Lithium Hydroxide → 4-((5-bromo-1-isopropyl-1H-pyrazol-4-yl)methyl)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid

HRID 537097Notes

Reaction equation

HRID 537097 reaction equation
[Br:1][C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[CH2:10][C:11]1([C:24]([O:26]CC)=[O:25])[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.[OH-].[Li+]>CO>[Br:1][C:2]1[N:6]([CH:7]([CH3:8])[CH3:9])[N:5]=[CH:4][C:3]=1[CH2:10][C:11]1([C:24]([OH:26])=[O:25])[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:13][CH2:12]1

Participants

4

Reactant 2

HCID 3939Lithium Hydroxide2×HCID 674915091-tert-butyl 4-ethyl 4-((5-bromo-1-isopropyl-1H-pyrazol-4-yl)methyl)piperidine-1,4-dicarboxylate

Product 1

HCID 674917184-((5-bromo-1-isopropyl-1H-pyrazol-4-yl)methyl)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acidYield 74.3%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of 1-tert-butyl 4-ethyl 4-((5-bromo-1-isopropyl-1H-pyrazol-4-yl)methyl)piperidine-1,4-dicarboxylate (14.5 g, 31.6 mmol) in methanol (50 mL) was added lithium hydroxide (1.52 g, 36.2 mmol) and the mixture was stirred at 80° C. for 18 hours. An additional portion of lithium hydroxide (2.55 g, 63.3 mmol) was added and the mixture was heated under vigorous reflux for 3 hours, cooled to room temperature, the solvent was removed in vacuo. The residue was washed with ethyl acetate, filtered, and the filtrate was saved. The solids were dissolved in 2 N aqueous sodium hydroxide (40 mL) and then acidified to pH 5 with 10% citric acid solution. The aqueous solution was extracted with ethyl acetate (3×40 mL), the organics were combined, dried over magnesium sulfate, filtered and then combined with the original filtrate. The solvent was removed from the filtrate under reduced pressure and the resulting residue was purified by flash column chromatography (ethyl acetate/heptanes) to afford 4-((5-bromo-1-isopropyl-1H-pyrazol-4-yl)methyl)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (10.1 g, 74%) as a colorless solid. +ESI (M+H) 429.9; 1H NMR (300 MHz, CDCl3, δ): 7.41 (s, 1H), 4.64 (m, 1H), 3.94 (m, 2H), 2.95 (m, 2H), 2.68 (m, 2H), 2.09 (m, 2H), 1.47 (m, 17H).

Workup

  1. temperaturethe mixture was heated
  2. temperatureunder vigorous reflux for 3 hours
  3. temperaturecooled to room temperature
  4. customthe solvent was removed in vacuo
  5. washThe residue was washed with ethyl acetate
  6. filtrationfiltered
  7. dissolutionThe solids were dissolved in 2 N aqueous sodium hydroxide (40 mL)
  8. extractionThe aqueous solution was extracted with ethyl acetate (3×40 mL)
  9. dry with materialdried over magnesium sulfate
  10. filtrationfiltered
  11. customThe solvent was removed from the filtrate under reduced pressure
  12. customthe resulting residue was purified by flash column chromatography (ethyl acetate/heptanes)

Sources & evidence

ORD record
ord-5aad6189654c4e5ba98fda79f35c6523
Source dataset
uspto-grants-2014_10
Patent number
US08859773B2

Reaction notes

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