头孢克肟合成工艺的研究
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摘要
头孢克肟是第三代口服头孢菌素类抗生素,它通过抑制细胞分裂时细胞壁的合成,从而起到杀菌作用,其对革兰氏阳性菌及革兰氏阴性菌均有较强的抗菌作用,且对β-内酰胺酶高度稳定,对产生β-内酰胺酶的细菌同样具有强大的杀菌力。目前已广泛应用于临床。
本课题主要对头孢克肟的合成工艺进行了研究和改进,包括以下三部分内容:
第一部分、对2-(2-氨基-4-噻唑)-2-[[(z)-(叔丁氧羰基)甲氧]亚氨]-乙酸(头孢克肟侧链酸)的合成工艺进行了探索,以一种未见文献报道的方法合成了头孢克肟侧链酸,以去甲氨噻肟乙酯为原料,经皂化、醚化、精制得头孢克肟侧链酸,所得产品收率高、质量好。对头孢克肟侧链酸活性酯的合成工艺进行了改进,以亚磷酸三乙酯为缩合剂,三乙胺为缚酸剂与2,2-二巯基苯并噻唑缩合制得了头孢克肟侧链酸活性硫酯。以7-AVCA与头孢克肟侧链酸活性硫酯为原料经酰胺化反应制得头孢克肟叔丁酯,再以甲酸甲基磺酸水解头孢克肟叔丁酯得头孢克肟甲基磺酸盐,精制得头孢克肟三水合物,总收率75%。
第二部分、以2-(2-氨基-4-噻唑)-2-[[(z)-(甲氧基羰基)甲氧]亚氨]-乙酸为原料在三苯基膦、三乙胺存在下与DM缩合制得2-(2-氨基-4-噻唑)-2-[[(z)-(甲氧基羰基)甲氧]亚氨]-乙酸-2-苯并噻唑硫酯酯。7-AVCA与2-(2-氨基噻唑-4-基)-2-[[(Z)-(甲氧基羰基)甲氧]亚胺]-乙酸-2-苯并噻唑硫酯经酰胺化反应制得头孢克肟甲酯,再以氢氧化钠水解头孢克肟甲酯得头孢克肟三水合物,总收率80%。
第三部分、对以上两种头孢克肟的制备方法进行对比,确定了一条成本较低、操作简便、易于实现工业化的合成方法。
在查阅文献的基础上对现有合成工艺进行了优化和改进,使各步中间体及最终产品均可得到高纯度的结晶及较高的收率,经检验头孢克肟三水合物的质量已达到药典标准。
Cefixime is the third generation semisynthetic cephalosporin for oral use which exerts for its antibiotic action by inhibiting the synthsis of the bacterium cell wall, It has great inhibition on both gram positive bacteria and gram negative bacteria,This antibiotic is hig hly stable to beta-lactamases, cefixime is widely used in clinical.
. Some improvements of synthetic methods about cefixime are researched,mainly includes the following works.
First part: The synthesis of 2-(2-aminothiazol-4-y1)-2-[[(Z)- (tert-butoxy carbonyl) methoxy]imino] acetic acid was studied,It was prepared from ethyl (Z) -2- hydroxyl -imino-2-(2-aminothiazol-4-yl) acetate via saponification, etherification and purification. The synthesis of 2-(2-aminothiazol-4-y1)-2-[[(Z)- (tert-butoxy carbonyl) methoxy]imino] acetic acid-2-S-mercaptobenzo-thiazolylester was researched. Condensate 2-(2- -aminothiazol-4-yl) - 2- [[(Z) (tert. butyoxy) carbonyloxy]imino]acetic acid with DM in presense of triethyl phosphate and triethylamine to get the target compound.cefixime was parapered from 7- amino -3- vinyclepalosperianic acid and 2-(2-aminothiazol-4-y1) -2-[[(Z)- (tert- butoxycarbonyl)methoxy]imino] acetic acid-2-S-mercaptobenzo- thiazolyl ester via amidation and hydrolysis,the total yield was 75 per.
Second part:The synthesis of 2-(2-aminothiazol-4-yl)-2-[[(Z)(methoxycarbonyl) -methoxy]imino] acetic acid-2-S-mercaptobenzothiazolylester was researched.Condensate 2-(2-aminothiazol-4-yl)-2-[[(methoxycarbonyl) methoxy]imino]-acetic acid with DM in presnce of tripenylphosphine to form the target conpound. Cefixime was synthesized from 7-amino-3-vinyclepalosperi- anic acid and 2-(2-aminothiazol-4-yl)-2-[[(Z) (methoxy carb -onyl)methoxy] imino]acetic acid -2-S-mercaptobenzo-thiazolylester via amidiation and hydrolysis, the total yield was 80 per.
