Binap, (A+-)- → US10266548, Example 27-1

HRID 1776431Notes

Reaction equation

HRID 1776431 reaction equation
[CH3:1][O:2][C:3]1[C:4]([NH2:27])=[N:5][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[N:10]=2)=[N:7][CH:8]=1.Br[C:29]1[CH:34]=[CH:33][N:32]=[CH:31][C:30]=1[C:35]([F:38])([F:37])[F:36].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>[CH3:1][O:2][C:3]1[C:4]([NH:27][C:29]2[CH:34]=[CH:33][N:32]=[CH:31][C:30]=2[C:35]([F:38])([F:37])[F:36])=[N:5][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[N:10]=2)=[N:7][CH:8]=1

Participants

7

Reactant 4

HCID 634876Binap, (A+-)-HCID 234369684-Bromo-3-(trifluoromethyl)pyridineHCID 23676156Sodium t-butoxideHCID 867324165-methoxy-2-[1-(4-methoxybenzyl)-1H-indazol-3-yl]pyrimidin-4-amine

Product 1

HCID 86732457US10266548, Example 27-1

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 6228DimethylformamideSolvent

Procedure

1 g of 5-methoxy-2-[1-(4-methoxybenzyl)-1H-indazol-3-yl]pyrimidin-4-amine (1-4-1, 2.77 mmol, 1. eq.), 938 mg of 4-bromo-3-(trifluoromethyl)pyridine (4.15 mmol, 1.5 eq.), 127 mg of Tris(dibenzylideneacetone)dipalladium (0) (0.138 mmol, 0.05 eq.), 345 mg of 1,1′-binaphthalene-2,2′-diylbis(diphenylphosphane) (0.553 mmol, 0.2 eq), 1.06 g of sodium 2-methylpropan-2-olate (97%) (11.1 mmol, 4 eq.) and 15 ml of N,N-dimethylformamide were stirred under nitrogen atmosphere for 24 hours at 100° C. bath temperature in a pressure pipe. The reaction mixture was washed with half-saturated aqueous ammonium chloride solution. The organic layer was extracted three times with dichloromethane. The combined organic layers were washed with brine and dried over magnesium sulfate and concentrated in vacuo. The residue was purified twice by flash chromatography (hexane/ethyl acetate/methanol) and preparative TLC. A crystallisation gave 56.9 mg (0.1 mmol, 3.73%) of the analytically pure target compound.

Workup

  1. washThe reaction mixture was washed with half-saturated aqueous ammonium chloride solution
  2. extractionThe organic layer was extracted three times with dichloromethane
  3. washThe combined organic layers were washed with brine
  4. dry with materialdried over magnesium sulfate
  5. concentrationconcentrated in vacuo
  6. customThe residue was purified twice by flash chromatography (hexane/ethyl acetate/methanol) and preparative TLC
  7. customA crystallisation
  8. customgave 56.9 mg (0.1 mmol, 3.73%) of the analytically pure target compound

Sources & evidence

ORD record
ord-d0ca400a3b864cdc84cb77e0006784aa
Source dataset
uspto-grants-2016_02
Patent number
US09265763B2

Reaction notes

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