Trimethylsilylacetylene → Ethyl 8-[(2,6-difluorobenzyl)oxy]-2-methyl-6-[(trimethylsilyl)ethynyl]imidazo[1,2-a]pyridine-3-carboxylate

HRID 1844148Notes

Reaction equation

HRID 1844148 reaction equation
Br[C:2]1[CH:3]=[C:4]([O:17][CH2:18][C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])[C:5]2[N:6]([C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=1.[CH3:27][Si:28]([C:31]#[CH:32])([CH3:30])[CH3:29]>O1CCOCC1.C(N(C(C)C)CC)(C)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.[Cu]I>[F:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([F:25])[C:19]=1[CH2:18][O:17][C:4]1[C:5]2[N:6]([C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=[C:2]([C:32]#[C:31][Si:28]([CH3:30])([CH3:29])[CH3:27])[CH:3]=1

Participants

6

Reactant 2

HCID 66111TrimethylsilylacetyleneHCID 86717880Ethyl 6-bromo-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylate

Product 1

HCID 86718172Ethyl 8-[(2,6-difluorobenzyl)oxy]-2-methyl-6-[(trimethylsilyl)ethynyl]imidazo[1,2-a]pyridine-3-carboxylate

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalystHCID 68856316Dioxane diisopropylethylamineSolvent

Conditions

Temperature
50 °C

Procedure

1 g of ethyl 6-bromo-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylate (Example 21A; 2.35 mmol; 1 equivalent) was initially charged in 52 ml of dioxane/diisopropylethylamine 1:1, and 165 mg of dichlorobis(triphenylphosphine)palladium(II) (0.24 mmol, 0.1 equivalents) and 45 mg of copper(I) iodide (0.24 mmol, 0.1 equivalents) were added. At RT, 1.3 ml of trimethylsilylacetylene (9.4 mmol, 4 equivalents) were slowly added dropwise. The resulting reaction mixture was stirred at 50° C. for 16 h. The mixture was then concentrated, water was added and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed twice with 10% strength aqueous sodium thiosulphate solution and then with saturated sodium chloride solution and dried over magnesium sulphate, and the filtrate was concentrated. The residue was dissolved in methanol and purified by preparative HPLC (column: Nucleodur C18 Gravity 50×200 mm, 10 μm, gradient: A=water+0.1% concentrated aqueous ammonia solution, B=acetonitrile, 0 min=30% B, 5 min=30% B, 23 min=100% B, 28 min=100% B, 28.2 min=30% B, 34 min=30% B, flow rate 110 ml/min, wavelength 220 nm). This gave 726 mg of a solid (89% pure, 62% of theory).

Workup

  1. additionwere added
  2. customThe resulting reaction mixture
  3. concentrationThe mixture was then concentrated
  4. additionwater was added
  5. extractionthe mixture was extracted three times with ethyl acetate
  6. washThe combined organic phases were washed twice with 10% strength aqueous sodium thiosulphate solution
  7. dry with materialwith saturated sodium chloride solution and dried over magnesium sulphate
  8. concentrationthe filtrate was concentrated
  9. dissolutionThe residue was dissolved in methanol
  10. custompurified by preparative HPLC (column
  11. customA=water+0.1% concentrated aqueous ammonia solution, B=acetonitrile, 0 min=30% B, 5 min=30% B, 23 min=100% B, 28 min=100% B, 28.2 min=30% B, 34 min=30% B, flow rate 110 ml/min, wavelength 220 nm

Sources & evidence

ORD record
ord-8cf3af3eeca740e6b8bd1879e9e7b407
Source dataset
uspto-grants-2015_02
Patent number
US08946215B2

Reaction notes

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