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

HRID 592474Notes

Reaction equation

HRID 592474 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.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([CH: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)=[N:23][CH:24]=1.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:18][C:19]2[CH:20]=[CH:21][C:22]([CH: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)=[N:23][CH:24]=2)[N:7]=1

Participants

8

Reactant 4

HCID 3283Diethyl EtherHCID 8471TriethylamineHCID 27827742,4-Dichloro-5-(trifluoromethyl)pyrimidineHCID 59128562tert-Butyl 4-(5-aminopyridin-2-yl)piperidine-1-carboxylate

Product 1

HCID 86712273tert-Butyl 4-(5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate

Reagents, catalysts & solvents 3

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

Procedure

2,4-Dichloro-5-(trifluoromethyl)pyrimidine (411 mg, 1.89 mmol) was stirred in 1:1 t-BuOH:DCE (100 mL) at room temperature. A 1.0 M ZnCl2 solution in Et2O (2.16 mL, 2.16 mmol) was added cautiously and after addition the mixture was stirred at room temperature for 20 minutes. tert-Butyl 4-(5-aminopyridin-2-yl)piperidine-1-carboxylate I9 (500 mg, 1.80 mmol) was added followed by NEt3 (0.30 mL, 2.16 mmol) and the mixture was stirred at room temperature for 44 hours. The organic solvents were evaporated to dryness and the crude tan solid was suspended in water (250 mL) and sonicated for 10 minutes. The solid was isolated by filtration, washed with water (2×100 mL) and air-dried to give a cream solid. The solid was adsorbed onto silica and purified by silica gel column chromatography (40 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A70 as an off white solid (346 mg, 42%). LCMS-A: rt 5.949 min; m/z 458 [M+H]+.

Workup

  1. customat room temperature
  2. additionafter addition the mixture
  3. addition(500 mg, 1.80 mmol) was added
  4. stirringthe mixture was stirred at room temperature for 44 hours
  5. customThe organic solvents were evaporated to dryness
  6. customsonicated for 10 minutes
  7. customThe solid was isolated by filtration
  8. washwashed with water (2×100 mL)
  9. customair-dried
  10. customto give a cream solid
  11. custompurified by silica gel column chromatography (40 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.)

Sources & evidence

ORD record
ord-e8ca336602af4644893cc927165b320e
Source dataset
uspto-grants-2016_01
Patent number
US09238644B2

Reaction notes

Loading…