Lapatinib synthesis

S. Radi, M. Stefko and J. Cerny, A Method of Producing the Key Intermediate of Lapatinib Synthesis, WO2014059956 (Al), 24 April 2014. 

A new synthesis of Lapatinib, an orally active drug for breast cancer, was described. The synthesis involved a palladium-catalyzed regioselective aryla-tion of furfural with 6-bromo-N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl) quinazolin-4-amine (14TL6007). 

Interesting recent results indicate that P450 3A5 is more active than P450 3A4 in some reactions. One is the activation of lapatinib [1481]. Another is the 0 -demethylation of thebaine (Fig. 9.17), a critical step in the synthesis of endogenous morphine [906], where P450 3A5 is > 10-fold more active than P450 3A4 [906]. The presence of P450 3A5 in brain (Sect. 7.21.1) may have implications in the relevance of the pathway. 

The synthesis of lapatinib involves a Suzuki-Miyaura coupling of a (5-formylfuran-2-yl)boronic derivative and an aryl iodide and was studied in detail by several teams. " In a recent patent,researchers from Zentiva noticed that in their own attempts to use commercial boronic acid, the excess of this reagent required for optimal conversions and purity was dependent on the source (a common issue with boronic acids, which are often contaminated with anhydrides and borinic acid). Thus, they turned to cyclic boronic esters as a more reliable intermediate, allowing correct control of the amount of boron reagent. Transposition of a process originally developed for the coupling of (5-formylfuran-2-yl)boronic acid was successful. The authors compared... 

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