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

HRID 380907

반응식

HRID 380907 반응식
C([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]#[CH:14])(OC(C)(C)C)=O.[C:15]([C:18]1[CH:19]=[C:20](/[CH:23]=[C:24]2\[C:25](=[O:35])[NH:26][C:27]3[C:32]\2=[C:31](I)[C:30]([F:34])=[CH:29][CH:28]=3)[NH:21][CH:22]=1)(=[O:17])[CH3:16].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.[Cu]I>[C:15]([C:18]1[CH:19]=[C:20](/[CH:23]=[C:24]2\[C:25](=[O:35])[NH:26][C:27]3[C:32]\2=[C:31]([C:14]#[C:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)[C:30]([F:34])=[CH:29][CH:28]=3)[NH:21][CH:22]=1)(=[O:17])[CH3:16]

참가 물질

11

반응물 3

HCID 962WaterHCID 11030701(S)-N-Boc-2-ethynylpyrrolidineHCID 18366029(Z)-3-[(4-Acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one

생성물 1

HCID 59959920(S)-(Z)-3-[(4-Acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-[(pyrrolidin-2-yl)ethynyl]-2H-indol-2-one

시약·촉매·용매 7

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)촉매HCID 178418397HCID 178418397, 화합물촉매HCID 6228Dimethylformamide용매HCID 6344Dichloromethane용매HCID 6422Trifluoroacetic acid용매HCID 8471Triethylamine용매HCID 8857Ethyl Acetate용매2회

실험 절차

Using Method C above, (S)-N-Boc-2-Ethynyl-pyrrolidine (220 mg, 1.13 mmol) (Example 87B) was coupled with (Z)-3-[(4-acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one (150 mg, 0.38 mmol) (Example 90B) using (Ph3P)4Pd (44 mg, 0.04 mmol) and a catalylic amount of CuI in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 7 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 0-5% MeOH in CH2Cl2 gradient. The intermediate that resulted from this process was dissolved in 6 mL of a 50% trifluoroacetic acid in CH2Cl2 solution that contained 0.3 mL of H2O at 0° C. and stirred for 2 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with ammonium hydroxide. The organic layer was dried over Na2SO4 and concentrated. The (S)-(Z)-3-[(4-Acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-[(pyrrolidin-2-yl)ethynyl]-2H-indol-2-one was obtained after silica gel column with a 0-10% MeOH in CH2Cl2 gradient and precipitation out of THF with excess of pentane. (Yield 56 mg, 41%).

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 0-5% MeOH in CH2Cl2 gradient
  5. customThe intermediate that resulted from this process
  6. customat 0° C.
  7. extractionextracted with ammonium hydroxide
  8. dry with materialThe organic layer was dried over Na2SO4
  9. concentrationconcentrated

출처 및 근거

ORD 기록
ord-0072eb1188324bf39e153bc8241d6766
출처 데이터셋
uspto-grants-2001_10
특허 번호
US06303793B1

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