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

HRID 884578Notes

Reaction equation

HRID 884578 reaction equation
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

Participants

6

Reactant 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

Product 1

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

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

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).

Workup

  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)

Sources & evidence

ORD record
ord-43d579fb78ab4c6b9aad55e342331792
Source dataset
uspto-grants-2012_08
Patent number
US08242125B2

Reaction notes

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