反应详情

A solution of 5-(5-chloro-2-difluoromethoxyphenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-4-ylamine (60.0 g, 154 mmol) in THF (100 mL) was added dropwise over 30 minutes to an ice/water cooled mixture of pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (27.8 g, 153 mmol), and DIPEA (49.5 g, 383 mmol) in THF (300 mL). On complete addition the mixture was left to stir at room temperature for 1 hour. The solvent was evaporated and the residue diluted with 0.5 N aqueous HCl and extracted with ethyl acetate. The combined organic extract was passed through Celite® to remove the residual solid and the filtrate washed with 1M aqueous K2CO3, water and brine, dried (Na2SO4) and evaporated to give a red solid. The solid was triturated with 10% diethyl ether in cyclohexane. The solid was collected by filtration, washed with 1:1 diethyl ether in cyclohexane and left to air dry to afford pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [5-(5-chloro-2-difluoromethoxyphenyl)-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazol-4-yl]amide as an off-white solid (59.2 g, 73%). 1H NMR (300 MHz, CDCl3): δ (ppm) 9.61 (s, 1H), 8.77-8.78 (m, 1H), 8.51 (dd, 1H), 8.36 (s, 1H), 7.65 (d, 1H), 7.52 (dd, 1H), 7.36 (d, 1H), 7.29 (s, 1H), 7.01 (dd, 1H), 6.42 (t, 1H), 5.39-5.41 (m, 2H), 3.60-3.64 (m, 2H), 0.87-0.89 (m, 2H), 0.09 (s, 9H).

1. temperaturecooled
2. additionOn complete addition the mixture
3. waitwas left
4. customThe solvent was evaporated
5. additionthe residue diluted with 0.5 N aqueous HCl
6. extractionextracted with ethyl acetate
7. extractionThe combined organic extract
8. customto remove the residual solid
9. washthe filtrate washed with 1M aqueous K2CO3, water and brine
10. dry with materialdried (Na2SO4)
11. customevaporated
12. customto give a red solid
13. customThe solid was triturated with 10% diethyl ether in cyclohexane
14. filtrationThe solid was collected by filtration
15. washwashed with 1:1 diethyl ether in cyclohexane
16. waitleft to air
17. customdry