Acetic Acid → (1R*,2R*,5R*)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-1-(4-fluorophenyl)-8-azabicyclo[3.2.1]octane

HRID 2088137Notes

Reaction equation

HRID 2088137 reaction equation
C([N:8]1[C@@H:13]2[CH2:14][CH2:15][C@@:9]1([C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[C@H:10]([O:16][CH2:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=1)[CH2:11][CH2:12]2)C1C=CC=CC=1.C(O)(=O)C>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[F:31][C:28]([F:29])([F:30])[C:20]1[CH:19]=[C:18]([CH2:17][O:16][C@@H:10]2[CH2:11][CH2:12][C@@H:13]3[NH:8][C@@:9]2([C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[CH2:15][CH2:14]3)[CH:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=1

Participants

5

Reactant 2

HCID 176Acetic AcidHCID 86586658(1R*,2R*,5R*)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-(4-fluorophenyl)-8-azabicyclo[3.2.1]octane

Product 1

HCID 86586659(1R*,2R*,5R*)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-1-(4-fluorophenyl)-8-azabicyclo[3.2.1]octaneYield 40.2%

Reagents, catalysts & solvents 2

HCID 9942167Palladium hydroxideCatalystHCID 8857Ethyl AcetateSolvent

Procedure

(1R*,2R*,5R*)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-(4-fluorophenyl)-8-azabicyclo[3.2.1]octane (Example 17; 1.51 g, 2.81 mmol) was dissolved in ethyl acetate (20 ml) and glacial acetic acid (2 ml) and 10% palladium hydroxide (200 mg) added and hydrogenated at 45 psi overnight. The reaction mixture was filtered then concentrated in vacuo. The oil was basified (4N sodium hydroxide) and the solution extracted with ethyl acetate (×3). The organics were dried (MgSO4) and concentrated in vacuo. The mixture was purified by flash column chromatography [7.5% methanol in dichloromethane] to give a yellow oil which solidified on standing to give the title compound (506 mg, 40%). The hydrochloride salt was made by adding 1 equivalent of 1N hydrogen chloride in diethyl ether to the title compound (31 mg, 0.06 mmol). A white solid formed which was triturated in diethyl ether and filtered then dried at 60° C. in vacuo (29.8 mg, 89%).

Workup

  1. customhydrogenated at 45 psi overnight
  2. filtrationThe reaction mixture was filtered
  3. concentrationthen concentrated in vacuo
  4. extractionthe solution extracted with ethyl acetate (×3)
  5. dry with materialThe organics were dried (MgSO4)
  6. concentrationconcentrated in vacuo
  7. customThe mixture was purified by flash column chromatography [7.5% methanol in dichloromethane]
  8. customto give a yellow oil which

Sources & evidence

ORD record
ord-42a4d26d703f43fbbcb93c40e7d3b661
Source dataset
uspto-grants-2004_04
Patent number
US06727249B2

Reaction notes

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