Trimethylsilylacetylene → 4-(4-Ethynyl-2-fluoro-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid ethyl ester

HRID 917784Notes

Reaction equation

HRID 917784 reaction equation
[CH2:1]([O:3][C:4]([C:6]1[C:11]([NH:12][C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][C:14]=2[F:20])=[CH:10][C:9](=[O:21])[N:8]([CH3:22])[CH:7]=1)=[O:5])[CH3:2].[C:23]([Si](C)(C)C)#[CH:24].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CN(C=O)C.[Cu]I.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>[CH2:1]([O:3][C:4]([C:6]1[C:11]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:23]#[CH:24])=[CH:15][C:14]=2[F:20])=[CH:10][C:9](=[O:21])[N:8]([CH3:22])[CH:7]=1)=[O:5])[CH3:2]

Participants

7

Reactant 3

HCID 66111TrimethylsilylacetyleneHCID 2724141Tetrabutylammonium FluorideHCID 11362025Ethyl 4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate

Product 1

HCID 117714024-(4-Ethynyl-2-fluoro-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid ethyl esterYield 88.8%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalystHCID 21974620tetrahydrofuran N,N-dimethylformamideSolvent

Procedure

4-(2-Fluoro-4-iodo-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid ethyl ester (1.0 g, 2.40 mmol) was reacted with ethynyl-trimethyl-silane (0.70 mL, 4.80 mmol) in the presence of CuI (0.23 g, 1.20 mmol), (Ph3P)2PdCl2 (0.085 g, 0.12 mmol) and TEA (10 mL) in THF/DMF (4:1, 25 mL) which was stirred at room temperature for 24 hours. The reaction mixture was filtered pass through a pad of alumina (neutral). The filtrate was partitioned between water (20 mL) and EtOAc (100 mL). The organic layer was dried and concentrated under reduced pressure. The resulting residue was dissolved in THF (10 mL) and treated with the tetrabutylammonium fluoride (1M in THF, 2.40 mL, 2.4 mmol) which was stirred at room temperature for 15 hours. The reaction was partitioned between water (20 mL), and EtOAc (100 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel (5% MeOH/CH2Cl2 as eluant) to give 4-(4-Ethynyl-2-fluoro-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid ethyl ester as a light brown solid (0.67 g, 88%). 1H NMR [(CDCl3, 400 MHz] δ9.56 (s, 1H), 8.22 (s, 1H), 7.38 (dd, J=10.1, 1.9 Hz, 1H), 7.25 (s, 2H), 6.01 (s, 1H), 4.38 (q, J=7.1 Hz, 2H), 3.53 (s, 3H), 3.09 (s, 1H), 1.38 (t, J=7.1 Hz, 3H). Anal. Calcd for C17H15FIN2O3: C, 64.96; H, 4.81; N, 8.91. Found: C, 64.89; H, 4.40; N, 8.64.

Workup

  1. filtrationThe reaction mixture was filtered pass through a pad of alumina (neutral)
  2. customThe filtrate was partitioned between water (20 mL) and EtOAc (100 mL)
  3. customThe organic layer was dried
  4. concentrationconcentrated under reduced pressure
  5. dissolutionThe resulting residue was dissolved in THF (10 mL)
  6. stirringwas stirred at room temperature for 15 hours
  7. customThe reaction was partitioned between water (20 mL), and EtOAc (100 mL)
  8. dry with materialThe organic layer was dried over MgSO4
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. customThe resulting residue was purified by column chromatography on silica gel (5% MeOH/CH2Cl2 as eluant)

Sources & evidence

ORD record
ord-14624939fb764c3d8b212edea37dfe94
Source dataset
uspto-grants-2007_09
Patent number
US07273877B2

Reaction notes

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