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

HRID 1924018Notes

Reaction equation

HRID 1924018 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[CH:34]=[CH:33][C:25]([CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:24][C:23]=1[F:35].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: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]([NH:8][C:22]2[CH:34]=[CH:33][C:25]([CH2:26][N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)=[CH:24][C:23]=2[F:35])=[N:6][CH:7]=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 534178184-(4-Bromo-3-fluorobenzyl)morpholine

Product 1

HCID 497820135-Fluoro-N-(2-fluoro-4-(morpholinomethyl)phenyl)-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amineYield 61.5%

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 (5.12 g, 18.46 mmol), 4-(4-bromo-3-fluorobenzyl)morpholine (5.06 g, 18.46 mmol), (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (0.152 g, 0.18 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.107 g, 0.18 mmol) and sodium tert-pentoxide (4.07 g, 36.92 mmol) in toluene (70 mL) were mixed and degassed. The mixture was stirred at 110° C. under nitrogen atmosphere overnight. The mixture was concentrated. Dichloromethane and water were added and the phases were separated. The organic phase was concentrated and the crude was purified by preparative HPLC. The pooled fractions were concentrated to about half volume. The residue was extracted with EtOAc (×2). The combined organic phases were concentrated and the residue was dried in vacuo at 40° C. for 24 h to give the title compound (5.34 g, 61%) as a solid.

Workup

  1. customdegassed
  2. concentrationThe mixture was concentrated
  3. additionDichloromethane and water were added
  4. customthe phases were separated
  5. concentrationThe organic phase was concentrated
  6. customthe crude was purified by preparative HPLC
  7. concentrationThe pooled fractions were concentrated to about half volume
  8. extractionThe residue was extracted with EtOAc (×2)
  9. concentrationThe combined organic phases were concentrated
  10. customthe residue was dried in vacuo at 40° C. for 24 h

Sources & evidence

ORD record
ord-37c90a6330bd4999b8e17f210478eea1
Source dataset
uspto-grants-2012_05
Patent number
US08178529B2

Reaction notes

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