Реакция #90809

Уравнение реакции

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

Выход 6.6%

Растворители

1,4-dioxane

Условия реакции

Обработка

1. 1
   workup.ADDITIONwere added
2. 2
   Температураthe suspension was refluxed overnight
3. 3
   ФильтрацияThe solid was filtered
4. 4
   Другоеthe reaction mixture was evaporated
5. 5
   ДругоеThe black oil was purified
6. 6
   Другоеby flush column chromatography on silica gel (5% EtOAc:DCM)
7. 7
   ДругоеThe combined fractions were evaporated
8. 8
   workup.DISSOLUTIONThe resulting oil was dissolved in dioxane (20 mL)
9. 9
   Температураthe reaction mixture was refluxed overnight
10. 10
    ДругоеThe layers were separated
11. 11
    Промывкаthe organic layer was washed with 20 ml of 1 M NaOH
12. 12
    Промывкаwashed with EtOAc
13. 13
    ПромывкаThe combined organic layers were washed with water, brine
14. 14
    Сушкаdried over MgSO4
15. 15
    Фильтрацияfiltered
16. 16
    ДругоеThe solution was evaporated
17. 17
    Фильтрацияfiltered

Методика

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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