Trifluoroacetic acid → 3-(2-(2-((2-Methoxy-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)benzamide

HRID 2272424Notes

Reaction equation

HRID 2272424 reaction equation
[C:1]([C:4]1[CH:5]=[C:6]([CH:41]=[CH:42][CH:43]=1)[CH2:7][CH2:8][C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)=[CH:22][C:21]=2[O:39][CH3:40])[N:10]=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C1COCC1>[CH3:40][O:39][C:21]1[CH:22]=[C:23]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:24]=[CH:25][C:20]=1[NH:19][C:11]1[N:10]=[C:9]([CH2:8][CH2:7][C:6]2[CH:5]=[C:4]([CH:43]=[CH:42][CH:41]=2)[C:1]([NH2:2])=[O:3])[C:14]([C:15]([F:16])([F:17])[F:18])=[CH:13][N:12]=1

Participants

4

Reactant 2

HCID 6422Trifluoroacetic acidHCID 68283219Tert-butyl 4-(4-((4-(3-carbamoylphenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidine-1-carboxylate

Product 1

HCID 601621213-(2-(2-((2-Methoxy-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)benzamideYield 85%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A mixture of tert-butyl 4-(4-((4-(3-carbamoylphenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidine-1-carboxylate (I36) (0.070 g, 0.12 mmol) and TFA (0.200 mL, 2.61 mmol) in THF (3 mL) was stirred 16 hours at room temperature. The mixture was concentrated under reduced pressure and azeotroped with toluene. The residue was then purified using a SCX cartridge (MeOH, 0.5% NH3/MeOH). The methanolic ammonia eluent was concentrated then dissolved in hot acetonitrile which was allowed to cool to room temperature. The cooled acetonitrile solution was filtered and the filtrate was concentrated, taken up in hot acetonitrile (2 mL) and water (1 mL) then freeze dried to give the title compound (5) (49.4 mg, 85%) as a white solid. A portion of this material was further purified by mass directed auto preparative HPLC to give the title compound (5) (4.5 mg) as a while solid; 1H NMR (400 MHz, d6-DMSO) δ 8.90 (m, 1H), 8.57 (s, 1H), 8.41 (s, 1H), 7.93 (s, 1H), 7.77 (s, 1H), 7.71 (m, 1H), 7.62 (dd, J=7.5, 7.5 Hz, 1H), 7.34 (m, 2H), 6.94 (dd, J=7.3, 1.6 Hz, 1H), 6.82 (ddd, J=7.9, 3.4, 1.5 Hz, 1H), 3.82 (s, 3H), 3.12 (m, 2H), 3.05 (m, 4H), 2.89 (m, 1H), 2.68 (m, 2H), 2.20 (m, 1H), 1.78 (m, 2H), 1.64 (m, 2H). LCMS Method C: rt 4.89 min; m/z 500.1[M+H]+.

Workup

  1. concentrationThe mixture was concentrated under reduced pressure
  2. customazeotroped with toluene
  3. customThe residue was then purified
  4. concentrationThe methanolic ammonia eluent was concentrated
  5. dissolutionthen dissolved in hot acetonitrile which
  6. temperatureto cool to room temperature
  7. filtrationThe cooled acetonitrile solution was filtered
  8. concentrationthe filtrate was concentrated
  9. dry with materialwater (1 mL) then freeze dried

Sources & evidence

ORD record
ord-c8df878ab0884c7d9858d344e9319d98
Source dataset
uspto-grants-2015_09
Patent number
US09120761B2

Reaction notes

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