Cesium carbonate → 3,5-Dichloro-4-[4-(2,6-dimethylpyrimidin-4-ylamino)pyrazolo[4,3-c]pyridin-2-yl]benzonitrile

HRID 626689Notes

Reaction equation

HRID 626689 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:20])[C:9]=1[N:10]1[CH:19]=[C:13]2[C:14](Cl)=[N:15][CH:16]=[CH:17][C:12]2=[N:11]1)[C:5]#[N:6].[NH2:21][C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([CH3:29])[N:23]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)[O:51]C2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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(#N)C>[OH-:51].[NH4+:6].[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:20])[C:9]=1[N:10]1[CH:19]=[C:13]2[C:14]([NH:21][C:22]3[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([CH3:29])[N:23]=3)=[N:15][CH:16]=[CH:17][C:12]2=[N:11]1)[C:5]#[N:6]

Participants

10

Reactant 4

HCID 10796Cesium carbonateHCID 680392,6-Dimethyl-4-aminopyrimidineHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 866970463,5-Dichloro-4-(4-chloropyrazolo[4,3-c]pyridin-2-yl)benzonitrile

Product 2

HCID 14923Ammonium HydroxideYield 0.1%HCID 696715893,5-Dichloro-4-[4-(2,6-dimethylpyrimidin-4-ylamino)pyrazolo[4,3-c]pyridin-2-yl]benzonitrileYield 268.1%

Reagents, catalysts & solvents 4

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 6342AcetonitrileSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

A suspension of 3,5-dichloro-4-(4-chloropyrazolo[4,3-c]pyridin-2-yl)benzonitrile (65 mg, 0.20 mmol), 4-amino-2,6-dimethylpyrimidine (27 mg, 0.22 mmol), Pd2(dba)3 (5 mg, 0.005 mmol), Xantphos (12 mg, 0.02 mmol) and cesium carbonate (91 mg, 0.28 mmol) in dioxane (2 mL) was sealed in a reaction vial, purged with nitrogen, and heated at 90° C. for 18 hours. The reaction mixture was cooled, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (30-100% ethyl acetate in cyclohexane), then by HPLC (gradient: 25 to 98% acetonitrile in water with 0.1% ammonium hydroxide), to afford the title compound as a white solid (22 mg, 27% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.41 (d, J=0.9 Hz, 1H), 8.51 (s, 2H), 8.08 (d, J=6.9 Hz, 1H), 7.67 (s, 1H), 7.54 (dd, J=6.9, 1.0 Hz, 1H), 2.73 (s, 3H), 2.58 (s, 3H). LCMS (Method B): RT=3.00 min, m/z: 410.15 [M+H+].

Workup

  1. customwas sealed in a reaction vial
  2. custompurged with nitrogen
  3. temperatureThe reaction mixture was cooled
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customThe residue was purified by silica gel flash chromatography (30-100% ethyl acetate in cyclohexane)

Sources & evidence

ORD record
ord-3d8faa150e7040c88e0e100047ffdfaf
Source dataset
uspto-grants-2016_04
Patent number
US09309240B2

Reaction notes

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