tert-Butanol → tert-Butyl {1-(1,4-dioxa-8-azaspiro[4.5]dec-8-ylcarbonyl)-5-[4-(trifluoromethyl)phenyl]piperidin-3-yl}carbamate

HRID 876256Notes

Reaction equation

HRID 876256 reaction equation
C([N:3]([CH2:6]C)CC)C.P(N=[N+]=[N-])(=O)(OC1C=CC=CC=1)[O:9]C1C=CC=CC=1.[O:27]1[C:31]2([CH2:36][CH2:35][N:34]([C:37]([N:39]3[CH2:44][CH:43]([C:45]4[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:47][CH:46]=4)[CH2:42][CH:41](C(O)=O)[CH2:40]3)=[O:38])[CH2:33][CH2:32]2)[O:30][CH2:29][CH2:28]1.[C:58]([OH:62])([CH3:61])([CH3:60])[CH3:59]>>[O:27]1[C:31]2([CH2:32][CH2:33][N:34]([C:37]([N:39]3[CH2:44][CH:43]([C:45]4[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:47][CH:46]=4)[CH2:42][CH:41]([NH:3][C:6](=[O:9])[O:62][C:58]([CH3:61])([CH3:60])[CH3:59])[CH2:40]3)=[O:38])[CH2:35][CH2:36]2)[O:30][CH2:29][CH2:28]1

Participants

5

Reactant 4

HCID 6386tert-ButanolHCID 8471TriethylamineHCID 123414Diphenylphosphoryl azideHCID 667617021-(1,4-Dioxa-8-azaspiro[4.5]dec-8-ylcarbonyl)-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid

Product 1

HCID 68075238tert-Butyl {1-(1,4-dioxa-8-azaspiro[4.5]dec-8-ylcarbonyl)-5-[4-(trifluoromethyl)phenyl]piperidin-3-yl}carbamate

Procedure

Activated molecular sieves 4 Å (about 8.4 g), 1.74 ml of triethylamine (12.5 mmol) and 3.15 g (11.4 mmol) of diphenyl phosphorazidate were added to the carboxylic acid from Example 60A (5.00 g, 10.4 mmol) in tert-butanol (189 ml), and the mixture was stirred under reflux overnight. The reaction solution was cooled, and the molecular sieves was then filtered off and thoroughly washed with ethyl acetate. The solvent was removed under reduced pressure and the residue was taken up in ethyl acetate. After washing with 2 N aqueous hydrogen chloride solution, saturated aqueous sodium bicarbonate solution and water, the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was used for the next step without further purification. Yield: 5.32 g (70% of theory, purity 71%)

Workup

  1. temperatureunder reflux overnight
  2. temperatureThe reaction solution was cooled
  3. filtrationthe molecular sieves was then filtered off
  4. washthoroughly washed with ethyl acetate
  5. customThe solvent was removed under reduced pressure
  6. washAfter washing with 2 N aqueous hydrogen chloride solution, saturated aqueous sodium bicarbonate solution and water
  7. dry with materialthe organic phase was dried over magnesium sulphate
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure
  10. customThe crude product was used for the next step without further purification

Sources & evidence

ORD record
ord-0d21451275094542bc0b7cc100248547
Source dataset
uspto-grants-2015_03
Patent number
US08987248B2

Reaction notes

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