tert-Butyl 3-(4-((4-((3-(2-methoxy-2-oxoethyl)pyridin-2-yl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate → tert-Butyl 3-(4-((4-(2-(3-(2-methoxy-2-oxoethyl)pyridin-2-yl)ethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate

HRID 1485286Notes

Reaction equation

HRID 1485286 reaction equation
[CH3:1][O:2][C:3](=[O:43])[CH2:4][C:5]1[C:6]([C:11]#[C:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([CH:30]4[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31]4)=[CH:26][CH:25]=3)[N:14]=2)=[N:7][CH:8]=[CH:9][CH:10]=1>CN(C=O)C.C(N(CC)CC)C.C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:43])[CH2:4][C:5]1[C:6]([CH2:11][CH2:12][C:13]2[C:18]([C:19]([F:22])([F:20])[F:21])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([CH:30]4[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:41])([CH3:40])[CH3:42])=[O:37])[CH2:31]4)=[CH:26][CH:25]=3)[N:14]=2)=[N:7][CH:8]=[CH:9][CH:10]=1

Participants

6

Reactant 1

HCID 71209448tert-Butyl 3-(4-((4-((3-(2-methoxy-2-oxoethyl)pyridin-2-yl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate

Product 1

HCID 71209105tert-Butyl 3-(4-((4-(2-(3-(2-methoxy-2-oxoethyl)pyridin-2-yl)ethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate

Reagents, catalysts & solvents 4

HCID 23938PalladiumCatalyst2×HCID 6228DimethylformamideSolvent4×HCID 8471TriethylamineSolvent2×HCID 8857Ethyl AcetateSolvent2×

Procedure

To a solution of tert-butyl 3-(4-((4-((3-(2-methoxy-2-oxoethyl)pyridin-2-yl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I147) (0.061 g, 0.10 mmol) in DMF (9 mL) and triethylamine (1 mL) was added a slurry of Pd/C (0.070 g) in DMF (3 mL). The resulting mixture was stirred under an atmosphere of hydrogen at room temperature for 16 hours. The crude reaction mixture was diluted with ethyl acetate then filtered through a pad of Celite. The Celite was washed with ethyl acetate and the filtrates combined. The solvent was removed in vacuo to give a brown oil which was taken up in DMF (9 mL) and triethylamine (1 mL). A slurry of Pd/C (0.070 g) in DMF (3 mL) was added and the resulting mixture was stirred under an atmosphere of hydrogen at room temperature for a further 19 hours. The crude reaction mixture was diluted with ethyl acetate then filtered through a pad of Celite. The Celite was washed with ethyl acetate and the filtrates combined. The solvent was removed in vacuo to give a brown oil which was chromatographed (Biotage Isolera: 25 g silica cartridge, 0-50% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I148) (0.030 g, 49%) as a yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 8.46 (dd, J=4.8, 1.7 Hz, 1H), 7.61-7.46 (m, 4H, NH), 7.19 (d, J=8.6 Hz, 2H), 7.12 (dd, J=7.7, 4.8 Hz, 1H), 4.35-3.99 (m), 3.72 (s, 2H), 3.70 (s, 3H), 3.37 (J=7.4 Hz, 2H), 3.28 (t, J=6.9 Hz, 2H), 2.80-2.57 (m, 3H), 2.07-1.95 (m), 1.91-1.69 (m, 2H), 1.69-1.50 (m, 3H), 1.46 (s, 9H). LCMS Method C: rt=6.00 min, m/z 600.2 [M+H]+.

Workup

  1. customThe crude reaction mixture
  2. filtrationthen filtered through a pad of Celite
  3. washThe Celite was washed with ethyl acetate
  4. customThe solvent was removed in vacuo
  5. customto give a brown oil which
  6. stirringthe resulting mixture was stirred under an atmosphere of hydrogen at room temperature for a further 19 hours
  7. customThe crude reaction mixture
  8. filtrationthen filtered through a pad of Celite
  9. washThe Celite was washed with ethyl acetate
  10. customThe solvent was removed in vacuo
  11. customto give a brown oil which
  12. customwas chromatographed (Biotage Isolera: 25 g silica cartridge, 0-50% EtOAc in petroleum benzine 40-60° C.)

Sources & evidence

ORD record
ord-d0819f5d43084b559aa3f9626e8aaab2
Source dataset
uspto-grants-2016_08
Patent number
US09421205B2

Reaction notes

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