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

HRID 2038636

反応式

HRID 2038636 の反応式
[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]

参加物

9

反応物 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

生成物 1

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

試薬・触媒・溶媒 4

HCID 83717Copper iodide触媒HCID 6093782Bis(acetonitrile)dichloropalladium触媒HCID 887Methanol溶媒HCID 6344Dichloromethane溶媒

実験手順

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.

後処理

  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))

出典と根拠

ORDレコード
ord-177ce7fb69d542e29ed5370427ee228d
出典データセット
uspto-grants-2013_11
特許番号
US08575391B2

関連ノート

読み込み中…