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Phosphoric Acid → (2-Chlorophenyl)-[2-(2-hydroxy-2-pyridin-4-yl-vinyl)pyridin-3-yl]methanone

HRID 130682
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HRID 130682 반응식
[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:10]1[C:11](F)=[N:12][CH:13]=[CH:14][CH:15]=1)[OH:9].[Br-].[K+].Cl[O-].[Na+].C(=O)(O)[O-].[Na+].[C:27]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1)(=[O:29])[CH3:28].[OH-].[Li+].[Cl-].[Na+].P(=O)(O)(O)O.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[C:11]([CH:28]=[C:27]([OH:29])[C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:9]
참가 물질실험 절차후처리출처 및 근거반응 노트

참가 물질

12

반응물 9

HCID 1004Phosphoric AcidHCID 3939Lithium HydroxideHCID 5234Sodium ChlorideHCID 11430Potassium CarbonateHCID 142824-AcetylpyridineHCID 253877Potassium BromideHCID 516892Sodium Bicarbonate
HCID 12711119
(2-Chloro-phenyl)-(2-fluoropyridin-3-yl)methanol
HCID 23665760Sodium Hypochlorite

생성물 1

HCID 136347867(2-Chlorophenyl)-[2-(2-hydroxy-2-pyridin-4-yl-vinyl)pyridin-3-yl]methanone

시약·촉매·용매 2

HCID 962Water용매2회HCID 6344Dichloromethane용매2회

실험 절차

To a solution of (2-chloro-phenyl)-(2-fluoropyridin-3-yl)methanol (140 g, 0.59 mol) in dichloromethane (1.1 L) under an argon atmosphere, add 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) (1.43 g, 9.15 mmol) and potassium bromide (10% w/w in water, 57.1 mL, 0.048 mol). To the resulting mixture add a solution of sodium hypochlorite (13% w/w active chlorine in water, 403 mL, 0.85 mol) and sodium bicarbonate (20.3 g, 0.24 mol) in water (403 mL) while stirring vigorously and while maintaining the temperature below 20° C. Continue stirring the reaction mixture for 30 min or until the reaction is complete. Separate the layers, and concentrate the organic layer to approximately 200 mL total volume. Add dimethylsulfoxide and concentrate until no dichloromethane remains in the solution. Add 4-acetylpyridine (107 g, 0.88 mol) and powdered lithium hydroxide (28.2 g, 1.17 mol) and stir at 60° C. for 2.5 h or until the reaction is complete. Cool to ambient temperature and add dichloromethane (1.4 L) and an aqueous solution of 10% sodium chloride (1.3 L) while maintaining the temperature between 20° C. and 24° C. Separate the layers and extract the aqueous layer with dichloromethane (1.4 L). Separate the layers and combine the organic layers. Wash the combined organic layers with an aqueous solution of 10% sodium chloride (3×2.6 L). Concentrate the organic layer to approximately 500 mL total volume, then add methanol (1.0 L). Concentrate under vacuum until the weight of the resulting residue is approximately 500 g, then add more methanol (207 mL). Heat the solution to 60° C. When the temperature reaches 45° C., add phosphoric acid (85% w/w in water, 67.4 g, 0.58 mol). Stir the resulting slurry at 22° C. for 16 h. Collect the resulting solid by filtration and wash with methanol (3×65 mL) and water (3×65 mL). Add the resulting solid to a solution of potassium carbonate (49.3 g, 0.356 mol) in water (714 mL) and stir for 4 h. Collect the resulting solid by filtration, wash with water (50 mL) and dry under vacuum at 50° C. to afford the title compound as an orange solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 4.89 (s, 2H) 6.93 (d, J=7.33 Hz, 1H) 7.09 (s, 1H) 7.11-7.17 (m, 2H) 7.24 (dd, J=7.58, 5.31 Hz, 1H) 7.40-7.67 (m, 15H) 7.71-7.77 (m, 3H) 7.85 (d, J=7.83 Hz , 1H) 7.89 (d, J=6.06 Hz, 2H) 8.15 (d, J=7.58 Hz, 1H) 8.50 (d, J=3.79 Hz, 1H) 8.62 (d, J=3.79 Hz, 3H) 8.67 (d, J=5.81 Hz, 2H) 8.73 (dd, J=4.80, 1.52 Hz, 1H) 8.83 (d, J=5.81 Hz, 1H).

후처리

  1. temperaturewhile maintaining the temperature below 20° C
  2. stirringContinue stirring the reaction mixture for 30 min
  3. customSeparate the layers
  4. concentrationconcentrate the organic layer to approximately 200 mL total volume
  5. concentrationAdd dimethylsulfoxide and concentrate until no dichloromethane
  6. customSeparate the layers
  7. extractionextract the aqueous layer with dichloromethane (1.4 L)
  8. customSeparate the layers
  9. washWash the combined organic layers with an aqueous solution of 10% sodium chloride (3×2.6 L)
  10. concentrationConcentrate the organic layer to approximately 500 mL total volume
  11. concentrationConcentrate under vacuum until the weight of the resulting residue
  12. additionadd more methanol (207 mL)
  13. temperatureHeat the solution to 60° C
  14. customreaches 45° C.
  15. stirringStir the resulting slurry at 22° C. for 16 h
  16. customCollect the resulting solid
  17. filtrationby filtration
  18. washwash with methanol (3×65 mL) and water (3×65 mL)
  19. stirringstir for 4 h
  20. customCollect the resulting solid
  21. filtrationby filtration
  22. washwash with water (50 mL)
  23. customdry under vacuum at 50° C.

출처 및 근거

ORD 기록
ord-753a280d2f2d4e6a9e6231671a558f18
출처 데이터셋
uspto-grants-2008_06
DOI
10.6084/m9.figshare.5104873.v1
특허 번호
US07381826B2

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