Diethyl Ether → Tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-(trifluoromethoxy)phenyl)piperidine-1-carboxylate

HRID 705769Notes

Reaction equation

HRID 705769 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][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[CH:21][C:20]=1[O:38][C:39]([F:42])([F:41])[F:40].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:24]=[CH:23][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)=[CH:21][C:20]=2[O:38][C:39]([F:42])([F:40])[F:41])[N:7]=1

Participants

8

Reactant 4

HCID 3283Diethyl EtherHCID 8471TriethylamineHCID 27827742,4-Dichloro-5-(trifluoromethyl)pyrimidineHCID 68283221Tert-butyl 4-(4-amino-3-(trifluoromethoxy)phenyl)piperidine-1-carboxylate

Product 1

HCID 86675845Tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-(trifluoromethoxy)phenyl)piperidine-1-carboxylateYield 33%

Reagents, catalysts & solvents 3

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

Conditions

Temperature
0 °C

Procedure

2,4-Dichloro-5-(trifluoromethyl)pyrimidine (0.110 g, 0.506 mmol) was stirred in a 1:1 t-BuOH:1,2-dichloroethane mixture (10 mL) at 0° C. A 1.0 M ZnCl2 solution in diethyl ether (0.578 mL, 0.578 mmol) was added cautiously, after addition the reaction was left stirring at 0° C. for 30 minutes. A solution of tert-butyl 4-(4-amino-3-(trifluoromethoxy)phenyl)piperidine-1-carboxylate (I47) (impure, ˜80% pure, 0.217 g, 0.482 mmol) in 1:1 t-BuOH:1,2-dichloroethane (5 mL) was added drop-wise at 0° C. followed by a solution of NEt3 (0.081 mL, 0.58 mmol) in 1:1 t-BuOH:1,2-dichloroethane (5 mL) and the reaction was allowed to warm to room temperature and was stirred for 18 hours, then at 60° C. for 24 hours. The organic solvents were evaporated vacuo and the crude gum was purified by silica gel chromatography (40 g Si cartridge, 0-40% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I48) (0.085 g, 33% yield) as a pale yellow oily solid; 1H NMR (400 MHz, d6-DMSO) δ 10.38 (s, 1H), 8.72 (s, 1H), 7.52 (cl, J=8.1 Hz, 1H), 7.33-7.29 (m, 2H), 4.13-4.04 (m, 2H), 2.88-2.72 (m, 3H), 1.79 (d, J=12.1 Hz, 2H), 1.56-1.44 (m, 2H), 1.42 (s, 9H). LCMS Method C: rt 7.02 min; m/z 539.0, 541.0 [M−H]−.

Workup

  1. customat 0° C
  2. additionafter addition the reaction
  3. waitwas left
  4. temperatureto warm to room temperature
  5. stirringwas stirred for 18 hours
  6. waitat 60° C. for 24 hours
  7. customThe organic solvents were evaporated vacuo
  8. customthe crude gum was purified by silica gel chromatography (40 g Si cartridge, 0-40% EtOAc in petroleum benzine 40-60° C.)

Sources & evidence

ORD record
ord-3292cd4bbced4be2b355ffe75c5387a3
Source dataset
uspto-grants-2015_11
Patent number
US09174946B2

Reaction notes

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