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

HRID 130683Notes

Reaction equation

HRID 130683 reaction equation
C1(S([C:10]2[C:15]([C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])=[O:17])=[CH:14][CH:13]=[CH:12][N:11]=2)(=O)=O)C=CC=CC=1.[C:25]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)(=[O:27])[CH3:26].N#N.[Li+].[OH-].C(O)(=O)C.[OH:42][P:43]([OH:46])([OH:45])=[O:44]>C(Cl)Cl.CS(C)=O>[P:43]([OH:46])([OH:45])([OH:44])=[O:42].[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]([C:15]1[C:10]([CH:26]=[C:25]([OH:27])[C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:17]

Participants

9

Reactant 6

HCID 176Acetic AcidHCID 947NitrogenHCID 1004Phosphoric AcidHCID 3939Lithium HydroxideHCID 142824-AcetylpyridineHCID 684356242-(Benzenesulfonyl)-3-(2-chlorobenzoyl)pyridine

Product 1

HCID 136347866(2-Chlorophenyl)-[2-(2-hydroxy-2-pyridin-4-yl-vinyl)pyridin-3-yl]methanone phosphate

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
70 °C

Procedure

The title compound may also be prepared by an alternative process, which is described below. Add (2-phenylsulfonyl-pyridin-3-yl)-(2-chlorophenyl)methanone (15 g) and 4-acetylpyridine (7.59 g; 1.5 eq) to DMSO (150 mL) under an inert atmosphere of N2. Heat the solution to 70° C., then add LiOH (4 g, 4 eq) in one portion. Stir the reaction mixture for 4 hours at that temperature. The mixture turns from red to dark brown during the reaction. Completion of the reaction may be checked by HPLC. After completion of the reaction, cool the reaction mixture to 15° C. with a cold-water bath, and add CH2Cl2 (150 mL). Quench the reaction mixture in 10 min with 10% NaCl (150 ml) containing acetic acid (9.58 mL; 4 eq). At the end of the addition, the temperature reaches approximately 27° C. Re-extract the aqueous layer with CH2Cl2 (150 ml). Combine the organic layers and wash with 10% NaCl (3×300 mL). Concentrate the combined organic layers to dryness under vacuum and re-dissolve the residue in MeOH (4.3 volumes). Cool the reaction mixture to 20° C., and add H3PO4 (85% w/w in water; 2.88 mL; 1 eq). Stir the suspension for 4 h at 20° C., filter, wash the precipitate with MeOH (2×15 mL) and dry under vacuum at 50° C. to yield the title compound as an orange solid.

Workup

  1. customdark brown during the reaction
  2. customCompletion of the reaction
  3. customAfter completion of the reaction
  4. temperaturecool the reaction mixture to 15° C. with a cold-water bath
  5. customQuench the reaction mixture in 10 min with 10% NaCl (150 ml)
  6. additionAt the end of the addition
  7. customreaches approximately 27° C
  8. washCombine the organic layers and wash with 10% NaCl (3×300 mL)
  9. concentrationConcentrate the combined organic layers to dryness under vacuum
  10. dissolutionre-dissolve the residue in MeOH (4.3 volumes)
  11. temperatureCool the reaction mixture to 20° C.
  12. stirringStir the suspension for 4 h at 20° C.
  13. filtrationfilter
  14. washwash the precipitate with MeOH (2×15 mL)
  15. customdry under vacuum at 50° C.

Sources & evidence

ORD record
ord-f24e078d6dd144949fcf75781e8000b5
Source dataset
uspto-grants-2008_06
Patent number
US07381826B2

Reaction notes

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