Acetonitrile → HCID 10977406, compound

HRID 394592Notes

Reaction equation

HRID 394592 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[CH:6]=[CH:5]2.C[Si]([C:22]#[CH:23])(C)C.C(N(CC)CC)C.C(#N)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:22]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[CH:6]=[CH:5]2)#[CH:23]

Participants

7

Reactant 4

HCID 6342AcetonitrileHCID 8471TriethylamineHCID 66111TrimethylsilylacetyleneHCID 15006438HCID 15006438, compound

Product 1

HCID 10977406HCID 10977406, compoundYield 35.1%

Reagents, catalysts & solvents 2

HCID 178418476HCID 178418476, compoundCatalystHCID 962WaterSolvent

Procedure

A mixture of 5-bromo-1-(4-fluorphenyl)-1H-indole (40 g) (prepared as described by Perregaard et al. J. Med. Chem. 1992 35, 1092-1101), (trimethylsilyl)acetylen (21.4 g), bis(triphenylphospine)palladium(II) dichloride (2.9 g) copper(I) iodide (1.3 g), triethylamine (40 mL) and acetonitrile (150 mL) was boiled under reflux for 8 hours. After cooling to room temperature, water was added and the resulting mixture was extracted with ethyl acetate (4×300 mL). The combined organic phases were washed with brine (2×800 mL), dried (Na2SO4) and the solvents evaporated in vacuo. A solution of the remaining oil and potassium hydroxide (12.1 g) in a mixture of methanol (500 mL) and water (200 mL) was boiled at reflux for 3 h. The volatile solvents were evaporated in vacuo and a mixture of water (200 mL) and ethyl acetate (1000 mL) was added. The phases were separated and the aqueous phase extracted with ethyl acetate (250 mL). The combined organic phases were dried (Na2SO4) and the volatile solvents evaporated in vacuo. Purification of the remaining oil by column chromatography on silica gel (dichloromethane/heptane 1:6) afforded crystalline pure title compound 18a (11.4 g): Sp 99-100° C.; 1H NMR (CDCl3) δ 3.00 (s, 1H), 6.55 (d, 1H), 7.20 (t, 2H), 7.25 (d, 1H), 7.35 (m, 2H), 7.40 (dd, 2H), 7.85 (broad s, 1H).

Workup

  1. temperatureunder reflux for 8 hours
  2. extractionthe resulting mixture was extracted with ethyl acetate (4×300 mL)
  3. washThe combined organic phases were washed with brine (2×800 mL)
  4. dry with materialdried (Na2SO4)
  5. customthe solvents evaporated in vacuo
  6. additionA solution of the remaining oil and potassium hydroxide (12.1 g) in a mixture of methanol (500 mL) and water (200 mL)
  7. temperatureat reflux for 3 h
  8. customThe volatile solvents were evaporated in vacuo
  9. additiona mixture of water (200 mL) and ethyl acetate (1000 mL)
  10. additionwas added
  11. customThe phases were separated
  12. extractionthe aqueous phase extracted with ethyl acetate (250 mL)
  13. dry with materialThe combined organic phases were dried (Na2SO4)
  14. customthe volatile solvents evaporated in vacuo
  15. customPurification of the remaining oil by column chromatography on silica gel (dichloromethane/heptane 1:6)

Sources & evidence

ORD record
ord-8fbe04832913401abdd192345dfde17f
Source dataset
uspto-grants-2003_08
Patent number
US06602889B1

Reaction notes

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