Study On The Novel Process For Synthesis Of Amlodipine

Amlodipine is one of the representative drugs called dihypmpyridine of third-generation calcium channel blockers(CCB).Amlodipine is mainly used for curing hypertensive and chest pain(angina).It has such advantages of little side effect,lowers blood reposefully and very long half-time in blood plasma.It does not bring irritability tachycardia,So it is very prospective to cure the heartfailure.There are many routes to synthesis amlodipine.Some of them suffer from the supply of material or the complicated manipulation,so that it isn't conducive to industrial production.This article designed a new way which was suitable for China's national conditions,on the basic of the analyse of the existed synthesis routes.It was started from the synthesis of 2,2-diethoxyacetic acidethylester with dichloroacetic acid,then with the catalysis of Lewis acid,2,2-dietho-xyacetic acdethylester was reverted to 2,2-diethoxyethanol through potass-ium borohydride.2,2-diethoxyethanol and 4-chlorine acetylacetic ether went through Williamson etherification reaction and thereafter Ene aminat-ion reaction under the weak ammonia condition in dilute ammonia solution and NH4C1 to from 3-amino-4-(2,2-diethoxyethoxyl)-2-ethyl crotonate(?);2-acetyl-3-(2-chlorphenyl)-methyl acrylate(?)was obtained from o-chlo-robenzaldehyde and methyl acetoacetate through Knoevenagel condensa-tion reaction;Compound(?)and compound(?)formed the intermediate of amlodipine 1,4-dihydro-2-(2,2-diethoxyethoxylmethyl)-6-methyl-4-(2-chlorphenyl)-3,5-dipicolinic acid ethyl methyl ester(?)by the reaction of Michael condensation reaction;Compound(?)reacted with hydroxy lamine hydrochloride to obtain aldoxime,then got the target product amlodipine under the reduction of sodium borohydride at-25?.The structures of the target compound and intermediates were identified and confirmed by IR,MS and NMR.Furthermore,the methods of analysis for content were studied by RP-HPLC.The mechanism of the key synthesis reaction was analyzed,the feature of the reaction and the technical process was researched and the factors such as the catalyst,the reaction tempreture and the reaction time,were also examined on the influence of the reaction yield and finally the preferable combination of the synthesis process parameters was collected:the catalyst was KBH4-Li2CO3,the mole ratio of the KBH4 and the ester was 2:1,the reaction time was 5 h and the yield was 68.5%;the mole ratio of the 2,2-diethoxyethanol,the 4-chlorine acetylacetic ether and the sodium hydride was 1:1:1.5,the reaction was reacted at room tempreture for 12 h and the(I)yield was 76.3%;the catalyst was the combination of ammonium acetate and acetic acid,the mole ratio of the o-chlorobenzaldehyde and methyl acetoacetate was 1.2:1,the(?)was obtained at the yield of 78.2%for 8 h;the absolute ethyl alcohol was used as solvent,the mole ratio of(?)and(?)was 1:1,the(?)was obtained at the yield of 75.3%for 48 h;the mole ratio of(?)and hydroxy lamine hydrochloride was 1:7,the reaction was carried on for 5 h,the intermediate aldoxime(?)was obtained and then the target product was collected at the yield of 40.8%by the reaction of(?)and sodium borohydride at the mole ratio of 1:8 for 4 h at-25?.The total yield of the route was 13.1%.There are the advantages in the process such as higher yield,brief step,simple operation and comparatively moderate reaction condition.It provided the theoretical basis and the feasible process parameters for the industrialization of CCB.