Binap, (A+-)- → 4-({2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methoxypyrimidin-4-yl}amino)pyridine-3-carbonitrile

HRID 1776428Notes

Reaction equation

HRID 1776428 reaction equation
[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[N:19]=[C:18]([NH2:20])[C:17]([O:21][CH3:22])=[CH:16][N:15]=2)=[N:6]1.Br[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][C:29]=1[C:34]#[N:35].C1(C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C(=CC=CC=2)C=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[Na+]>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].CN(C)C=O>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[N:19]=[C:18]([NH:20][C:28]3[CH:33]=[CH:32][N:31]=[CH:30][C:29]=3[C:34]#[N:35])[C:17]([O:21][CH3:22])=[CH:16][N:15]=2)=[N:6]1

Participants

7

Reactant 4

HCID 634876Binap, (A+-)-HCID 223295224-Bromopyridine-3-carbonitrileHCID 23676156Sodium t-butoxideHCID 867324252-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methoxypyrimidin-4-amine

Product 1

HCID 867324544-({2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methoxypyrimidin-4-yl}amino)pyridine-3-carbonitrile

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 6228DimethylformamideSolvent

Procedure

175 mg of 2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methoxypyrimidin-4-amine (1-11-1, 0.501 mmol, 1. eq.), 101 mg of 4-bromopyridine-3-carbonitrile (0.551 mmol, 1.1 eq.), 115 mg of Tris(dibenzylideneacetone)dipalladium (0) (0.125 mmol, 0.25 eq.), 156 mg of 1,1′-binaphthalene-2,2′-diylbis(diphenylphosphane) (0.25 mmol, 0.5 eq), 144 mg of sodium 2-methylpropan-2-olate (97%) (1.503 mmol, 3 eq.) and 52 ml of N,N-dimethylformamide were stirred under nitrogen atmosphere for 30 minutes at 100° C. and 300 W in a CEM microwave. The reaction mixture was washed with half-saturated aqueous sodium chloride solution. The organic layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (hexane/dichloromethane/methanol) and preparative HPLC. A crystallisation from dichloromethane/methanol gave 5.8 mg (0.01 mmol, 2.6%) of the analytically pure target compound.

Workup

  1. washThe reaction mixture was washed with half-saturated aqueous sodium chloride solution
  2. extractionThe organic layer was extracted twice with ethyl acetate
  3. washThe combined organic layers were washed with brine
  4. dry with materialdried over sodium sulfate
  5. concentrationconcentrated in vacuo
  6. customThe residue was purified by flash chromatography (hexane/dichloromethane/methanol) and preparative HPLC
  7. customA crystallisation from dichloromethane/methanol
  8. customgave 5.8 mg (0.01 mmol, 2.6%) of the analytically pure target compound

Sources & evidence

ORD record
ord-e5ed52edc03240d4961df295345bb194
Source dataset
uspto-grants-2016_02
Patent number
US09265763B2

Reaction notes

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