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

반응식

HRID 366713 반응식
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]

참가 물질

10

반응물 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-one2회

생성물 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

시약·촉매·용매 6

HCID 178418397HCID 178418397, 화합물촉매HCID 6228Dimethylformamide용매HCID 6344Dichloromethane용매HCID 6422Trifluoroacetic acid용매HCID 8471Triethylamine용매HCID 8857Ethyl Acetate용매2회

실험 절차

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%).

후처리

  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

출처 및 근거

ORD 기록
ord-3c29e096011740cdb69dee8f4eeb1d73
출처 데이터셋
uspto-grants-2000_10
특허 번호
US06130239

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