盐酸乐卡地平的合成

Synthesis of Lercanidipine Hydrochloride

以肉桂酸、氯化亚砜、甲胺等为原料经傅克烷烃化、酰氯化、酰胺化,再用KBH4/ZnC l2体系还原酰胺得到中间体N-甲基-3,3-二苯基丙胺Ⅴ;以2-甲基烯丙基氯为原料,经水合得到中间体1-氯-2-甲基-2-丙醇Ⅵ;再由Ⅴ、Ⅵ合成关键中间体侧链醇2,N-二甲基-N-(3,3-二苯基丙基)-1-氨基-2-丙醇Ⅶ,最后和母核1,4-二氢-2,6-二甲基-4-(3-硝基苯基)-5-甲氧羰基-3-吡啶羧酸(DHPCOOH)对接得到乐卡地平Ⅷ,6步反应总得率23.2%,各中间体及产物结构经MS以及1HNMR确证。

Alkylation of benzene with cinnamic acid （ Ⅰ ） via Fridel-Crafts reaction gave 3,3-diphenylpropanoic acid （ Ⅱ ）, which was subsequently converted into the corresponding acid chloride （ Ⅲ ） and further converted into N-methyl-3,3-diphenylpropanamide （Ⅳ） by reaction with methylamine in methanol. Ⅳ was efficiently reduced with the KBHa/ZnCl2 system to give N-methyl-3, 3- diphenylpropanamine （ Ⅴ ）. 2-Methylallyl chloride was hydrated with 80% sulfuric acid to get 1-chloro- 2-methyl-2-propanol（Ⅵ）. Then Ⅴ reacted with Ⅵ to get the key intermediate 2,N-dimethyl-N-（3,3- diphenylpropyl ） -1-amino-2-propanol （ Ⅶ ）. Finally, Ⅶ and 2, 6-dimethy4-（ 3-nitrophenyl ） -5- methoxycarboxyl-1,4-dihydropyridine-3-carboxylic acid（DHPCOOH） were connected to form the target product lercanidipine hydrochloride （Ⅷ）. Total yield of the seven steps was 23.2%, and structures of the product Ⅷ and key intermediates were verified by ESI -MS and ^1HNMR.