Cesium carbonate → (R)-2-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-5-(4-(methylsulfonyl)benzyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine

HRID 1631791Notes

Reaction equation

HRID 1631791 reaction equation
Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[CH2:7][C@@H:6]3[CH2:23][O:24][CH2:25][CH2:26][N:5]3[C:4]=2[N:3]=1.[F:27][CH:28]([F:38])[C:29]1[NH:33][C:32]2[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=2[N:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>CN(C=O)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].O.CCOC(C)=O>[F:38][CH:28]([F:27])[C:29]1[N:30]([C:2]2[N:11]=[CH:10][C:9]3[N:8]([CH2:12][C:13]4[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=4)[CH2:7][C@@H:6]4[CH2:23][O:24][CH2:25][CH2:26][N:5]4[C:4]=3[N:3]=2)[C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=1

Participants

9

Reactant 4

HCID 10796Cesium carbonateHCID 5977032-(difluoromethyl)-1H-1,3-benzodiazoleHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl2×HCID 86670093(R)-2-chloro-5-(4-(methylsulfonyl)benzyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine

Product 1

HCID 60196760(R)-2-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-5-(4-(methylsulfonyl)benzyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridineYield 21.4%

Reagents, catalysts & solvents 4

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst2×HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
130 °C

Procedure

A mixture of (R)-2-chloro-5-(4-(methylsulfonyl)benzyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x10 50 mg, 0.127 mmol), 2-(difluoromethyl)-1H-benzo[d]imidazole (21.29 mg, 0.127 mmol), cesium carbonate (61.9 mg, 0.190 mmol), tris(dibenzylideneacetone)dipalladium(0) (4.64 mg, 5.06 μmol) and 2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl (4.83 mg, 10.13 μmol) in DMF 253 μL was heated to 130° C. in a microwave for 40 minutes. Additional tris(dibenzylideneacetone)dipalladium(0) (4.64 mg, 5.06 μmol) and 2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl (4.83 mg, 10.13 μmol) were added, and the reaction mixture was heated to 130° C. in a microwave for 1 hour. EtOAc and water were added and the mixture was filtered through Celite and extracted with EtOAc (2×). The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2—NH2, 30-100% EtOAc/hexane gradient) to afford the title compound as a yellow solid (14.3 mg, 21.4%). 1H NMR (400 MHz, CDCl3) δ 3.08 (s, 3H), 3.19-3.38 (m, 4H), 3.68 (td, J=12.00, 2.78 Hz, 1H), 3.83-3.92 (m, 1H), 3.94-4.02 (m, 1H), 4.11-4.20 (m, 1H), 4.44-4.63 (m, 3H), 7.36-7.75 (m, 6H), 7.93-8.01 (m, 3H), 8.17-8.23 (m, 1H). ESI-MS m/z [M+H]+ calc'd for C25H24F2N6O3S, 527.16. found 527.3.

Workup

  1. temperaturethe reaction mixture was heated to 130° C. in a microwave for 1 hour
  2. filtrationthe mixture was filtered through Celite
  3. extractionextracted with EtOAc (2×)
  4. washThe combined extracts were washed with brine
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe residue was purified by column chromatography (SiO2—NH2, 30-100% EtOAc/hexane gradient)

Sources & evidence

ORD record
ord-4c90442da097460e892eac867ce9329b
Source dataset
uspto-grants-2014_07
Patent number
US08791107B2

Reaction notes

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