Acetone → HCID 57781092, compound

HRID 1690758Notes

Reaction equation

HRID 1690758 reaction equation
C(N(CC)[C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[C:6]=1[CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:32][C:33]([CH3:35])=[O:34].[OH-].[K+].Cl>C1COCC1.O1CCOCC1.C(OCC)(=O)C>[F:12][C:7]1[C:8]([F:11])=[CH:9][CH:10]=[C:5]2[C:6]=1[CH:13]([N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)[C:33]([CH3:35])([CH3:32])[O:34][C:4]2=[O:19]

Participants

9

Reactant 5

HCID 180AcetoneHCID 313Hydrochloric AcidHCID 14797Potassium HydroxideHCID 2733832Lithium HexamethyldisilazideHCID 57781089HCID 57781089, compound

Product 1

HCID 57781092HCID 57781092, compound

Reagents, catalysts & solvents 3

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
-78 °C

Procedure

N,N-Diethyl-3,4-difluoro-2-imidazol-1-ylmethyl-benzamide (0.832 g, 2.695 mmol) is dissolved in THF (15 mL) and cooled to −78° C. LHMDS (1.0M in THF, 4.0 mL, 4.0 mmol) is added over 5 min, resulting in a dark brown solution. After another 10 min, acetone (0.79 g, 13.47 mmol) is added. After 30 min, the mixture is quenched with a pH 7 aqueous buffer and extracted twice with ethyl acetate. The combined organic phase is dried over magnesium sulfate and concentrated in vacuo to give a brown residue, which is redissolved in dioxane (25 mL). 1M aqueous KOH (13.5 mL, 13.5 mmol) is added. The solution is heated to 65° C. After 3 h, the mixture is cooled with a water bath, and acidified to pH=1 with conc. HCl. The mixture is heated to 65° C. After 1 h, the mixture is diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate, water and brine, dried over magnesium sulfate and filtered through a cotton plug. Concentration in vacuo gives a residue which is purified by silica gel flash chromatography (methylene chloride-methanol, 49:1 to 97:3) to give 5,6-difluoro-4-imidazol-1-yl-3,3-dimethyl-isochroman-1-one as an oil, which is converted to its HCl salt to give a solid; MS (ESI) m/z 279.1 (M+H); 1H NMR (400 MHz, MeOD) of the HCl salt, δ ppm 1.34 (s, 3 H), 1.61 (s, 3 H), 6.29 (s, 1 H), 7.46 (br. s., 1 H), 7.53 (br. s., 1 H), 7.66-7.75 (m, 1 H), 8.20 (ddd, J=8.8, 4.6, 1.6 Hz, 1 H), 8.79 (br. s., 1 H).

Workup

  1. customresulting in a dark brown solution
  2. waitAfter 30 min
  3. customthe mixture is quenched with a pH 7 aqueous buffer
  4. extractionextracted twice with ethyl acetate
  5. dry with materialThe combined organic phase is dried over magnesium sulfate
  6. concentrationconcentrated in vacuo
  7. customto give a brown residue, which
  8. temperatureThe solution is heated to 65° C
  9. waitAfter 3 h
  10. temperaturethe mixture is cooled with a water bath
  11. temperatureThe mixture is heated to 65° C
  12. waitAfter 1 h
  13. washwashed with saturated aqueous sodium bicarbonate, water and brine
  14. dry with materialdried over magnesium sulfate
  15. filtrationfiltered through a cotton plug
  16. concentrationConcentration in vacuo
  17. customgives a residue which
  18. customis purified by silica gel flash chromatography (methylene chloride-methanol, 49:1 to 97:3)

Sources & evidence

ORD record
ord-33a8a3221ca64f3eaf2a116c4ae580f1
Source dataset
uspto-grants-2012_04
Patent number
US08153674B2

Reaction notes

Loading…