Lithium Hydroxide → 4-(2-Methylpiperidin-1-yl)-3-nitrobenzoic acid

HRID 400750Notes

Reaction equation

HRID 400750 reaction equation
F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH3:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][NH:18]1.[OH-].[Li+]>CN(C=O)C.O.C1COCC1>[CH3:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][N:18]1[C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]

Participants

7

Reactant 3

HCID 3939Lithium HydroxideHCID 79742-MethylpiperidineHCID 21277355Ethyl 4-fluoro-3-nitrobenzoate

Product 1

HCID 431767024-(2-Methylpiperidin-1-yl)-3-nitrobenzoic acidYield 80%

Reagents, catalysts & solvents 3

HCID 962WaterSolvent2×HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
50 °C

Procedure

A mixture of ethyl 4-fluoro-3-nitrobenzoate (Chontec, 25 g; 117.28 mmol) and 2-methylpiperidine (41.54 mL; 351.84 mmol) in DMF (100 mL) was heated at 50° C. for 2 hours The reaction was cooled to RT and diluted with water (100 mL), extracted with EtOAc, dried over MgSO4 and concentrated giving a yellow oil. The residue was taken up in THF (250 mL) and lithium hydroxide (14.04 g; 586.41 mmol) was added followed by water (250 mL). The reaction mixture was stirred at RT for 2 days. After evaporation of THF, the solution was diluted with water and washed with Et2O. The aqueous layer was acidified to pH 5 with AcOH, extracted with Et2O, dried over MgSO4 and concentrated affording the title compound as a yellow solid (24.81 g, 80%). 1H NMR (DMSO-d6) δ 13.09 (br s, 1H), 8.23-8.22 (d, J=2.14 Hz, 1H), 8.04-8.01 (dd, J=8.72 Hz, 2.19 Hz, 1H), 7.44-7.41 (d, J=8.94 Hz, 1H), 3.63-3.61 (m, 1H), 3.22-3.18 (m, 1H), 2.89-2.85 (m, 1H), 1.78-1.44 (m, 6H), 1.06-1.04 (d, J=6.65 Hz, 3H). HPLC (Method A) Rt 3.96 min (Purity: 97.9%). LC/MS (Method B): 265.2 (M+H)+; 263.2 (M+H)−.

Workup

  1. temperaturewas cooled to RT
  2. extractionextracted with EtOAc
  3. dry with materialdried over MgSO4
  4. concentrationconcentrated
  5. customgiving a yellow oil
  6. customAfter evaporation of THF
  7. additionthe solution was diluted with water
  8. washwashed with Et2O
  9. extractionextracted with Et2O
  10. dry with materialdried over MgSO4
  11. concentrationconcentrated

Sources & evidence

ORD record
ord-0d3d1eda317848c387c72b39efcf77b7
Source dataset
uspto-grants-2014_06
Patent number
US08741923B2

Reaction notes

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