Potassium Carbonate → (3R)-3-ethyl-1-(2-((2-methyl-1,3-thiazol-5-yl)amino)pyrimidin-4-yl)-2-oxopyrrolidine-3-carbonitrile hydrochloride

HRID 714888Notes

Reaction equation

HRID 714888 reaction equation
[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@:10]([CH2:15][CH3:16])([C:13]#[N:14])[C:9]2=[O:17])[CH:5]=[CH:4][N:3]=1.[CH3:18][C:19]1[S:20][C:21]([NH2:24])=[CH:22][N:23]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C(O)(C)(C)C.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:1].[CH2:15]([C@:10]1([C:13]#[N:14])[CH2:11][CH2:12][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:24][C:21]3[S:20][C:19]([CH3:18])=[N:23][CH:22]=3)[N:7]=2)[C:9]1=[O:17])[CH3:16]

Participants

7

Reactant 4

HCID 11430Potassium CarbonateHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 208298802-Methyl-1,3-thiazol-5-amineHCID 117840665(3R)-1-(2-chloropyrimidin-4-yl)-3-ethyl-2-oxopyrrolidine-3-carbonitrile

Product 1

HCID 117840893(3R)-3-ethyl-1-(2-((2-methyl-1,3-thiazol-5-yl)amino)pyrimidin-4-yl)-2-oxopyrrolidine-3-carbonitrile hydrochlorideYield 10.3%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 6386tert-ButanolSolvent

Procedure

To a mixture of (3R)-1-(2-chloropyrimidin-4-yl)-3-ethyl-2-oxopyrrolidine-3-carbonitrile (100 mg) obtained in Step A of Example 8, 2-methyl-1,3-thiazol-5-amine (56 mg), potassium carbonate (110 mg) and dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (58 mg) in tert-butanol (1.0 mL) was added tris(dibenzylideneacetone)dipalladium(0) (22 mg), and the mixture was stirred for 5 hr with heated under reflux. 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 (hexane/ethyl acetate). To a solution of the obtained compound (26 mg) in ethanol (2.0 mL) was added 1 M hydrochloric acid (80 μL), and the mixture was stirred at room temperature for 5 min. The solvent was evaporated under reduced pressure, and the residue was recrystallized (ethanol) to give the title compound (15 mg).

Workup

  1. temperaturewith heated
  2. temperatureunder reflux
  3. customThe insoluble substance was removed by filtration through Celite
  4. customthe solvent was evaporated under reduced pressure
  5. customThe residue was purified by silica gel column chromatography (hexane/ethyl acetate)
  6. additionTo a solution of the obtained compound (26 mg) in ethanol (2.0 mL) was added 1 M hydrochloric acid (80 μL)
  7. stirringthe mixture was stirred at room temperature for 5 min
  8. customThe solvent was evaporated under reduced pressure
  9. customthe residue was recrystallized (ethanol)

Sources & evidence

ORD record
ord-1d052eeb7c8e491db6e905342eba5eea
Source dataset
uspto-grants-2015_11
Patent number
US09187453B2

Reaction notes

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