Diethyl Ether → 4-Chloro-N-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

HRID 592481Notes

Reaction equation

HRID 592481 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.[CH3:18][N:19]1[CH:23]=[C:22]([NH2:24])[CH:21]=[N:20]1.CCN(C(C)C)C(C)C>ClCCCl.CC(O)(C)C.[Cl-].[Cl-].[Zn+2]>[Cl:13][C:11]1[C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][N:8]=[C:7]([NH:24][C:22]2[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=2)[N:12]=1

Participants

7

Reactant 4

HCID 3283Diethyl EtherHCID 81531DiisopropylethylamineHCID 27827742,4-Dichloro-5-(trifluoromethyl)pyrimidineHCID 47709901-methyl-1H-pyrazol-4-amine

Product 1

HCID 867123374-Chloro-N-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

Reagents, catalysts & solvents 2

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

Conditions

Temperature
50 °C

Procedure

ZnCl2 in Et2O (1M, 23.2 mL, 23.2 mmol) was added to 2,4-dichloro-5-trifluoromethylpyrimidine (5.2 mL, 39 mmol) in DCE:t-BuOH (1:1, 150 mL) under a nitrogen atmosphere. The mixture was stirred for 45 minutes before addition of 1-methyl-1H-pyrazol-4-amine (1.880 g, 19.36 mmol) in DCE/t-BuOH (1:1, 150 mL) and DIPEA (3.2 mL, 18 mmol). The mixture was heated to 50° C. for 16 hours, cooled and filtered using vacuum filtration. The solid was washed with MeOH and the filtrate concentrated under reduced pressure before being poured into water. The resulting precipitate was collected under vacuum filtration and washed with water then petroleum benzine 40-60° C. and finally dissolved in Et2O and filtered. The Et2O filtrate was concentrated under reduced pressure to give the crude product which was further purified in batches by a combination of trituration with Et2O and cyclohexane or silica gel column chromatography (0-30% EtOAc in petroleum benzine 40-60° C.) then combined to give the title compound A74 (1.6 g, 30%). 1H NMR (400 MHz, d-DMSO) δ ppm 10.66-10.58 (m, 1H), 8.77-8.68 (m, 1H), 7.93-7.86 (m, 1H), 7.53 (s, 1H), 3.88-3.78 (m, 3H).

Workup

  1. temperaturecooled
  2. filtrationfiltered
  3. filtrationvacuum filtration
  4. washThe solid was washed with MeOH
  5. concentrationthe filtrate concentrated under reduced pressure
  6. additionbefore being poured into water
  7. filtrationThe resulting precipitate was collected under vacuum filtration
  8. washwashed with water
  9. dissolutionpetroleum benzine 40-60° C. and finally dissolved in Et2O
  10. filtrationfiltered
  11. concentrationThe Et2O filtrate was concentrated under reduced pressure
  12. customto give the crude product which
  13. customwas further purified in batches by a combination of trituration with Et2O and cyclohexane or silica gel column chromatography (0-30% EtOAc in petroleum benzine 40-60° C.)

Sources & evidence

ORD record
ord-432f44a3bc8f49238ec6569cf0b5a1a7
Source dataset
uspto-grants-2016_01
Patent number
US09238644B2

Reaction notes

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