【作者】 陈春光；

【导师】 冯亚青；

【作者基本信息】 天津大学 ， 应用化学， 2013， 博士

【摘要】 头孢唑兰作为高效低毒的第四代注射用头孢菌素，在治疗由细菌引起的各类疾病等临床医疗领域具有重要意义。论文对头孢唑兰及其C-3位、C-7位侧链中间体进行了合成路线和工艺条件的研究，分别合成了咪唑并[1,2-b]哒嗪和2-(5-氨基-1,2,4-噻二唑-3-基)-2-(Z)-甲氧亚胺基乙酸苯并噻唑硫酯，并与母核7-氨基头孢烷酸(7-ACA)结合，进行了头孢唑兰的全合成工作。探索了在形成噻二唑环后引入甲氧亚胺基，合成C-7位侧链(Z)-2-(5-氨基-1,2,4-噻二唑-3-基)-2-甲氧亚胺基乙酸的方法。以丙二腈为起始原料，与HCl、甲醇进行pinner醇解反应，生成3-甲氧基-3-亚胺基丙腈。与甲醇继续反应，得到3,3,3-三甲氧基丙腈，通过对该步反应机理的研究，选择适合的工艺条件，使收率提高到85%。发现3,3,3-三甲氧基丙腈脱甲醇生成3,3-二甲氧基丙烯腈是可逆化学反应，未反应原料可循环使用。碱性条件下，3,3-二甲氧基丙烯腈与羟胺基团闭环反应得5-甲氧基-3-氨基异恶唑，经取代，成环，氧化，水解从而制得2-(5-氨基-1,2,4-噻二唑-3-基)-2-(Z)-甲氧亚胺基乙酸。与先引入甲氧亚胺基的工艺路线相比，显著提高了合成转化效率和收率。总收率提高到40%以上。二硫化二苯并噻唑(DM)是合成多种头孢菌素C-7位侧链的保护基。论文选择无毒混合溶剂对2-巯基苯并噻唑(M)进行精制，以氧气做氧化剂，氧化氮气体为载氧剂，在流化床反应器中实现“爆晶”工艺条件，通过一步化学反应，制得初熔点达到183℃，纯度达到98.8%以上的药用DM，生产过程可实现无三废排放。以马来酸酐为起始原料，强酸为反应介质,可显著提高马来酰肼的收率。采取一锅法合成中间体3,6-二氯哒嗪，产品收率由二步法的74.4%提高至88%。采用微波辅助合成3-氨基-6-氯哒嗪，反应时间从17小时缩短到0.5小时之内。在咪唑环形成过程中，以乙醇为溶剂，采用价格低廉的氯乙醛，简化了反应后处理过程。在6-氯咪唑并[1,2-b]哒嗪脱氯过程中,使用钯炭作催化剂,在常压下通入氢气即可得到咪唑并[1,2-b]哒嗪，各单步收率均高于80%，总收率69%，具有的工业应用价值。以国内生产的7-ACA、自制的氨噻二唑肟乙酸苯并噻唑硫酯和咪唑并[1,2-b]哒嗪，合成出盐酸头孢唑兰，其特征参数与文献值相符合。更多还原

【Abstract】 Cefozopran, the fourth generation of injection cephalosporins, has the advantagesof low toxicity and high activity, which played an important role in the treatment ofvarious diseases caused by bacteria in clinical medical field. This article focused onthe synthetic works of the C-3, C-7side-chains of Cefozopran, succeeded insynthesizing2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(Z) methoxyimino amino acid andimidazo [1,2-b] pyridazine, these two intermediates reacted with the nucleus，7-aminocephalosporanic acid (7-ACA) which produced Cefozopran, the wholesynthesis process was introduced.This paper chooses the synthetic route which introduce methoxy imino functionalgroup after the formation of thiadiazole ring to produce the C-7side chain(Z)-2-(5-amino-1,2,4-thiadiazole oxadiazole3-yl)-2-methoxy imino acid.Malononitrile was used as the starting material and reacted with HCl and methanol toproduce3-methoxy-3-imino propionitrile. The following reaction produced3,3,3-trimethoxy-propionitrile which can loose one methanol molecule to generate3,3-dimethoxy-acrylonitrile.5-methoxy-3-amino-isoxazole was got by cyclized withhydroxylamine, with substitution reaction, cyclization, oxidation and hydrolysis toproduce (Z)-2-(5-amino-1,2,4-thiadiazole oxadiazole3-yl)-2-methoxy imino acid.Compared with the route which introduces methoxy imino route functional groupprior to the formation of thiadiazole ring, this route improved the yield and theefficiency of the reaction, total yield exceeded40%.2,2-Dibenzothiazole, disulfide (DM) is the protecting group for the synthesis ofC-7side chains of variety of cephalosporins. This paper chose the mixed solvent torefine2-Mercaptobenzothiazole (M), used oxygen as the oxidant, nitric oxide as theoxygen carrier, produced medicine grade DM in fluidized bed reactor. The oxidationof M is a kind of free radical reaction. The mixed solvent has good solubility towardsM, DM is the only solid phase which precipitated from the reaction system. Thismixed solvent reduced the phase numbers and shorten the mass transfer path; Nitricoxide gas is the oxygen carrier which can carry oxygen between gas-liquid bi-phase toachieve rapid transmission; the application of fluidized bed reactor eliminated the reactant diffusion effects. All of the factors mentioned above in this article werecombined together, Bring in the ‘explosive crystallization of DM’ in industry. The DMwhich produced under the conditions of ‘explosive crystallization’ appeared rod-like,easy to wash, the melting point reached183°C, the purity was98.8%, in accordancewith the needs of the pharmaceutical industry.This paper used maleic anhydride as the starting material, synthesized imidazo [1,2-b] pyridazine through hydrazinolysis, halogenation, ammonolysis, cyclization anddehalogenation. Strong acids were applied as the reaction medium in first step, theyield of maleic hydrazide can be reached up to96%.3,6-dichloro-pyridazine wassynthesized by a new one-pot method which increased the yield from74.4%to88%.3-amino-6-chloro pyridazine could be synthesized by microwave-assistedammonolysis, which could shorten the reaction time from17hours to0.5hours.During the formation of imidazole ring, with ethanol as the solvent, the use oflow-cost chloroacetaldehyde could simplify the reaction process. In the hydrogenationof the6-chloro-imidazo [1,2-b] pyridazine, palladium carbon was used as the catalyst,the reaction could be accomplished under atmospheric pressure. Since eachsingle-step yield was higher than80%, the total yield achieved69%, this syntheticroute was considered to be practical in industry.Hydrochloric Cefozopran was synthesized by using domestic produced7-ACA,self-made (Z)-2-(5-amino-1,2,4-thiadiazole oxadiazole3-yl)-2-methoxy imino acidbenzothiazole thioesters and imidazole [1,2-b] pyridazine, which characteristicparameters were consistent with literature values.更多还原