反应详情

4-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-2-[tetrahydro-2H-pyran-4-yl(trifluoroacetyl)amino]benzoic acid trifluoroacetate (1 mmol, 531 mg) was dissolved in DCM and two drops of anhydrous DMF under nitrogen atmosphere. Oxalyl chloride (0.17 ml, 2 mmol) was added and the mixture was stirred at room temperature for 2 hours. Solvents were evaporated to obtain a yellow powder. The solid was redissolved in THF under an argon atmosphere and cooled at −20° C. DIPEA (0.56 ml, 3.2 mmol) was added. 5-(3,5-Difluorobenzyl)-1H-indazol-3-amine, dissolved in 10 mL of dry THF was then added dropwise in 15′. The reaction mixture was kept at −20° C. for 6 hours then the temperature was allowed to raise at room temperature overnight. The reaction was quenched with 15 mL of NaHCO3 5% and extracted twice with AcOEt (15 ml). Solvents were then evaporated and the residue was redissolved in 20 ml of MeOH. TEA (10 mmol, 1.5 ml) was added and the mixture was heated to 65° C. for 3 hr. Then the reaction was cooled to room temperature and the solvents removed to yield the crude product which was purificated by means of silica gel flash chromatography (AcOEt/MeOH/NH3 Aq. 85:15:05) to yield the title compound as a white powder (258 mg, 0.45 mmol, 45%).

1. customSolvents were evaporated
2. customto obtain a yellow powder
3. temperaturecooled at −20° C
4. additionwas then added dropwise in 15′
5. waitThe reaction mixture was kept at −20° C. for 6 hours
6. temperatureto raise at room temperature overnight
7. customThe reaction was quenched with 15 mL of NaHCO3 5%
8. extractionextracted twice with AcOEt (15 ml)
9. customSolvents were then evaporated
10. dissolutionthe residue was redissolved in 20 ml of MeOH
11. temperaturethe mixture was heated to 65° C. for 3 hr
12. temperatureThen the reaction was cooled to room temperature
13. customthe solvents removed
14. customto yield the crude product which