以3- 羟基丙腈、2,2,6- 三甲基-4H-1,3- 二氧环己烯-4- 酮、3- 硝基苯甲醛、β- 氨基巴豆酸甲酯为原料，经Hantzsch反应、选择性水解、奎尼丁拆分得中间体(R)-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；另外，以反式-4- 羟基-L- 脯氨酸为原料，经脱羧、苄基化、Mitsunobu 反应、水解反应得中间体(S) -3- 羟基-1- 苄基吡咯烷；两个中间体经缩合得盐酸巴尼地平，纯度99.3％，ee 值99.45％ , 总收率10％。
Abstract
(R)-2,6-Dimethyl-4-(3-nitrophenyl)-5-(methoxycarbonyl)-1,4-dihydropyridine-3-carboxylic acid, a key intermediate of barnidipine, was synthesized from 3-hydroxylpropionitrile, 2,2,6-trimethyl-4H-1,3-dioxin-4-one, 3-nitrobenzaldehyde and methyl 3-aminobut-2-enoate via Hantzsch condensation, selective hydrolysis
and resolution with quinidine. Another crucial intermediate (S)-1-benzyl-3-pyrrolidinol was obtained from trans-4-hydroxy-L-proline via decarboxylation, benzylation, Mitsunobu reaction and hydrolysis. Then the two intermediates were subjected to a condensation to afford the title product with an overall yield of 10％, a purity of 99.3％ and ee value of 99.45％.
关键词
盐酸巴尼地平 /
钙离子拮抗剂 /
合成
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Key words
barnidipine hydrochloride /
calcium ion antagonist /
synthesis
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参考文献
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脚注
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基金
贵州省普通高等学校工程研究中心(黔教合KY字[2014] 219号)、贵州医科大学博士启动基金(院博合J字[2015]006号)、贵州省卫生计生委科学技术基金(gzwjkj2014-2-102)、贵州省化学合成药物研发利用工程技术研究中心(黔科合[2016]平台人才5402)
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