达比加群酯降解杂质的合成

Synthesis of the Degradation Impurities of Dabigatran Etexilate Mesylate

摘要: 目的为了更好的控制甲磺酸达比加群酯的质量，合成达比加群酯的5个降解杂质。方法以N-2-(4-氰基苯基)氨基甲基-1甲基-1H-5-苯并咪唑羰基-N-2-吡啶基-β-氨基丙酸乙酯为原料，经过成脒反应、酰胺反应、水解反应制备了杂质 A~E 。结果所得产物经¹H-NMR，LC-MS和¹³C-NMR初步确证了结构，收率≥65%。结论该合成路线反应条件温和，产品纯度高。

Abstract: OBJECTIVE To perform the quality control of dabigatran etexilate mesylate, five degradation impurities recorded in quality specifications are prepared. METHODS Five degradation impurities A-E were synthesized from N-2-(4-cyanophenyl)aminomethyl-1-methyl-1H-benzimidazol-5-ylcarbonyl-N-2-pyridinyl-β-alanine ethyl ester, via amidine reaction, amidation reaction and hydrolytic reaction. RESULTS The strutures of five degradation impurities were established by ¹H-NMR, LC-MS and ¹³C-NMR, with yield ≥65%. CONCLUSION The reaction condition is mild, and the purity is high.