Nitrogen → Tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate

HRID 1485176Notes

Reaction equation

HRID 1485176 reaction equation
Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.N#N.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1.CCN(CC)CC>CO.O.[Cl-].[Zn+2].[Cl-].ClCCCl.CC(O)(C)C>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]3)=[CH:18][CH:17]=2)[N:7]=1

Participants

9

Reactant 4

HCID 947NitrogenHCID 8471TriethylamineHCID 27827742,4-Dichloro-5-(trifluoromethyl)pyrimidineHCID 21940085tert-Butyl 4-(4-aminophenyl)piperidine-1-carboxylate

Product 1

HCID 86675716Tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylateYield 88%

Reagents, catalysts & solvents 4

HCID 3007855ZincchlorideCatalystHCID 887MethanolSolventHCID 962WaterSolventHCID 21868497Tert-butyl alcohol 1,2-dichloroethaneSolvent3×

Conditions

Temperature
0 °C

Procedure

Zinc chloride (1.0 M in Et2O) (1.97 mL, 1.97 mmol) was added to a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (0.384 g, 1.77 mmol) in 1:1 DCE/t-BuOH (10 mL) at 0° C. under a stream of N2 gas. The mixture was stirred for 1 hour at 0° C. and then tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (I44) (0.453 g, 1.64 mmol) in 1:1 DCE/tBuOH (7 mL) was added. A solution of NEt3 (0.251 mL, 1.80 mmol) in 1:1 DCE/t-BuOH (8 mL) was next added dropwise at 0° C. The reaction mixture was vigorously stirred for a further 30 minutes at 0° C. after the final addition and then at room temperature for 24 hours. The solvent was removed in vacuo to afford a brown oily residue which was purified by column chromatography on silica gel (0-20% EtOAc in petroleum benzine 40-60° C.) to yield a pale yellow solid. The solid was suspended in MeOH (10 mL) and water (10 mL). The resulting precipitate was filtered to afford the title compound (I45) (0.658 g, 88%) as a white solid; 1H NMR (400 MHz, d6-DMSO) δ 10.60 (s, 1H), 8.77 (d, J=0.5 Hz, 1H), 7.59 (d, J=8.5 Hz, 2H), 7.23 (d, J=8.6 Hz, 2H), 4.13-3.98 (m, 2H), 2.80 (bs, 2H), 2.69-2.61 (m, 1H), 1.74 (d, J=12.4 Hz, 2H), 1.53-1.39 (m, 11H). LCMS Method C: rt 6.81 min; m/z 401 [M-tButyl+2H]+, 357 [M-Boc+2H]+.

Workup

  1. stirringThe reaction mixture was vigorously stirred for a further 30 minutes at 0° C. after the final
  2. additionaddition
  3. waitat room temperature for 24 hours
  4. customThe solvent was removed in vacuo
  5. customto afford a brown oily residue which
  6. customwas purified by column chromatography on silica gel (0-20% EtOAc in petroleum benzine 40-60° C.)
  7. customto yield a pale yellow solid
  8. filtrationThe resulting precipitate was filtered

Sources & evidence

ORD record
ord-e2048c8b88cf4109bb66540c11ffdb0e
Source dataset
uspto-grants-2016_08
Patent number
US09421205B2

Reaction notes

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