Synthesis Of New Anti-hypertensive Drug Amlodipine

Amlodipine, invented by Pfizer company, is a new drug treating angina and hypertension. It has the advantages of long effect and less side-effect. In this paper, amlodipine maleate was obtained through six steps by Hantzsch reaction. Considering the cost and yield, each reaction was optimized. The optimized conditions are as following: Phthalic anhydride reacted with monoethanol amine at the ratio of 1:1 in xylene for 2.5h to form N-(2-hydroxethyl)phthalimide(I), yield 92.2%; (I) reacted with 4-chloroethyl acetoacetate in the presence of sodium hydride in dry THF for 20h to obtain ethyl 4[2-(phthalimido)ethoxy] acetoacetate(II), yield 93.4%; (II) reacted with ammonia at the ratio of 1:2 for 4h at the room temperature to prepare 3-amino-4-(2-(phthalimido)ethoxy)crotonate(III), yield 67.9%; 2-chlorobenzaldehyde reacted with methyl acetylacetoacetate in the presence of pyridine and acetic acid an catalyst in toluene for 2h to form methyl 2-(2-chlorocenzylidine)acetoacetate(IV), yield 95.0%; III reacted with IV in ethanol for 20h to obtain (V), yield 52.0%. Recycling the raw materials, the final yield of cyclization can reach 72.5%; V was stirred in 35% ethanolic methylamine solution at room temperature for 3h, and then the maleic acid was add at the ratio of 1:1. After stirring for 2h, the aimed product was obtained at the yield of 91.8%. The total yield of the route reached 36.9%.The cyclization of the dihydropyridine by Hantzsch reaction is the key of the routine. The process of cyclization was given on the basis of the simulated results by the molecular simulation software of Materials Studio and the mechanism of Hantzsch reaction. The influence of the structure of compound III on the cyclization was analyzed and confirmed by the microwave reaction.