丁酸氯维地平4种杂质的合成

Synthesis of Four Impurities of Clevidipine Butyrate

目的合成丁酸氯维地平的4个杂质。方法以2, 3-二氯苯甲醛、乙酰乙酸乙酯、双乙烯酮、3-羟基丙腈、丁酸氯甲酯为起始原料,经酯化、缩合、环合得到4-(2, 3-二氯苯基)-1, 4-二氢-2, 6-二甲基-3, 5-吡啶二羧酸乙酯氰乙基酯(A);A在丙酮中经氢氧化钠选择性水解得到4-(2, 3-二氯苯基)-1, 4-二氢-2, 6-二甲基-3, 5-吡啶二羧酸单乙酯(B);B在乙腈和碳酸钾的混合溶液中与丁酸氯甲酯发生酯化反应生成4-(2, 3-二氯苯基)-1, 4-二氢-2, 6-二甲基-3, 5-吡啶二羧酸乙酯丁酰氧基甲酯(C)。C氧化得到杂质4-(2, 3-二氯苯基)-2, 6-二甲基-3, 5-吡啶二羧酸乙酯丁酰氧基甲酯(D)。结果 4个目标物经质谱(MS),核磁共振氢谱(1H-NMR),核磁共振碳谱(13C-NMR)确证其化学结构。结论合成的4个杂质可作为丁酸氯维地平质量控制对照品。本工艺操作可行,原料易得。

Objective To synthesize four impurities of clevidipine butyrate. Methods Using 2, 3-dichlorobenzaldehyde, ethyl acetoacetate, diketene, 3-hydroxypropionitrile and chloromethyl butyrate as starting materials, 4-(2, 3-dichlorophenyl)-1, 4-dihydro-2, 6-dimethyl-3, 5-pyridyldicarboxylic acid ethyl cyanoethyl ester(A) was obtained by esterification, condensation and cyclization. A was selectively hydrolyzed by sodium hydroxide in acetone to obtain 4-(2, 3-dichlorophenyl)-1, 4-dihydro-2, 6-dimethyl-3, 5-pyridinedicarboxylic acid monoethyl ester(B). B was esterified with chloromethyl butyrate in a mixed solution of acetonitrile and potassium carbonate to produce 4-(2, 3-dichlorophenyl)-1, 4-dihydro-2, 6-dimethyl-3, 5-pyridinedicarboxylate butyryloxymethyl(C). C was oxidized to obtain an impurity 4-(2, 3-dichlorophenyl)-2, 6-dimethyl-3, 5-pyridinedicarboxylic acid ethyl butyryloxymethyl ester(D). Results The chemical structures of the four target chemicals were confirmed by MS, 1H-NMR and 13C-NMR. Conclusion The synthesized four impurities can be used as reference for quality control of clevidipine butyrate. The process is feasible and the raw materials are easily available.