Hydrochloric Acid → (1R*,2R*,5R*)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-8-(2-hydroxyethyl)-1-phenyl-8-azabicyclo[3.2.1]octane hydrochloride

HRID 2088162Notes

Reaction equation

HRID 2088162 reaction equation
[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[NH:22][C@@:16]2([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17][CH2:18]3)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:38][CH2:39][OH:40].[ClH:41]>CN(C)C=O.C(OCC)C.O>[ClH:41].[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[N:22]([CH2:38][CH2:39][OH:40])[C@@:16]2([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:17][CH2:18]3)[CH:4]=[C:3]([C:2]([F:29])([F:1])[F:30])[CH:8]=1

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 108982-Bromoethanol2×HCID 11430Potassium CarbonateHCID 86586647(1R*,2R*,5R*)-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octane

Product 1

HCID 86586695(1R*,2R*,5R*)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-8-(2-hydroxyethyl)-1-phenyl-8-azabicyclo[3.2.1]octane hydrochloride

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 3283Diethyl EtherSolventHCID 6228DimethylformamideSolvent

Procedure

(1R*,2R*,5R*)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octane (Example 60; 345 mg, 0.80 mmol) was dissolved in dimethylformamide (3 ml) and potassium carbonate (331 mg, 2.40 mmol) added. This was stirred for 5 minutes at room temperature then 2-bromoethanol (0.086 ml, 1.21 mmol) added and the reaction mixture heated for 5 days at 60° C. Only a small amount of starting material had converted to product so a further 25 equivalents of 2-bromoethanol (1.42 ml, 20 mmol) was added and the temperature increased to 80° C. overnight. The reaction mixture was poured into water and extracted with ethyl acetate (×3), dried (MgSO4) and concentrated in vacuo to give a brown oil. This was purified by flash column chromatography [5%-20% ethyl acetate in iso-hexane] to give a yellow oil and the hydrochloride salt was made by adding 1 equivalent of hydrogen chloride in diethyl ether (1N). The title compound was filtered off and dried at 60° C. in vacuo.

Workup

  1. temperaturethe reaction mixture heated for 5 days at 60° C
  2. additionwas added
  3. temperaturethe temperature increased to 80° C. overnight
  4. extractionextracted with ethyl acetate (×3)
  5. dry with materialdried (MgSO4)
  6. concentrationconcentrated in vacuo
  7. customto give a brown oil
  8. customThis was purified by flash column chromatography [5%-20% ethyl acetate in iso-hexane]
  9. customto give a yellow oil
  10. filtrationThe title compound was filtered off
  11. customdried at 60° C. in vacuo

Sources & evidence

ORD record
ord-4fe1e5f0d1ed41f6a1ca3f50cf30ae84
Source dataset
uspto-grants-2004_04
Patent number
US06727249B2

Reaction notes

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