Part three:Comparison of these two synthetic route of cefixime, An easier,lower cost and more prone to industrialization way was identified.
On the base of literatures,the synthetic route of cefixime was optimized and improved.The products can be obtained in high purity and good yield in above process.As a result ,this process provides highly pure cefixime trihydrate in good yield and conven–ience for production.
本课题主要对头孢克肟的合成工艺进行了研究和改进,包括以下三部分内容:
第一部分、对2-(2-氨基-4-噻唑)-2-[[(z)-(叔丁氧羰基)甲氧]亚氨]-乙酸(头孢克肟侧链酸)的合成工艺进行了探索,以一种未见文献报道的方法合成了头孢克肟侧链酸,以去甲氨噻肟乙酯为原料,经皂化、醚化、精制得头孢克肟侧链酸,所得产品收率高、质量好。对头孢克肟侧链酸活性酯的合成工艺进行了改进,以亚磷酸三乙酯为缩合剂,三乙胺为缚酸剂与2,2-二巯基苯并噻唑缩合制得了头孢克肟侧链酸活性硫酯。以7-AVCA与头孢克肟侧链酸活性硫酯为原料经酰胺化反应制得头孢克肟叔丁酯,再以甲酸甲基磺酸水解头孢克肟叔丁酯得头孢克肟甲基磺酸盐,精制得头孢克肟三水合物,总收率75%。
第二部分、以2-(2-氨基-4-噻唑)-2-[[(z)-(甲氧基羰基)甲氧]亚氨]-乙酸为原料在三苯基膦、三乙胺存在下与DM缩合制得2-(2-氨基-4-噻唑)-2-[[(z)-(甲氧基羰基)甲氧]亚氨]-乙酸-2-苯并噻唑硫酯酯。7-AVCA与2-(2-氨基噻唑-4-基)-2-[[(Z)-(甲氧基羰基)甲氧]亚胺]-乙酸-2-苯并噻唑硫酯经酰胺化反应制得头孢克肟甲酯,再以氢氧化钠水解头孢克肟甲酯得头孢克肟三水合物,总收率80%。
第三部分、对以上两种头孢克肟的制备方法进行对比,确定了一条成本较低、操作简便、易于实现工业化的合成方法。
在查阅文献的基础上对现有合成工艺进行了优化和改进,使各步中间体及最终产品均可得到高纯度的结晶及较高的收率,经检验头孢克肟三水合物的质量已达到药典标准。
Cefixime is the third generation semisynthetic cephalosporin for oral use which exerts for its antibiotic action by inhibiting the synthsis of the bacterium cell wall, It has great inhibition on both gram positive bacteria and gram negative bacteria,This antibiotic is hig hly stable to beta-lactamases, cefixime is widely used in clinical.
. Some improvements of synthetic methods about cefixime are researched,mainly includes the following works.
First part: The synthesis of 2-(2-aminothiazol-4-y1)-2-[[(Z)- (tert-butoxy carbonyl) methoxy]imino] acetic acid was studied,It was prepared from ethyl (Z) -2- hydroxyl -imino-2-(2-aminothiazol-4-yl) acetate via saponification, etherification and purification. The synthesis of 2-(2-aminothiazol-4-y1)-2-[[(Z)- (tert-butoxy carbonyl) methoxy]imino] acetic acid-2-S-mercaptobenzo-thiazolylester was researched. Condensate 2-(2- -aminothiazol-4-yl) - 2- [[(Z) (tert. butyoxy) carbonyloxy]imino]acetic acid with DM in presense of triethyl phosphate and triethylamine to get the target compound.cefixime was parapered from 7- amino -3- vinyclepalosperianic acid and 2-(2-aminothiazol-4-y1) -2-[[(Z)- (tert- butoxycarbonyl)methoxy]imino] acetic acid-2-S-mercaptobenzo- thiazolyl ester via amidation and hydrolysis,the total yield was 75 per.
Second part:The synthesis of 2-(2-aminothiazol-4-yl)-2-[[(Z)(methoxycarbonyl) -methoxy]imino] acetic acid-2-S-mercaptobenzothiazolylester was researched.Condensate 2-(2-aminothiazol-4-yl)-2-[[(methoxycarbonyl) methoxy]imino]-acetic acid with DM in presnce of tripenylphosphine to form the target conpound. Cefixime was synthesized from 7-amino-3-vinyclepalosperi- anic acid and 2-(2-aminothiazol-4-yl)-2-[[(Z) (methoxy carb -onyl)methoxy] imino]acetic acid -2-S-mercaptobenzo-thiazolylester via amidiation and hydrolysis, the total yield was 80 per.
Part three:Comparison of these two synthetic route of cefixime, An easier,lower cost and more prone to industrialization way was identified.
