Cesium carbonate → (3S)-3-cyclopropyl-1-(2-((1-(1-(hydroxymethyl)cyclopropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-oxopyrrolidine-3-carbonitrile

HRID 714843Notes

Reaction equation

HRID 714843 reaction equation
Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@:10]([CH:15]3[CH2:17][CH2:16]3)([C:13]#[N:14])[C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[N:22][N:23]([C:25]2([CH2:28][OH:29])[CH2:27][CH2:26]2)[CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])O.[Na+]>O1CCCC1.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.C(#N)C>[CH:15]1([C@:10]2([C:13]#[N:14])[CH2:11][CH2:12][N:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:19][C:20]4[CH:21]=[N:22][N:23]([C:25]5([CH2:28][OH:29])[CH2:26][CH2:27]5)[CH:24]=4)[N:7]=3)[C:9]2=[O:18])[CH2:17][CH2:16]1

Participants

9

Reactant 5

HCID 10796Cesium carbonateHCID 516892Sodium BicarbonateHCID 634876Binap, (A+-)-HCID 91618623(1-(4-amino-1H-pyrazol-1-yl)cyclopropyl)methanolHCID 117840203(3S)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile

Product 1

HCID 71766894(3S)-3-cyclopropyl-1-(2-((1-(1-(hydroxymethyl)cyclopropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-oxopyrrolidine-3-carbonitrileYield 24.6%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8028TetrahydrofuranSolventHCID 18373917Acetonitrile--water (1/1)Solvent

Conditions

Temperature
90 °C

Procedure

To a solution of (3S)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile (200 mg) obtained in Step E of Example 103, (1-(4-amino-1H-pyrazol-1-yl)cyclopropyl)methanol (120 mg) obtained in Step C of Example 128, cesium carbonate (500 mg) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (71 mg) in tetrahydrofuran (10 mL) was added tris(dibenzylideneacetone)dipalladium(0) (70 mg), and the mixture was stirred at 90° C. for 10 hr under argon atmosphere. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate). The obtained crude product was subjected to HPLC (C18, mobile phase: water/acetonitrile (containing 5 mM AcONH4), to the obtained fraction was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized (ethyl acetate/diisopropyl ether) to give the title compound (71 mg).

Workup

  1. customThe solvent was evaporated under reduced pressure
  2. customthe residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate)
  3. customThe obtained crude product
  4. extractionthe mixture was extracted with ethyl acetate
  5. dry with materialThe extract was dried over anhydrous magnesium sulfate
  6. concentrationconcentrated under reduced pressure
  7. customThe residue was recrystallized (ethyl acetate/diisopropyl ether)

Sources & evidence

ORD record
ord-3bae1e8940e84fa2856d2f03a3f3b19b
Source dataset
uspto-grants-2015_11
Patent number
US09187453B2

Reaction notes

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