Cesium carbonate → 4-[7-Bromo-4-(6-methyl-pyrimidin-4-ylamino)-pyrazolo[4,3-c]pyridin-2-yl]-3,5-dichlorobenzonitrile

HRID 626728Notes

Reaction equation

HRID 626728 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:21])[C:9]=1[N:10]1[CH:20]=[C:13]2[C:14](Br)=[N:15][CH:16]=[C:17]([Br:18])[C:12]2=[N:11]1)[C:5]#[N:6].[CH3:22][C:23]1[N:28]=[CH:27][N:26]=[C:25]([NH2:29])[CH:24]=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].C(OCC)(=O)C>[Br:18][C:17]1[C:12]2[C:13](=[CH:20][N:10]([C:9]3[C:2]([Cl:1])=[CH:3][C:4]([C:5]#[N:6])=[CH:7][C:8]=3[Cl:21])[N:11]=2)[C:14]([NH:29][C:25]2[CH:24]=[C:23]([CH3:22])[N:28]=[CH:27][N:26]=2)=[N:15][CH:16]=1

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 5728526-Methylpyrimidin-4-amineHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 866970583,5-Dichloro-4-(4,7-dibromo-pyrazolo[4,3-c]pyridin-2-yl)-benzonitrile

Product 1

HCID 696714794-[7-Bromo-4-(6-methyl-pyrimidin-4-ylamino)-pyrazolo[4,3-c]pyridin-2-yl]-3,5-dichlorobenzonitrileYield 57%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

A suspension of 3,5-dichloro-4-(4,7-dibromo-pyrazolo[4,3-c]pyridin-2-yl)-benzonitrile (70 mg, 0.16 mmol), 6-methylpyrimidin-4-ylamine (18 mg, 0.17 mmol), Pd2(dba)3 (7 mg, 0.008 mmol), Xantphos (9 mg, 0.016 mmol) and cesium carbonate (104 mg, 0.31 mmol) in dioxane (3 mL) was sealed in a microwave vial, purged with nitrogen, and heated at 90° C. for 3.5 hours. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant residue was purified by silica gel flash chromatography (0-100% ethyl acetate in cyclohexane), then futher triturated with diethyl ether then ethyl acetate to afford the title compound as a white solid (42 mg, 57% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.90 (s, 1H), 9.35 (s, 1H), 8.71 (d, J=1.2 Hz, 1H), 8.50 (s, 2H), 8.37 (s, 1H), 8.17 (s, 1H), 2.45 (s, 3H). LCMS (Method B): RT=3.75 min, m/z: 476 [M+H+].

Workup

  1. customwas sealed in a microwave vial
  2. custompurged with nitrogen
  3. temperatureThe reaction mixture was cooled
  4. custompartitioned between ethyl acetate and water
  5. dry with materialThe organic layer was dried over anhydrous sodium sulfate
  6. concentrationconcentrated under reduced pressure
  7. customThe resultant residue was purified by silica gel flash chromatography (0-100% ethyl acetate in cyclohexane)
  8. customfuther triturated with diethyl ether

Sources & evidence

ORD record
ord-2f98c649246c4da9a7f5843b3340379d
Source dataset
uspto-grants-2016_04
Patent number
US09309240B2

Reaction notes

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