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

HRID 592348Notes

Reaction equation

HRID 592348 reaction equation
CCOCC.Cl[C:7]1[N:12]=[C:11]([Cl:13])[C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][N:8]=1.[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:13][C:11]1[C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][N:8]=[C:7]([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:12]=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

A 1.0 M ZnCl2 solution in Et2O (1.14 mL, 1.14 mmol) was added cautiously to a stirred solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (217 mg, 0.999 mmol) in a 1:1 t-BuOH:DCE mixture (50 mL) at room temperature. After completion of the addition stirring was continued for 20 minutes then tert-butyl 4-(5-aminopyridin-2-yl)piperidine-1-carboxylate (I9) (263 mg, 0.952 mmol) followed by Et3N (0.159 mL, 1.14 mmol) were added. The resulting mixture was stirred at room temperature for 48 hours then the volatiles were evaporated under reduced pressure and the resulting residue was purified using silica gel column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 0-55% EtOAc in petroleum benzine 40-60° C.) to give the title compound K5 as a white solid (155 mg, 36%); 1H NMR (400 MHz, d6-DMSO) δ 10.75 (s, 1H), 8.82 (s, 1H), 8.73 (d, J=2.4 Hz, 1H), 8.00 (dd, J=8.5, 2.4 Hz, 1H), 7.30 (d, J=8.5 Hz, 1H), 4.11-4.01 (m, 2H), 2.93-2.75 (m, 3H), 1.81 (d, J=11.1 Hz, 2H), 1.63-1.50 (m, 2H), 1.41 (s, 9H). LCMS-A: rt 5.604 min; m/z 458, 460 [M+H]+.

Workup

  1. customat room temperature
  2. additionAfter completion of the addition
  3. additionwere added
  4. stirringThe resulting mixture was stirred at room temperature for 48 hours
  5. customthe volatiles were evaporated under reduced pressure
  6. customthe resulting residue was purified
  7. customsilica gel column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 0-55% EtOAc in petroleum benzine 40-60° C.)

Sources & evidence

ORD record
ord-31eaf9e93a534629936a77dd6434d044
Source dataset
uspto-grants-2016_01
Patent number
US09238644B2

Reaction notes

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