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

HRID 592345Notes

Reaction equation

HRID 592345 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.ClC(Cl)C.C(O)(C)(C)C.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30]2)=[CH:25][CH:24]=1.CCN(CC)CC>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:22][C:23]2[CH:24]=[CH:25][C:26]([CH:29]3[CH2:30][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32]3)=[CH:27][CH:28]=2)[N:7]=1

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 27827742,4-Dichloro-5-(trifluoromethyl)pyrimidineHCID 56956222tert-Butyl 3-(4-aminophenyl)azetidine-1-carboxylateHCID 86704321Dichloroethane t-butanol

Product 1

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

Reagents, catalysts & solvents 2

HCID 3007855ZincchlorideCatalystHCID 887MethanolSolvent

Procedure

Zinc 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 1:1 dichloroethane/tert-butanol (64 mL) at room temperature under nitrogen. After stirring for 10 minutes, tert-butyl 3-(4-aminophenyl)azetidine-1-carboxylate (I7) (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 solid residue and the resulting suspension sonicatated 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 sonicated for 30 seconds. The resulting suspension was filtered and the filter cake was washed with MeOH (3 mL) then dried to give the title compound K4 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), 3.80 (s, 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 solid residue
  4. waitthe resulting suspension sonicatated for 2 minutes
  5. filtrationThe suspension was filtered
  6. customthe filter cake dried
  7. custompurified
  8. customto give a white solid
  9. customsonicated for 30 seconds
  10. filtrationThe resulting suspension was filtered
  11. washthe filter cake was washed with MeOH (3 mL)
  12. customthen dried

Sources & evidence

ORD record
ord-2b821ddd7b8d4e549c7b34ae1170e0c6
Source dataset
uspto-grants-2016_01
Patent number
US09238644B2

Reaction notes

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