反応 #306983

反応方程式

LiOH

2-Methylpiperidine

methyl 3-cyano-4-fluorobenzoate

2-fluoro-5-formylbenzonitrile

→

title compound

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

溶媒

DMF

water

THF

water

反応条件

後処理

1. 1
   その他prepared
2. 2
   その他The solution was partitioned between EtOAc and water
3. 3
   その他the phases separated
4. 4
   洗浄The organic layer was washed with 0.1M HCl
5. 5
   乾燥with NaCl sat. solution, dried over magnesium sulfate
6. 6
   その他Evaporation under reduced pressure
7. 7
   その他afforded a greenish oil
8. 8
   workup.STIRRINGthe reaction mixture was stirred at RT for 16 hours
9. 9
   洗浄washed with Et2O
10. 10
    workup.ADDITIONby addition of 1M HCl
11. 11
    抽出extracted with EtOAc
12. 12
    乾燥The organic phase was dried over magnesium sulfate
13. 13
    濃縮concentrated in vacuo
14. 14
    その他to give a slightly yellow oil
15. 15
    その他The oil was triturated in a mixture of EtOAc and n-pentane
16. 16
    ろ過the resulting precipitate was filtered
17. 17
    その他dried

実験手順

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)+.

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