Breast Cancer Human Epidermal Growth Factor Tyrosine Kinase Inhibitors

Breast Cancer Human Epidermal Growth Factor Tyrosine Kinase Inhibitors 

Title Heterocyclic Compounds, Oxazole Derivatives, Process for Preparation of the Same, and Use Thereof A. Tasaka et al US Patent 6,984,653 (January 10, 2006) Assignee Takeda Pharmaceutical Company Limited Utility Treatment of Breast Cancer 

Invention Significance The human epidermal growth factor receptor-2 

A suspension of 4-trifluoromethylcinnamic acid (19.4 g) and six drops of DMF in 100 ml TFIF was treated with 11.7 ml oxalyl chloride at 0°C, then stirred 2 hours at ambient temperature, and concentrated. The residue was dissolved in 60 ml EtOAc, then poured into 120 ml mixture of 25% NFl4OH/EtOAc, 5 1, and the water layer salted out. The organic layer was extracted once with 650 ml EtOAc/THF, 12 1, and twice with 100 ml EtOAc, then dried with MgS04, and concentrated. The residue was recrystallized using EtOAc/hexane and 18.0g product isolated as colorless plate crystals. 

A mixture of the Step 1 product (17.9g) and 1,3-dichloroacetone (14.8 g) dissolved in 83 ml toluene was refluxed 9 hours using the Dean-Stark apparatus. After cooling, the mixture was diluted with water, then extracted with EtOAc, washed with brine, dried, and concentrated. The residue was purified by chromatography using silica gel with hexane/EtOAc, 6 1-5 1, and 15.1 g product isolated as colorless needle crystals. 

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