반응 #306983

반응 방정식

LiOH

2-Methylpiperidine

methyl 3-cyano-4-fluorobenzoate

2-fluoro-5-formylbenzonitrile

→

title compound

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

용매

DMF

water

THF

water

반응 조건

후처리

1. 1
   기타prepared
2. 2
   기타The solution was partitioned between EtOAc and water
3. 3
   기타the phases separated
4. 4
   세척The organic layer was washed with 0.1M HCl
5. 5
   건조with NaCl sat. solution, dried over magnesium sulfate
6. 6
   기타Evaporation under reduced pressure
7. 7
   기타afforded a greenish oil
8. 8
   workup.STIRRINGthe reaction mixture was stirred at RT for 16 hours
9. 9
   세척washed with Et2O
10. 10
    workup.ADDITIONby addition of 1M HCl
11. 11
    추출extracted with EtOAc
12. 12
    건조The organic phase was dried over magnesium sulfate
13. 13
    농축concentrated in vacuo
14. 14
    기타to give a slightly yellow oil
15. 15
    기타The oil was triturated in a mixture of EtOAc and n-pentane
16. 16
    여과the resulting precipitate was filtered
17. 17
    기타dried

실험 절차

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)+.

출처