicrobial susceptibility patterns form the Sentry Antimicrobial surverllance Program[J]. antimicrob agents chemother,1999,43(2):447-449.
[2] Neu H C.Macrolides:Chemistry, pharmacology and clinical use.First edition [M]. Paris : Arnette Blackwell,1993.1-26.
[3] Robert L.Bunch.,James M. Mcguire..Erythromycin, its salts, and method of preparation[P]. US:2653899,1953.9.29.
[4] Tamburasov Z.,Djokic S.,et al..Erythromycin oxime and 9-amino-3- o-clandinosul-5-o- desosaminyl-6,11,12-trihydroxy-2,4,6,8,10,12-hexamethyl- pentadecane-olide[P]. US:347814,1969.
[5] Massey E.H.,Kitchell B.,et al..Erythromycinlamine[J].tetrahedron Lett,1970,11(2):157-160.)
[6] Adachi T.,Morimoto S.,et al..Process of oxime Erythromycin[P].JP:62087599,1987.4.22.
[7] Masahiro H.,Tomomichi Y.,et al..process for preparing Erythromycin A oxime ro a salt thereof[P].EP:0342990,1989.11.23.
[8] Michael B.G , et al..epimeric azahomoErythromycin A derivative and intermediates therefore[P].EP:109253,1984.5.23.
[9]李峰,陈辉.红霉素肟合成工艺研究[J].河南化工,2008,25(8):26-27.
[10]石岩,钱国华,梁建华等.红霉素肟合成反应研究[J].合成化学,2001,9(2):172-174.
[11]邓志华,梁建华.红霉素A肟的新合成方法[J].中国药物化学杂志,2003,13(2):89-92.
[12]李瑞建,王伟.9-(E)-红霉素肟的合成工艺改进[J].中国药物化学杂志,2008,18(5):379-380.
[13]刘天麟,谢建华.肟、肟醚(酯)类化合物的构型转化及其机理[J].化学通报,1997,9:19-24.
[14] Slobodan Djoki.,Gabrijela Kobrehel.,Gorjana Lazarevski. et al..Erythromycin series. Part 11. Ring expansion of Erythromycin A oxime by the Beckmann rearrangement.[J].J. Chem. Soc., Perkin Trans.,1986,1:1881-1889.
[15] Wilkening , Robert R..Novel process for the preparation of 9-deoxo-9(z)- hydroxyiminoErythromycin A[P]. EP:0503949,1997 .2.12.
[16] BASSET, Francois,DURAND, Thierry,GUEVEL, Ronan et al..METHOD FORPREPARING AND ISOLATING 9-DEOXO-9(Z)-HYDROXYIMINOERYTHROMYCIN A[P]. WO:2001/046211,2001.
[17]覃宁.罗红霉素的工艺研究[J].广东医学,2003,13(6):23-24.
[18]阮秀云,李杰,隋虎峰.阿奇霉素的不良反应[J].中国药事,2009.23(6):612-613,617.
[19]彭西,李梦云,李英伦,等.鸡阿奇霉素的慢性毒性实验研究[J].中国兽医学报,2008,28(6).
[20]中华人民共和国农业部公告[2005]第560号.《兽药地方标准废止目录》[Z].
[21] European Medicines Agency Veterinary Medicines and Inspections. EMEA/CVMP/ 220772/2008 [EB/OL]. Committee for medicinal products for verterinary use.
[22] European Medicines Agency Veterinary Medicines and Inspections .V-129-en6[EB/OL]. www.emea.europa.eu/vetdocs/PDFs/EPAR/V-129-en6.pdf
[23] P.Leon,F. Lhermitte,G.Oddon,et al.Process for the preparation of 9-deoxo-8a-aza- (8a-alkyl)-8a-homoErythromycin A derivatives from 9-deoxo-9(Z)–hydroxyimino ErythromycinA[P]:US,6482931 B2,11.19.2002.
[24] Robert R.Wilkening,Maplewood,et al.8a-aza-8a-homoErythromycin cyclic iminoethers[P]. US patent:USP 5,189,159 A,2.23.1993.
