Réaction #306983

Équation de réaction

LiOH

2-Methylpiperidine

methyl 3-cyano-4-fluorobenzoate

2-fluoro-5-formylbenzonitrile

→

title compound

3-cyano-4-(2-methylpiperidin-1-yl)benzoic acid

Solvants

DMF

water

THF

water

Conditions de réaction

Traitement

1. 1
   Autreprepared
2. 2
   AutreThe solution was partitioned between EtOAc and water
3. 3
   Autrethe phases separated
4. 4
   LavageThe organic layer was washed with 0.1M HCl
5. 5
   Séchagewith NaCl sat. solution, dried over magnesium sulfate
6. 6
   AutreEvaporation under reduced pressure
7. 7
   Autreafforded a greenish oil
8. 8
   workup.STIRRINGthe reaction mixture was stirred at RT for 16 hours
9. 9
   Lavagewashed with Et2O
10. 10
    workup.ADDITIONby addition of 1M HCl
11. 11
    Extractionextracted with EtOAc
12. 12
    SéchageThe organic phase was dried over magnesium sulfate
13. 13
    Concentrationconcentrated in vacuo
14. 14
    Autreto give a slightly yellow oil
15. 15
    AutreThe oil was triturated in a mixture of EtOAc and n-pentane
16. 16
    Filtrationthe resulting precipitate was filtered
17. 17
    Autredried

Mode opératoire

2-Methylpiperidine (2.38 mL; 20.29 mmol; 5 eq.) 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 (Aldrich; 49, 408-9), (727 mg; 4.06 mmol; 1 eq.) 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 0.1M HCl then with NaCl sat. solution, dried over magnesium sulfate. Evaporation under reduced pressure afforded a greenish oil. The latter was taken up in THF (10 mL), LiOH (340.57 mg; 8.12 mmol; 2 eq.) then 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 1M HCl and extracted with EtOAc. The organic phase was dried over magnesium sulfate and concentrated in vacuo to give a slightly yellow oil. The oil was triturated in a mixture of EtOAc and n-pentane and the resulting precipitate was filtered and dried to afford the title compound as an off-white solid. 1H NMR (DMSO-d6, 300 MHz) δ 13 (hr 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)+.

Source