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

HRID 705765Notes

Reaction equation

HRID 705765 reaction equation
[CH2:1]([C:3]1[CH:4]=[C:5]([CH:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]1[N:15]=[C:14]([C:16]#[C:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:13]([C:29]([F:32])([F:31])[F:30])=[CH:12][N:11]=1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:33]2[CH2:34][CH2:35][N:36]([C:39]([O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:40])[CH2:37][CH2:38]2)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]1[N:15]=[C:14]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:13]([C:29]([F:32])([F:31])[F:30])=[CH:12][N:11]=1)[CH3:2]

Participants

4

Reactant 1

HCID 71232247tert-Butyl 4-(3-ethyl-4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate

Product 1

HCID 71232244tert-Butyl 4-(3-ethyl-4-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylateYield 57%

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 702EthanolSolvent2×

Procedure

tert-Butyl 4-(3-ethyl-4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I42) (311 mg, 0.499 mmol) was dissolved in ethanol (20 mL), and a slurry of Pd/C (150 mg) in ethanol (2 mL) was added. The mixture was stirred under hydrogen for 18 hours, filtered through celite, washing the celite with ethanol (20 mL) and the filtrate concentrated. The mixture was taken up in ethanol (20 mL), and a slurry of Pd/C (150 mg) in ethanol (2 mL) was added followed by triethylamine (20 μL). The mixture was stirred under hydrogen for 18 hours, filtered through celite, the celite washed with ethanol (10 mL) and the combined filtrates evaporated. The residue was taken up in DMF (10 mL), a slurry of Pd/C (150 mg) in DMF (2 mL) was added and the mixture stirred under hydrogen. After 16 hours the mixture was filtered through celite, and the celite washed with ethyl acetate (100 mL). The combined filtrate was evaporated to give a pale green oil. Chromatography (12 g silica cartridge, 0-60% ethyl acetate/petroleum benzine 40-60° C.) gave the title compound (I43) (177.1 mg, 57% yield) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J=0.5 Hz, 1H), 7.73 (d, J=8.1 Hz, 1H), 7.25-7.16 (m, 4H), 7.12-7.07 (m, 2H), 7.06 (s, 1H), 4.25 (br s, 2H), 3.72 (s, 2H), 3.67 (s, 3H), 3.14-3.01 (m, 4H), 2.81 (t, J=12.2 Hz, 2H), 2.72-2.59 (m, 3H), 1.84 (d, J=13.0 Hz, 2H), 1.69-1.56 (m, overlaps with water in solvent), 1.49 (s, 9H), 1.26 (t, J=7.1 Hz, 3H). LCMS: rt 7.16 min; m/z 627.2 [M+H]+; 571.1 [M-tBu+2H]+; m/z 625.2 [M−H]−.

Workup

  1. filtrationfiltered through celite
  2. washwashing the celite with ethanol (20 mL)
  3. concentrationthe filtrate concentrated
  4. additiona slurry of Pd/C (150 mg) in ethanol (2 mL) was added
  5. stirringThe mixture was stirred under hydrogen for 18 hours
  6. filtrationfiltered through celite
  7. washthe celite washed with ethanol (10 mL)
  8. customthe combined filtrates evaporated
  9. additiona slurry of Pd/C (150 mg) in DMF (2 mL) was added
  10. stirringthe mixture stirred under hydrogen
  11. filtrationAfter 16 hours the mixture was filtered through celite
  12. washthe celite washed with ethyl acetate (100 mL)
  13. customThe combined filtrate was evaporated
  14. customto give a pale green oil

Sources & evidence

ORD record
ord-b10e8233477b4b39ad853b262c834b3b
Source dataset
uspto-grants-2015_11
Patent number
US09174946B2

Reaction notes

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