1,2-Dimethoxyethane → tert-butyl (1R*,3S,4R*,5S)-5-fluoro-3-[6-(5-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylate

HRID 1409053Notes

Reaction equation

HRID 1409053 reaction equation
Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([C@@H:12]3[C@H:17]4[CH2:18][C@H:14]([CH2:15][C@@H:16]4[F:19])[N:13]3[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N:5][C:4]=2[CH:3]=1.[CH3:27][C:28]1[C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30](C(OC(C)(C)C)=O)[N:29]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[F:19][C@H:16]1[CH2:15][C@H:14]2[CH2:18][C@@H:17]1[C@@H:12]([C:6]1[NH:7][C:8](=[O:11])[C:9]3[S:10][C:2]([C:32]4[CH:31]=[N:30][NH:29][C:28]=4[CH3:27])=[CH:3][C:4]=3[N:5]=1)[N:13]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]

Participants

6

Reactant 4

HCID 80711,2-DimethoxyethaneHCID 10340Sodium CarbonateHCID 53216815Tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-YL)-1H-pyrazole-1-carboxylateHCID 136341380tert-Butyl (1R*,3S,4R*,5S)-3-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-5-fluoro-2-azabicyclo[2.2.1]heptane-2-carboxylate

Product 1

HCID 136341379tert-butyl (1R*,3S,4R*,5S)-5-fluoro-3-[6-(5-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylateYield 35.2%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
100 °C

Procedure

tert-Butyl (1R*,3S,4R*,5S)-3-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-5-fluoro-2-azabicyclo[2.2.1]heptane-2-carboxylate (300 mg) and tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (416 mg), sodium carbonate (215 mg), 1,2-dimethoxyethane (3.0 mL) and water (1.5 mL) were placed in a flask, and the atmosphere in the flask was purged with argon. [1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane complex (1:1) (55 mg) was added, and the atmosphere in the flask was purged again with argon. The reaction system was stirred at 100° C. for 3 hr, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained pale-yellow solid was purified by high performance liquid chromatography {column: L-column 2 ODS (20 mm i.d.×50 mm L), mobile phase: 0.1% aqueous trifluoroacetic acid solution/0.1% trifluoroacetic acid-acetonitrile solution}. The object fraction was neutralized with saturated aqueous sodium hydrogen carbonate, and the mixture was concentrated under reduced pressure. The residue was collected by filtration and washed with water (3 mL) to give the title compound (106 mg) as a colorless solid.

Workup

  1. customthe atmosphere in the flask was purged with argon
  2. addition[1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane complex (1:1) (55 mg) was added
  3. customthe atmosphere in the flask was purged again with argon
  4. concentrationconcentrated under reduced pressure
  5. customThe residue was purified by silica gel column chromatography (ethyl acetate/hexane)
  6. customthe obtained pale-yellow solid was purified by high performance liquid chromatography {column
  7. concentrationthe mixture was concentrated under reduced pressure
  8. filtrationThe residue was collected by filtration
  9. washwashed with water (3 mL)

Sources & evidence

ORD record
ord-268d9a5535154f0e8e1915132904a4c7
Source dataset
uspto-grants-2014_12
Patent number
US08921354B2

Reaction notes

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