1-Methylimidazole → (+/-)-5-{6-[Hydroxy-(1-methyl-1H-imidazol-2-yl)-methyl]-pyrimidin-4-yloxy}-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide

HRID 45111

반응식

HRID 45111 반응식
[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.C([Li])CCC.[F:12][C:13]([F:42])([F:41])[C:14]1[CH:15]=[C:16]([NH:20][C:21]([N:23]2[C:31]3[C:26](=[CH:27][C:28]([O:32][C:33]4[CH:38]=[C:37]([CH:39]=[O:40])[N:36]=[CH:35][N:34]=4)=[CH:29][CH:30]=3)[CH:25]=[CH:24]2)=[O:22])[CH:17]=[CH:18][CH:19]=1>C1COCC1>[F:41][C:13]([F:12])([F:42])[C:14]1[CH:15]=[C:16]([NH:20][C:21]([N:23]2[C:31]3[C:26](=[CH:27][C:28]([O:32][C:33]4[CH:38]=[C:37]([CH:39]([OH:40])[C:3]5[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=5)[N:36]=[CH:35][N:34]=4)=[CH:29][CH:30]=3)[CH:25]=[CH:24]2)=[O:22])[CH:17]=[CH:18][CH:19]=1

참가 물질

5

반응물 3

HCID 13901-MethylimidazoleHCID 866430855-(6-Formyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amideHCID 178418339Butyllithium

생성물 1

HCID 59394516(+/-)-5-{6-[Hydroxy-(1-methyl-1H-imidazol-2-yl)-methyl]-pyrimidin-4-yloxy}-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide

시약·촉매·용매 1

HCID 8028Tetrahydrofuran용매2회

반응 조건

온도
-78 °C

실험 절차

To a solution of 1-methyl-1H-imidazole (77 mg, 0.94 mmol) in 5 mL THF at −78° C. is added n-butyllithium (1.6 M in hexane, 0.44 mL). The solution is stirred at −78° C. for 1 h. Then, a solution of 5-(6-formyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide (200 mg, 0.47 mmol) in THF (5 mL) is added. The reaction is allowed to warm up to rt and stir overnight. At that time the reaction is quenched with water and then extracted with EtOAc (3×25 mL). The combined organic layers are washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue is then purified with semi-prep HPLC (C18; 30-100% I/H2O with 0.1% TFA) to give the title compound. The fractions are pololed and the pH is adjusted to 9 with sodium bicarbonate. The product is extracted with EtOAc. The organic layer is washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated to give the title compound. MS (ESI) m/z 509.0 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.59 (d, J=1.01 Hz, 1 H), 8.36 (d, J=9.09 Hz, 1 H), 8.06 (s, 1 H), 7.94 (d, J=3.79 Hz, 1 H), 7.90 (d, J=7.83 Hz, 1 H), 7.57 (m, 2 H), 7.46 (d, J=2.02 Hz, 1 H), 7.29 (s, 1 H), 7.16 (dd, J=8.97, 2.40 Hz, 1 H), 7.05 (d, J=1.26 Hz, 1 H), 6.85 (d, J=1.26 Hz, 1 H), 6.75 (d, J=3.54 Hz, 1 H), 5.91 (s, 1 H), 3.72 (s, 3 H).

후처리

  1. temperatureto warm up to rt
  2. stirringstir overnight
  3. customAt that time the reaction is quenched with water
  4. extractionextracted with EtOAc (3×25 mL)
  5. washThe combined organic layers are washed with brine
  6. dry with materialdried over anhydrous Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe residue is then purified with semi-prep HPLC (C18; 30-100% I/H2O with 0.1% TFA)

출처 및 근거

ORD 기록
ord-c71104fe9b1c44508d66756d27056151
출처 데이터셋
uspto-grants-2013_09
특허 번호
US08541432B2

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