Methanol → 7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[(4-methoxyphenyl)ethynyl]thieno[3,2-b]pyridine-6-carbonitrile

HRID 1611521Notes

Reaction equation

HRID 1611521 reaction equation
[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21](I)[S:22][C:13]=12.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)#[CH:25].CO>C(N(CC)CC)C.C1C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21]([C:25]#[C:24][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[S:22][C:13]=12

Participants

8

Reactant 3

HCID 887MethanolHCID 2510201-Ethynyl-4-methoxybenzeneHCID 103902087-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile

Product 1

HCID 222566357-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[(4-methoxyphenyl)ethynyl]thieno[3,2-b]pyridine-6-carbonitrileYield 68.4%

Reagents, catalysts & solvents 4

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 241BenzeneSolvent2×HCID 8471TriethylamineSolvent2×

Procedure

A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile (134 mg, 0.28 mmol), 1-ethynyl-4-methoxybenzene (50 μL, 0.39 mmol), 3 mg of tetrakis(triphenylphosphine)palladium(0) and 5 mg of copper(I) iodide in 2 mL of triethylamine and 7 mL of benzene is heated at reflux for 24 hours. An additional 1 mL of triethylamine and 4 mL of benzene are added and the reaction is heated at reflux for 6 hours. The mixture is cooled to room temperature and 2 mL of methanol are added. The solvents are removed in vacuo and the residue is treated with 10 mL of ethyl acetate. The insoluble material is removed by filtration, washing with ethyl acetate. The filtrate is washed with 10% aqueous hydrochloric acid, water, and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 4:1 hexane:ethyl acetate to provide 92 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[(4-methoxyphenyl)ethynyl]thieno[3,2-b]pyridine-6-carbonitrile as yellow crystals, mp 249-250° C.; 1H NMR (DMSO-d6) δ 3.81 (s, 3H), 3.86 (s, 3H), 7.01 (d, J=7 Hz, 2H), 7.40 (s, 1H), 7.55 (d, J=7 Hz, 2H), 7.70 (s, 1H), 7.79 (s, 1H), 8.65 (s, 1H), 9.81 (s, 1H); MS 477.9, 479.9 (M−H)−.

Workup

  1. temperatureis heated
  2. temperatureat reflux for 24 hours
  3. temperaturethe reaction is heated
  4. temperatureat reflux for 6 hours
  5. customThe solvents are removed in vacuo
  6. additionthe residue is treated with 10 mL of ethyl acetate
  7. customThe insoluble material is removed by filtration
  8. washwashing with ethyl acetate
  9. washThe filtrate is washed with 10% aqueous hydrochloric acid, water, and saturated aqueous sodium chloride
  10. dry with materialdried over magnesium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated in vacuo
  13. customThe residue is purified by flash column chromatography
  14. washeluting with 4:1 hexane

Sources & evidence

ORD record
ord-369a05a6fcb0465c9e810c2dc93b16dd
Source dataset
uspto-grants-2006_01
Patent number
US06987116B2

Reaction notes

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