Triethylamine → tert-Butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoyl)piperazine-1-carboxylate

HRID 1778980Notes

Reaction equation

HRID 1778980 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.ClCCCl.CC(O)(C)C.[NH2:22][C:23]1[CH:43]=[CH:42][C:26]([C:27]([N:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)=[O:28])=[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]([C:27]([N:29]3[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:39])([CH3:41])[CH3:40])=[O:36])[CH2:33][CH2:34]3)=[O:28])=[CH:42][CH:43]=2)[N:7]=1

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 2763355Tert-butyl 4-(4-aminobenzoyl)piperazine-1-carboxylateHCID 27827742,4-Dichloro-5-(trifluoromethyl)pyrimidineHCID 21868497Tert-butyl alcohol 1,2-dichloroethane3×

Product 1

HCID 86712646tert-Butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoyl)piperazine-1-carboxylate

Reagents, catalysts & solvents 2

HCID 3007855ZincchlorideCatalystHCID 887MethanolSolvent

Conditions

Temperature
0 °C

Procedure

Zinc(II) chloride (1.0 M in Et2O; 2.00 mL, 2.00 mmol) was added to a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (0.399 g, 1.84 mmol) in 1:1 DCE/t-BuOH (15 mL) at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred for 1 hour at 0° C. and then tert-butyl 4-(4-aminobenzoyl)piperazine-1-carboxylate (A21) (0.510 g, 1.67 mmol) in 1:1 DCE/tBuOH (15 mL) was added. A solution of Et3N (0.256 mL, 1.84 mmol) in 1:1 DCE/t-BuOH (15 mL) was added dropwise at 0° C. and the resulting mixture was vigorously stirred for a further 30 minutes at 0° C. then at room temperature for 16 hours. The volatiles were removed in vacuo to afford a brown residue which was purified by silica gel column chromatography (Biotage Isolera, 25 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to yield a pale yellow solid. The solid was suspended in MeOH (15 mL) and water (15 mL) and the resulting suspension filtered to give the title compound A22 as a white solid (0.561 g, 69%); 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 7.68 (d, J=8.7 Hz, 2H), 7.64 (s, 1H), 7.45 (d, J=8.6 Hz, 2H), 3.87-3.30 (m, 8H), 1.47 (s, 9H). LCMS-A: rt 6.206 min; m/z 484.1 [M−H]−.

Workup

  1. stirringthe resulting mixture was vigorously stirred for a further 30 minutes at 0° C.
  2. waitat room temperature for 16 hours
  3. customThe volatiles were removed in vacuo
  4. customto afford a brown residue which
  5. customwas purified by silica gel column chromatography (Biotage Isolera, 25 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.)
  6. customto yield a pale yellow solid
  7. filtrationwater (15 mL) and the resulting suspension filtered

Sources & evidence

ORD record
ord-508725508ca54353a159784c650f0c43
Source dataset
uspto-grants-2016_02
Patent number
US09266864B2

Reaction notes

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