Triethylamine → tert-Butyl 3-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)azetidine-1-carboxylate

HRID 1779041Notes

Reaction equation

HRID 1779041 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.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21]2)=[CH:16][CH:15]=1.CCN(CC)CC>ClCCCl.CC(O)(C)C.CO.[Cl-].[Zn+2].[Cl-]>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([CH:20]3[CH2:21][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23]3)=[CH:18][CH:19]=2)[N:7]=1

Participants

7

Reactant 3

HCID 8471TriethylamineHCID 27827742,4-Dichloro-5-(trifluoromethyl)pyrimidineHCID 56956222tert-Butyl 3-(4-aminophenyl)azetidine-1-carboxylate

Product 1

HCID 86712272tert-Butyl 3-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)azetidine-1-carboxylate

Reagents, catalysts & solvents 3

HCID 3007855ZincchlorideCatalystHCID 887MethanolSolventHCID 21868497Tert-butyl alcohol 1,2-dichloroethaneSolvent

Procedure

Zinc(II) chloride (1.0 M in Et2O; 4.83 mL, 4.83 mmol) was added to a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (0.769 g, 3.54 mmol) in DCE/t-BuOH (64 mL) at room temperature under nitrogen. After stirring for 10 minutes, tert-butyl 3-(4-aminophenyl)azetidine-1-carboxylate (A77) (0.800 g, 3.22 mmol) was added followed by Et3N (1.08 mL, 7.73 mmol). The resulting mixture was stirred at room temperature for 20 hours then the volatiles removed in vacuo. Water was added to the residue and the resulting suspension sonicated for 2 minutes. The suspension was filtered and the filter cake dried then adsorbed onto silica gel and purified using column chromatography (CombiFlash Rf, 40 g SiO2 cartridge, 10-40% EtOAc in cyclohexane) to give a white solid. The solid was suspended in MeOH (7 mL) and the resulting suspension sonicated for 30 seconds. The suspension was filtered and the filter cake washed with MeOH (3 mL), then dried to give the title compound A78 as a white solid (0.777 g, 56%); 1H NMR (300 MHz, d6-DMSO) δ 10.6 (s, 1H), 8.79 (s, 1H), 7.66 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 4.23 (t, J=7.6 Hz, 2H), 3.85-3.74 (m, 3H), 1.40 (s, 9H). LCMS-B: rt 8.810 min; m/z 429 [M+H]+.

Workup

  1. stirringThe resulting mixture was stirred at room temperature for 20 hours
  2. customthe volatiles removed in vacuo
  3. additionWater was added to the residue
  4. customthe resulting suspension sonicated for 2 minutes
  5. filtrationThe suspension was filtered
  6. customthe filter cake dried
  7. custompurified
  8. customto give a white solid
  9. customthe resulting suspension sonicated for 30 seconds
  10. filtrationThe suspension was filtered
  11. washthe filter cake washed with MeOH (3 mL)
  12. customdried

Sources & evidence

ORD record
ord-4d76d0da2c82466887e542a8b4a58399
Source dataset
uspto-grants-2016_02
Patent number
US09266864B2

Reaction notes

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