Research On Synthesis Of The Key Intermediate Of Efonidipine

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.