Diethyl Ether → tert-Butyl 2-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate

HRID 1485166Notes

Reaction equation

HRID 1485166 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]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][N:26]2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[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:20]=[CH:21][C:22]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][N:26]3[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:23][CH:24]=2)[N:7]=1

Participants

8

Reactant 4

HCID 3283Diethyl EtherHCID 8471TriethylamineHCID 27827742,4-Dichloro-5-(trifluoromethyl)pyrimidineHCID 46835477Tert-butyl 2-(4-aminophenyl)piperidine-1-carboxylate

Product 1

HCID 86675715tert-Butyl 2-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylateYield 67%

Reagents, catalysts & solvents 3

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

Conditions

Temperature
0 °C

Procedure

2,4-Dichloro-5-(trifluoromethyl)pyrimidine (0.101 g, 0.464 mmol) was stirred in a 1:1 t-BuOH:1,2-dichloroethane mixture (10 mL) at 0° C. and a 1.0 M ZnCl2 solution in diethyl ether (0.530 mL, 0.530 mmol) was added cautiously over 20 minutes. After addition, the reaction was left stirring at 0° C. for 30 minutes and a solution of tert-butyl 2-(4-aminophenyl)piperidine-1-carboxylate (I36) (0.122 g, 0.441 mmol) in 1:1 t-BuOH:1,2-dichloroethane (4 mL) was added drop-wise over 15 minutes at 0° C. followed by a solution of triethylamine (0.074 μL, 0.530 mmol) in 1:1 t-BuOH:1,2-dichloroethane (4 mL) and the reaction was allowed to warm to room temperature and was stirred for 60 hours. Volatiles were evaporated in vacuo and the resulting residue was suspended in water (40 mL), the suspension was sonicated for 40 minutes and the product was collected by filtration, the solid was washed with water (5×10 mL) and dried under a high vacuum to give the title compound (I37) (0.135 g, 67% yield) as a pale pink solid. LCMS Method C: rt 6.96 min; m/z 455.2, 457.2 M−H]−.

Workup

  1. additionAfter addition
  2. waitthe reaction was left
  3. temperatureto warm to room temperature
  4. stirringwas stirred for 60 hours
  5. customVolatiles were evaporated in vacuo
  6. customthe suspension was sonicated for 40 minutes
  7. filtrationthe product was collected by filtration
  8. washthe solid was washed with water (5×10 mL)
  9. customdried under a high vacuum

Sources & evidence

ORD record
ord-8645a9ad53e44b3e9601b27f5b7c2e1b
Source dataset
uspto-grants-2016_08
Patent number
US09421205B2

Reaction notes

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