Cesium carbonate → 1,1-Dimethylethyl (3S)-3-({[7-(1-ethyl-1H-pyrazol-4-yl)-1,6-naphthyridin-5-yl]oxy}methyl)-3-fluoro-1-piperidinecarboxylate

HRID 473324Notes

Reaction equation

HRID 473324 reaction equation
Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([O:12][CH2:13][C@:14]2([F:27])[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]2)[N:3]=1.[CH2:28]([N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1)[CH3:29].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:28]([N:30]1[CH:34]=[C:33]([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[N:9]3)=[C:4]([O:12][CH2:13][C@:14]3([F:27])[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]3)[N:3]=2)[CH:32]=[N:31]1)[CH3:29]

Participants

8

Reactant 3

HCID 10796Cesium carbonateHCID 113790451-Ethyl-1H-pyrazole-4-boronic acid, pinacol esterHCID 866768021,1-Dimethylethyl (3S)-3-{[(7-chloro-1,6-naphthyridin-5-yl)oxy]methyl}-3-fluoro-1-piperidinecarboxylate

Product 1

HCID 682098821,1-Dimethylethyl (3S)-3-({[7-(1-ethyl-1H-pyrazol-4-yl)-1,6-naphthyridin-5-yl]oxy}methyl)-3-fluoro-1-piperidinecarboxylateYield 86.9%

Reagents, catalysts & solvents 4

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Procedure

A mixture of 1,1-dimethylethyl (3S)-3-{[(7-chloro-1,6-naphthyridin-5-yl)oxy]methyl}-3-fluoro-1-piperidinecarboxylate (1.1 g, 2.78 mmol), 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.679 g, 3.06 mmol) and caesium carbonate (2.263 g, 6.95 mmol) in 1,4-dioxane (16 ml) and water (3 ml) was degassed with nitrogen before adding tetrakis(triphenylphosphine)palladium (0) (0.096 g, 0.083 mmol). This was heated under reflux for 18 h. The reaction was partitioned between ethyl acetate and aqueous ammonium chloride. The aqueous was re-extracted with ethyl acetate and the combined organics were washed with brine, passed through a hydrophobic frit and concentrated in vacuo to give crude product. This was dissolved in DCM and purified through silica (20 g) eluting with a gradient of ethyl acetate in DCM. The product eluted in neat ethyl acetate. Appropriate fractions were combined and concentrated in vacuo to yield the title compound as a pinkish cream foam (1.10 g).

Workup

  1. customwas degassed with nitrogen
  2. temperatureThis was heated
  3. temperatureunder reflux for 18 h
  4. customThe reaction was partitioned between ethyl acetate and aqueous ammonium chloride
  5. extractionThe aqueous was re-extracted with ethyl acetate
  6. washthe combined organics were washed with brine
  7. concentrationconcentrated in vacuo
  8. customto give crude product
  9. custompurified through silica (20 g)
  10. washeluting with a gradient of ethyl acetate in DCM
  11. washThe product eluted in neat ethyl acetate
  12. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-a99d654c132d4e459e3a7336f15b883c
Source dataset
uspto-grants-2014_01
Patent number
US08633319B2

Reaction notes

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