Synthesis Of Lercanidipine Hydrochloride

The antihypertensive drug lercanidipine hydrochloride was developed by Recodati Co. of Italy in 1997. As a new 1, 4-dihydropyridine calcium ion blocker, it is characterized by its high vascular-selectivity and long-lasting effect.The project designed a nine-step route fitting for industrial preparation,total yield is 37.1%.A1kylation of benzene with cinnamic acid (11) via the Fridel-Crafts reaction gave 3,3-diphenylpropanoic acid(12),which was subsequently converted to the acid chloride(13),then reacted with methylamine in methanol to obtain N-methyl-3,3- diphenylpropanamide (14).This amide was efficiently reduced with the KBH4/ZnCl2 system to give N-methyl-3,3-diphenylpropanamine(6);3-chloroisopropene was hydrolyzed with 80% sulfuric acid to get 1-chloro-2-methyl- 2-Propan then reacted with(6) to get the key intermediate 2,N-dimethyl-N- (3,3-dlphenylpropyl)-1-amino-2- propanol (2).Finally,(2) and 2,6-dimethy-4-(3- nitrophenyl)-1,4-dihydrpyridine-3-5- dimethoxycarboxyl DHPCOOH(3)were connected to gain the target product lercanidipine hydrochloride (1).We used 3-nitrobenzaldehyde as raw material to react with Methyl acetoacetate, ammonium-bicarbonate (Hantzsch reaction),then hydrolyze one methoxycarbonyl selectively in methanol with sodium hydroxide to obtain DHPCOOH.We also made some improvement in the synthesis procedure:1 The intermediate 3, 3-diphenylpropanoic chloride(13) was prepared in CH2Cl2 instead of benzene as solvent, adding DMF as catalyst. The reaction time was reduced from 8h to 1.5h.2 The intermediate N-methyl-3, 3-diphenylpropanamide(14) was obtained in the methylamine's methanol solvent instead of methylamine gas It was proved that this change had minimal pathway reaction and the operation was more convenient.3 Using KBH4/ZnCl2 system which was cheaper than NaBH4/HAc to reduce N-methyl-3,3-diphenylpropanamide(14) to N-methyl-3,3-diphenylpropanamine(6). This method hasn't been reported yet.4 Adding sodium hydroxide to absorb hydrochloride which came out during the preparation of 2, N-dimethyl-N-(3, 3-dlphenylpropyl)-1-amino-2-propanol(2). It not only saved the amount of N-methyl-3, 3-diphenylpropanamine(6), but also was very facile for treatment after reaction.