Dimethylformamide → 5-(3-Amino-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-1-yl)-2-methoxybenzonitrile

HRID 1662262Notes

Reaction equation

HRID 1662262 reaction equation
Cl[C:2]1[CH:3]=[C:4]([C:10]2([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:28]=[N:29][CH:30]=[N:31][CH:32]=4)[CH:22]=3)[C:18]3[C:13](=[C:14]([F:19])[CH:15]=[CH:16][CH:17]=3)[C:12]([NH2:20])=[N:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[CH3:62][N:63](C=O)C>[C-]#N.[Zn+2].[C-]#N.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].O>[NH2:20][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([CH:3]=2)[C:62]#[N:63])([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]3[CH:28]=[N:29][CH:30]=[N:31][CH:32]=3)[CH:22]=2)[N:11]=1

Participants

7

Reactant 3

HCID 6228DimethylformamideHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 585795171-(3-Chloro-4-methoxyphenyl)-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine

Product 1

HCID 462027425-(3-Amino-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-1-yl)-2-methoxybenzonitrileYield 45%

Reagents, catalysts & solvents 3

HCID 11186Zinc cyanide (Zn(CN)2)CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolvent

Conditions

Temperature
160 °C

Procedure

1-(3-Chloro-4-methoxyphenyl)-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine (190 mg, 0.43 mmol), zinc cyanide (0.024 mL, 0.38 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (52.6 mg, 0.13 mmol), tris(dibenzylideneacetone)dipalladium(0) (58.7 mg, 0.06 mmol), DMF (5 mL) and a drop of water were added into a vial and heated in a microwave reactor for 1 h at 160° C. The mixture was filtered, diluted with MeOH and purified by preparative HPLC. The fractions containing the desired product were pooled and the MeCN removed in vacuo. The resulting aqueous residue was diluted with saturated aqueous NaHCO3 and extracted with DCM. The combined organics were passed through a phase separator (Sorbent), concentrated and dried in vacuum oven at 40° C. over night, to afford 85 mg (45%) of the title compound.

Workup

  1. filtrationThe mixture was filtered
  2. additiondiluted with MeOH
  3. custompurified by preparative HPLC
  4. additionThe fractions containing the desired product
  5. customthe MeCN removed in vacuo
  6. additionThe resulting aqueous residue was diluted with saturated aqueous NaHCO3
  7. extractionextracted with DCM
  8. concentrationconcentrated
  9. customdried in vacuum oven at 40° C. over night

Sources & evidence

ORD record
ord-59a95533886a47c0829a6dbf14501d76
Source dataset
uspto-grants-2011_10
Patent number
US08030500B2

Reaction notes

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