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

HRID 2088182Notes

Reaction equation

HRID 2088182 reaction equation
F[C:2](F)(F)[C:3]([OH:5])=O.[CH2:8]([N:15]1[C@@H:20]2[C@H:21](C(O)=O)[CH2:22][C@@:16]1([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C@H:17]([O:26][CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=1)[CH2:18][CH2:19]2)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(Cl)(=O)C(Cl)=O.[N-:54]=[N+:55]=[N-:56].[Na+].[N-:58]=C=O>ClCCl.CN(C)C=O.C1COCC1.O>[C:3]([NH:58][C@@H:21]1[CH2:22][C@:16]2([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[N:15]([CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C@H:20]1[CH2:19][CH2:18][C@@:17]2([N:54]=[N+:55]=[N-:56])[O:26][CH2:27][C:28]1[CH:29]=[C:30]([C:38]([F:41])([F:39])[F:40])[CH:31]=[C:32]([C:34]([F:37])([F:35])[F:36])[CH:33]=1)(=[O:5])[CH3:2]

Participants

9

Reactant 4

HCID 33557Sodium Azide2×HCID 65578Oxalyl chlorideHCID 105034IsocyanateHCID 86586685(1R*,2R*,5S*,6R*)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octan-6-carboxylic acid trifluoroacetate2×

Product 1

HCID 86586722(1R*,2R*,5S*,6R*)-6-Acetamidoazido-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octaneYield 82%

Reagents, catalysts & solvents 4

HCID 6228DimethylformamideCatalystHCID 962WaterSolventHCID 6344DichloromethaneSolvent2×HCID 8028TetrahydrofuranSolvent

Procedure

(1R*,2R*,5S*,6R*)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octan-6-carboxylic acid (free base of Example 53; 377 mg, 0.67 mmol) was dissolved in dichloromethane (10 ml) and dimethylformamide (2 drops) and the mixture cooled to 0° C. then oxalyl chloride (0.063 ml, 0.72 mmol) added. The mixture was then left to warm to room temperature and stirred for 2 hours. The mixture was concentrated in vacuo then carried through crude. Acid chloride (389 mg, 0.67 mmol) was taken up in dichloromethane (10 ml) and sodium azide (48 mg, 0.74 mmol) added and the mixture stirred at room temperature for 3 days. A further 48 mg of sodium azide was added and the mixture further stirred overnight. The reaction mixture was then concentrated in vacuo and carried through crude. The isocyanate (394 mg, 0.70 mmol) was dissolved in THF (3 ml) and water (3 ml) and the mixture refluxed for 4 hours. The reaction mixture was then extracted with ethyl acetate (×2), dried (MgSO4) and concentrated in vacuo to give the title compound as a beige solid (307 mg, 82%).

Workup

  1. waitThe mixture was then left
  2. concentrationThe mixture was concentrated in vacuo
  3. stirringthe mixture stirred at room temperature for 3 days
  4. customthe mixture further stirred overnight
  5. concentrationThe reaction mixture was then concentrated in vacuo
  6. extractionThe reaction mixture was then extracted with ethyl acetate (×2)
  7. dry with materialdried (MgSO4)
  8. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-e7513db4fe1143febb1d19d9c3f2430f
Source dataset
uspto-grants-2004_04
Patent number
US06727249B2

Reaction notes

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