Water → 1,1-Dimethylethyl (3R)-3-({[7-(1-ethyl-1H-pyrazol-4-yl)-1,6-naphthyridin-5-yl]amino}methyl)-3-fluoro-1-piperidinecarboxylate

HRID 473320Notes

Reaction equation

HRID 473320 reaction equation
C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([N:9]1[CH:13]=[C:12](B2OC(C)(C)C(C)(C)O2)[CH:11]=[N:10]1)[CH3:8].Cl[C:24]1[CH:33]=[C:32]2[C:27]([CH:28]=[CH:29][CH:30]=[N:31]2)=[C:26]([NH:34][CH2:35][C@:36]2([F:49])[CH2:41][CH2:40][CH2:39][N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37]2)[N:25]=1.O>O1CCOCC1.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]>[CH2:7]([N:9]1[CH:13]=[C:12]([C:24]2[CH:33]=[C:32]3[C:27]([CH:28]=[CH:29][CH:30]=[N:31]3)=[C:26]([NH:34][CH2:35][C@:36]3([F:49])[CH2:41][CH2:40][CH2:39][N:38]([C:42]([O:44][C:45]([CH3:47])([CH3:46])[CH3:48])=[O:43])[CH2:37]3)[N:25]=2)[CH:11]=[N:10]1)[CH3:8]

Participants

7

Reactant 4

HCID 962WaterHCID 10796Cesium carbonateHCID 113790451-Ethyl-1H-pyrazole-4-boronic acid, pinacol esterHCID 866768011,1-Dimethylethyl (3R)-3-{[(7-chloro-1,6-naphthyridin-5-yl)amino]methyl}-3-fluoro-1-piperidinecarboxylate

Product 1

HCID 682099441,1-Dimethylethyl (3R)-3-({[7-(1-ethyl-1H-pyrazol-4-yl)-1,6-naphthyridin-5-yl]amino}methyl)-3-fluoro-1-piperidinecarboxylate

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
150 °C

Procedure

To a 2-5 mL microwave vial under nitrogen was added caesium carbonate (990 mg, 3.04 mmol) and 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (292 mg, 1.317 mmol) (Boron Molecular). 1,1-Dimethylethyl (3R)-3-{[(7-chloro-1,6-naphthyridin-5-yl)amino]methyl}-3-fluoro-1-piperidinecarboxylate (400 mg, 1.013 mmol) was dissolved in 1,4-dioxane (4 ml) and water (0.8 ml) and added in one aliquot. Nitrogen was bubbled through the resultant suspension for ˜2 min. Tetrakis(triphenylphosphine)palladium (0) (117 mg, 0.101 mmol) was then added in one portion and nitrogen bubbled through the yellow suspension for a further ˜1 min. The microwave vial was sealed and heated at 150° C. in a microwave reactor for 1 h. LCMS showed the reaction had gone to completion. The reaction was partitioned between water (20 ml) and ethyl acetate (20 ml). The aqueous layer was further extracted with ethyl acetate (2×20 ml) and the combined organics washed with brine (10 ml). The organics were dried (Na2SO4) and concentrated in vacuo.

Workup

  1. customNitrogen was bubbled through the resultant suspension for ˜2 min
  2. custombubbled through the yellow suspension for a further ˜1 min
  3. customThe microwave vial was sealed
  4. customThe reaction was partitioned between water (20 ml) and ethyl acetate (20 ml)
  5. extractionThe aqueous layer was further extracted with ethyl acetate (2×20 ml)
  6. washthe combined organics washed with brine (10 ml)
  7. dry with materialThe organics were dried (Na2SO4)
  8. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-4e1d425754844e8a896a2d77e601e9e8
Source dataset
uspto-grants-2014_01
Patent number
US08633319B2

Reaction notes

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