반응 #90809

반응 방정식

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

수율 6.6%

용매

1,4-dioxane

반응 조건

후처리

1. 1
   workup.ADDITIONwere added
2. 2
   온도the suspension was refluxed overnight
3. 3
   여과The solid was filtered
4. 4
   기타the reaction mixture was evaporated
5. 5
   기타The black oil was purified
6. 6
   기타by flush column chromatography on silica gel (5% EtOAc:DCM)
7. 7
   기타The combined fractions were evaporated
8. 8
   workup.DISSOLUTIONThe resulting oil was dissolved in dioxane (20 mL)
9. 9
   온도the reaction mixture was refluxed overnight
10. 10
    기타The layers were separated
11. 11
    세척the organic layer was washed with 20 ml of 1 M NaOH
12. 12
    세척washed with EtOAc
13. 13
    세척The combined organic layers were washed with water, brine
14. 14
    건조dried over MgSO4
15. 15
    여과filtered
16. 16
    기타The solution was evaporated
17. 17
    여과filtered

실험 절차

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]+.

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