Synthesis Of Felodipine And Optically Active Felodipine

Felodipine is the second generation1,4-dihydropyridine calcium channel blocker developed by Astra Pharma in Sweden to treat hypertension. It has been approved that the slow-released tablets of felodipine have good anti-hypertension effect and tolerance reported by many foreign studies. It has been applied as first-line drug since it has similar or better anti-hypertension effect compared with this kind of drugs, whether it is used separately or combined with other drugs.In this paper, Felodipine was synthesized in one step economically. The protocol mentioned below improved yields with a simple route. Moreover, we also studied the synthesis of felodipine diastereoisomer, and got the R(+)-felodipine. Finally, The intermediates and target products were characterized by NMR and MS.The equimolar2,3-dichlorobenzylidine, ethyl acetoacetate and methyl-3-aminocrotonate are dissolved in ethanol and refluxed to give Felodipine under a nitrogen atmosphere, in the presence of sodium dithionite via hantzsch reaction. Methyl acetoacetate was reacted with ammonium acid carbonate to afford methyl-3-aminocrotonate completely and the total yield is above80%.A novel green method was discovered to resolve recemic Felodipine. Firstly, S-mandelic acid was esterified to give its methyl ester, then it was transesterificated with methyl acetoacetate, after that, the knoevenagel, Michael reaction and cyclization were applied to give1,4-dihydro-2,6-dimethyl-4R-(2,3-dichlorophenyl)-3,5-pyridinedicarboxy lic acid methyl S-man-delic methyl ester, the diastereomers were recrystallized thrice to give the single diastereomer from acetonitrile. In following two steps, hydrolyzation and esterfication, R(+)-felodipine was converted with this six-steps route.Iodine was found to be a practical and useful Lewis acid catalyst for the transesterification reaction and toluene was used as an entrainer to remove methanol. Concentrated sulfuric acid catalyzed efficiently Knoevenagel condensation with2,3-dichlorobenzaldehyde under solvent free condition. The preferrable feeding sequence is methyl S-mandelic acetocaetate, concentrated sulfuric acid with stirring, and2,3-dichlorobenzylidine with a range of45-60℃. The optimal conditions of Michael reaction was provided below:ethanol as solvent and acetonitrile used in recrystallization;6b was hydrolysed selectively by excessive sodium hydroxide. Finally,4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid methyl ester was esterifi- cated by ethyl bromide and potassium iodide to afford the target product.