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

HRID 1779004Notes

Reaction equation

HRID 1779004 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 (2.16 mL, 2.16 mmol) was added cautiously to a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (411 mg, 1.89 mmol) in 1:1 t-BuOH:DCE (100 mL) at room temperature and the resulting mixture stirred at room temperature for 20 minutes. tert-Butyl 4-(5-aminopyridin-2-yl)piperidine-1-carboxylate (K4) (500 mg, 1.80 mmol) was added followed by Et3N (0.30 mL, 2.16 mmol) then stirring was continued for 44 hours at room temperature. The volatiles were removed in vacuo and the residue was suspended in water (250 mL). The resulting suspension was sonicated for 10 minutes then filtered, washing the filter cake with water (2×100 mL). The filter cake was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A44 as an off white solid (346 mg, 42%); 1H NMR (400 MHz, d6-DMSO) δ 10.74 (s, 1H), 8.81 (s, 1H), 8.73 (d, J=2.4 Hz, 1H), 8.00 (dd, J=8.5, 2.5 Hz, 1H), 7.30 (d, J=8.5 Hz, 1H), 4.05 (d, J=11.8 Hz, 2H), 2.82 (m, 3H), 1.81 (d, J=11.1 Hz, 2H), 1.55 (m, 2H), 1.41 (s, 9H). LCMS-A: rt 5.949 min; m/z 458 [M+H]+.

Workup

  1. customThe volatiles were removed in vacuo
  2. customThe resulting suspension was sonicated for 10 minutes
  3. filtrationthen filtered
  4. washwashing the filter cake with water (2×100 mL)
  5. custompurified by column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.)

Sources & evidence

ORD record
ord-f99558afdfc54f87b79d3e475dc36974
Source dataset
uspto-grants-2016_02
Patent number
US09266864B2

Reaction notes

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