Sodium 2-methylbutan-2-olate → N-(2,5-Difluoro-4-(morpholinomethyl)phenyl)-5-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine

HRID 1924019Notes

Reaction equation

HRID 1924019 reaction equation
[F:1][C:2]1[C:3]([C:9]2[N:13]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:12]([CH3:20])=[N:11][CH:10]=2)=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.Br[C:22]1[C:34]([F:35])=[CH:33][C:25]([CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[C:24]([F:36])[CH:23]=1.CCC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[F:35][C:34]1[CH:33]=[C:25]([CH2:26][N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)[C:24]([F:36])=[CH:23][C:22]=1[NH:8][C:5]1[N:4]=[C:3]([C:9]2[N:13]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:12]([CH3:20])=[N:11][CH:10]=2)[C:2]([F:1])=[CH:7][N:6]=1

Participants

7

Reactant 3

HCID 2733478Sodium 2-methylbutan-2-olateHCID 166654985-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amineHCID 595438614-(4-Bromo-2,5-difluorobenzyl)morpholine

Product 1

HCID 49781787N-(2,5-Difluoro-4-(morpholinomethyl)phenyl)-5-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amineYield 64.3%

Reagents, catalysts & solvents 3

HCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)CatalystHCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 1140TolueneSolvent

Conditions

Temperature
110 °C

Procedure

5-Fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (0.876 g, 3.16 mmol), 4-(4-bromo-2,5-difluorobenzyl)morpholine (0.923 g, 3.16 mmol), Sodium tert-pentoxide (0.696 g, 6.32 mmol, (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (0.026 g, 0.03 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.018 g, 0.03 mmol) in toluene (10 mL) were mixed and degassed. The mixture was stirred at 110° C. under a nitrogen atmosphere overnight. The mixture was concentrated. Dichloromethane and water was added and the phases were separated. The organic phase was concentrated and the crude was purified by prep HPLC. The pooled fractions were concentrated to about half volume and the residue was extracted with EtOAc (×2). The organic phases were concentrated and the residue was dried under vacuum at 40° C. over a weekend to give the title compound (0.992 g, 64%) as a solid.

Workup

  1. customdegassed
  2. concentrationThe mixture was concentrated
  3. additionDichloromethane and water was added
  4. customthe phases were separated
  5. concentrationThe organic phase was concentrated
  6. customthe crude was purified by prep HPLC
  7. concentrationThe pooled fractions were concentrated to about half volume
  8. extractionthe residue was extracted with EtOAc (×2)
  9. concentrationThe organic phases were concentrated
  10. customthe residue was dried under vacuum at 40° C. over a weekend

Sources & evidence

ORD record
ord-d6c389ecaf0240e7823f10878351043c
Source dataset
uspto-grants-2012_05
Patent number
US08178529B2

Reaction notes

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