头孢药物中间体的合成及其配合物的研究
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摘要
(Z)-2-(2-氨基-4-噻唑)-2-甲氧亚胺基乙酸(氨噻肟酸)、氨噻肟酸苯并噻唑巯酯(AE-活性酯)、2-巯基-4-甲基-5-噻唑乙酸是第三代头孢菌素的重要侧链中间体,市场需求量大,加强对其研究开发具有重要意义。本课题研究了头孢药物中间体氨噻肟酸、AE-活性酯、2-巯基-4-甲基-5-噻唑乙酸的合成新工艺,合成了分别以氨噻肟酸和2-巯基-4-甲基-5-噻唑乙酸为配体的过渡金属配合物,包括四部分内容。
1.氨噻肟酸的合成新工艺研究。以乙酰乙酸乙酯为原料,在酸性条件下和亚硝酸乙酯进行肟化反应生成2-亚硝基乙酰乙酸乙酯,用硫酸二甲酯甲基化后再经溴化,与硫脲环合水解酸析后得到氨噻肟酸。重点考察了亚硝酸乙酯作为肟化剂的反应结果,研究了用TLC在线监测溴化反应的方法,并用正交设计实验考察环合反应的优化条件。新工艺节省了有机溶剂的使用,简化了操作,总收率达到45.7 %,产物熔点和红外谱图与对照品一致。
2. AE-活性酯的合成新工艺研究。以氨噻肟酸和二硫化二苯并噻唑为原料,体积比为1/1的二氯甲烷乙腈混合溶剂为反应溶剂,亚磷酸三乙酯替代三苯基膦,通过正交设计实验得到反应的优化条件,按氨噻肟酸/二硫化二苯并噻唑/三乙胺/亚磷酸三乙酯物质的量比为1/1.05/1.1/1投料,反应温度10~15℃,亚磷酸三乙酯滴加时间3 h,体积比为1/1的二氯甲烷乙腈混合溶剂为反应溶剂,收率可达86.7 %。研究了母液溶剂的回收套用,选择合适干燥剂使回收的溶剂达到原料要求。
3. 2-巯基-4-甲基-5-噻唑乙酸的合成新工艺研究。乙酰丙酸乙酯经溴素卤代,与二硫氨基甲酸铵环化缩合,碱性水解酸析得目标产物。溴化反应温度0~5℃,溴素滴加时间2~3 h,环化缩合反应条件确定以体积比1/5乙醇水混合溶剂为反应溶剂,催化剂作用下,溴化产物/二硫氨基甲酰铵物质的量比为1/1.1,目标产物总收率可达61.3%。
4.氨噻肟酸(HL~1)和2-巯基-4-甲基-5-噻唑乙酸(H_2~L2)过渡金属配合物
2-(2-amino-4-thiazolyl)-2-(Z)-methoxyiminoacetic acid ( HL1 ) and its derivative 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyiminoacetic acid 2-benzth iazolyl thioester ( AE ) and 2-mercapto-4-methyl-1,3-thiazol-5-yl-acetic acid ( H2L2 ) are important intermediates of many third generation Cephalosporins, and their demands are increased constantly with the development of new Cephalosporins. So it is deserved to work on their synthesis methods.
The synthesis methods of intermediates metioned above are researched. The paper is divided into four parts to discuss.
1. The novel synthesis method of HL1. The compound is synthesized by using ethyl acetoacetate as raw material followed by steps of oximation, methylination, bromination, cyclocondensation and hydrolyzation. The method focuses on the oximation result in the presense of C2H5NO2 as reaction reagent, the TLC method to detect the bromination process,and the optimized condition of cyclocondensation through orthogonal design experiment. Its total yield is up to 45.7 %, and the structure is confirmed by IR spectrum and melt point of the product.
