3-(Trifluoromethyl)phenyl isocyanate → 4-Fluoro-5-(6-methanesulfonylmethyl-pyrimidin-4-yloxy)-2-methyl-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide

HRID 45113

Reaktionsgleichung

Reaktionsgleichung von HRID 45113
[F:1][C:2]1[C:10]([O:11][C:12]2[CH:17]=[C:16]([CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:23])[NH:6]2.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[N:34]([C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=1)=[C:35]=[O:36]>C1COCC1>[F:44][C:43]([F:45])([F:46])[C:39]1[CH:38]=[C:37]([NH:34][C:35]([N:6]2[C:7]3[C:3](=[C:2]([F:1])[C:10]([O:11][C:12]4[CH:17]=[C:16]([CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[N:15]=[CH:14][N:13]=4)=[CH:9][CH:8]=3)[CH:4]=[C:5]2[CH3:23])=[O:36])[CH:42]=[CH:41][CH:40]=1

Komponenten

5

Edukt 3

HCID 94833-(Trifluoromethyl)phenyl isocyanateHCID 2733832Lithium HexamethyldisilazideHCID 593945944-Fluoro-5-(6-methanesulfonylmethyl-pyrimidin-4-yloxy)-2-methyl-1H-indole

Produkt 1

HCID 593941124-Fluoro-5-(6-methanesulfonylmethyl-pyrimidin-4-yloxy)-2-methyl-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 8028TetrahydrofuranLösungsmittel2×

Reaktionsbedingungen

Temperatur
-78 °C

Versuchsvorschrift

4-Fluoro-5-(6-methanesulfonylmethyl-pyrimidin-4-yloxy)-2-methyl-1H-indole (250 mg, 0.745 mmol) in THF (10 mL) is cooled to −78° C. and a 1 M solution of LiHMDS in THF (1.86 mL, 1.86 mmol) is added. After 12 min 1-isocyanato-3-(trifluoromethyl)-benzene (0.12 mL, 0.895 mmol) is added and the reaction is allowed to stir at −78° C. After 1 h the reaction is quenched with saturated aqueous NH4Cl and then extracted with (3×100 mL) EtOAc, The organic phases are combined and washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue is purified FCC (0-3% MeOH/DCM) to provide 4-fluoro-5-(6-methanesulfonylmethyl-pyrimidin-4-yloxy)-2-methyl-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide. MS (ESI) m/z 523.1 (M+1); 1H NMR (400 MHz, DMSO-d6) ppm 10.99 (s, 1 H), 8.77 (d, J=1.01 Hz, 1 H), 8.12 (s, 1 H), 7.91 (s, 1 H), 7.66 (s, 1 H), 7.53 (d, J=9.35 Hz, 2 H), 7.36 (d, J=1.01 Hz, 1 H), 7.20 (d, J=7.33 Hz, 1 H), 6.64 (s, 1 H), 4.73 (s, 2 H), 3.13 (s, 3 H), 2.59 (s, 3 H).

Aufarbeitung

  1. customAfter 1 h the reaction is quenched with saturated aqueous NH4Cl
  2. extractionextracted with (3×100 mL) EtOAc
  3. washwashed with brine
  4. dry with materialdried over Na2SO4
  5. concentrationconcentrated in vacuo
  6. customThe residue is purified FCC (0-3% MeOH/DCM)

Quellen und Nachweise

ORD-Eintrag
ord-6e6f9df6a7464933b2d1673c534441cd
Quelldatensatz
uspto-grants-2013_09
Patentnummer
US08541432B2

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