2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → N-(4-(((3S,5S)-3,5-Dimethylmorpholino)methyl)-2,5-difluorophenyl)-5-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine

HRID 1924023Notes

Reaction equation

HRID 1924023 reaction equation
Cl[C:2]1[C:16]([F:17])=[CH:15][C:5]([CH2:6][N:7]2[C@@H:12]([CH3:13])[CH2:11][O:10][CH2:9][C@@H:8]2[CH3:14])=[C:4]([F:18])[CH:3]=1.[F:19][C:20]1[C:21]([C:27]2[N:31]([CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:30]([CH3:38])=[N:29][CH:28]=2)=[N:22][C:23]([NH2:26])=[N:24][CH:25]=1.CC(C)([O-])C.[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.CN(C=O)C.ClCCl.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]>[CH3:13][C@@H:12]1[N:7]([CH2:6][C:5]2[C:4]([F:18])=[CH:3][C:2]([NH:26][C:23]3[N:22]=[C:21]([C:27]4[N:31]([CH:32]5[CH2:33][CH2:34][O:35][CH2:36][CH2:37]5)[C:30]([CH3:38])=[N:29][CH:28]=4)[C:20]([F:19])=[CH:25][N:24]=3)=[C:16]([F:17])[CH:15]=2)[C@@H:8]([CH3:14])[CH2:9][O:10][CH2:11]1

Participants

9

Reactant 4

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 166654985-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amineHCID 23665647Potassium tert-butoxideHCID 59543857HCID 59543857, compound

Product 1

HCID 49782014N-(4-(((3S,5S)-3,5-Dimethylmorpholino)methyl)-2,5-difluorophenyl)-5-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amineYield 7.2%

Reagents, catalysts & solvents 4

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
120 °C

Procedure

(3S,5S)-4-(4-Chloro-2,5-difluorobenzyl)-3,5-dimethylmorpholine (0.118 g, 0.43 mmol), 5-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (0.142 g, 0.51 mmol) and potassium tert-butoxide (0.058 g, 0.51 mmol) were mixed in dioxane (2 mL) and DMF (0.5 mL). Argon was bubbled through the mixture for 2 minutes. Pd2(dba)3 (0.047 g, 0.05 mmol) and X-Phos (0.049 g, 0.10 mmol) were added and the reaction mixture was heated in a microwave reactor at 120° C. for 40 minutes. The mixture was diluted with dichloromethane and was filtered though a plug of diatomaceous earth. The filter plug was washed with dichloromethane and methanol. The filtrate was concentrated and purified by preparative HPLC. The fractions containing product were pooled. NaHCO3 (aq) was added and the mixture was extracted with dichloromethane (×3). The combined organic phases were dried (MgSO4) and evaporated to give the title compound as a solid (16 mg, 7.2%).

Workup

  1. customArgon was bubbled through the mixture for 2 minutes
  2. filtrationwas filtered though a plug of diatomaceous earth
  3. washThe filter plug was washed with dichloromethane and methanol
  4. concentrationThe filtrate was concentrated
  5. custompurified by preparative HPLC
  6. additionThe fractions containing product
  7. additionNaHCO3 (aq) was added
  8. extractionthe mixture was extracted with dichloromethane (×3)
  9. dry with materialThe combined organic phases were dried (MgSO4)
  10. customevaporated

Sources & evidence

ORD record
ord-14a9c04549d341eb95905a153a89ec23
Source dataset
uspto-grants-2012_05
Patent number
US08178529B2

Reaction notes

Loading…