Lithium Hydroxide → 3-Cyano-4-(2-methylpiperidin-1-yl)benzoic acid

HRID 400736

Reaktionsgleichung

Reaktionsgleichung von HRID 400736
[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.[C:8]([C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1F)[C:13]([O:15]C)=[O:14])#[N:9].FC1C=CC(C=O)=CC=1C#N.[Li+].[OH-]>CN(C=O)C.C1COCC1.O>[C:8]([C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1[N:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]1[CH3:1])[C:13]([OH:15])=[O:14])#[N:9]

Komponenten

8

Edukt 4

HCID 3939Lithium HydroxideHCID 79742-MethylpiperidineHCID 27695822-Fluoro-5-formylbenzonitrileHCID 45790123Methyl 3-cyano-4-fluorobenzoate

Produkt 1

HCID 594957013-Cyano-4-(2-methylpiperidin-1-yl)benzoic acid

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 962WaterLösungsmittel2×HCID 6228DimethylformamideLösungsmittelHCID 8028TetrahydrofuranLösungsmittel

Versuchsvorschrift

2-Methylpiperidine (2.38 mL; 20.29 mmol) was added to a solution of methyl 3-cyano-4-fluorobenzoate, prepared as described in J. Med. Chem. 2004, 47, 1339-1350 from 2-fluoro-5-formylbenzonitrile (727 mg; 4.06 mmol) in DMF (4 mL). The resulting mixture was stirred at RT for 2 days. The solution was partitioned between EtOAc and water and the phases separated. The organic layer was washed with HCl (0.1 M) and brine, dried over MgSO4. Evaporation under reduced pressure afforded a greenish oil. The latter was taken up in THF (10 mL), LiOH (340 mg; 8.12 mmol) and water (10 mL) were added and the reaction mixture was stirred at RT for 16 hours. The resulting solution was diluted with water and washed with Et2O. The aqueous layer was made acidic (pH 2) by addition of HCl (1M) and extracted with EtOAc. The organic phase was dried over MgSO4 and concentrated in vacuo to give a light yellow oil that precipitated upon trituration with a mixture of EtOAc and n-pentane to give the title compound as an off-white solid. 1H NMR (DMSO-d6) δ 13 (br s, 1H), 8.08 (d, J=2.1 Hz, 1H), 8.01 (dd, J=8.8, 2.1 Hz, 1H), 7.18 (d, J=8.9 Hz, 1H), 4.12-4.08 (m, 1H), 3.35-3.25 (m, 2H), 1.84-1.53 (m, 6H), 1.09 (d, J=6.6 Hz, 3H). LC/MS (Method B): 243.2 (M−H)−; 245.2 (M+H)+.

Aufarbeitung

  1. customprepared
  2. customThe solution was partitioned between EtOAc and water
  3. customthe phases separated
  4. washThe organic layer was washed with HCl (0.1 M) and brine
  5. dry with materialdried over MgSO4
  6. customEvaporation under reduced pressure
  7. customafforded a greenish oil
  8. stirringthe reaction mixture was stirred at RT for 16 hours
  9. washwashed with Et2O
  10. additionby addition of HCl (1M)
  11. extractionextracted with EtOAc
  12. dry with materialThe organic phase was dried over MgSO4
  13. concentrationconcentrated in vacuo
  14. customto give a light yellow oil
  15. customthat precipitated upon trituration with a mixture of EtOAc and n-pentane

Quellen und Nachweise

ORD-Eintrag
ord-d450ba435f0c48b9bb62264d2978e094
Quelldatensatz
uspto-grants-2014_06
Patentnummer
US08741923B2

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