2-Morpholinoethanol → {1-[4-Cyano-3-fluoro-5-(2-morpholin-4-yl-ethoxy)-phenyl]-piperidin-4-yl}-carbamic acid tert-butyl ester

HRID 2054894

Reaction equation

HRID 2054894 reaction equation
[C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18](F)[C:17]([C:21]#[N:22])=[C:16]([F:23])[CH:15]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[OH:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[C:18]([O:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:17]([C:21]#[N:22])=[C:16]([F:23])[CH:15]=2)[CH2:12][CH2:13]1)([CH3:2])([CH3:4])[CH3:3]

Participants

5

Reactant 3

HCID 611632-MorpholinoethanolHCID 2724254Sodium bis(trimethylsilyl)amideHCID 21090459[1-(4-Cyano-3,5-difluoro-phenyl)-piperidin-4-yl]-carbamic acid tert-butyl ester

Product 1

HCID 59656697{1-[4-Cyano-3-fluoro-5-(2-morpholin-4-yl-ethoxy)-phenyl]-piperidin-4-yl}-carbamic acid tert-butyl esterYield 61%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

To a solution of 0.10 g (0.30 mmol) of [1-(4-cyano-3,5-difluoro-phenyl)-piperidin-4-yl]-carbamic acid tert-butyl ester and 0.040 mL (0.33 mmol) of 4-(2-hydroxyethyl)-morpholine in THF (15 mL), cooled to 0° C., was added 0.60 mL (0.60 mmol) of sodium bis(trimethylsilyl)amide as a 1.0 M solution in THF. The reaction was stirred at 0° C. for 30 min then warmed to 60° C. for 6 h. The reaction was cooled to room temperature and excess base was consumed by the addition of a saturated aqueous solution of NH4Cl. The mixture was diluted with H2O and washed with EtOAc. The combined organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue was purified by flash silica gel chromatography to provide 0.081 g (61%) of {1-[4-cyano-3-fluoro-5-(2-morpholin-4-yl-ethoxy)-phenyl]-piperidin-4-yl}-carbamic acid tert-butyl ester as a white foam.

Workup

  1. temperaturethen warmed to 60° C. for 6 h
  2. temperatureThe reaction was cooled to room temperature
  3. customexcess base was consumed by the addition of a saturated aqueous solution of NH4Cl
  4. additionThe mixture was diluted with H2O
  5. washwashed with EtOAc
  6. washThe combined organic phase was washed with brine
  7. dry with materialdried over anhydrous Na2SO4
  8. concentrationconcentrated under reduced pressure
  9. customThe crude residue was purified by flash silica gel chromatography

Sources & evidence

ORD record
ord-0d54c701f14443d08aaf7a22baf65017
Source dataset
uspto-grants-2008_02
Patent number
US07329764B2

Linked notes

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