Diethyl Ether → Tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate

HRID 1485133Notes

Reaction equation

HRID 1485133 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.C(OCC)C.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(N(CC)CC)C>[Cl-].[Cl-].[Zn+2].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:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[N:7]=1

Participants

8

Reactant 4

HCID 3283Diethyl EtherHCID 8471TriethylamineHCID 27827742,4-Dichloro-5-(trifluoromethyl)pyrimidineHCID 11011301tert-Butyl 4-(4-aminophenyl)piperazine-1-carboxylate

Product 1

HCID 86675713Tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylateYield 98.8%

Reagents, catalysts & solvents 3

HCID 3007855ZincchlorideCatalystHCID 111,2-DichloroethaneSolvent3×HCID 6386tert-ButanolSolvent3×

Conditions

Temperature
0 °C

Procedure

2,4-Dichloro-5-(trifluoromethyl)pyrimidine (2.39 g, 11.0 mmol) was stirred in a 1:1 t-BuOH:1,2-dichloroethane mixture (80 mL) at 0° C. and a 1.0 M ZnCl2 solution in diethyl ether (12.6 mL, 12.6 mmol) was added cautiously over 20 minutes and the reaction was left stirring at 0° C. for 30 minutes. A solution of tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate (I2) (2.92 g, 10.5 mmol) in 1:1 t-BuOH:1,2-dichloroethane (40 mL) was added drop-wise over 15 minutes at 0° C. followed by a solution of triethylamine (1.76 mL, 12.6 mmol) in 1:1 t-BuOH:1,2-dichloroethane (40 mL) and the reaction was allowed to warm to room temperature and was stirred for 18 hours. The organic solvents were evaporated in vacuo and the crude yellow oily solid was suspended in water (400 mL), the suspension was sonicated for 30 minutes and the product was collected by filtration, the solid was washed with water (10×20 mL) and dried under a high vacuum to give the title compound (I3) (4.75 g, 98% yield) as a beige solid; 1H NMR (400 MHz, d6-DMSO) δ 10.45 (s, 1H), 8.72 (s, 1H), 7.50 (d, J=8.5 Hz, 2H), 6.96 (d, J=9.0 Hz, 2H), 3.50-3.42 (m, 4H), 3.09-3.02 (m, 4H), 1.42 (s, 9H). LCMS Method C: rt 6.56 min; m/z 456.2, 458.1 [M−H]−.

Workup

  1. waitthe reaction was left
  2. temperatureto warm to room temperature
  3. stirringwas stirred for 18 hours
  4. customThe organic solvents were evaporated in vacuo
  5. customthe suspension was sonicated for 30 minutes
  6. filtrationthe product was collected by filtration
  7. washthe solid was washed with water (10×20 mL)
  8. customdried under a high vacuum

Sources & evidence

ORD record
ord-9599eae0ddd142c28a5a06c639da0e55
Source dataset
uspto-grants-2016_08
Patent number
US09421205B2

Reaction notes

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