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

HRID 1971379

Reaktionsgleichung

Reaktionsgleichung von HRID 1971379
[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

Komponenten

5

Edukt 3

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

Produkt 1

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

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 8028TetrahydrofuranLösungsmittel2×

Reaktionsbedingungen

Temperatur
-78 °C

Versuchsvorschrift

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 pooled 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).

Aufarbeitung

  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)

Quellen und Nachweise

ORD-Eintrag
ord-880b5edc00a246a69a3d23e5f7a99d93
Quelldatensatz
uspto-grants-2013_04
Patentnummer
US08431584B2

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