Acetic Acid → (R)-2-(4-(3-(2-methylpyridin-4-yl)-3-oxo-1-o-tolylpropyl)phenyl)acetic acid

HRID 1617819Notes

Reaction equation

HRID 1617819 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.C(OCC)(=O)[CH2:27][C:28]([O:30]CC)=[O:29].C(O)(=O)C.[OH-].[Li+].S([O-])(O)(=O)=O.[K+].[Cl-].[NH4+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CO>[CH3:18][C:14]1[CH:13]=[C:12]([C:10](=[O:11])[CH2:9][C@H:8]([C:5]2[CH:4]=[CH:3][C:2]([CH2:27][C:28]([OH:30])=[O:29])=[CH:7][CH:6]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH:17]=[CH:16][N:15]=1

Participants

10

Reactant 6

HCID 176Acetic AcidHCID 3939Lithium HydroxideHCID 7761Diethyl MalonateHCID 25517Ammonium ChlorideHCID 516920Potassium bisulfateHCID 66666695(R)-3-(4-Bromo-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one

Product 1

HCID 66666225(R)-2-(4-(3-(2-methylpyridin-4-yl)-3-oxo-1-o-tolylpropyl)phenyl)acetic acidYield 59.1%

Reagents, catalysts & solvents 3

HCID 27342152-(Di-tert-butylphosphino)biphenylCatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 887MethanolSolvent

Conditions

Temperature
135 °C

Procedure

A mixture of (R)-3-(4-bromophenyl)-1-(2-methylpyridin-4-yl)-3-o-tolylpropan-1-one (example 142, step 2; 3.5 g, 8.88 mmol), diethyl malonate (67.5 g, 421 mmol) sodium hydride (724 mg, 18.1 mmol), tris(dibenzylideneacetone)dipalladium(0) (475 mg, 518 μmol) and 2-(di-tert-butylphosphino)biphenyl (155 mg, 518 μmol) in was heated at 135° C. for 90 min. After cooling the reaction mixture was partitioned between sat. aq. ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in water (13 mL) and acetic acid (19 mL, 19.8 mmol) then under cooling conc. sulfuric acid (11.9 g, 116 mmol) was added dropwise at a temperature below 30° C. The reaction mixture was heated at 120° C. for 16 h, then partitioned between 2 M aq. sodium hydroxide solution and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in tetrahydrofuran (110 mL), then after addition of 1 M aq. lithium hydroxide solution (350 mL, 350 mmol) and methanol (110 mL) the reaction mixture was stirred for 3 h at room temperature. After addition of 1 M aq. potassium hydrogensulfate solution (60 mL) and sat. aq. ammonium chloride solution (100 mL) the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. Chromatography (SiO2) produced the title compound (1.96 g, 59%). White foam, MS (ESI+): m/z=374.3 ([M+H]+).

Workup

  1. temperatureAfter cooling the reaction mixture
  2. customwas partitioned between sat. aq. ammonium chloride solution and ethyl acetate
  3. washThe organic layer was washed with brine
  4. dry with materialdried over magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. dissolutionThe residue was dissolved in water (13 mL)
  8. temperatureThe reaction mixture was heated at 120° C. for 16 h
  9. custompartitioned between 2 M aq. sodium hydroxide solution and ethyl acetate
  10. washThe organic layer was washed with brine
  11. dry with materialdried over sodium sulfate
  12. filtrationfiltered
  13. concentrationconcentrated in vacuo
  14. dissolutionThe residue was dissolved in tetrahydrofuran (110 mL)
  15. extractionwas extracted with ethyl acetate
  16. washThe organic layer was washed with brine
  17. dry with materialdried over sodium sulfate
  18. filtrationfiltered
  19. concentrationconcentrated

Sources & evidence

ORD record
ord-a06b150409584ed6a54eb0889079f6aa
Source dataset
uspto-grants-2014_07
Patent number
US08765730B2

Reaction notes

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