头孢他啶侧链酸合成新工艺研究
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摘要
头孢他啶侧链酸是合成头孢他啶的原料药的重要原料。一般主要是以乙酰乙酸甲酯或乙酰乙酸乙酯为起始原料,经肟化和溴代两步反应,制得去甲基氨噻肟酸甲(或乙)酯,将该酯与α溴代异丁酸叔丁酯进行醚化反应,再将所得的醚化产物进行部分水解,就可得到头孢他啶侧链酸。该工艺路线存在副反应多,污染严重等问题。由于有大量卤化氢产生,设备腐蚀严重。目前国内只能处于小规模生产阶段,总生产能力约20吨/年左右。据不完全统计,目前国内对该产品的需求量在100吨/年以上。头孢他啶侧链酸的生产供应已经严重制约了我国头孢他啶原药的发展。
为了克服传统工艺的缺点,本课题以双乙烯酮为起始原料,经卤化、酯化制备4-卤代乙酰乙酸乙酯,将4-卤代乙酰乙酸乙酯进行肟化、环合反应制备去甲基氨噻肟酸乙酯,再将去甲基氨噻肟酸乙酯进行醚化和水解反应制备头孢他啶侧链酸。我们对新工艺进行了大量的实验研究,对实验结果进行了详细的讨论,优选出新工艺的最佳反应条件,制定出适合我国工业实际情况生产的工艺方案。
新工艺具有以下特点:
1、采用双乙烯酮为起始原料,获得4-卤代乙酰乙酸乙酯,避免了直接使用乙酰乙酸乙酯卤化反应中的多卤代的发生,从根本上减少头孢他啶侧链酸现有工艺中副产物的产生,所得去甲基氨噻肟酸乙酯含量可达97%以上,去甲基氨噻肟酸乙酯不仅是生产头孢他啶侧链酸的重要中间体,而且也是头孢克肟侧链酸等其他抗生素产品的关键中间体。
2、以双乙烯酮为起始原料,经卤化、酯化制备4-卤代乙酰乙酸乙酯的合成工艺,反应过程中无卤化氢产生,三废少;
3、以双乙烯酮为起始原料合成头孢他啶侧链酸,累计收率可达40%以上(以双乙烯酮计),产品质量稳定可靠。
总之,该工艺路线具有很强的市场竞争力,是一条非常适合工业化生产的方法。
Side chain acid of ceftazidime is an important raw material of ceftazidime. General mainly using acetyl methyl acetate or ethyl acetoacetate as starting material, via bromination and oxim two-step reaction, obtained ethyl-(Z)-2-hydroxyimino-2-(2-aminothiazol-4-yl) acetate(EHATA). EHATA reacted with t-butyl 2-bromo isobutyrate ,then the product of etherification was partial hydrolysised . Side chain acid of ceftazidime can be obtained. But there existed many problems in this reaction routes. For example, serious pollution problems. Due to a large number of hydrogen bromide or hydrogen chloride produced, serious equipment corrosion. Current domestic production only in a small-scale stage, The total production capacity is about 20 tons / year around. According to incomplete statistics, the domestic demand for side chain acid of ceftazidime is 100 tons / year above. The production and supply of side chain acid of ceftazidime has seriously constrained the development of original drug.
To make up for the shortcomings of traditional crafts, The subject used the diketene as starting materials, via halogenation and esterification , gived 4 - halogenated ethyl acetoacetate. The side chain ccid of ceftazidime was synthesized from 4 - halogenated ethyl acetoacetate by oxime reaction, cyclic condensation , etherification and hydrolysis. We carried out a lot of experimental studies. To obtain a new optimization technology in the best conditions. the experimental results are discussed in detail.
This new process has the following features:
1.Diketene used as starting materials of 4 - halogenated ethyl acetoacetate. Avoid Multihalogenation reaction in the Traditional crafts using ethyl(methyl) acetoacetate as starting materials . Fundamentally reduced the formation of by-products. In the process , the purity of EHATA was more than 97%. EHATA is not only the key intermediate of the side chain acid of ceftazidime, but also the important Intermediates of other antibiotic products, such as cefixime.
2、Using diketene as the starting material of 4 - halogenated ethyl acetoacetate, no halodrogen chloride or hydrogen bromide be generated in the process, waste less;
3、The side chain acid of ceftazidime was synthesized from diketene by chloridation, esterification, oxime reaction, cyclic condensation , etherification and hydrolysis. The total yield was more than 40%. The purity was more than 98. 5%.
On the whole, The new process is A very suitable method for industrial production.
