反应详情

The solution of 2-[(2,5-dichloro-4-pyridinyl)amino]benzonitrile (110 g, 396 mmol), 3-methyl-1-(1-methylethyl)-1H-pyrazol-5-amine (55.1 g, 396 mmol), and cesium carbonate (387 g, 1187 mmol) in 1,4-dioxane (2.5 L) was degassed by N2 stream, and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (19.71 g, 31.7 mmol) followed by palladium acetate (3.55 g, 15.83 mmol) were added. The reaction mixture was heated to reflux for overnight under N2. The reaction mixture was filtered and the liquid was concentrated. Ethyl acetate (1500 mL), followed by 1 M HCl (1000 mL) were added. Layers were separated. Ethyl acetate was washed with 1 M HCl until no product was observed by HPLC (1000 mL total, 1×). HCl phases were combined, and backwashed with ethyl acetate (3×1000 mL), until the product peak was relativity pure in the HCL layer. The HCl layer was then basified with NaOH (50 w/w followed by 1 M) to ph˜4 resulting in a cloudy solution. Ethyl acetate (2000 mL) was added and layers were separated. The ethyl acetate was washed with brine and evaporated. After neutralization—after addition of ethyl acetate—the reaction mixture was filtered to get some product. Also isolation of product during evaporation can be done by filtration of white solid, which comes from the mother liquor. All solids and evaporated products were combined. 2-[(5-Chloro-2-{[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]amino}-4-pyridinyl)amino]benzonitrile (80 g, 207 mmol, 52.4% yield) was isolated as a yellow solid. 1H NMR (400 MHz, DMSO-d6) ppm 1.24 (d, J=6.57 Hz, 6 H) 2.08 (s, 3 H) 4.34 (quin, J=6.57 Hz, 1 H) 5.87 (s, 1 H) 5.97 (s, 1 H) 7.41 (td, J=7.58, 1.01 Hz, 1 H) 7.47 (d, J=8.08 Hz, 1 H) 7.75 (td, J=7.83, 1.52 Hz, 1 H) 7.90 (dd, J=7.83, 1.52 Hz, 1 H) 7.94 (s, 1 H) 8.42 (d, J=17.43 Hz, 2 H); HPLC Rt=2.36 min, MS (ESI): [M+H]+=367.1, 368.1.

1. additionwere added
2. temperatureThe reaction mixture was heated
3. temperatureto reflux for overnight under N2
4. filtrationThe reaction mixture was filtered
5. concentrationthe liquid was concentrated
6. additionwere added
7. customLayers were separated
8. washEthyl acetate was washed with 1 M HCl until no product
9. customresulting in a cloudy solution
10. customlayers were separated
11. washThe ethyl acetate was washed with brine
12. customevaporated
13. additionAfter neutralization—after addition of ethyl acetate—the reaction mixture
14. filtrationwas filtered
15. customto get some product
16. customAlso isolation of product during evaporation
17. filtrationcan be done by filtration of white solid, which
18. customAll solids and evaporated products