[25]徐珍,吕早生.离子液体在有机合成中的应用新进展[J].化学与生物工程,2009,26(3):11-14.
[26]李汝雄,王建基.绿色溶剂离子液体的制备与应用.[J ] .化工进展,2002 ,21 (1) :43-48.
[27] SHI Feng ,PENGJia-jian ,DENG You-quan. Highly efficient ionic liquid-mediated palladium complex catalyst system for the oxidative carbonylationof amines [J].J.Catal.,2003,219 (2) :372-375.
[28]邓友全,杜正银,李作鹏.酮肟经贝克曼重排反应制备酰胺的方法[P].CN:200510096933.6,2005.
[29] PENG Jia-jian ,DENG You-quan. Catalytic Beckmann rearrangement of ketoximes in ionic liquids [J]. Tet rahedron Letters , 2001 , 42 (3) : 4032405.
[30]邓友全.离子液体-性质、制备和应用[M].北京:中国石化出版社,2006.p-212
[31]彭家建,邓友全.离子液体系中催化环己酮肟重排制己内酰胺[J].石油化工,2001,30(2):19-29.
[32]张伟,吴巍,张树忠等.1-丁基-3-甲基咪唑六氟磷酸盐中PC15催化的两相贝克曼重排反应[J].石油炼制与化工,2004,35(1):47-50.
[33] Robert R. Wilkening, Ronald W.et al.the synthesis of novel 8a-AZA-a-HomoErythromycin devivatives via the Beckmann rearrangement of (9Z)-Erythromycin A oxime[J] Bioorganic & Medicinal chemistry Letters,Vol.3,No.6:1287-1292,1993.
[34] Leon,Patrick.,Largeau,Denis,Durand,Thierry et al..2-AZABICYCLOHEPTANE DERIVATIVES,PREPARATION AND APPLICATION THEREOF[P].WO:1996/038447A1,1996.
[35]沈萍,范秀荣,微生物学实验[M].北京:高等教育出版社,1999:97-113.
[2] Neu H C.Macrolides:Chemistry, pharmacology and clinical use.First edition [M]. Paris : Arnette Blackwell,1993.1-26.
[3] Robert L.Bunch.,James M. Mcguire..Erythromycin, its salts, and method of preparation[P]. US:2653899,1953.9.29.
[4] Tamburasov Z.,Djokic S.,et al..Erythromycin oxime and 9-amino-3- o-clandinosul-5-o- desosaminyl-6,11,12-trihydroxy-2,4,6,8,10,12-hexamethyl- pentadecane-olide[P]. US:347814,1969.
[5] Massey E.H.,Kitchell B.,et al..Erythromycinlamine[J].tetrahedron Lett,1970,11(2):157-160.)
[6] Adachi T.,Morimoto S.,et al..Process of oxime Erythromycin[P].JP:62087599,1987.4.22.
[7] Masahiro H.,Tomomichi Y.,et al..process for preparing Erythromycin A oxime ro a salt thereof[P].EP:0342990,1989.11.23.
[8] Michael B.G , et al..epimeric azahomoErythromycin A derivative and intermediates therefore[P].EP:109253,1984.5.23.
[9]李峰,陈辉.红霉素肟合成工艺研究[J].河南化工,2008,25(8):26-27.
[10]石岩,钱国华,梁建华等.红霉素肟合成反应研究[J].合成化学,2001,9(2):172-174.
[11]邓志华,梁建华.红霉素A肟的新合成方法[J].中国药物化学杂志,2003,13(2):89-92.
[12]李瑞建,王伟.9-(E)-红霉素肟的合成工艺改进[J].中国药物化学杂志,2008,18(5):379-380.
[13]刘天麟,谢建华.肟、肟醚(酯)类化合物的构型转化及其机理[J].化学通报,1997,9:19-24.
