Potassium Carbonate → (3S,5S)-3-cyclopropyl-1-(2-((1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-5-methyl-2-oxopyrrolidine-3-carbonitrile hydrochloride

HRID 714911Notes

Reaction equation

HRID 714911 reaction equation
[CH:1]1([C@:4]2([C:11]#[N:12])[CH2:8][C@H:7]([CH3:9])[NH:6][C:5]2=[O:10])[CH2:3][CH2:2]1.[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]2[CH:22]=[N:23][N:24]([C:26]([CH3:30])([CH3:29])[CH2:27][OH:28])[CH:25]=2)[N:15]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[ClH:13].[CH:1]1([C@:4]2([C:11]#[N:12])[CH2:8][C@H:7]([CH3:9])[N:6]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]4[CH:22]=[N:23][N:24]([C:26]([CH3:30])([CH3:29])[CH2:27][OH:28])[CH:25]=4)[N:15]=3)[C:5]2=[O:10])[CH2:2][CH2:3]1

Participants

7

Reactant 4

HCID 11430Potassium CarbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 1178401582-(4-((4-chloropyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-2-methylpropan-1-olHCID 117840409(3S,5S)-3-cyclopropyl-5-methyl-2-oxo-pyrrolidine-3-carbonitrile

Product 1

HCID 117840974(3S,5S)-3-cyclopropyl-1-(2-((1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-5-methyl-2-oxopyrrolidine-3-carbonitrile hydrochlorideYield 20.1%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
85 °C

Procedure

To a mixture of (3S,5S)-3-cyclopropyl-5-methyl-2-oxopyrrolidine-3-carbonitrile (150 mg) obtained in Step B of Example 358, 2-(4-((4-chloropyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-2-methylpropan-1-ol (200 mg) obtained in Step E of Example 347, potassium carbonate (210 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (26 mg) in toluene (2.0 mL) was added tris(dibenzylideneacetone)dipalladium(0) (14 mg), and the mixture was stirred overnight at 85° C. The insoluble substance was removed by filtration through Celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate), and to a solution of the residue (200 mg) in ethanol (2.0 mL) was added 1 M hydrochloric acid (0.51 mL). The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized (diisopropyl ether/ethyl acetate) to give the title compound (65 mg).

Workup

  1. customThe insoluble substance was removed by filtration through Celite
  2. customthe solvent was evaporated under reduced pressure
  3. customThe residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate)
  4. additionto a solution of the residue (200 mg) in ethanol (2.0 mL) was added 1 M hydrochloric acid (0.51 mL)
  5. concentrationThe reaction mixture was concentrated under reduced pressure
  6. customthe residue was recrystallized (diisopropyl ether/ethyl acetate)

Sources & evidence

ORD record
ord-540368aea634455bb0a34cabb81a959f
Source dataset
uspto-grants-2015_11
Patent number
US09187453B2

Reaction notes

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