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

HRID 62531ノート

反応式

HRID 62531 の反応式
[Cl:1][C:2]1[CH:9]=[CH:8][C:5](C#N)=[C:4]([NH:10][C:11]2[C:16]([Cl:17])=[CH:15][N:14]=[C:13](Cl)[CH:12]=2)[CH:3]=1.[CH3:19][C:20]1[CH:24]=[C:23]([NH2:25])[N:22]([CH:26]([CH3:28])[CH3:27])[N:21]=1.[C:29](=[O:32])([O-])[O-:30].[Cs+].[Cs+].C1C=CC(P(C2C(OC3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=CC=3)=CC=CC=2)C2C=CC=CC=2)=CC=1.[OH-].[Na+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:29]([OH:30])=[O:32])=[C:4]([NH:10][C:11]2[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([NH:25][C:23]3[N:22]([CH:26]([CH3:28])[CH3:27])[N:21]=[C:20]([CH3:19])[CH:24]=3)[CH:12]=2)[CH:3]=1

参加物

8

反応物 5

HCID 10796Cesium carbonateHCID 14798Sodium HydroxideHCID 1210181-Isopropyl-3-methyl-1H-pyrazol-5-amineHCID 4285986Bis[2-(diphenylphosphino)phenyl] etherHCID 575169164-Chloro-2-[(2,5-dichloro-4-pyridinyl)amino]benzonitrile

生成物 1

HCID 667692534-Chloro-2-[(5-chloro-2-{[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]amino}-4-pyridinyl)amino]benzoic acid収率 6.6%

試薬・触媒・溶媒 2

HCID 167845palladium(II) acetate触媒HCID 312751,4-Dioxane溶媒

実験手順

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]+.

後処理

  1. additionwere added
  2. temperaturethe suspension was refluxed overnight
  3. filtrationThe solid was filtered
  4. customthe reaction mixture was evaporated
  5. customThe black oil was purified
  6. customby flush column chromatography on silica gel (5% EtOAc:DCM)
  7. customThe combined fractions were evaporated
  8. dissolutionThe resulting oil was dissolved in dioxane (20 mL)
  9. temperaturethe reaction mixture was refluxed overnight
  10. customThe layers were separated
  11. washthe organic layer was washed with 20 ml of 1 M NaOH
  12. washwashed with EtOAc
  13. washThe combined organic layers were washed with water, brine
  14. dry with materialdried over MgSO4
  15. filtrationfiltered
  16. customThe solution was evaporated
  17. filtrationfiltered

出典と根拠

ORDレコード
ord-91c325cc551249b8be6b8a74a6c314ad
出典データセット
uspto-grants-2016_09
特許番号
US09446034B2

反応ノート

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