Water → (3Z)-5-fluoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylidene]-4-{2-[(2S)-pyrrolidin-2-yl]ethynyl}-2,3-dihydro-1H-indol-2-one

HRID 366713

反応式

HRID 366713 の反応式
C([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]#[CH:14])(OC(C)(C)C)=O.[F:15][C:16]1[C:17](I)=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])/[C:19]/2=[CH:26]\[C:27]1[NH:28][CH:29]=[CH:30][C:31]=1[O:32][CH3:33].O>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.FC(F)(F)C(O)=O.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:15][C:16]1[C:17]([C:14]#[C:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])/[C:19]/2=[CH:26]\[C:27]1[NH:28][CH:29]=[CH:30][C:31]=1[O:32][CH3:33]

参加物

10

反応物 3

HCID 962WaterHCID 11030701(S)-N-Boc-2-ethynylpyrrolidineHCID 18363902(3Z)-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylidene]-2,3-dihydro-1H-indol-2-one2 回

生成物 1

HCID 23645082(3Z)-5-fluoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylidene]-4-{2-[(2S)-pyrrolidin-2-yl]ethynyl}-2,3-dihydro-1H-indol-2-one

試薬・触媒・溶媒 6

HCID 178418397HCID 178418397、化合物触媒HCID 6228Dimethylformamide溶媒HCID 6344Dichloromethane溶媒HCID 6422Trifluoroacetic acid溶媒HCID 8471Triethylamine溶媒HCID 8857Ethyl Acetate溶媒2 回

実験手順

Using Method C above, (S)-N-Boc-2-ethynyl-pyrrolidine (100 mg, 0.52 mmol) (Example 87B) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.13 mmol) (Starting Material 6) using (Ph3P)4Pd (15 mg, 0.01 mmol) and a catalytic amount of Cul in a mixture of DMF (4 mL) and Et3N (4 mL) as solvent at 80° C. for 4 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4, concentrated and the residue was chromatographed on a silica gel column with a 40-70% EtOAc in hexanes gradient. The intermediate that was obtained from this operation was directly dissolved at 0° C., in 5 mL of a solution of 50% trifluoroacetic acid in CH2Cl2 that contained 0.2 mL of H2O and stirred for 2.5 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with ammonium hydroxide. The organic layer was dried over Na2SO4 and concentrated. (S)-(Z)-1,3-Dihydro-5-fluoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-4-[(pyrrolidin-2-yl)ethynyl]-2H-indol-2-one was obtained after reverse phase column chromatography with 0-90% MeOH in H2O gradient, a silica gel column chromatography with neat THF and a precipitatiion out of THF with excess of hexanes. (Yield 8 mg, 18%).

後処理

  1. extractionextracted with H2O
  2. dry with materialThe organic layer was dried over Na2SO4
  3. concentrationconcentrated
  4. customthe residue was chromatographed on a silica gel column with a 40-70% EtOAc in hexanes gradient
  5. customThe intermediate that was obtained from this operation
  6. extractionextracted with ammonium hydroxide
  7. dry with materialThe organic layer was dried over Na2SO4
  8. concentrationconcentrated

出典と根拠

ORDレコード
ord-3c29e096011740cdb69dee8f4eeb1d73
出典データセット
uspto-grants-2000_10
特許番号
US06130239

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