Cesium carbonate → 3-Chloro-2-{7-fluoro-4-[6-(1-hydroxyethyl)-pyrimidin-4-ylamino]-pyrazolo[4,3-c]pyridin-2-yl}-benzonitrile

HRID 626757Notes

Reaction equation

HRID 626757 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.[NH2:21][C:22]1[N:27]=[CH:26][N:25]=[C:24]([CH:28]([OH:30])[CH3:29])[CH:23]=1.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]>[Cl:19][C:18]1[C:11]([N:9]2[CH:8]=[C:7]3[C:2]([NH:21][C:22]4[CH:23]=[C:24]([CH:28]([OH:30])[CH3:29])[N:25]=[CH:26][N:27]=4)=[N:3][CH:4]=[C:5]([F:20])[C:6]3=[N:10]2)=[C:12]([CH:15]=[CH:16][CH:17]=1)[C:13]#[N:14]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 696711341-(6-Aminopyrimidin-4-yl)-ethanolHCID 866970642-(4-Bromo-7-fluoropyrazolo[4,3-c]pyridin-2-yl)-3-chlorobenzonitrile

Product 1

HCID 696714003-Chloro-2-{7-fluoro-4-[6-(1-hydroxyethyl)-pyrimidin-4-ylamino]-pyrazolo[4,3-c]pyridin-2-yl}-benzonitrileYield 25%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
150 °C

Procedure

A mixture of 2-(4-bromo-7-fluoropyrazolo[4,3-c]pyridin-2-yl)-3-chlorobenzonitrile (211 mg, 0.61 mmol), 1-(6-aminopyrimidin-4-yl)-ethanol (92 mg, 0.66 mmol), Pd2(dba)3 (14 mg, 0.015 mmol), Xantphos (35 mg, 0.06 mmol) and cesium carbonate (391 mg, 1.2 mmol) in dioxane (4.0 mL) was de-gassed and purged with nitrogen and the reaction mixture was heated at 150° C. in the microwave for 30 minutes. 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 (ethyl acetate) to afford the title compound as a beige solid (61 mg, 25% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.84 (s, 1H), 9.47 (d, J=2.5 Hz, 1H), 8.72 (d, J=1.2 Hz, 1H), 8.59 (s, 1H), 8.24-8.21 (m, 2H), 8.02 (d, J=3.5 Hz, 1H), 7.90 (t, J=8.1 Hz, 1H), 5.54 (d, J=4.6 Hz, 1H), 4.70-4.63 (m, 1H), 1.39 (d, J=6.6 Hz, 3H). LCMS (Method B): RT=2.92 min, m/z: 410 [M+H+].

Workup

  1. customwas de-gassed
  2. custompurged with nitrogen
  3. customThe resultant mixture was partitioned between ethyl acetate and water
  4. customThe layers were separated
  5. washthe organic layer was washed with brine
  6. dry with materialdried over anhydrous sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customThe residue was purified by silica gel flash chromatography (ethyl acetate)

Sources & evidence

ORD record
ord-bd13ade94ced4e87945fa9d7ba23b684
Source dataset
uspto-grants-2016_04
Patent number
US09309240B2

Reaction notes

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