[14] Slobodan Djoki.,Gabrijela Kobrehel.,Gorjana Lazarevski. et al..Erythromycin series. Part 11. Ring expansion of Erythromycin A oxime by the Beckmann rearrangement.[J].J. Chem. Soc., Perkin Trans.,1986,1:1881-1889.
[15] Wilkening , Robert R..Novel process for the preparation of 9-deoxo-9(z)- hydroxyiminoErythromycin A[P]. EP:0503949,1997 .2.12.
[16] BASSET, Francois,DURAND, Thierry,GUEVEL, Ronan et al..METHOD FORPREPARING AND ISOLATING 9-DEOXO-9(Z)-HYDROXYIMINOERYTHROMYCIN A[P]. WO:2001/046211,2001.
[17]覃宁.罗红霉素的工艺研究[J].广东医学,2003,13(6):23-24.
[18]阮秀云,李杰,隋虎峰.阿奇霉素的不良反应[J].中国药事,2009.23(6):612-613,617.
[19]彭西,李梦云,李英伦,等.鸡阿奇霉素的慢性毒性实验研究[J].中国兽医学报,2008,28(6).
[20]中华人民共和国农业部公告[2005]第560号.《兽药地方标准废止目录》[Z].
[21] European Medicines Agency Veterinary Medicines and Inspections. EMEA/CVMP/ 220772/2008 [EB/OL]. Committee for medicinal products for verterinary use.
[22] European Medicines Agency Veterinary Medicines and Inspections .V-129-en6[EB/OL]. www.emea.europa.eu/vetdocs/PDFs/EPAR/V-129-en6.pdf
[23] P.Leon,F. Lhermitte,G.Oddon,et al.Process for the preparation of 9-deoxo-8a-aza- (8a-alkyl)-8a-homoErythromycin A derivatives from 9-deoxo-9(Z)–hydroxyimino ErythromycinA[P]:US,6482931 B2,11.19.2002.
[24] Robert R.Wilkening,Maplewood,et al.8a-aza-8a-homoErythromycin cyclic iminoethers[P]. US patent:USP 5,189,159 A,2.23.1993.
[25]徐珍,吕早生.离子液体在有机合成中的应用新进展[J].化学与生物工程,2009,26(3):11-14.
[26]李汝雄,王建基.绿色溶剂离子液体的制备与应用.[J ] .化工进展,2002 ,21 (1) :43-48.
[27] SHI Feng ,PENGJia-jian ,DENG You-quan. Highly efficient ionic liquid-mediated palladium complex catalyst system for the oxidative carbonylationof amines [J].J.Catal.,2003,219 (2) :372-375.
[28]邓友全,杜正银,李作鹏.酮肟经贝克曼重排反应制备酰胺的方法[P].CN:200510096933.6,2005.
[29] PENG Jia-jian ,DENG You-quan. Catalytic Beckmann rearrangement of ketoximes in ionic liquids [J]. Tet rahedron Letters , 2001 , 42 (3) : 4032405.
[30]邓友全.离子液体-性质、制备和应用[M].北京:中国石化出版社,2006.p-212
[31]彭家建,邓友全.离子液体系中催化环己酮肟重排制己内酰胺[J].石油化工,2001,30(2):19-29.
[32]张伟,吴巍,张树忠等.1-丁基-3-甲基咪唑六氟磷酸盐中PC15催化的两相贝克曼重排反应[J].石油炼制与化工,2004,35(1):47-50.
[33] Robert R. Wilkening, Ronald W.et al.the synthesis of novel 8a-AZA-a-HomoErythromycin devivatives via the Beckmann rearrangement of (9Z)-Erythromycin A oxime[J] Bioorganic & Medicinal chemistry Letters,Vol.3,No.6:1287-1292,1993.
[34] Leon,Patrick.,Largeau,Denis,Durand,Thierry et al..2-AZABICYCLOHEPTANE DERIVATIVES,PREPARATION AND APPLICATION THEREOF[P].WO:1996/038447A1,1996.
[35]沈萍,范秀荣,微生物学实验[M].北京:高等教育出版社,1999:97-113.