Cesium carbonate → 3-{6-[2-(2-Chloro-6-cyanophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridin-4-ylamino]-pyridin-3-yl}-azetidine-1-carboxylic acid tert-butyl ester

HRID 626761Notes

Reaction equation

HRID 626761 reaction equation
Br[C:2]1[C:7]2=[CH:8][N:9]([C:11]3[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:12]=3[C:13]#[N:14])[N:10]=[C:6]2[C:5]([F:20])=[CH:4][N:3]=1.[C:21]([O:25][C:26]([N:28]1[CH2:31][CH:30]([C:32]2[CH:33]=[N:34][C:35]([NH2:38])=[CH:36][CH:37]=2)[CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>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]>[C:21]([O:25][C:26]([N:28]1[CH2:29][CH:30]([C:32]2[CH:33]=[N:34][C:35]([NH:38][C:2]3[C:7]4=[CH:8][N:9]([C:11]5[C:12]([C:13]#[N:14])=[CH:15][CH:16]=[CH:17][C:18]=5[Cl:19])[N:10]=[C:6]4[C:5]([F:20])=[CH:4][N:3]=3)=[CH:36][CH:37]=2)[CH2:31]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 58044110HCID 58044110, compoundHCID 866970642-(4-Bromo-7-fluoropyrazolo[4,3-c]pyridin-2-yl)-3-chlorobenzonitrile

Product 1

HCID 696749593-{6-[2-(2-Chloro-6-cyanophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridin-4-ylamino]-pyridin-3-yl}-azetidine-1-carboxylic acid tert-butyl esterYield 64.1%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
80 °C

Procedure

A mixture of 2-(4-bromo-7-fluoropyrazolo[4,3-c]pyridin-2-yl)-3-chlorobenzonitrile (106 mg, 0.3 mmol), 3-(6-aminopyridin-3-yl)-azetidine-1-carboxylic acid tert-butyl ester (57 mg, 0.35 mmol), Pd2(dba)3 (7 mg, 0.0075 mmol), Xantphos (17 mg, 0.03 mmol) and cesium carbonate (196 mg, 0.6 mmol) in dioxane (3.0 mL) was degassed and purged with nitrogen. The reaction mixture was heated at 80° C. overnight. After cooling to room temperature, the resultant mixture was partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (50-60% ethyl acetate in cyclohexane) to afford the title compound as a brown solid (100 mg, 64% yield). LCMS (Method C): RT=2.54 min, m/z: 520 [M+H+].

Workup

  1. customwas degassed
  2. custompurged with nitrogen
  3. temperatureAfter cooling to room temperature
  4. customthe resultant mixture was partitioned between ethyl acetate and water
  5. customThe layers were separated
  6. washthe organic layer was washed with brine
  7. dry with materialdried over anhydrous sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure
  10. customThe residue was purified by silica gel flash chromatography (50-60% ethyl acetate in cyclohexane)

Sources & evidence

ORD record
ord-95ebeda07fc54d1a95430146ee79e568
Source dataset
uspto-grants-2016_04
Patent number
US09309240B2

Reaction notes

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