Trifluoroacetic acid → (+/-)-5-[6-(3-Carbamoyl-pyrrolidin-1-ylmethyl)-pyrimidin-4-yloxy]-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide

HRID 1887614

Reaktionsgleichung

Reaktionsgleichung von HRID 1887614
C(O[C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13](=[O:15])[NH2:14])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[F:23][C:24]([F:57])([F:56])[C:25]1[CH:26]=[C:27]([NH:31][C:32]([N:34]2[C:42]3[C:37](=[CH:38][C:39]([O:43][C:44]4[N:49]=[CH:48][N:47]=[C:46](COS(C)(=O)=O)[CH:45]=4)=[CH:40][CH:41]=3)[CH:36]=[CH:35]2)=[O:33])[CH:28]=[CH:29][CH:30]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:56][C:24]([F:23])([F:57])[C:25]1[CH:26]=[C:27]([NH:31][C:32]([N:34]2[C:42]3[C:37](=[CH:38][C:39]([O:43][C:44]4[CH:45]=[C:46]([CH2:6][N:8]5[CH2:12][CH2:11][CH:10]([C:13](=[O:15])[NH2:14])[CH2:9]5)[N:47]=[CH:48][N:49]=4)=[CH:40][CH:41]=3)[CH:36]=[CH:35]2)=[O:33])[CH:28]=[CH:29][CH:30]=1

Komponenten

6

Edukt 4

HCID 6422Trifluoroacetic acidHCID 81531DiisopropylethylamineHCID 4571096Tert-butyl 3-carbamoylpyrrolidine-1-carboxylateHCID 46224264methanesulfonic acid 6-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyrimidin-4-ylmethyl ester

Produkt 1

HCID 59394341(+/-)-5-[6-(3-Carbamoyl-pyrrolidin-1-ylmethyl)-pyrimidin-4-yloxy]-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 6344DichloromethaneLösungsmittel

Versuchsvorschrift

3-Carbamoyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.22 g, 1.03 mmol) is dissolved in DCM (5 mL). TFA (2 mL, 26.0 mmol) is added and the reaction is allowed to stir at rt overnight. The solvent is removed in vacuo and THF (5.0 mL) is added followed by methanesulfonic acid 6-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyrimidin-4-ylmethyl ester (0.347 g, 0.685 mmol) and DIEA (0.60 mL, 3.42 mmol). The reaction is heated at 60° C. for 19 h. The solvent is removed in vacuo and the residue separated by FCC (0-15%, 10% NH3MeOH/DCM) to provide (±)-5-[6-(3-carbamoyl-pyrrolidin-1-ylmethyl)-pyrimidin-4-yloxy]-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide. MS (ESI) m/z 524.9 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 10.41 (s, 1H), 8.72 (s, 1H), 8.30 (d, J=8.84 Hz, 1H), 8.14 (d, J=3.79 Hz, 1H), 8.10 (s, 1H), 7.97 (s, 1H), 7.65 (t, J=8.08 Hz, 1H), 7.51 (d, J=2.53 Hz, 2H), 7.16 (dd, J=8.84, 2.27 Hz, 1H), 7.12 (s, 1H), 6.81 (d, J=3.54 Hz, 1H), 3.63 (br. S., 1H), 3.14 (d, J=7.33 Hz, 1H), 2.94 (br. S., 1H), 1.99 (br. S., 1H), 1.25 (d, J=6.06 Hz, 6H).

Aufarbeitung

  1. customThe solvent is removed in vacuo and THF (5.0 mL)
  2. additionis added
  3. temperatureThe reaction is heated at 60° C. for 19 h
  4. customThe solvent is removed in vacuo
  5. customthe residue separated by FCC (0-15%, 10% NH3MeOH/DCM)

Quellen und Nachweise

ORD-Eintrag
ord-dd2079801ec343339a8ea1e9975925a3
Quelldatensatz
uspto-grants-2013_08
Patentnummer
US08501756B2

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