Water → (1R*,2R*,5R*)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-1-(4-fluorophenyl)-8-[(1-methyl-1,2,4-triazol-3-yl)methyl]-8-azabicyclo[3.2.1]octane hydrochloride

HRID 2088138Notes

Reaction equation

HRID 2088138 reaction equation
[F:1][C:2]([F:31])([F:30])[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][C:26]([F:29])=[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+].[CH3:38][N:39]1[CH:43]=[N:42][C:41]([CH2:44][Cl:45])=[N:40]1.O>CN(C)C=O>[ClH:45].[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[N:22]([CH2:44][C:41]4[N:42]=[CH:43][N:39]([CH3:38])[N:40]=4)[C@@:16]2([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH2:17][CH2:18]3)[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1

Participants

6

Reactant 4

HCID 962WaterHCID 11430Potassium CarbonateHCID 103744983-(Chloromethyl)-1-methyl-1H-1,2,4-triazoleHCID 86586659(1R*,2R*,5R*)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-1-(4-fluorophenyl)-8-azabicyclo[3.2.1]octane

Product 1

HCID 86586660(1R*,2R*,5R*)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-1-(4-fluorophenyl)-8-[(1-methyl-1,2,4-triazol-3-yl)methyl]-8-azabicyclo[3.2.1]octane hydrochloride

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

(1R*,2R*,5R*)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-1-(4-fluorophenyl)-8-azabicyclo[3.2.1]octane (Example 18; 101 mg, 0.23 mmol), potassium carbonate (159 mg, 1.15 mmol), and 1-methyl-3-chloromethyl-1,2,4 triazole (386 mg, 2.30 mmol) were combined in dimethylformamide and heated at 80° C. for 5 days. The reaction mixture was poured into water and extracted with ethyl acetate (×3), dried (MgSO4) and concentrated in vacuo to give a yellow oil. This was purified by flash column chromatography [7.5% methanol in dichloromethane] to give desired product. The hydrochloride salt was made by adding 1 equivalent of 1N hydrogen chloride in diethyl ether to a solution in diethyl ether. The salt was further purified by SCX cartridge eluting with methanol then ammonia in methanol. The ammonia washings were collected and concentrated in vacuo and the hydrochloride salt made by adding 1 equivalent of 1N hydrogen chloride in diethyl ether to a solution in-diethyl ether. The solid formed was filtered and dried at 60° C. in vacuo to give the title compound.

Workup

  1. extractionextracted with ethyl acetate (×3)
  2. dry with materialdried (MgSO4)
  3. concentrationconcentrated in vacuo
  4. customto give a yellow oil
  5. customThis was purified by flash column chromatography [7.5% methanol in dichloromethane]

Sources & evidence

ORD record
ord-d7ea110cc2bb41ca818a18385f727e31
Source dataset
uspto-grants-2004_04
Patent number
US06727249B2

Reaction notes

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