Diisopropylamine → tert-Butyl 4-(1-(3-fluoro-2-pivalamidophenyl)-1-hydroxy-3-methoxy-3-oxopropan-2-yl)piperidine-1-carboxylate

HRID 501983Notes

Reaction equation

HRID 501983 reaction equation
C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:30])[CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.[H-].[Na+].[F:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH:40]=[O:41])[C:35]=1[NH:42][C:43](=[O:48])[C:44]([CH3:47])([CH3:46])[CH3:45]>O1CCCC1>[F:33][C:34]1[C:35]([NH:42][C:43](=[O:48])[C:44]([CH3:46])([CH3:45])[CH3:47])=[C:36]([CH:40]([OH:41])[CH:16]([CH:17]2[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:21][CH2:22]2)[C:15]([O:14][CH3:13])=[O:30])[CH:37]=[CH:38][CH:39]=1

Participants

7

Reactant 5

HCID 7912DiisopropylamineHCID 24758Sodium hydrideHCID 1514280tert-Butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylateHCID 59424313N-(2-Fluoro-6-formylphenyl)pivalamideHCID 178418339Butyllithium

Product 1

HCID 59424341tert-Butyl 4-(1-(3-fluoro-2-pivalamidophenyl)-1-hydroxy-3-methoxy-3-oxopropan-2-yl)piperidine-1-carboxylateYield 81%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent4×

Conditions

Temperature
-78 °C

Procedure

Diisopropylamine (3.40 mL, 24.2 mmol) was dissolved in tetrahydrofuran (70 mL). The mixture was cooled to −78° C. Butyllithium (2 M in cyclohexane, 12.2 μL, 24.4 mmol) was added dropwise to the reaction. The mixture was held at −78° C. with stirring and held for 20 minutes. A solution of tert-butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (5.20 g, 20.2 mmol) in tetrahydrofuran (15 mL) was added to the mixture dropwise. The mixture was held at −78° C. with stirring and held for 45 min. In a separate flask, sodium hydride (60% in mineral oil, 970 mg, 24.3 mmol) was washed with hexanes then suspended in tetrahydrofuran (50 mL). The mixture was cooled to 0° C. A solution of N-(2-Fluoro-6-formylphenyl)pivalamide (4.50 g, 20.2 mmol) in tetrahydrofuran (20 mL) was added to the mixture dropwise. The mixture was held at 0° C. with stirring and held for 1 h. The above prepared aldehyde mixture was added to the ester mixture dropwise over 1.25 h. The mixture was held at −78° C. with stirring and held for 1 h. The reaction was quenched with aqueous ammonium chloride, warmed to room temperature, and diluted with water. The mixture was extracted ethyl acetate (2×) and the aqueous phase was discarded. The material was dried (magnesium sulfate), filtered, and concentrated to dryness. Silica gel chromatography gave the title compound as white foam in 81% yield. Mass spec.: 381.2 (M-C4H8O2+H)+.

Workup

  1. customwas held at −78° C.
  2. customwas held at −78° C.
  3. stirringwith stirring
  4. waitheld for 45 min
  5. temperatureThe mixture was cooled to 0° C
  6. customwas held at 0° C.
  7. stirringwith stirring
  8. waitheld for 1 h
  9. customwas held at −78° C.
  10. stirringwith stirring
  11. waitheld for 1 h
  12. customThe reaction was quenched with aqueous ammonium chloride
  13. temperaturewarmed to room temperature
  14. additiondiluted with water
  15. extractionThe mixture was extracted ethyl acetate (2×)
  16. dry with materialThe material was dried (magnesium sulfate)
  17. filtrationfiltered
  18. concentrationconcentrated to dryness

Sources & evidence

ORD record
ord-611ba01bd631458ea8ddd61f65369ab5
Source dataset
uspto-grants-2010_08
Patent number
US07772244B2

Reaction notes

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