2. The novel synthesis method of AE . The compound is synthesized by using HL1 and 2-(1,3-benzothiazol-2-yldithio)-1, 3-benz othiazole (DM) as raw material , dichloromethane / acetonitrile (volume ratio 1/1) mixture as reaction solvent, and triethyl phosphate replaces the expensive triphenyphosphine. Through orthogonal design experiment the optimized condition is obtained.the material mol ratio of HL1 /DM/ triethylamine /triethyl phosphate is 1/1.05/1.1/1, the reaction temp.is 10~15℃, and the drop time of triethyl phosphate is 3h, under such condition the yield is up to 86.7 %. The solvents are recycled by distillation in the presence of desiccant.
3. The novel synthesis method of H_2L~2.The compound is synthesized from ethyl
1.氨噻肟酸的合成新工艺研究。以乙酰乙酸乙酯为原料,在酸性条件下和亚硝酸乙酯进行肟化反应生成2-亚硝基乙酰乙酸乙酯,用硫酸二甲酯甲基化后再经溴化,与硫脲环合水解酸析后得到氨噻肟酸。重点考察了亚硝酸乙酯作为肟化剂的反应结果,研究了用TLC在线监测溴化反应的方法,并用正交设计实验考察环合反应的优化条件。新工艺节省了有机溶剂的使用,简化了操作,总收率达到45.7 %,产物熔点和红外谱图与对照品一致。
2. AE-活性酯的合成新工艺研究。以氨噻肟酸和二硫化二苯并噻唑为原料,体积比为1/1的二氯甲烷乙腈混合溶剂为反应溶剂,亚磷酸三乙酯替代三苯基膦,通过正交设计实验得到反应的优化条件,按氨噻肟酸/二硫化二苯并噻唑/三乙胺/亚磷酸三乙酯物质的量比为1/1.05/1.1/1投料,反应温度10~15℃,亚磷酸三乙酯滴加时间3 h,体积比为1/1的二氯甲烷乙腈混合溶剂为反应溶剂,收率可达86.7 %。研究了母液溶剂的回收套用,选择合适干燥剂使回收的溶剂达到原料要求。
3. 2-巯基-4-甲基-5-噻唑乙酸的合成新工艺研究。乙酰丙酸乙酯经溴素卤代,与二硫氨基甲酸铵环化缩合,碱性水解酸析得目标产物。溴化反应温度0~5℃,溴素滴加时间2~3 h,环化缩合反应条件确定以体积比1/5乙醇水混合溶剂为反应溶剂,催化剂作用下,溴化产物/二硫氨基甲酰铵物质的量比为1/1.1,目标产物总收率可达61.3%。
4.氨噻肟酸(HL~1)和2-巯基-4-甲基-5-噻唑乙酸(H_2~L2)过渡金属配合物
2-(2-amino-4-thiazolyl)-2-(Z)-methoxyiminoacetic acid ( HL1 ) and its derivative 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyiminoacetic acid 2-benzth iazolyl thioester ( AE ) and 2-mercapto-4-methyl-1,3-thiazol-5-yl-acetic acid ( H2L2 ) are important intermediates of many third generation Cephalosporins, and their demands are increased constantly with the development of new Cephalosporins. So it is deserved to work on their synthesis methods.
The synthesis methods of intermediates metioned above are researched. The paper is divided into four parts to discuss.
1. The novel synthesis method of HL1. The compound is synthesized by using ethyl acetoacetate as raw material followed by steps of oximation, methylination, bromination, cyclocondensation and hydrolyzation. The method focuses on the oximation result in the presense of C2H5NO2 as reaction reagent, the TLC method to detect the bromination process,and the optimized condition of cyclocondensation through orthogonal design experiment. Its total yield is up to 45.7 %, and the structure is confirmed by IR spectrum and melt point of the product.
2. The novel synthesis method of AE . The compound is synthesized by using HL1 and 2-(1,3-benzothiazol-2-yldithio)-1, 3-benz othiazole (DM) as raw material , dichloromethane / acetonitrile (volume ratio 1/1) mixture as reaction solvent, and triethyl phosphate replaces the expensive triphenyphosphine. Through orthogonal design experiment the optimized condition is obtained.the material mol ratio of HL1 /DM/ triethylamine /triethyl phosphate is 1/1.05/1.1/1, the reaction temp.is 10~15℃, and the drop time of triethyl phosphate is 3h, under such condition the yield is up to 86.7 %. The solvents are recycled by distillation in the presence of desiccant.
