Acetone → 4-[5-(1-Hydroxy-ethyl)-imidazol-1-yl]-3,3-dimethyl-isochroman-1-one

HRID 1690733Notes

Reaction equation

HRID 1690733 reaction equation
[CH3:1][C:2]1([CH3:20])[CH:11]([N:12]2[C:16]([CH:17]=[O:18])=[CH:15][N:14]=[CH:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:19])[O:3]1.[CH3:21][Mg]Br.C(OCCCC)CCC.CC(C)=O>C1COCC1.O>[OH:18][CH:17]([C:16]1[N:12]([CH:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:19])[O:3][C:2]2([CH3:20])[CH3:1])[CH:13]=[N:14][CH:15]=1)[CH3:21]

Participants

7

Reactant 4

HCID 180AcetoneHCID 8909Butyl etherHCID 248026903-(3,3-dimethyl-1-oxo-isochroman-4-yl)-3H-imidazole-4-carbaldehydeHCID 178418573HCID 178418573, compound

Product 1

HCID 577811344-[5-(1-Hydroxy-ethyl)-imidazol-1-yl]-3,3-dimethyl-isochroman-1-one

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 3-(3,3-dimethyl-1-oxo-isochroman-4-yl)-3H-imidazole-4-carbaldehyde (0.500 g, 1.852 mmol) (Example 9a) in THF (20 mL) at −78° C. is added 1M methyl magnesium bromide in dibutyl ether (2.41 mL, 2.41 mmol). The reaction mixture is stirred at −78° C. for 3 h, whereupon acetone (2 mL) is added. The mixture is allowed to warm to ambient temperature and then poured into water (50 mL). The mixture is extracted with ethyl acetate. The combined organic phase is washed with water, dried over Na2SO4 and concentrated in vacuo. The residue is purified by silica gel chromatography (gradient methanol in dichloromethane, 1% to 5%) to give 4-[5-(1-hydroxy-ethyl)-imidazol-1-yl]-3,3-dimethyl-isochroman-1-one as a white solid. Resolution of all four stereoisomers of the title compound is achieved by chiral HPLC. Stereoisomer A is separated with a ChiralPak IA column using an 85:15 heptane-isopropanol mobile phase. The remaining three stereoisomers are resolved with a ChiralPak AD using an 85:15 heptane-ethanol mobile phase to give stereoisomer B (tr=61.4 min), stereoisomer C (tr=76.7 min) and stereoisomer D (tr=94.9 min)

Workup

  1. additionis added
  2. extractionThe mixture is extracted with ethyl acetate
  3. washThe combined organic phase is washed with water
  4. dry with materialdried over Na2SO4
  5. concentrationconcentrated in vacuo
  6. customThe residue is purified by silica gel chromatography (gradient methanol in dichloromethane, 1% to 5%)

Sources & evidence

ORD record
ord-d790d2f6bb864924b46e5df2fb7058cd
Source dataset
uspto-grants-2012_04
Patent number
US08153674B2

Reaction notes

Loading…