反应详情

温度

125 °C

A solution of 3-amino-5-(trifluoromethyl)benzonitrile (0.075 g, 0.40 mmol) in DMA (1 mL) was placed in a 1-dram vial with a teflon-lined septum cap, and the solvent was purged with argon. 15A (0.100 g, 0.269 mmol), cesium carbonate (0.351 g, 1.076 mmol), copper (I) iodide (0.026 g, 0.134 mmol), Xantphos (0.031 g, 0.054 mmol), and Pd2(dba)3 (0.025 g, 0.027 mmol) were added in one portion, and the suspension was pump/purged three times with argon. The vessel was heated to 125° C. for 45 min. and then cooled to room temperature. The solids were removed via filtration through CELITE® and washed with THF. The filtrate was concentrated under reduced pressure and diluted with water and EtOAc. The layers were separated, and the aqueous phase extracted with EtOAc (3×10 mL). The organics were combined, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was dissolved in DCM and purified by flash chromatography (SiO2, hexanes to 40% EtOAc/hexanes, 12 g column, 30 mL/min., 20 min. gradient, monitoring at 254 nm). The fractions were concentrated, dissolved in DCM (1 mL) and treated with triethylsilane (0.430 mL, 2.7 mmol) and TFA (0.3 mL) at room temperature. After 20 minutes, the volatiles were removed via a stream of nitrogen, and the residue was triturated with MeOH. The solid was isolated via filtration, suspended in 1:1 1N HCl/MeCN, and lyophilized overnight, furnishing Example 15, (0.080 g, 0.181 mmol, 67.3% yield) as a gray solid. HPLC: Rt=4.160 min. (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min. gradient, monitored at 220 nm). MS (ES): m/z=402.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.98 (1H, s), 8.52 (1H, s), 8.25 (1H, s), 8.20 (1H, s), 7.82 (1H, s), 7.68 (1H, s), 5.99 (1H, s), 3.54-3.62 (2H, m), 3.40-3.52 (2H, m), 3.30 (3H, s).

1. customcap
2. customthe solvent was purged with argon
3. customthe suspension was pump/purged three times with argon
4. temperaturecooled to room temperature
5. customThe solids were removed via filtration through CELITE®
6. washwashed with THF
7. concentrationThe filtrate was concentrated under reduced pressure
8. additiondiluted with water and EtOAc
9. customThe layers were separated
10. extractionthe aqueous phase extracted with EtOAc (3×10 mL)
11. washwashed with water and brine
12. dry with materialdried over anhydrous sodium sulfate
13. filtrationfiltered
14. concentrationconcentrated
15. dissolutionThe crude product was dissolved in DCM
16. custompurified by flash chromatography (SiO2, hexanes to 40% EtOAc/hexanes, 12 g column, 30 mL/min., 20 min. gradient, monitoring at 254 nm)
17. concentrationThe fractions were concentrated
18. dissolutiondissolved in DCM (1 mL)
19. customthe volatiles were removed via a stream of nitrogen
20. customthe residue was triturated with MeOH
21. customThe solid was isolated via filtration
22. waitlyophilized overnight
23. customfurnishing Example 15, (0.080 g, 0.181 mmol, 67.3% yield) as a gray solid