3. The novel synthesis method of H_2L~2.The compound is synthesized from ethyl
引文
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[4] Nakayama, E.F., Koichi; Muramatsu, Shigeki; Miyauchi, Masao; Watanabe, Katsuhiko; Ide, Junya., Cephalosporin antibiotics. I. Synthesis and structure-activity relationships of 3-thiazoliomethyl derivatives. Journal of Antibiotics, 1991. 44(8): 854~863
[5] 张致平.抗生素科学的进展.中国药学杂志,1999,32(11): 698~699
[6] 徐兆瑜.7-ADCA 和 7-ACA 的应用和市场.化工技术经济,2004,22(4): 18~23
[7] Okita, T.I., Kiyoto; Hasegawa, Toshifumi; Iimura, Seiji; Masuyoshi, Shinji; Kamachi, Hajime; Kamei, Hideo. , Synthesis and antibacterial activity of cephalosporins having a catechol in the C3 side chain. Journal of Antibiotics 1993. 46(5): 833-889
[8] 彭司勋.药物化学进展. 第一版.北京: 化学工业出版社,2001,166~170
[9] 汤光,李大魁.现代临床药物学.第一版,北京: 化学工业出版社, 1993,15~16
[10] 卞兰芳,韩伟红.头孢类抗生素的特点及合理应用.天津药学,2000,12(1): 48~49
[11] 靳长俊,王贞.孢菌素新进展. 山东医药工业,1998, 17(1): 15~16
[12] 时振洲,刘钮钮,秦葵等.头孢菌素进展. 医师进修杂志,1997,20(7): 381~382
[13] 任吉民,张增梅,李华,张立.国外头孢菌素市场发展综述. 中国制药信息,2004,20(11): 32~34
[14] 任吉民.国内头孢菌素类市场发展综述.中国制药信息,2004, 20(11): 29~32
[15] 吕咏梅.我国头孢类抗生素及其中间体生产与市场.医药中间体及其化工原料,2004,(4): 1~5
[16] 王序梅,邓连荣.头孢菌素产品应用情况与展望.河北医药,2004,26(12): 93~94
[17] 王荣耕.头孢类抗生素用侧链市场分析.精细与专用化学品,2000,(7): 11~12
[18] Walker, D.G. New cephalosporin acylating agents derived from syn-2- (2-aminothiazol-4-yl)-2-methoxyiminoacetic acid , Application to the synthesis of cefepime sulfate . Tetrahedron Letters, 1990,31(45): 6481~6484
[19] 唐建国.2-(2-氨基-1,3 噻唑-4)-2-羟基亚胺基丁酸衍生物的合成.国外抗生素分册, 1989,10(5): 344~347
[20] 朱赛芬,严招春.氨噻肟酸生产技术与应用.化工生产与技术,2001,8(5): 39~41
[21] 王之攘.氨噻肟酸的制法.四川化工,1989,(4): 41~43
[22] 李从宝,赵美法.氨噻肟酸的生产和应用(上).化工科技市场,2002(10): 15~20
[23] Daloia, E.L., G.; Melton, J., Roubie, J. , A convenient method for the preparation of (Z)-(2-aminothiazol-4-yl)-2-methoxyiminoacetyl chloride hydrochloride. Synthetic Communications, 1993, 23(18): 2617~22
[24] 葛洪玉,张静,方志杰.氨噻肟酸的生产及工艺评析.江苏化工,2005,33(1): 47~50
[25] 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,1997,22(3): 22~24
[26] 傅徳才，周鸿娟．2-甲氧亚胺基乙酰乙酸乙酯的合成研究.化学世界,1997,38(2): 88~90
[27] 傅德才,周鸿娟.氨噻肟乙酸生产过程中溴化反应的研究.化学世界,1999(4): 185~186
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