On the base of literatures,the synthetic route of cefixime was optimized and improved.The products can be obtained in high purity and good yield in above process.As a result ,this process provides highly pure cefixime trihydrate in good yield and conven–ience for production.
引文
[1]尤启东,药物化学.第一版.北京:化学工业出版社.2004:469-471
[2]李正化.药物化学.第三版.北京:人民卫生出版社.1993:395-400
[3]张诗海,赵美法.急需开发的的医药原料药——头孢克肟,精细与专用化学品,2003,12:10-14。
[4]曹小明,张展翅.头孢菌素类抗生素发展与研究概况.江西化工2008,31(2),22-23
[5]刘家健,头孢菌素类品种研发与生产现状探讨,中国抗生素杂志,2006 ,2(31)。
[6] A GERD , L JOHANNES. Antibacterial Cephalosporins .US2003/0191105A1,2003-10-09.
[7]王彦青.盐酸头孢吡肟合成工艺的研究.沈阳药科大学硕士学位论文。2007-06-10
[8]古碧霞.头孢硫脒治疗支气管炎的疗效观察.中国抗生素杂志,2005,30(2):117
[9]邓燕,头孢硫脒与头孢呋辛治疗儿童急性下呼吸道感染85例随机对照观察.中国抗生素杂志, 2004,29(1):57
[10]吴荣深,钟勇.头孢硫脒在160例急诊外科感染中的应用.中国抗生素杂志,2004,29 (3):179
[11]唐英春.88株细菌β-内酰胺酶及对世福素体内最低抑菌浓度的检测报告.实用临床医学,1994 2 :151.
[12]闫志刚,白树华,陈振阳等.头孢克肟的临床抗感染研究.中国临床药理学杂志,2001,17(2)150-153.
[13]吴霞飞译.头孢克肟应用于转换治疗的评价.国外医药-合成药生化制剂分册,1998 19(6)344-346.
[14]李小荣.口服头孢克肟用于转换治疗的国内现状.中国抗生素杂志,2008,33(8) 506-508.
[15] N Rex, M Brogden-eborah, R Campoli,Cefixime a Review of Its Antibacterial Activity, Pharmaco -kineticProperties and Therapeautic Potential.Drags, 1989;8::524-550.
[16] X D Liu,Xie L, J P Gao,et al.Cefixime Absorption Kinetics After Oral Administration to Humans .Eur Drug Metab Pharmacokinet,1997;22:185~188.
[17] G ASCHER; J LUDESCHER , H STURM ,New process For The Perperation of Cephalosporines And Novel Intermediates In This Process . EP0503453,1992-03-04
[18] Y Dae-chul, W Y Seung , G S dong,Process for The Preparing Cephalosporin Antibiotics Using New Thiazole Compound. US6384212.2002-05-07.
[19]胡艾希,袁帅,宋又群等.头孢克肟的合成.中国医药工业杂志, 2004.35(1):3-4.
[20]周永健,孟红,赵平等.一种头孢克肟的制备方法:CN ,1696134A .2005-10-01.
[21] C Walter, A Marco, P Giovanni,et al. A Prosess for The Preparation of Cefixime via Arkyl-or Aryl -sulfonates:WO,03/040148.2003-05-15.
[22] L Johannes, M Ludwig, S Hubert,Purification Process.US6313289: 2001-11-06
[23] L Johannes, S Hubert, D Martin,et al. Purification Process.WO9831685: 1998-07-23.
[24] A Furlenmeier, Z W Hofhen, C N Hubschwerlen,et al.Process for The Manufacture of 1-Sulpho-2-Oxoazetidine Carboxylic Acid Imtemediates via Catalytic Ester Clearage.US4652651.1984-03-24.
[25] R B Parthasaradhi, R K Rathnakar, R R Raji,An Improved Process For The Preparation of Cefixime,WO2006103686.2006-10-05.
[26] M Decristoforo, J Ludescher,H Sturm, et al. Process for The Purification of Cephalosporin Derivative:US, 6825345. 2004 - 11 - 30.
[27] D Martin,L Johannes,S Hubert,et al. Process for Purification of a Cephalosporin Derivative:WO,9951607.1999-10-14
[28] P R Bandi, R R Kura, R R Rapolu,et al. An Improved Process for The Preparation of Cefixime:WO,2006103686.2006-10-05
[29]潘行远.河源市制药工程技术研究开发中心.一种头孢克肟地合成方法.CN101016305A,2007-08-15
[30] A C sisodia, D Das, A K Sharma,et al.Cefixime Preparation,[P].GB2330140 1998-10-08
[31] A K Sharma, A Malhotra.Method of Preparation of an Orally Active Cephalosporin Antibiotic -Cefixime.Pt 102062 1994-10-6
[32] O D Tyagi, D R Rane, S Mahajan,Process et al.For The Preparation of Cefixime, WO200606 7806 . 2006-06-29. [33 ] R Heymes , A Lutz. 3-Acetoxymethyl-7-(hydroxyimi-noacetamido)- Cephal-osporanic Acid Derivatives . US4283396 , 1981-00-00.
