Reacción #90809

Ecuación de reacción

DPEPhos

4-chloro-2-[(2,5-dichloro-4-pyridinyl)amino]benzonitrile

3-methyl-1-(1-methylethyl)-1H-pyrazol-5-amine

cesium carbonate

sodium hydroxide

→

4-Chloro-2-[(5-chloro-2-{[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]amino}-4-pyridinyl)amino]benzoic acid

Rendimiento 6.6%

Disolventes

1,4-dioxane

Condiciones de reacción

Tratamiento posterior

1. 1
   workup.ADDITIONwere added
2. 2
   Temperaturathe suspension was refluxed overnight
3. 3
   FiltraciónThe solid was filtered
4. 4
   Otrothe reaction mixture was evaporated
5. 5
   OtroThe black oil was purified
6. 6
   Otroby flush column chromatography on silica gel (5% EtOAc:DCM)
7. 7
   OtroThe combined fractions were evaporated
8. 8
   workup.DISSOLUTIONThe resulting oil was dissolved in dioxane (20 mL)
9. 9
   Temperaturathe reaction mixture was refluxed overnight
10. 10
    OtroThe layers were separated
11. 11
    Lavadothe organic layer was washed with 20 ml of 1 M NaOH
12. 12
    Lavadowashed with EtOAc
13. 13
    LavadoThe combined organic layers were washed with water, brine
14. 14
    Secadodried over MgSO4
15. 15
    Filtraciónfiltered
16. 16
    OtroThe solution was evaporated
17. 17
    Filtraciónfiltered

Procedimiento

A solution of 4-chloro-2-[(2,5-dichloro-4-pyridinyl)amino]benzonitrile (2.8 g, 9.38 mmol), 3-methyl-1-(1-methylethyl)-1H-pyrazol-5-amine (1.305 g, 9.38 mmol) and cesium carbonate (9.17 g, 28.1 mmol) in 1,4-dioxane (40 mL) was degassed. DPEPhos (0.404 g, 0.750 mmol) followed by palladium acetate (0.084 g, 0.375 mmol) were added, and the suspension was refluxed overnight. The solid was filtered, the reaction mixture was evaporated. The black oil was purified by flush column chromatography on silica gel (5% EtOAc:DCM). The combined fractions were evaporated. The resulting oil was dissolved in dioxane (20 mL) and sodium hydroxide (20 mL, 20.00 mmol) was added and the reaction mixture was refluxed overnight. The layers were separated and the organic layer was washed with 20 ml of 1 M NaOH. The aqueous layers were combined and washed with EtOAc. The combined organic layers were washed with water, brine and dried over MgSO4 and filtered. The solution was evaporated, suspended in acetonitrile and filtered. 4-Chloro-2-[(5-chloro-2-{[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]amino}-4-pyridinyl)amino]benzoic acid (260 mg, 0.619 mmol, 6.60% yield) was isolated as a yellow solid. 1H NMR (400 MHz, DMSO-d6) ppm 1.28 (d, J=6.57 Hz, 6 H) 1.91 (s, 1 H) 2.13 (s, 3 H) 4.43 (quin, J=6.57 Hz, 1 H) 5.97 (s, 1 H) 6.78 (s, 1 H) 7.05 (dd, J=8.46, 1.89 Hz, 1 H) 7.48 (d, J=1.77 Hz, 1 H) 7.96 (d, J=8.34 Hz, 1 H) 8.03 (s, 1 H) 8.61 (s, 1H); HPLC Rt=2.70 min, MS (ESI): 420.1, 422.0 [M+H]+.

Fuente