4,4,4-trifluorocrotononitrile → 4,4,4-Trifluoro-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile

HRID 880582노트

반응식

HRID 880582 반응식
[NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.[CH:23](/[C:29]#[N:30])=[CH:24]\[C:25]([F:28])([F:27])[F:26]>C(#N)C>[F:26][C:25]([F:28])([F:27])[CH:24]([N:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1)[CH2:23][C:29]#[N:30]

참가 물질

4

반응물 2

HCID 57087824,4,4-trifluorocrotononitrileHCID 426313464-(1H-Pyrazol-4-yl)-7-(2-(trimethylsilyl)ethoxy)methyl-7 H-pyrrolo(2,3-d)-pyrimidine

생성물 1

HCID 574776494,4,4-Trifluoro-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile수율 91.3%

시약·촉매·용매 1

HCID 6342Acetonitrile용매

실험 절차

To a flask equipped with a mechanical stirrer, nitrogen inlet and thermowell was added compound 4-(1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (5, 1424 g, 4.52 mol) and acetonitrile (14 L). The resulting suspension was added 4,4,4-trifluorocrotonitrile (32, 601.6 g, 4.97 mol, 1.1 equiv) followed by 1,8-diazobicyclo[5.4.0]undec-7-ene (DBU, 67 mL, 0.452 mol, 0.1 equiv). A slight exotherm (5° C.) was noted upon the addition of the DBU. The reaction mixture was stirred at room temperature for 30 minutes when TLC and LCMS showed the reaction was deemed complete. The reaction mixture was then concentrated under reduced pressure to remove most of the solvent and the residue was purified by two silica gel columns (3 Kg each) for chromatography purification. The column was eluting with 2:1 heptane/ethyl acetate (30 L) followed by 1:1 heptane/ethyl acetate (30 L). The fractions containing pure desired product (33) were combined and concentrated under reduced pressure to afford racemic 4,4,4-trifluoro-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)butanenitrile (33, Racemic SEM-protected compound, 1802 g, 1973 g theoretical, 91.3% yield) as a thick oil, which was directly used in subsequent chiral column separation without further purification. For 33: 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.99 (s, 1H), 8.79 (s, 1H), 8.56 (s, 1H), 7.80 (d, 1H, J=3.7 Hz), 7.09 (d, 1H, J=3.7 Hz), 6.05 (m, 1H), 5.63 (s, 2H), 3.82 (dd, 1H, J=17.5, 10.6 Hz), 3.66 (dd, 1H, J=17.0, 4.9 Hz), 3.50 (t, 2H, J=7.9 Hz), 0.80 (t, 2H, J=8.2 Hz), −0.145 (s, 9H); 13C NMR (DMSO-d6, 100 MHz) δ ppm 151.7, 151.3, 149.5, 140.8, 132.9, 130.4, 123.2 (JCF=282 Hz), 121.9, 116.2, 113.5, 100.2, 72.3, 65.7, 57.8 (JCF=32.4 Hz), 17.1, −1.46; C19H23F3N6OSi (MW, 436.51), LCMS (EI) m/e 437 (M++H).

후처리

  1. customTo a flask equipped with a mechanical stirrer, nitrogen inlet
  2. concentrationThe reaction mixture was then concentrated under reduced pressure
  3. customto remove most of the solvent
  4. customthe residue was purified by two silica gel columns (3 Kg each) for chromatography purification
  5. washThe column was eluting with 2:1 heptane/ethyl acetate (30 L)
  6. additionThe fractions containing pure desired product (33)
  7. concentrationconcentrated under reduced pressure

출처 및 근거

ORD 기록
ord-9dde85fb6df64a3984b78a3ce66b78dd
출처 데이터셋
uspto-grants-2015_03
특허 번호
US08993582B2

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