Potassium Carbonate → (4S,6S)-4-(5-amino-2-fluoropyridin-3-yl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine

HRID 930370Notes

Reaction equation

HRID 930370 reaction equation
Br[C:2]1[CH:3]=[C:4]([C@:9]2([CH2:20][F:21])[CH2:14][C@@H:13]([C:15]([F:18])([F:17])[F:16])[O:12][C:11]([NH2:19])=[N:10]2)[C:5]([F:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)C([NH2:32])=O.CN[C@@H]1CCCC[C@H]1NC>[Cu]I.CO.O.O1CCOCC1>[NH2:32][C:2]1[CH:3]=[C:4]([C@:9]2([CH2:20][F:21])[CH2:14][C@@H:13]([C:15]([F:18])([F:17])[F:16])[O:12][C:11]([NH2:19])=[N:10]2)[C:5]([F:8])=[N:6][CH:7]=1

Participants

8

Reactant 4

HCID 11430Potassium CarbonateHCID 67717TrifluoroacetamideHCID 2733821trans-N,N'-dimethyl-1,2-cyclohexanediamineHCID 86732196(4S,6S)-4-(5-bromo-2-fluoropyridin-3-yl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine

Product 1

HCID 86732195(4S,6S)-4-(5-amino-2-fluoropyridin-3-yl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amineYield 80.4%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 312751,4-DioxaneSolventHCID 22242641Methanol--water (1/1)Solvent

Conditions

Temperature
120 °C

Procedure

In a microwave tube was added (4S,6S)-4-(5-bromo-2-fluoropyridin-3-yl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (0.90 g, 2.406 mmol), potassium carbonate (1.330 g, 9.62 mmol) and copper(I) iodide (0.092 g, 0.481 mmol), 2,2,2-trifluoroacetamide (0.544 g, 4.81 mmol) and molecular sieves. The vial was purged with nitrogen followed by addition of dioxane 15 mL and trans-N,N′-dimethyl-1,2-cyclohexanediamine (0.152 ml, 0.962 mmol). The vial was sealed and heated at 120° C. for 2.5 h. To this mixture were added MeOH/water (8/4 mL) and the resulting mixture was heated at 80° C. for 3 h. The mixture was extracted with methylene chloride. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography on silica gel using a gradient of 0-5% 2M NH3 in MeOH/methylene chloride to afford (4S,6S)-4-(5-amino-2-fluoropyridin-3-yl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (0.60 g, 1.934 mmol, 80% yield). MS m/z=311.0 [M+H]+. Calculated for C11H11F5N4O: 310.2.

Workup

  1. customThe vial was purged with nitrogen
  2. customThe vial was sealed
  3. temperaturethe resulting mixture was heated at 80° C. for 3 h
  4. extractionThe mixture was extracted with methylene chloride
  5. dry with materialThe combined organic layers were dried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe crude material was purified by column chromatography on silica gel using a gradient of 0-5% 2M NH3 in MeOH/methylene chloride

Sources & evidence

ORD record
ord-fd328a6e810d4958819bc0557e042800
Source dataset
uspto-grants-2016_03
Patent number
US09296734B2

Reaction notes

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