抗癌药物拉帕替尼两个杂质的合成

Synthesis of Two Impurities of Anticancer Drug Lapatinib

目的合成抗癌药物拉帕替尼的两个杂质。方法以N-[3-氯-4-[(3-氟苄基)氧基]苯基]-6-碘喹唑啉-4-胺为起始原料,经Suzuki偶联反应,得到N-[3-氯-4-[(3-氟苄基)氧基]苯基]-6-[(5-甲酰基)呋喃-2-基]-4-喹唑啉胺,直接与还原剂NaBH(OAc)3反应,得到特定杂质N-[3-氯-4-[(3-氟苄基)氧基]苯基]-6-(5-羟甲基呋喃-2-基)-4-喹唑啉胺;起始原料经Suzuki反应后,与2-甲砜基乙胺反应,在NaBH(OAc)3作用下得粗品,经制备液相分离,得到另一特定杂质双[[5-[4-[[3-氯-4-[(3-氟苄基)氧基]苯基]氨基]喹唑啉-6-基]呋喃-2-基]甲基][2-(甲磺酰基)乙基]胺。结果两个目标物经质谱(MS),核磁共振氢谱(1H NMR)确证其化学结构。结论合成的两个杂质可作为拉帕替尼质量控制对照品,本工艺操作可行,原料易得。

Objective To synthesize two impurities of lapatinib. Methods One special impurity N-[3-chloro-4-[（3- fluorobenzyl）oxy]phenyl]-6-[5-（forrnyl）furan-2-yl] quinazolin -4-amine was synthesized from N-[3-chloro-4-[（3- fluorobenzyl）oxy] phenyl]-6-iodoquinazolin-4-amine through Suzuki cross-coupling reaction, then was treated with NaBH（OAc）3; the starting material after Suzuki cross-coupling reaction was treated with 2-（methylsulfony）ethylamine, then NaBH（OAc）3 was added to give crude product of the other impurity, bis[[5-[4-[[3-chloro-4-[（3-fluorobenzyl）oxy] phenyl]amino]quinazolin-6-yl]furan-2-yl]methyl][2-（methylsulfonyl）ethyl]amine, and the impurity was separated by preparative liquid chromatography. Results The structure of two impurities of lapatinib were verified by MS and 1H NMR. Conclusion The two specified impurities can be used as the reference substances of the related substances in the quality control of Laptinib. The reaction conditions were mild and the raw materials were cheap.