昂拉地韦潜在基因毒性杂质的合成、表征和检测

Synthesis,Characterization and Detection of Potential Genotoxic Impurity of Onradivir

为了对流感I类新药昂拉地韦的潜在基因毒性杂质进行研究,合成了昂拉地韦原料药中潜在基因毒性杂质3-叠氮基-5-氟-1-(四氢-2 H-吡喃-2-基)-^(1)H-吡唑并[3,4-b]吡啶(SMI-H),其结构通过核磁共振氢谱、碳谱、质谱进行表征。采用自行开发并验证的液相色谱-质谱法(LC-MS)对昂拉地韦原料药和关键起始物料3-溴-5-氟-1-(四氢-2 H-吡喃-2-基)-^(1)H-吡唑并[3,4-b]吡啶(SMI)进行杂质的检测。结果表明:在昂拉地韦中未检出该杂质,而在SMI中有检出(0.1%~0.2%),但杂质含量低于标准限度(≤0.3%),因此昂拉地韦的安全风险是可控的。

This article aims to study the potential genotoxic impurities of the new class I influenza drug,Onradivir.3-Azide-5-fluoro-1-(tetrahydro-2 H-pyrano-2-yl)-^(1)H-pyrazole[3,4-b]pyridine(SMI-H),which is a potentially genotoxic impurity in the Onradivir,was synthesized with 2-chloro-5-fluoronicotinonitrile as the starting material.The structure of the target compound was identified by ^(1)H NMR,^(13)C NMR and MS(ESI).The content detection was established by LC-MS method and the results showed that it was not detected in the Onradivir,but in the SMI(0.1%~0.2%).The impurity content was lower than the standard limitation(≤0.3%).So the safety risk was controllable in the Onradivir.