Acetic Acid → [1-(1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl)-cyclopropyl]acetonitrile

HRID 1451533Notes

Reaction equation

HRID 1451533 reaction equation
O=[C:2]([CH3:10])[CH2:3][C:4]1([CH2:7][C:8]#[N:9])[CH2:6][CH2:5]1.Cl.[Br:12][C:13]1[CH:29]=[CH:28][C:16]([CH2:17][N:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)N)=[CH:15][CH:14]=1.C(O)(=O)C.Cl>C1(C)C=CC=CC=1>[Br:12][C:13]1[CH:29]=[CH:28][C:16]([CH2:17][N:18]2[C:20]3[C:21](=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[C:3]([C:4]3([CH2:7][C:8]#[N:9])[CH2:6][CH2:5]3)=[C:2]2[CH3:10])=[CH:15][CH:14]=1

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 313Hydrochloric AcidHCID 190416812-[1-(2-Oxopropyl)cyclopropyl]acetonitrileHCID 19041688N-(p-Bromobenzyl)-N-(4-methoxyphenyl)hydrazine hydrochloride

Product 1

HCID 19041631[1-(1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl)-cyclopropyl]acetonitrileYield 84.5%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

To a 0° C. mixture of the ketone from Step 4 (920 mg, 6.71 mmol) and the hydrazine from Step 5 (2.15 g, 7.0 mmol) in 35 mL toluene was added acetic acid (0.97 mL, 17 mmol). The mixture was warmed to room temperature and stirred 1 h, then concentrated to dryness. The residue was dissolved in toluene and heptane and concentrated again and the process repeated until there was no more acetic acid remaining. The residue was then dissolved in 30 mL dioxane and treated with HCl (4M solution in dioxane, 4 mL, 16 mmol). The mixture was heated to 60° C. for 1.5 h, then cooled and partitioned between water and ethyl acetate. The organic phase was washed with saturated NaHCO3 and brine, dried over MgSO4 and evaporated. Purification by flash chromatography (15% ethyl acetate/hexanes) provided 2.32 g of the title compound.

Workup

  1. concentrationconcentrated to dryness
  2. dissolutionThe residue was dissolved in toluene
  3. concentrationheptane and concentrated again
  4. dissolutionThe residue was then dissolved in 30 mL dioxane
  5. temperatureThe mixture was heated to 60° C. for 1.5 h
  6. temperaturecooled
  7. custompartitioned between water and ethyl acetate
  8. washThe organic phase was washed with saturated NaHCO3 and brine
  9. dry with materialdried over MgSO4
  10. customevaporated
  11. customPurification by flash chromatography (15% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-23fb8eea524143e492707746f13c9390
Source dataset
uspto-grants-1997_02
Patent number
US05604253

Reaction notes

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