拉帕替尼合成工艺研究

Practical synthesis of lapatinib

报道了拉帕替尼二对甲苯磺酸盐一水合物(1)的合成工艺研究。以6-碘喹唑啉-4-酮(3)为起始原料,依次经氯化反应(收率88%)、与5-甲酰基呋喃-2-硼酸的Suzuki偶联反应(收率96%)、与2-(甲砜基)乙胺的还原胺化(收率94%)、与一水合对甲苯磺酸成盐(收率87%)和四氢呋喃-水(8∶2)结晶(收率70%)等5步操作制备目标产物1,总收率48%。各中间体和目标产物经1HNMR、13CNMR、ESI-MS表征。在工艺优化中革除了柱色谱及对环境不友好的过量氯化剂、含卤溶剂,采用易于回收的非均相催化剂钯炭替代昂贵和难以处理的均相催化剂。所研制的合成工艺路线各步收率均较高,而且操作简便,无需特殊试剂和条件,预期适合工业化生产的要求。

This paper deals with the development of a practical process for lapatinib tosylate monohydrate（ 1）, a molecule-targeted antitumor agent. The target product 1 was synthesized from commercially available 6-iodoquinazolin-4-one（3） in a five-step process with an overall yield of 48% via chlorination（88% yield）, palladium car- bon catalyzed Suzuki coupling with 5-formyl-2-furylboronic acid（96% yield）, reduetive amination with 2-（ meth- ylsulfone） ethylamine（94% yield）, salt formation with p-toluenesulfonie acid monohydrate（87% yield）, and final crystallization from THF-water （ 8 ： 2） （70% yield）. The intermediates and the target product were characterized by melting points, I H NMR, 13C NMR, and ESI-MS. During our optimized process, chromatography, large excess of chlorinating agent and halogenated solvent that are unfriendly to the environment were all removed; expensive and difficult-to-handle homogeneous catalyst was successfully substituted with heterogeneous catalyst palladium carbon which could be recovered easily. In conclusion, this streamlined synthetic process of lapatinib tosylate mono- hydrate（1） highlights excellent yield in almost every procedure, ease of operation, robustness, as well as green chemistry, and thus should be amenable to large-scale production.