Diethyl Ether → 4-Chloro-5-(trifluoromethyl)-N-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-2-amine

HRID 592383Notes

Reaction equation

HRID 592383 reaction equation
[CH3:1]COCC.Cl[C:7]1[N:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[C:9]([Cl:17])[N:8]=1.[NH2:18][C:19]1[CH:20]=N[C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=1.CCN(C(C)C)C(C)C>CC(O)(C)C.ClCCCl.[Cl-].[Zn+2].[Cl-].O>[Cl:17][C:9]1[C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][N:12]=[C:7]([NH:18][C:19]2[CH:24]=[N:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:1][CH:20]=2)[N:8]=1

Participants

8

Reactant 4

HCID 3283Diethyl EtherHCID 81531DiisopropylethylamineHCID 27827742,4-Dichloro-5-(trifluoromethyl)pyrimidineHCID 142909062-(Trifluoromethyl)pyrimidin-5-amine

Product 1

HCID 867122984-Chloro-5-(trifluoromethyl)-N-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-2-amine

Reagents, catalysts & solvents 3

HCID 3007855ZincchlorideCatalystHCID 962WaterSolventHCID 21868497Tert-butyl alcohol 1,2-dichloroethaneSolvent2×

Conditions

Temperature
40 °C

Procedure

A 1.0 M solution of zinc chloride in Et2O (18.5 mL, 18.5 mmol) was added to a solution of 2,6-dichloro-5-trifluoromethylpyrimidine (2.81 g, 13.0 mmol) in t-BuOH/DCE (1:1, 50 mL) at 0° C. over a period of 20 minutes then the resulting mixture was stirred for 1 hour. A solution of 5-amino-2-trifluoromethylpyrimidine (2.00 g, 12.3 mmol) and DIPEA (3.22 mL, 18.5 mmol) in t-BuOH/DCE (1:1, 30 mL) was added over 20 minutes then the resulting mixture was stirred at room temperature for 4 days, before heating to 40° C. and stirred for a further 24 hours. The volatiles were removed under reduced pressure to give a solid residue. Water (100 mL) was added and the suspension sonicated for 30 minutes. The resulting mixture was extracted with EtOAc (3×100 mL) and CHCl3 (100 mL). The organic extracts were combined, passed through a phase separation cartridge and the volatiles were evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Biotage Isolera, 2×40 g SiO2, 0-25% EtOAc in petroleum benzine 40-60° C.) to give the title compound A16 as a white solid (1.78 g, 42%); 1H NMR (400 MHz, d6-DMSO) δ 11.21 (s, 1H), 9.02 (d, J=2.5 Hz, 1H), 8.96-8.89 (m, 1H), 8.40 (dd, J=8.6, 2.2 Hz, 1H), 7.92 (d, J=8.6 Hz, 1H). LCMS-A: rt 5.931 min; m/z 343 [M+H]+.

Workup

  1. stirringthe resulting mixture was stirred at room temperature for 4 days
  2. stirringstirred for a further 24 hours
  3. customThe volatiles were removed under reduced pressure
  4. customto give a solid residue
  5. customthe suspension sonicated for 30 minutes
  6. extractionThe resulting mixture was extracted with EtOAc (3×100 mL) and CHCl3 (100 mL)
  7. custompassed through a phase separation cartridge
  8. customthe volatiles were evaporated under reduced pressure
  9. customThe residue was purified by silica gel column chromatography (Biotage Isolera, 2×40 g SiO2, 0-25% EtOAc in petroleum benzine 40-60° C.)

Sources & evidence

ORD record
ord-81e347d9148b4a58b421bb3b6d26c3c4
Source dataset
uspto-grants-2016_01
Patent number
US09238644B2

Reaction notes

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