为了克服传统工艺的缺点,本课题以双乙烯酮为起始原料,经卤化、酯化制备4-卤代乙酰乙酸乙酯,将4-卤代乙酰乙酸乙酯进行肟化、环合反应制备去甲基氨噻肟酸乙酯,再将去甲基氨噻肟酸乙酯进行醚化和水解反应制备头孢他啶侧链酸。我们对新工艺进行了大量的实验研究,对实验结果进行了详细的讨论,优选出新工艺的最佳反应条件,制定出适合我国工业实际情况生产的工艺方案。
新工艺具有以下特点:
1、采用双乙烯酮为起始原料,获得4-卤代乙酰乙酸乙酯,避免了直接使用乙酰乙酸乙酯卤化反应中的多卤代的发生,从根本上减少头孢他啶侧链酸现有工艺中副产物的产生,所得去甲基氨噻肟酸乙酯含量可达97%以上,去甲基氨噻肟酸乙酯不仅是生产头孢他啶侧链酸的重要中间体,而且也是头孢克肟侧链酸等其他抗生素产品的关键中间体。
2、以双乙烯酮为起始原料,经卤化、酯化制备4-卤代乙酰乙酸乙酯的合成工艺,反应过程中无卤化氢产生,三废少;
3、以双乙烯酮为起始原料合成头孢他啶侧链酸,累计收率可达40%以上(以双乙烯酮计),产品质量稳定可靠。
总之,该工艺路线具有很强的市场竞争力,是一条非常适合工业化生产的方法。
Side chain acid of ceftazidime is an important raw material of ceftazidime. General mainly using acetyl methyl acetate or ethyl acetoacetate as starting material, via bromination and oxim two-step reaction, obtained ethyl-(Z)-2-hydroxyimino-2-(2-aminothiazol-4-yl) acetate(EHATA). EHATA reacted with t-butyl 2-bromo isobutyrate ,then the product of etherification was partial hydrolysised . Side chain acid of ceftazidime can be obtained. But there existed many problems in this reaction routes. For example, serious pollution problems. Due to a large number of hydrogen bromide or hydrogen chloride produced, serious equipment corrosion. Current domestic production only in a small-scale stage, The total production capacity is about 20 tons / year around. According to incomplete statistics, the domestic demand for side chain acid of ceftazidime is 100 tons / year above. The production and supply of side chain acid of ceftazidime has seriously constrained the development of original drug.
To make up for the shortcomings of traditional crafts, The subject used the diketene as starting materials, via halogenation and esterification , gived 4 - halogenated ethyl acetoacetate. The side chain ccid of ceftazidime was synthesized from 4 - halogenated ethyl acetoacetate by oxime reaction, cyclic condensation , etherification and hydrolysis. We carried out a lot of experimental studies. To obtain a new optimization technology in the best conditions. the experimental results are discussed in detail.
This new process has the following features:
1.Diketene used as starting materials of 4 - halogenated ethyl acetoacetate. Avoid Multihalogenation reaction in the Traditional crafts using ethyl(methyl) acetoacetate as starting materials . Fundamentally reduced the formation of by-products. In the process , the purity of EHATA was more than 97%. EHATA is not only the key intermediate of the side chain acid of ceftazidime, but also the important Intermediates of other antibiotic products, such as cefixime.
2、Using diketene as the starting material of 4 - halogenated ethyl acetoacetate, no halodrogen chloride or hydrogen bromide be generated in the process, waste less;
3、The side chain acid of ceftazidime was synthesized from diketene by chloridation, esterification, oxime reaction, cyclic condensation , etherification and hydrolysis. The total yield was more than 40%. The purity was more than 98. 5%.
On the whole, The new process is A very suitable method for industrial production.