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[2]李正化.药物化学.第三版.北京:人民卫生出版社.1993:395-400
[3]张诗海,赵美法.急需开发的的医药原料药——头孢克肟,精细与专用化学品,2003,12:10-14。
[4]曹小明,张展翅.头孢菌素类抗生素发展与研究概况.江西化工2008,31(2),22-23
[5]刘家健,头孢菌素类品种研发与生产现状探讨,中国抗生素杂志,2006 ,2(31)。
[6] A GERD , L JOHANNES. Antibacterial Cephalosporins .US2003/0191105A1,2003-10-09.
[7]王彦青.盐酸头孢吡肟合成工艺的研究.沈阳药科大学硕士学位论文。2007-06-10
[8]古碧霞.头孢硫脒治疗支气管炎的疗效观察.中国抗生素杂志,2005,30(2):117
[9]邓燕,头孢硫脒与头孢呋辛治疗儿童急性下呼吸道感染85例随机对照观察.中国抗生素杂志, 2004,29(1):57
[10]吴荣深,钟勇.头孢硫脒在160例急诊外科感染中的应用.中国抗生素杂志,2004,29 (3):179
[11]唐英春.88株细菌β-内酰胺酶及对世福素体内最低抑菌浓度的检测报告.实用临床医学,1994 2 :151.
[12]闫志刚,白树华,陈振阳等.头孢克肟的临床抗感染研究.中国临床药理学杂志,2001,17(2)150-153.
[13]吴霞飞译.头孢克肟应用于转换治疗的评价.国外医药-合成药生化制剂分册,1998 19(6)344-346.
[14]李小荣.口服头孢克肟用于转换治疗的国内现状.中国抗生素杂志,2008,33(8) 506-508.
[15] N Rex, M Brogden-eborah, R Campoli,Cefixime a Review of Its Antibacterial Activity, Pharmaco -kineticProperties and Therapeautic Potential.Drags, 1989;8::524-550.
[16] X D Liu,Xie L, J P Gao,et al.Cefixime Absorption Kinetics After Oral Administration to Humans .Eur Drug Metab Pharmacokinet,1997;22:185~188.
[17] G ASCHER; J LUDESCHER , H STURM ,New process For The Perperation of Cephalosporines And Novel Intermediates In This Process . EP0503453,1992-03-04
[18] Y Dae-chul, W Y Seung , G S dong,Process for The Preparing Cephalosporin Antibiotics Using New Thiazole Compound. US6384212.2002-05-07.
[19]胡艾希,袁帅,宋又群等.头孢克肟的合成.中国医药工业杂志, 2004.35(1):3-4.
[20]周永健,孟红,赵平等.一种头孢克肟的制备方法:CN ,1696134A .2005-10-01.
[21] C Walter, A Marco, P Giovanni,et al. A Prosess for The Preparation of Cefixime via Arkyl-or Aryl -sulfonates:WO,03/040148.2003-05-15.
[22] L Johannes, M Ludwig, S Hubert,Purification Process.US6313289: 2001-11-06
[23] L Johannes, S Hubert, D Martin,et al. Purification Process.WO9831685: 1998-07-23.
[24] A Furlenmeier, Z W Hofhen, C N Hubschwerlen,et al.Process for The Manufacture of 1-Sulpho-2-Oxoazetidine Carboxylic Acid Imtemediates via Catalytic Ester Clearage.US4652651.1984-03-24.
[25] R B Parthasaradhi, R K Rathnakar, R R Raji,An Improved Process For The Preparation of Cefixime,WO2006103686.2006-10-05.
[26] M Decristoforo, J Ludescher,H Sturm, et al. Process for The Purification of Cephalosporin Derivative:US, 6825345. 2004 - 11 - 30.
[27] D Martin,L Johannes,S Hubert,et al. Process for Purification of a Cephalosporin Derivative:WO,9951607.1999-10-14
[28] P R Bandi, R R Kura, R R Rapolu,et al. An Improved Process for The Preparation of Cefixime:WO,2006103686.2006-10-05
[29]潘行远.河源市制药工程技术研究开发中心.一种头孢克肟地合成方法.CN101016305A,2007-08-15
[30] A C sisodia, D Das, A K Sharma,et al.Cefixime Preparation,[P].GB2330140 1998-10-08
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