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

HRID 2038636

반응식

HRID 2038636 반응식
[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]

참가 물질

9

반응물 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

생성물 1

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

시약·촉매·용매 4

HCID 83717Copper iodide촉매HCID 6093782Bis(acetonitrile)dichloropalladium촉매HCID 887Methanol용매HCID 6344Dichloromethane용매

실험 절차

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.

후처리

  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))

출처 및 근거

ORD 기록
ord-177ce7fb69d542e29ed5370427ee228d
출처 데이터셋
uspto-grants-2013_11
특허 번호
US08575391B2

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