Potassium Phosphate, Tribasic → 3-Amino-6-(4-((2-methoxyethoxy)-methoxy)-3-(trifluoromethyl)phenyl)-4-(methylamino)picolinonitrile

HRID 517944Notes

Reaction equation

HRID 517944 reaction equation
[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][C:9]=1[C:23]([F:26])([F:25])[F:24].[NH2:27][C:28]1[C:29]([C:37]#[N:38])=[N:30][C:31](Cl)=[CH:32][C:33]=1[NH:34][CH3:35].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CCOC(C)=O.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(Cl)Cl.O.O1CCOCC1>[NH2:27][C:28]1[C:29]([C:37]#[N:38])=[N:30][C:31]([C:11]2[CH:12]=[CH:13][C:8]([O:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[C:9]([C:23]([F:24])([F:25])[F:26])[CH:10]=2)=[CH:32][C:33]=1[NH:34][CH3:35]

Participants

10

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 75806TricyclohexylphosphineHCID 576575713-Amino-6-chloro-4-methylamino-pyridine-2-carbonitrileHCID 672941552-(4-((2-Methoxyethoxy)methoxy)-3-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Product 1

HCID 672942413-Amino-6-(4-((2-methoxyethoxy)-methoxy)-3-(trifluoromethyl)phenyl)-4-(methylamino)picolinonitrileYield 28%

Reagents, catalysts & solvents 5

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
110 °C

Procedure

2-(4-((2-Methoxyethoxy)methoxy)-3-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.83 g), 3-amino-6-chloro-4-(methylamino)-picolinonitrile (1.55 g), tris(dibenzylideneacetone)dipalladium (0) (0.389 g), tricyclohexylphosphine (0.286 g) and potassium phosphate (3.60 g) were charged to a 100 ml flask. Dioxane (30 ml) and water (12 ml) were added and the mixture placed under a nitrogen atmosphere. The reaction was heated to 110° C. for 3 hours and allowed to stand at room temperature for 2 hours. The mixture was diluted with EtOAc (200 ml) filtered through celite, washed with water (3×200 ml), dried over sodium sulphate and then solvent was evaporated under reduced pressure to yield crude product as a brown oil. DCM was added to the residue causing a pale brown solid to crash out of solution. The mixture was filtered and the solid washed with a small amount of DCM followed by ether to afford 3-amino-6-(4-((2-methoxyethoxy)-methoxy)-3-(trifluoromethyl)phenyl)-4-(methylamino)picolinonitrile (28% yield). The liquors were purified by flash chromatography (340 g silica column; 2:1, 1:1, 0:1 heptane/EtOAc mobile phase) to afford further 3-amino-6-(4-((2-methoxyethoxy)-methoxy)-3-(trifluoromethyl)phenyl)-4-(methylamino)picolinonitrile (49% yield).

Workup

  1. filtrationfiltered through celite
  2. washwashed with water (3×200 ml)
  3. dry with materialdried over sodium sulphate
  4. customsolvent was evaporated under reduced pressure
  5. customto yield crude product as a brown oil
  6. filtrationThe mixture was filtered
  7. washthe solid washed with a small amount of DCM

Sources & evidence

ORD record
ord-37025f90d9154601a7786641f0cc1558
Source dataset
uspto-grants-2015_08
Patent number
US09115126B2

Reaction notes

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