Sulfuric Acid → 4-{[2-(2,5-Dimethyl-phenyl)-acetyl]-hydroxy-amino}-1-methoxy-piperidine-4-carboxylic acid methyl ester

HRID 1473779Notes

Reaction equation

HRID 1473779 reaction equation
[C:1]([C:3]1([N:11]([OH:23])[C:12](=[O:22])[CH2:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[CH3:21])[CH2:8][CH2:7][N:6]([O:9][CH3:10])[CH2:5][CH2:4]1)#N.S(=O)(=O)(O)[OH:25].[C:29](=O)([O-])[OH:30].[Na+]>CO>[CH3:29][O:30][C:1]([C:3]1([N:11]([C:12](=[O:22])[CH2:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[CH3:21])[OH:23])[CH2:8][CH2:7][N:6]([O:9][CH3:10])[CH2:5][CH2:4]1)=[O:25]

Participants

5

Reactant 3

HCID 1118Sulfuric AcidHCID 516892Sodium BicarbonateHCID 58427949N-(4-cyano-1-methoxy-piperidin-4-yl)-2-(2,5-dimethyl-phenyl)-N-hydroxy-acetamide

Product 1

HCID 584280434-{[2-(2,5-Dimethyl-phenyl)-acetyl]-hydroxy-amino}-1-methoxy-piperidine-4-carboxylic acid methyl ester

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

To a solution of N-(4-cyano-1-methoxy-piperidin-4-yl)-2-(2,5-dimethyl-phenyl)-N-hydroxy-acetamide (1.5 g, 4.73 mmol) in methanol (15 ml) at 0° C. was added concentrated sulfuric acid (1.26 ml, 2.3 g, 23.64 mmol) slowly dropwise and the reaction mixture was stirred at reflux for 40 hours. The mixture was poured on ice (50 g), neutralized carefully with a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate (5×). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The oily residue was purified by chromatography on silica gel (ethyl acetate/hexane 2:1) to afford 136 mg of an off-white solid. This material was triturated with a tert-butyl methyl ether/hexane 1:4 solution (2-3 ml), filtered and dried. Yield: 82 mg of 4-{[2-(2,5-dimethyl-phenyl)-acetyl]-hydroxy-amino}-1-methoxy-piperidine-4-carboxylic acid methyl ester (title compound P3ii.1) as a white solid, mp 140-142° C.

Workup

  1. temperatureat reflux for 40 hours
  2. additionThe mixture was poured on ice (50 g)
  3. extractionextracted with ethyl acetate (5×)
  4. washThe combined organic layers were washed with brine
  5. dry with materialdried over sodium sulfate
  6. concentrationconcentrated
  7. customThe oily residue was purified by chromatography on silica gel (ethyl acetate/hexane 2:1)

Sources & evidence

ORD record
ord-30a49d8de5594ec98ffa1935741a14de
Source dataset
uspto-grants-2015_04
Patent number
US09018135B2

Reaction notes

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