Potassium Carbonate → 5-(5-(3-Amino-4-fluoro-1-(pyridin-4-yl)-1H-isoindol-1-yl)-2-fluorophenyl)nicotinonitrile

HRID 1662247Notes

Reaction equation

HRID 1662247 reaction equation
[C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:8]=1)#[N:2].Br[C:19]1[CH:20]=[C:21]([C:26]2([C:37]3[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=3)[C:34]3[C:29](=[C:30]([F:35])[CH:31]=[CH:32][CH:33]=3)[C:28]([NH2:36])=[N:27]2)[CH:22]=[CH:23][C:24]=1[F:25].C(=O)([O-])[O-].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C>[NH2:36][C:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])[C:26]([C:21]2[CH:20]=[CH:19][C:24]([F:25])=[C:23]([C:7]3[CH:6]=[N:5][CH:4]=[C:3]([CH:8]=3)[C:1]#[N:2])[CH:22]=2)([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)[N:27]=1

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 164142165-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile3×HCID 585794771-(3-Bromo-4-fluorophenyl)-4-fluoro-1-(pyridin-4-yl)-1H-isoindol-3-amine

Product 1

HCID 462069765-(5-(3-Amino-4-fluoro-1-(pyridin-4-yl)-1H-isoindol-1-yl)-2-fluorophenyl)nicotinonitrileYield 8.1%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)Catalyst3×HCID 6228DimethylformamideSolvent

Procedure

3-Cyanopyridine-5-boronic acid pinacol ester (58.1 mg, 0.25 mmol), 1-(3-bromo-4-fluorophenyl)-4-fluoro-1-(pyridin-4-yl)-1H-isoindol-3-amine (67.4 mg, 0.17 mmol), [1,1′-bis (diphenylphosphino)ferrocene]palladium(II) chloride (6.88 mg, 8.42 μmol), 2 M aqueous potassium carbonate (0.253 mL, 0.51 mmol) and DMF (2.00 mL) were put in a microwave vial and irradiated in a microwave oven at 110° C. for 20 min. Additional 3-cyanopyridine-5-boronic acid pinacol ester (25.2 mg, 0.11 mmol) and [1,1′-bis (diphenylphosphino)ferrocene]palladium(II) chloride (6.88 mg, 8.42 μmol) were added and the resulting mixture was irradiated at 110° C. for 30 min. Additional 3-cyanopyridine-5-boronic acid pinacol ester (25.2 mg, 0.11 mmol) and [1,1′-bis (diphenylphosphino)ferrocene]palladium(II) chloride (6.88 mg, 8.42 μmol) were added and the resulting mixture was irradiated at 110° C. for 30 min. The product was purified by preparative HPLC. The desired fractions were pooled and concentrated in vacuo. The residue was partitioned between water and ethyl acetate (×3). The organic layer was collected, dried (Na2SO4), filtered and concentrated in vacuo. The residue was redissolved in methanol and concentrated in vacuo three times to give the title compound 5.80 mg, (7.4% yield).

Workup

  1. customirradiated in a microwave oven at 110° C. for 20 min
  2. customthe resulting mixture was irradiated at 110° C. for 30 min
  3. customthe resulting mixture was irradiated at 110° C. for 30 min
  4. customThe product was purified by preparative HPLC
  5. concentrationconcentrated in vacuo
  6. customThe residue was partitioned between water and ethyl acetate (×3)
  7. customThe organic layer was collected
  8. dry with materialdried (Na2SO4)
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. dissolutionThe residue was redissolved in methanol
  12. concentrationconcentrated in vacuo three times

Sources & evidence

ORD record
ord-dd6a6988ad2f44b087675a08d2f6c159
Source dataset
uspto-grants-2011_10
Patent number
US08030500B2

Reaction notes

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