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Lapatinib Ditosylate (GW572016, GW2016, Tykerb, Tyverb) is a potent EGFR and ErbB2 inhibitor with IC50 of 10.8 and 9.2 nM, respectively.

Reversible dual inhibitor of ErbB1 and ErbB2 tyrosine kinases. Antineoplastic

Lapatinib, an ErB-1 and ErB-2 dual kinase inhibitor, was launched for the treatment of advanced or metastatic HER2 (ErbB2) positive breast cancer in women who have received prior therapy. The drug was discovered and developed by GlaxoSmithKline and is also currently being evaluated for several additional cancer indications.

The synthesis started with Williamson ether synthesis between 2-chloro-4-nitrophenol (58) and 3-fluorobenzyl bromide to give ether 59 in the following scheme; however, no specific yields were provided. Reduction of the nitro group of compound 59 by catalytic hydrogenation over Pt/C and subsequent condensation of the resulting aniline with 4-chloro-6-iodoquinazoline (61) in refluxing i-PrOH afforded compound 62. 4-Chloro-6-iodoquinazoline (61) was prepared by reacting 6-iodoquinazolin- 4(3H)-one (60) with POCl3 in the presence of triethylamine. Compound 62 was subjected to Stille coupling with 5- dioxolanyl-2-(tributylstannyl)furan (63) in the presence of PdCl2(PPh3)2 to give 64. Acidic hydrolysis of acetal 64 using HCl in THF/H2O provided the corresponding aldehyde which was further subjected to reductive amination with 2-(methan-esulfonyl)ethylamine in the presence of sodium triacetoxyborohydride to yield lapatinib. Lapatinib was treated with ptoluenesulfonic acid solution to give lapatinib ditosylate (IX).

EGFR: 10.8 nM (IC₅₀, Cell Free Assay); ErbB2: 9.2 nM (IC₅₀, Cell Free Assay)

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