Trimethylsilylacetylene → 2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-(3-oxo-isoxazolidin-2-ylmethyl)-benzamide

HRID 2038636Notes

Reaction equation

HRID 2038636 reaction equation
[F:1][C:2]1[C:3]([NH:23][C:24]2[CH:29]=[CH:28][C:27](I)=[CH:26][C:25]=2[F:31])=[C:4]([CH:12]=[C:13]([CH2:16][N:17]2[C:21](=[O:22])[CH2:20][CH2:19][O:18]2)[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].[CH:32](N(CC)C(C)C)(C)[CH3:33].C[Si](C#C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CO.C(Cl)Cl.CC#N.CC#N.Cl[Pd]Cl.[Cu](I)I>[C:32]([C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:3]2[C:2]([F:1])=[C:14]([F:15])[C:13]([CH2:16][N:17]3[C:21](=[O:22])[CH2:20][CH2:19][O:18]3)=[CH:12][C:4]=2[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6])=[C:25]([F:31])[CH:26]=1)#[CH:33]

Participants

9

Reactant 4

HCID 66111TrimethylsilylacetyleneHCID 81531DiisopropylethylamineHCID 2724141Tetrabutylammonium FluorideHCID 116281803,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(3-oxo-isoxazolidin-2-ylmethyl)-benzamide

Product 1

HCID 116980742-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-(3-oxo-isoxazolidin-2-ylmethyl)-benzamideYield 37%

Reagents, catalysts & solvents 4

HCID 83717Copper iodideCatalystHCID 6093782Bis(acetonitrile)dichloropalladiumCatalystHCID 887MethanolSolventHCID 6344DichloromethaneSolvent

Procedure

3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(3-oxo-isoxazolidin-2-ylmethyl)-benzamide (36.9 mg, 66.9 μmol) obtained in Example 37, bis(acetonitrile)dichloropalladium (II) (3.5 mg, 13.5 μmol), 3,3′,3″-phosphinidine-tris(benzenesulfonic acid)trisodium salt (19.0 mg, 33.4 μmol), and copper iodide (I) (2.6 mg, 13.6 μmol) were suspended in methanol (2.5 ml) under a nitrogen atmosphere. To this suspension, N,N-diisopropylethylamine (14.0 μl, 80.4 μmol) and trimethylsilylacetylene (47.3 μl, 334.7 μmol) were added at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was diluted with methylene chloride (30 ml), and washed with saturated brine (2×15 ml). The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resultant residue was dissolved in THF (2 ml). To this solution, tetrabutylammonium fluoride (1.0 M solution in THF, 0.10 ml, 0.10 mmol) was added, and the mixture was stirred for 1 hour, and then concentrated under reduced pressure. The resultant residue was purified by preparative TLC (EtOAc/MeOH (8:1)) to give 2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-(3-oxo-isoxazolidin-2-ylmethyl)-benzamide (Compound G-5, 11.1 mg, 37%) as a brown oil.

Workup

  1. washwashed with saturated brine (2×15 ml)
  2. dry with materialThe organic layer was dried over anhydrous magnesium sulfate
  3. concentrationconcentrated under reduced pressure
  4. dissolutionThe resultant residue was dissolved in THF (2 ml)
  5. stirringthe mixture was stirred for 1 hour
  6. concentrationconcentrated under reduced pressure
  7. customThe resultant residue was purified by preparative TLC (EtOAc/MeOH (8:1))

Sources & evidence

ORD record
ord-177ce7fb69d542e29ed5370427ee228d
Source dataset
uspto-grants-2013_11
Patent number
US08575391B2

Reaction notes

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