拉帕替尼合成工艺的研究进展

Research progress on the synthetic technology of Lapatinib

拉帕替尼(Lapatinib)是一种口服的新型小分子表皮生长因子酪氨酸激酶抑制剂(TKIs),临床治疗Ⅱ型人表皮生长因子受体过度表达引起的晚期或转移性乳腺癌。本文回顾了近十年以来有关拉帕替尼生产及应用的文献及专利,介绍了拉帕替尼的主要工艺合成路线,系统阐述其3种关键中间体(包括3-氯-4-(3-氟苄氧基)苯胺(2)、N-(3-氯-4-(3-氟苄氧基)苯基)-6-碘喹唑啉-4-胺(3)和5-[4-[3-氯-4-[(3-氟苄氧基)苯基]氨基]-6-喹唑啉]-2-呋喃甲醛(4))和两种关键原料(苯并嘧啶和2-甲砜基乙胺盐酸盐)的合成工艺,研究了各种路线之间的异同与特点,比较各条路线的优劣,指出了各种关键中间体、原料和终产物拉帕替尼的最优合成工艺。

Lapatinib,a new kind of epidermal growth factor tyrosine kinase inhibitors of small molecules,is employed for clinical therapy of the advanced or metastatic breast cancer induced by the overexpression of human epidermal growth factor receptor-Ⅱ. This paper reviews the relevantliteratures and patents about the production and application of Lapatinib in the last ten years,mainly introduces the synthetic process of Lapatinib and expounds systematically the synthetic process of its three key intermediates（3-chloro-4-（3-fluorobenzyloxy）aniline,N-[3-chloro-4-（3-fluorobenzyloxy） phenyl]-6-iodoquinazolin-4-amine and 5-（4-（（3-chloro-4-（（3-fluorobenzyl）oxy） phenyl）amino） quinazolin-6-yl）furan-2-carbaldehyde） and two key raw materials（quinazoline and 2-aminoethylmethylsulfonehydrochloride）. The differences and features of various routes and the advantages and disadvantages of various routes are discussed. Optimal synthestic technology of the key intermediates raw materials and the final products-Lapatinib is presented.