Study On The Synthesis Of Lapatinib And Its Intermediates

The research and development of lapatinib, a dual inhibitor of EGFR/HER-2, by GlaxoSmithKline(GSK) is for the treatment of breast cancer, and its chemical name is N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-(5-((2-(methylsulfonyl)ethylamino) methyl)furan-2-yl)quinazolin-4-amine bis(4-methylbenzenesulfonate) monohydrate. Its synthesis was studied with 2-amino-5-iodobenzoic acid as starting material, which was subjected to cyclization with formimidamide acetate to produce 4-hydroxy-6-iod- oquinazolin, which reacted with thionyl chloride to get 4-chloride-6-iodoquinazolin, and then was condensed with 3-chloro-4-(3-fluorobenzyloxy)aniline to gain the key intermediate N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-iodoquinazolin-4-amine, and its Suzuki coupling reaction with 5-formylfuran-2-boric acid was carried out and followed by reductive amination reaction with 2-(methylsulfonyl)ethanamine and salt formation with 4-methylbenzene-sulfonic acid hydrate to generate the final target compound.In the above route, 4-hydroxy as well as 4-chloro-6-iodoquinazolin had extremely poor solubility that resulted in diluted solutions and a large excess of thionyl chloride being used for the chlorination step, which led to serious problems in experimental treatment and environmental protection. Therefore, 2-aminobenzonitrile was chosen as starting material to be iodized or bromined to produce 2-amino- 5-iodo(bromo)benzonitrile, which was condensed with N,N-dimethylformamide dimethyl acetal (DMF DMA) and the amidine product was obtained by condensation under reduced pressure to remove excessive DMF DMA. Glacial acetic acid and 3-chloro-4-(3-fluorobenzyloxy) aniline were directly added to the condensation, and the so-called Dimroth rearrangement proceeds to generate the key intermediate N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-iodoquinazolin-4-amine with an overall yield of 82.4% based on 2-amino-5-iodobenzonitrile, compared with the yield of 77% in the prior route from 2-amino-5-iodobenzoic acid. The improved route is more environment-protecting and is more convenient for the one-pot operation, which is favorable to enlarge the production.The other intermediate, 2-(methylsulfonyl)ethanamine was also studied. Owing to some shortcomings of the methods in literatures, a completely new and unreported process was designed with phthalimide potassium as starting material and Gabriel reaction was conducted with 2-chloroethyl methyl sulfide, and through hydrogen peroxide oxidation, acid hydrolysis to give the target compound with a total yield 51%. The cheap materials and simple and easy operation in the reaction are the advantages of the new process.