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

HRID 1971387

반응식

HRID 1971387 반응식
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

참가 물질

6

반응물 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

생성물 1

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

시약·촉매·용매 1

HCID 6344Dichloromethane용매

실험 절차

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, 1 H), 8.72 (s, 1 H), 8.30 (d, J=8.84 Hz, 1 H), 8.14 (d, J=3.79 Hz, 1 H), 8.10 (s, 1 H), 7.97 (s, 1 H), 7.65 (t, J=8.08 Hz, 1 H), 7.51 (d, J=2.53 Hz, 2 H), 7.16 (dd, J=8.84, 2.27 Hz, 1 H), 7.12 (s, 1 H), 6.81 (d, J=3.54 Hz, 1 H), 3.63 (br. S., 1 H), 3.14 (d, J=7.33 Hz, 1 H), 2.94 (br. S., 1 H), 1.99 (br. S., 1 H), 1.25 (d, J=6.06 Hz, 6 H).

후처리

  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)

출처 및 근거

ORD 기록
ord-5a143a84f68b45d9b54f18e726971e22
출처 데이터셋
uspto-grants-2013_04
특허 번호
US08431584B2

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