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

HRID 219801

反応式

HRID 219801 の反応式
[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]

参加物

8

反応物 4

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

生成物 1

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

試薬・触媒・溶媒 3

HCID 962Water溶媒2 回HCID 6228Dimethylformamide溶媒HCID 8028Tetrahydrofuran溶媒

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)+.

後処理

  1. customprepared
  2. customThe solution was partitioned between EtOAc and water
  3. customthe phases separated
  4. washThe organic layer was washed with 0.1M HCl
  5. dry with materialwith NaCl sat. solution, dried over magnesium sulfate
  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 1M HCl
  11. extractionextracted with EtOAc
  12. dry with materialThe organic phase was dried over magnesium sulfate
  13. concentrationconcentrated in vacuo
  14. customto give a slightly yellow oil
  15. customThe oil was triturated in a mixture of EtOAc and n-pentane
  16. filtrationthe resulting precipitate was filtered
  17. customdried

出典と根拠

ORDレコード
ord-7c9942221af5435585a8c9503ea85398
出典データセット
uspto-grants-2012_06
特許番号
US08202865B2

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