【作者】 张华；

【导师】 李雯；

【作者基本信息】 郑州大学 ， 制药工程， 2015， 硕士

【摘要】 依福地平,一种新型的1,4-二氢吡啶类抗高血压药物,具有L型和T型钙通道双重阻滞作用。该药由日本日产化学工业株式会社和泽利亚制药公司联合开发,并于1994年在日本上市,具有血管选择性高、不良反应少等优点。临床上用于治疗原发性高血压、肾性高血压以及心绞痛患者。由于该药的药效持久,血管选择性高,特别适用于老年性高血压。依福地平可由两个关键中间体3-氨基-2-丁烯酸-2-(N-苄基-N-苯基)氨基乙酯(氨基片段中间体)和3-(5,5-二甲基-2-氧代-2-[1,3,2]二氧杂磷杂环己基)-4-(3-硝基苯基)-丁-3-烯-2-酮(磷杂环片段中间体)经环合反应得到。其中,氨基片段中间体现有的制备方法存在着条件苛刻、原子经济性差、环境不友好的缺点。因此,开发氨基片段中间体的可规模化制备的工艺条件具有重要的经济价值和学术意义。本论文的研究内容为:在文献报道的现有路线的基础上,进行氨基片段中间体的合成路线的探索和合成工艺条件的优化,其具体步骤为:(一)亲核取代反应生成2-(N-苯基-N-苄基)氨基乙醇以N-苄基苯胺和2-氯乙醇为原料,经亲核取代反应制得2-(N-苯基-N-苄基)氨基乙醇,反应的较佳工艺条件为:N-苄基苯胺和2-氯乙醇取代反应的分子摩尔比为1:5,反应温度在60℃时,产物质量最好。该步骤尝试了四丁基溴化铵作为反应的相转移催化剂,结果发现该催化剂可加速反应的进行,提高了收率。该步骤还改进了后处理方式,采用直接萃取的方法获得该步骤产物,避免了文献报道的减压蒸馏操作,所获得产物不需进一步纯化即可用于下一步反应,经以上改进,反应时间由8h缩短至5h,产物收率从78.9%提高到89.3%。(二)酯交换反应生成3-氧代丁酸-2-(N-苄基-N-苯基)氨基乙酯以乙酰乙酸乙酯为反应溶剂,经酯交换反应制得3-氧代丁酸-2-(N-苄基-N-苯基)氨基乙酯,优化后的反应条件为2-(N-苯基-N-苄基)氨基乙醇与乙酰乙酸乙酯的摩尔比为1:4,反应温度控制在100℃,反应时间5h,尝试了三种强酸作反应的催化剂,其中使用对甲苯磺酸作为催化剂收率较理想,同时研究了不同催化剂载体对催化活性和稳定性的影响。采用二氧化硅为载体,制成固体催化剂,使催化剂可以回收利用,并减少了酸性催化剂对设备的腐蚀。(三)氨基取代反应生成3-氨基-2-丁烯酸-2-(N-苄基-N-苯基)氨基乙酯以氨水和氨气为氨源,经氨基取代反应制得3-氨基-2-丁烯酸-2-(N-苄基-N-苯基)氨基乙酯(氨基片段中间体)。较佳的工艺条件为:3-氧代丁酸-2-(N-苄基-N-苯基)氨基乙酯在常温下与氨水反应,反应时间5h,然后在-10℃下与NH3反应,反应时间1h。改进后的工艺方法,条件温和,反应时间短,收率高。三步反应总收率为63.4%。产物经MS和1HNMR确证。本文对依福地平中间体1-(5,5-二甲基-2-氧代-1,3-二氧杂-2-磷杂环己基)-2-氧代丙烷(磷杂环片段中间体)的合成路线进行探索,并对其反应工艺进行了研究。依福地平氨基片段中间体所获得的制备工艺可达到公斤级制备,操作简单,收率较高。更多还原

【Abstract】 Efonidipin is a new 1,4-dihydropyridine calcium antagonists,with the activity of blocking both L- and T-type calcium channel. It co-developed by Nissan Chemical Industries and Zeria pharmaceuticals company, was first launched in Japan in 1994. Efonidipine has satisfactory clinical effects on the essential hypertension, renal hypertendion and angina pectoris. Efonidipine has broad application prospects in the treatment of cardiovascular and cerebrovascular diseases, especially for hypertension in the old patient.Efonidipine can be disconnected into distinct fragments: 2-[(N-benzyl-N-phenyl)amino]ethyl-3-amino-2-butenoate(amine intermediate) and 3-(5,5-dimethyl-2-oxo-[1,3,2]-dioxaphorinane-2-yl)-4-(3-nitrophenyl)-but-3-en-2-one(phosphorus heterocyclic intermediate). The existing preparation method of amine intermediate have shortcomings of strict production conditions,poor economy and not being environmentally friendly. Therefore, the optimization method for the amino intermediates has important economic value and academic significance.This paper aims at the research of synthesic route of amino fragment intermediate, studied the synthesis process conditions of the intermsdiate, and found their optimum conditions.1.The synthesis of 2-(N-phenyl-N-benzyl)amino ethanol by nucleophic substitutionThe optimum process conditions are obtained: the molar of N-benzyl aniline and 2-chloride ethanol is 1:4, the rate of reactions rosed in the presence of tetrabutyl ammonium bromide as phase transfer catalyst, The post-processing process was simplified in this study. The products were not purified via vacuum distillation and column chromatography after the reaction. This synthetic process is suitable for industrial preparation.The modified method shorten the reaction time from 8h to 5h,the yield is improved from 78.9% to 89.3%.2.The synthesis of 2-[(N-benzyl-N-phenyl) amino]ethyl ester-3-oxo-butenote by transesterificationThe 2-[(N-benzyl-N-phenyl) amino]ethyl ester-3-oxo-bute-note was synthesised by transesterification with ethyl acetoacetate as solvent. The reaction conditions are optimized, the molar of 2-(N-phenyl-N-benzyl)amino ethanol and ethyl acetoacetate is 1:4, reaction temperature is 100℃, reaction time is 5h. In addition,three kinds of acid catalysts were investigated in this paper.the result is that : it can successfully promot the the reaction to get ideal recovery when use p-toluenesulfonic acid as catalyst, we compared the catalytic activity and stability of some solid catalyst with different supports. The result showed silicon dioxide as catalyst carrier is most appropriate.catalyst can be recycled in this method. And the corrosion of acid catalyst on equipments was reduced.3.The synthesis of 2-[(N-benzyl-N-phenyl)amino]ethyl ester-3-amino-2-butenote by amino substitution reaction.The 2-[(N-benzyl-N-phenyl)amino]ethyl ester-3-amino-2-butenote was synthesised by amino substitution reaction with using ammonia as the soure of the amino. The optimum process conditions are obtained: first, 3-oxo-butanoic acid-2-(N-benzylN-phenyl) amino ethyl ester react with ammonia at room temperature for 5h, then decreased the temperature to-10℃, and the reaction with ammonia at the temperature is 1h. After that,there are a lot of white crystal precipitation, it is the target object, amino fragment intermediate.In this paper,the process experiments and post-processing were simplified. The reaction was mild and the reaction time was short. The overall yield is 63.4%. The target compound was identified by MS and 1HNMR.In this paper, the synthesic route of Efonidipine’s phosphorus heterocyclic intermediate, 2-acetonyl-2-oxo-1,3,2-dioxaphosphorinane was researched and the reaction process was studied. For Efonidipine’s amine intermediate, the ultimate process conditions could reach kg preparation,the process is easy to operate,and is of high yield.更多还原