引文
1、王荣耕,头孢他啶,精细与专用化学品,2003(10)14-15;
2、陈芬儿,有机药物合成法(第一卷),中国医药科技出版社.614-617;
3、山下柏,JP:58 219 156 1983-06-03;
4、有田博昭、池田一浩JP:9194 470 1996-01-11;
5、唐建国,(Z)-2-(2-氨基-4-噻唑基)-2-羟亚氨基丁酸衍生物的合成,国外药学:抗生素分册1989.10(5)334-347;
6、Ochiai M,Morimoto A,matsushita Y,et al.Synthesis and structure-activity,relationships,of7β-[2-(2-aminothiazol-4-yl)acetam ido]cephalosporin,derivativesⅣ.Synthesis.of 2-(2-aninothazol-4-yl)-2-methoxyiminmcetic acid derivatives and related compounds[J].J Antibiotics,1981,34(2):160-168;
7、傅德才,头孢菌素抗生素与氨噻肟酸,河北化工,1977,1,52-55
8、小柳信一郎、土屋正三,JP:782 254,1993-09-14;
9、小柳信一郎、岩崎史哲,JP:797 368,1993-09-29;
10、杨艺虹,张珩,(Z)-2-(2-氨基-4-噻唑)-2-羟亚氨基乙酸乙酯的合成工艺改进,精细化工中间体,2003,33(1),14-15
11、小柳信一郎、土屋正三,JP:797 369,1993-09-29;
12、岩崎史哲、土屋正三,JP:841 041,1994-08-01;
13、小柳信一郎、土屋正三,JP:967 353,1995-08-30;
14、刘志平,金惠明,周振国,去甲氨噻肟酸乙酯生产新工艺的研究,上海化工,1988,22(3),22-26;
15.Hong-WooLee,TeeWoekang.Synthetic.Comminucation.1998.28(1):35-44;
16、FURLENMEIER ANDRE(CH);HOFHEINZ WERNER,Process for the manufacture of 1-sulpho-2-oxoazetidine carboxylic acid intermediates via catalytic ester cleavage,US4652651,1987-03-24;
17、陆豫、赖卫华,氯代乙酰乙酸乙酯的合成,南昌大学学报(理科版),1999,23(4):316;
18、邹盛欧,双乙烯酮的开发应用和市场前景,精细与专用化学品2002,1, 10-12;
19、刘彩娟,王银华,双乙烯酮在医药中间体合成中的应用,精细与专用化学品2006,14(3、4),10-12;
20、王荣耕,赵有贵,双乙烯酮在医药中间体中的应用,精细化工原料及中间体,2006(1)30-33;
21、DUFOUR CLAUDE,Procede perfectionne de preparation des derives halogenes en position gamma des esters beta cetoniques,FR1438387,1966-05-13;
22、PROCIDA,Biocidal Compositions.,FR1535450,1968-08-09;
23.HEYLES RENE(FR);LUTZ ANDRE(FR),Novel 3-acetoxymethyl-7-(iminoacetamido)-cephalosporanic acid derivatives,US4376203,1983-03-08;
24、FURLENMEIER ANDRE(EH);HOFHEINZ WERNER(CH);HUBSCHWERLEN CHRISTIAN N(FR);ISENRING HANS P(CH),Process for the manufacture of 1-sulpho-2-oxoazetidine carboxylic acid intermediates via catalytic ester cleavage,US4652651,1987-03-24;
25、傅德才,冀学时,李忠民,头孢他啶侧链酸活性酯的合成,中国医药工业杂志,2002,33(1):523-24;
26、KAWABATA TAKEO;MIYASHITA MASAHIKO;TAISHA AKIRA.PRODUCTION.OF 2-(2-AMINOTHIAZOL-4-YL)-2-(SYN)-HYDROXYIMINOACETIC ACID ESTER,JP63126870,1988-05-30;
27、段行信,实用精细有机合成手册,化学工业出版社,134;
28.Richardson,lowry,Mechanism and Therory in organic Chemistry(Second Edition):635-37;
29、山东省化工研究院,氨噻肟酸的合成研究(内部鉴定资料),14-15;
30、段行信,实用精细有机合成手册,化学工业出版社,480-482;
31、唐培堃主编,《精细有机合成化学与工艺学》,天津大学出版社,366-367;
32、唐培堃主编,《精细有机合成化学与工艺学》,天津大学出版社,233-234;
33、山东省化工研究院,氨噻肟酸的合成研究(内部鉴定资料),22-23;
34、DUERCKHEIMER WALTER DR(DE),Crystalline modification of ceftazidim,US4624948,1986-11-25;
35、G.P.Leslie Grady,Jr.Glen T.Daigger Henry C.Lim.废水生物处理(第二版)[M].北京:化学工艺出版社,2003
36、Beil.3,Ⅳ,1550
37、GB617-88化学试剂熔点范围测定通用方法;
38、实用有机化学手册,上海科技出版社;
39、张贵芹,李德波,反相液相色谱法测定去甲氨噻肟酸乙酯的含量,山东化工,2005,34(4),43-44;
40、张贵芹,邱娟,反相液相色谱法测定头孢他啶侧链酸的含量,化学工程师,2007,137(2),38-39:
2、陈芬儿,有机药物合成法(第一卷),中国医药科技出版社.614-617;
3、山下柏,JP:58 219 156 1983-06-03;
4、有田博昭、池田一浩JP:9194 470 1996-01-11;
5、唐建国,(Z)-2-(2-氨基-4-噻唑基)-2-羟亚氨基丁酸衍生物的合成,国外药学:抗生素分册1989.10(5)334-347;
6、Ochiai M,Morimoto A,matsushita Y,et al.Synthesis and structure-activity,relationships,of7β-[2-(2-aminothiazol-4-yl)acetam ido]cephalosporin,derivativesⅣ.Synthesis.of 2-(2-aninothazol-4-yl)-2-methoxyiminmcetic acid derivatives and related compounds[J].J Antibiotics,1981,34(2):160-168;
7、傅德才,头孢菌素抗生素与氨噻肟酸,河北化工,1977,1,52-55
8、小柳信一郎、土屋正三,JP:782 254,1993-09-14;
9、小柳信一郎、岩崎史哲,JP:797 368,1993-09-29;
10、杨艺虹,张珩,(Z)-2-(2-氨基-4-噻唑)-2-羟亚氨基乙酸乙酯的合成工艺改进,精细化工中间体,2003,33(1),14-15
11、小柳信一郎、土屋正三,JP:797 369,1993-09-29;
12、岩崎史哲、土屋正三,JP:841 041,1994-08-01;
13、小柳信一郎、土屋正三,JP:967 353,1995-08-30;
14、刘志平,金惠明,周振国,去甲氨噻肟酸乙酯生产新工艺的研究,上海化工,1988,22(3),22-26;
15.Hong-WooLee,TeeWoekang.Synthetic.Comminucation.1998.28(1):35-44;
16、FURLENMEIER ANDRE(CH);HOFHEINZ WERNER,Process for the manufacture of 1-sulpho-2-oxoazetidine carboxylic acid intermediates via catalytic ester cleavage,US4652651,1987-03-24;
17、陆豫、赖卫华,氯代乙酰乙酸乙酯的合成,南昌大学学报(理科版),1999,23(4):316;
18、邹盛欧,双乙烯酮的开发应用和市场前景,精细与专用化学品2002,1, 10-12;
19、刘彩娟,王银华,双乙烯酮在医药中间体合成中的应用,精细与专用化学品2006,14(3、4),10-12;
20、王荣耕,赵有贵,双乙烯酮在医药中间体中的应用,精细化工原料及中间体,2006(1)30-33;
21、DUFOUR CLAUDE,Procede perfectionne de preparation des derives halogenes en position gamma des esters beta cetoniques,FR1438387,1966-05-13;
22、PROCIDA,Biocidal Compositions.,FR1535450,1968-08-09;
23.HEYLES RENE(FR);LUTZ ANDRE(FR),Novel 3-acetoxymethyl-7-(iminoacetamido)-cephalosporanic acid derivatives,US4376203,1983-03-08;
24、FURLENMEIER ANDRE(EH);HOFHEINZ WERNER(CH);HUBSCHWERLEN CHRISTIAN N(FR);ISENRING HANS P(CH),Process for the manufacture of 1-sulpho-2-oxoazetidine carboxylic acid intermediates via catalytic ester cleavage,US4652651,1987-03-24;
25、傅德才,冀学时,李忠民,头孢他啶侧链酸活性酯的合成,中国医药工业杂志,2002,33(1):523-24;
26、KAWABATA TAKEO;MIYASHITA MASAHIKO;TAISHA AKIRA.PRODUCTION.OF 2-(2-AMINOTHIAZOL-4-YL)-2-(SYN)-HYDROXYIMINOACETIC ACID ESTER,JP63126870,1988-05-30;
27、段行信,实用精细有机合成手册,化学工业出版社,134;
28.Richardson,lowry,Mechanism and Therory in organic Chemistry(Second Edition):635-37;
29、山东省化工研究院,氨噻肟酸的合成研究(内部鉴定资料),14-15;
30、段行信,实用精细有机合成手册,化学工业出版社,480-482;
31、唐培堃主编,《精细有机合成化学与工艺学》,天津大学出版社,366-367;
32、唐培堃主编,《精细有机合成化学与工艺学》,天津大学出版社,233-234;
33、山东省化工研究院,氨噻肟酸的合成研究(内部鉴定资料),22-23;
34、DUERCKHEIMER WALTER DR(DE),Crystalline modification of ceftazidim,US4624948,1986-11-25;
35、G.P.Leslie Grady,Jr.Glen T.Daigger Henry C.Lim.废水生物处理(第二版)[M].北京:化学工艺出版社,2003
36、Beil.3,Ⅳ,1550
37、GB617-88化学试剂熔点范围测定通用方法;
38、实用有机化学手册,上海科技出版社;
39、张贵芹,李德波,反相液相色谱法测定去甲氨噻肟酸乙酯的含量,山东化工,2005,34(4),43-44;
40、张贵芹,邱娟,反相液相色谱法测定头孢他啶侧链酸的含量,化学工程师,2007,137(2),38-39: