Practical synthesis of lapatinib

This paper deals with the development of a practical process for lapatinib tosylate monohydrate(〖STHZ〗1〖STBZ〗)，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 carbon catalyzed Suzuki coupling with 5-formyl-2-furylboronic acid(96% yield)，reductive amination with 2-(methylsulfone)ethylamine(94% yield)，salt formation with p-toluenesulfonic 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，¹H 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 monohydrate( 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.