Reacción #306983

Ecuación de reacción

LiOH

2-Methylpiperidine

methyl 3-cyano-4-fluorobenzoate

2-fluoro-5-formylbenzonitrile

→

title compound

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

Disolventes

DMF

water

THF

water

Condiciones de reacción

Tratamiento posterior

1. 1
   Otroprepared
2. 2
   OtroThe solution was partitioned between EtOAc and water
3. 3
   Otrothe phases separated
4. 4
   LavadoThe organic layer was washed with 0.1M HCl
5. 5
   Secadowith NaCl sat. solution, dried over magnesium sulfate
6. 6
   OtroEvaporation under reduced pressure
7. 7
   Otroafforded a greenish oil
8. 8
   workup.STIRRINGthe reaction mixture was stirred at RT for 16 hours
9. 9
   Lavadowashed with Et2O
10. 10
    workup.ADDITIONby addition of 1M HCl
11. 11
    Extracciónextracted with EtOAc
12. 12
    SecadoThe organic phase was dried over magnesium sulfate
13. 13
    Concentraciónconcentrated in vacuo
14. 14
    Otroto give a slightly yellow oil
15. 15
    OtroThe oil was triturated in a mixture of EtOAc and n-pentane
16. 16
    Filtraciónthe resulting precipitate was filtered
17. 17
    Otrodried

Procedimiento

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)+.

Fuente