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

HRID 1778950Notes

Reaction equation

HRID 1778950 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.CCOCC.[C:18]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].CCN(CC)CC>[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:37][C:34]2[CH:35]=[CH:36][C:31]([CH:28]3[CH2:27][CH2:26][N:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:30][CH2:29]3)=[CH:32][CH:33]=2)[N:7]=1

Participants

8

Reactant 4

HCID 3283Diethyl EtherHCID 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-carboxylate

Reagents, catalysts & solvents 3

HCID 3007855ZincchlorideCatalystHCID 111,2-DichloroethaneSolventHCID 6386tert-ButanolSolvent

Procedure

2,4-Dichloro-5-(trifluoromethyl)pyrimidine (4.12 g, 19.0 mmol) was stirred in a 1:1 t-BuOH:DCE mixture (400 mL) at room temperature. A 1.0 M ZnCl2 solution in Et2O (21.7 mL, 21.7 mmol) was added cautiously and after addition the reaction was stirred at room temperature for 10 minutes. 1-Boc-4-(4-aminophenyl)piperidine (5.00 g, 18.1 mmol) was then added followed by Et3N (6.05 mL, 43.4 mmol) and the resulting mixture was stirred at room temperature overnight. The organic solvents were evaporated and the resulting solid was suspended in water (500 mL). The suspension was sonicated for 30 minutes and then filtered. The filter cake was washed with water (2×100 mL) and dried under high vacuum to give the title compound K5 as a tan solid (8.11 g, 98%); 1H NMR (400 MHz, d6-DMSO) δ 10.61 (s, 1H), 8.78 (s, 1H), 7.59 (d, J=8.4 Hz, 2H), 7.23 (d, J=8.5 Hz, 2H), 4.07 (d, J=11.1 Hz, 2H), 2.80 (s, 2H), 2.65 (t, J=12.0 Hz, 1H), 1.74 (d, J=12.3 Hz, 2H), 1.42 (s, 11H). LCMS-A: rt 6.834 min; m/z 457 [M+H]+.

Workup

  1. customat room temperature
  2. additionafter addition the reaction
  3. stirringthe resulting mixture was stirred at room temperature overnight
  4. customThe organic solvents were evaporated
  5. customThe suspension was sonicated for 30 minutes
  6. filtrationfiltered
  7. washThe filter cake was washed with water (2×100 mL)
  8. customdried under high vacuum

Sources & evidence

ORD record
ord-b44ae551cdde45e898a4e90bcc338387
Source dataset
uspto-grants-2016_02
Patent number
US09266864B2

Reaction notes

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