Imidazole → (8R,10R)-8-((1H-Imidazol-1-yl)methyl)-10-(5-chlorofuran-2-yl)-5-(3-fluorophenyl)-1,3-dimethyl-7,8-dihydro-1H-pyrimido[4',5':3,4]pyrrolo[2,1-c][1,4]oxazine-2,4(3H,10H)-dione

HRID 624578Notes

Reaction equation

HRID 624578 reaction equation
CS(O[CH2:6][C@@H:7]1[O:12][CH:11]([C:13]2[O:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[C:10]2=[C:19]3[N:32]([CH3:33])[C:31](=[O:34])[N:30]([CH3:35])[C:29](=[O:36])[C:20]3=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[N:9]2[CH2:8]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:43]1[CH:47]=[CH:46][N:45]=[CH:44]1>C(#N)C.O>[N:43]1([CH2:6][C@@H:7]2[O:12][C@@H:11]([C:13]3[O:14][C:15]([Cl:18])=[CH:16][CH:17]=3)[C:10]3=[C:19]4[N:32]([CH3:33])[C:31](=[O:34])[N:30]([CH3:35])[C:29](=[O:36])[C:20]4=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[N:9]3[CH2:8]2)[CH:47]=[CH:46][N:45]=[CH:44]1

Participants

6

Reactant 3

HCID 795Imidazole2×HCID 10796Cesium carbonate2×HCID 86722903((8R)-10-(5-Chlorofuran-2-yl)-5-(3-fluorophenyl)-1,3-dimethyl-2,4-dioxo-2,3,4,7,8,10-hexahydro-1H-pyrimido[4',5':3,4]pyrrolo[2,1-c][1,4]oxazin-8-yl)methyl methanesulfonate

Product 1

HCID 90218895(8R,10R)-8-((1H-Imidazol-1-yl)methyl)-10-(5-chlorofuran-2-yl)-5-(3-fluorophenyl)-1,3-dimethyl-7,8-dihydro-1H-pyrimido[4',5':3,4]pyrrolo[2,1-c][1,4]oxazine-2,4(3H,10H)-dione

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of ((8R)-10-(5-chlorofuran-2-yl)-5-(3-fluorophenyl)-1,3-dimethyl-2,4-dioxo-2,3,4,7,8,10-hexahydro-1H-pyrimido[4′,5′:3,4]pyrrolo[2,1-c][1,4]oxazin-8-yl)methyl methanesulfonate (117 mg, 0.217 mmol), cesium carbonate (142 mg, 0.435 mmol) and imidazole (22.51 mg, 0.331 mmol) in acetonitrile (6 mL) was heated at 80° C. for 16 hours, then at 85° C. for 3.5 hours. Further portions of imidazole (22.51 mg, 0.331 mmol) and cesium carbonate (142 mg, 0.435 mmol) were added and the mixture heated for a further 2 hours. The mixture was cooled to room temperature, diluted with water (30 ml) and extracted with DCM (2×30 ml). The combined organic extracts were washed with brine (30 ml) passed through a hydrophobic frit and evaporated under vacuum. Purification by chromatography on silica, eluting with 0-100% EtOAc/hexane then with 0-10% MeOH/DCM, afforded the title compound as a mixture of diastereomers.

Workup

  1. temperaturethe mixture heated for a further 2 hours
  2. temperatureThe mixture was cooled to room temperature
  3. extractionextracted with DCM (2×30 ml)
  4. washThe combined organic extracts were washed with brine (30 ml)
  5. customevaporated under vacuum
  6. customPurification by chromatography on silica
  7. washeluting with 0-100% EtOAc/hexane

Sources & evidence

ORD record
ord-4640150bface46b7822d1b5353851bd3
Source dataset
uspto-grants-2016_04
Patent number
US09303035B2

Reaction notes

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