Sodium hydride → (1R*,2R*,5S*,6R*)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-cyano-1-phenyl-8-azabicyclo[3.2.1]octane

HRID 2088201Notes

Reaction equation

HRID 2088201 reaction equation
[H-].[Na+].[F:3][C:4]([F:18])([F:17])[C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[CH2:8]Br.[CH2:19]([N:26]1[C@@H:31]2[C@H:32]([C:34]#[N:35])[CH2:33][C@@:27]1([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@H:28]([OH:36])[CH2:29][CH2:30]2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH2:19]([N:26]1[C@@H:31]2[C@H:32]([C:34]#[N:35])[CH2:33][C@@:27]1([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@H:28]([O:36][CH2:8][C:7]1[CH:6]=[C:5]([C:4]([F:18])([F:17])[F:3])[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=1)[CH2:29][CH2:30]2)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 1225733,5-Bis(trifluoromethyl)benzyl bromideHCID 69890225(1R*,2R*,5S*,6R*)-8-Benzyl-6-cyano-1-phenyl-8-azabicyclo[3.2.1]octan-2-ol

Product 1

HCID 86586749(1R*,2R*,5S*,6R*)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-cyano-1-phenyl-8-azabicyclo[3.2.1]octaneYield 88.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
50 °C

Procedure

Sodium hydride (0.3 g, 7.5 mmol, 60% in oil) was added portionwise to a solution of 3,5-bis(trifluoromethyl)benzyl bromide (2.5 g, 8.3 mmol) and (1R*,2R*,5S*,6R*)-8-benzyl-6-cyano-1-phenyl-8-azabicyclo[3.2.1]octan-2-ol (Description 31; 1.4 g, 4.4 mmol) in THF (20 ml). The mixture was stirred at 50° C. for 18 hours then cooled with an ice-bath and quenched by dropwise addition of water. The mixture was partitioned between brine and ethyl acetate. The organic layer was separated, dried (MgSO4), filtered and concentrated. Chromatography on silica gel eluting with 2.5, 5, 10 and 20% ethyl acetate/iso-hexanes afforded the title compound (2.12 g, 88%).

Workup

  1. temperaturethen cooled with an ice-bath
  2. customquenched by dropwise addition of water
  3. customThe mixture was partitioned between brine and ethyl acetate
  4. customThe organic layer was separated
  5. dry with materialdried (MgSO4)
  6. filtrationfiltered
  7. concentrationconcentrated

Sources & evidence

ORD record
ord-e526b1e1d1814940825cc9135244a450
Source dataset
uspto-grants-2004_04
Patent number
US06727249B2

Reaction notes

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