Synthesis Of Azelnidipine

The calcium antagonist azelnidipine, co-developed by Sankyo and Ube, was launched in Japan in 2003 for the treatment of hypertension. Azelnidipine was prepared by benzhydrylamine, epichlorohydrin, cyanoacetic acid, isopropyl acetoacetate, 3-nitrobenzaldehyde in this paper. The intermediates and final products were characterized by NMR and MS.Isopropyl 2-(3-nitrobenzylidene) acetoacetate was obtained by employing 3-nitrobenzaldehyde and isopropyl acetoacetate. A solution of 3-nitrobenzaldehyde and isopropyl acetoacetate in isopropanol containing a catalytic amount of piperidinium acetate was stirred at 50-55℃for 1h and standed to room temperature for 48h. The crystal was collected by filtration and was recrystallized by isopropanol. Yield was 77%. 1-Benzhydryl-3-azetidinol was synthesized by benzhydrylamine with epichlorohydrin. A solution of benzhydrylamine with epichlorohydrin in isopropanol was allowed to stand protected from light to room temperature for 48h, then refluxed for 72h. Yield was 65%. (1-Benzhydryl-3-azetidinyl) cyanoacetate was obtained through the esterification of cyanoacetic acid with 1-benzhydryl-3-azetidinol. DCC was added to a solution of cyanoacetic acid and 1-benzhydryl-3-azetidinol in THF and was stirred at 50-55℃for 10h. The crude product washed with cold methanol and petroleum ether. Yield was 90%. (1-benzhydryl-3-azetidinyl) cyanoacetate were converted to (1-benzhydryl-3- azetidinyl) 3-amino-3-ethoxyacrylate with hydrogen chloride, which were subjected to the next reaction without further purification, and (1-benzhydryl-3-azetidinyl)3,3-diaminoacrylate was synthesized by it with ammonium acetate. The crude product was recrystallized with acetonitril. Yield was 86%. Azelnidipine was synthesized by a modified Michael reaction with (1- benzhydryl-3-azetidinyl)3,3-diaminoacrylate and isopropyl 2-(3-nitrobenzylidene) acetoacetate. The crude product was recrystalized by methanol. Yield was 89%.Azelnidipine was recrystallized from ethyl acetate and cyclohexane toα-crystal form, and from xylene toβ-crystal form, the purity was over 99.5%. The total yield was 34% and it was more than other routes.