5-((7-(Trifluoromethyl)-5-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)ethynyl)pyridin-2-amine

911112-17-9

911114-11-9

911115-16-7

GENERAL STEPS: A suspension of compound 13 (17.6 g), sodium carbonate (23.0 g) and sodium hydroxide (3.0 g) in toluene (200 mL) was heated to 100 to 105 °C under reduced pressure (about 800 mbar) and stirred at this temperature for 6 to 10 hours. During the reaction, the distilled toluene was continuously replaced with fresh toluene to keep the reaction volume constant. After the reaction is complete (<2% starting material residue), the mixture is cooled to 50 °C. Half the volume of toluene was distilled under reduced pressure. Methyl tert-butyl ether (MeTHF, 120 mL) and water (120 mL) were added and the two-phase mixture was stirred for 30 minutes. After standing and layering, the lower aqueous layer was removed. The organic layer was polished and filtered, washed with water (40 mL) and subsequently concentrated to dryness. The residue was dissolved in 150 mL of MeTHF. Over a period of 2 to 3 hours, this solution was slowly added to a hot solution (70-75°C) of compound 7 (36.0 g), copper (I) iodide (334 mg), bis(triphenylphosphine) palladium (II) dichloride (557 mg), triphenylphosphine (414 mg) and triethylamine (25.5 mL) in MeTHF (145 mL). The resulting suspension was continued to be stirred at 70-75°C for 14 hours. Upon completion of the reaction, the mixture was cooled to 30 °C and treated with water (150 mL) and 25% aqueous ammonium hydroxide solution (30 mL). After stirring the two-phase mixture for 30 minutes, it was allowed to stand for 20 minutes to allow layering. After removing the aqueous layer, the MeTHF layer was washed twice with a mixture of water (150 mL) and 25% aqueous ammonium hydroxide (30 mL). Subsequently, the MeTHF layer was washed with water (3 x 150 mL). The organic layer was polished and filtered and the filtrate was treated with n-tributylphosphine (1.0 mL). MeTHF was removed by complete distillation and replaced with ethanol (total 500 mL) at atmospheric pressure. The resulting suspension (~300mL) was heated to reflux and stirred at reflux for 2 hours and subsequently cooled to room temperature overnight. The product was collected by filtration and washed with ethanol (50 mL). The wet crystals were dried to constant weight at 50 °C and <30 mbar to give 29.3 g (83% yield based on Compound 7) of the target compound A as red crystals with a purity of 99.5% (HPLC, % area) and an assay value of 99.0% (HPLC, % w/w).