Dimethyl Sulfoxide → 7-[4-Nitro-3-(trifluoromethyl)phenyl]-7-azabicyclo[2.2.1]heptane

HRID 400984Notes

Reaction equation

HRID 400984 reaction equation
F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].CS(C)=O.Cl.[CH:26]12[NH:32][CH:29]([CH2:30][CH2:31]1)[CH2:28][CH2:27]2>CCOC(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:32]2[CH:26]3[CH2:31][CH2:30][CH:29]2[CH2:28][CH2:27]3)=[CH:3][C:4]=1[C:11]([F:14])([F:13])[F:12])([O-:10])=[O:9]

Participants

6

Reactant 4

HCID 679Dimethyl SulfoxideHCID 10340Sodium CarbonateHCID 2230945-Fluoro-2-nitrobenzotrifluorideHCID 162795037-Azabicyclo[2.2.1]heptane hydrochloride

Product 1

HCID 575168437-[4-Nitro-3-(trifluoromethyl)phenyl]-7-azabicyclo[2.2.1]heptane

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
55 °C

Procedure

4-fluoro-1-nitro-2-(trifluoromethyl)benzene (8) (901 g, 4.309 mol) was introduced into a 30 L jacketed vessel, along with sodium carbonate (959.1 g, 9.049 mol) and DMSO (5 L, 5.5 vol) under nitrogen atmosphere, with stirring. 7-azabicyclo[2.2.1]heptane hydrochloride (9) (633.4 g, 4.740 mol) was then added to the vessel in portions, and the temperature was gradually raised to 55° C. The reaction was monitored by HPLC, and when the substrate was <1% AUC, the reaction was considered complete. The mixture was then diluted with 10 vol EtOAc and washed with water (5.5 vol) three times. The organic layer was then concentrated to 4 vol and cyclohexane was added and concentrated to 4 vol. The process of adding cyclohexane and concentrating the resulting solution to 4 vol was repeated until all the EtOAc was removed, and the total volume in the flask was about 4 vol containing cyclohexane. The reaction mixture was heated to 60° C. on a rotary evaporator for 30 min. The solution was then cooled to room temperature with stirring or rotation for 3 h. All the solid then crystallized, and was concentrated to dryness to provid 7-[4-nitro-3-(trifluoromethyl)phenyl]-7-azabicyclo[2.2.1]heptane (10A).

Workup

  1. washwashed with water (5.5 vol) three times
  2. concentrationThe organic layer was then concentrated to 4 vol and cyclohexane
  3. additionwas added
  4. concentrationconcentrated to 4
  5. concentrationThe process of adding cyclohexane and concentrating the resulting solution to 4 vol
  6. customwas removed
  7. additioncontaining cyclohexane
  8. temperatureThe reaction mixture was heated to 60° C. on a rotary evaporator for 30 min
  9. temperatureThe solution was then cooled to room temperature
  10. customAll the solid then crystallized
  11. concentrationwas concentrated to dryness

Sources & evidence

ORD record
ord-e07a2163bb714970a35cda65d02c0346
Source dataset
uspto-grants-2014_06
Patent number
US08741922B2

Reaction notes

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