Diethyl Ether → tert-Butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzyl)piperazine-1-carboxylate

HRID 1485227Notes

Reaction equation

HRID 1485227 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(OCC)C.[NH2:22][C:23]1[CH:42]=[CH:41][C:26]([CH2:27][N:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)=[CH:25][CH:24]=1.C(N(CC)CC)C>[Cl-].[Zn+2].[Cl-].C(O)(C)(C)C>[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]([CH2:27][N:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[CH2:30][CH2:29]3)=[CH:41][CH:42]=2)[N:7]=1

Participants

8

Reactant 5

HCID 3283Diethyl EtherHCID 63651,1-Dichloroethane3×HCID 8471TriethylamineHCID 27827742,4-Dichloro-5-(trifluoromethyl)pyrimidineHCID 12045001tert-Butyl 4-((4-aminophenyl)methyl)piperazine-1-carboxylate

Product 1

HCID 86675725tert-Butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzyl)piperazine-1-carboxylate

Reagents, catalysts & solvents 2

HCID 3007855ZincchlorideCatalystHCID 6386tert-ButanolSolvent3×

Procedure

2,4-Dichloro-5-(trifluoromethyl)pyrimidine (0.546 g, 2.52 mmol) in 1:1 dichloroethane: tert-butanol was cooled to 0° C. under nitrogen. A 1.0 M solution of zinc(II) chloride in diethyl ether (3.43 mL, 3.34 mmol) was added, and the mixture stirred for one hour at 0° C. tert-Butyl 4-(4-aminobenzyl)piperazine-1-carboxylate (I93) (0.667 g, 2.29 mmol) in 1:1 dichloroethane: tert-butanol (20 mL) was added dropwise over thirty minutes, followed by triethylamine (0.351 mL, 2.52 mmol) in 1:1 dichloroethane: tert-butanol (10 mL). The mixture was stirred overnight, allowing the ice bath to come to room temperature over this time. The mixture was concentrated onto silica gel and chromatographed (40 g silica cartridge, 0-100% ethyl acetate/petroleum benzine 40-60° C.) to give a residue which was triturated with petroleum benzine 40-60° C. to give the title compound (I94) (0.976 g, 90%) as an off white solid; 1H NMR (400 MHz, d4-MeOD) δ 8.68 (d, J=0.6 Hz, 1H), 7.85 (d, J=8.6 Hz, 2H), 7.51 (d, J=8.6 Hz, 2H), 4.30 (s, 2H), 3.27-3.00 (br, overlaps with solvent), 1.47 (s, 9H). LCMS Method C: 5.08 min; m/z 472.1 [M+H]+; m/z 470.1 [M−H]−.

Workup

  1. customto come to room temperature over this time
  2. concentrationThe mixture was concentrated onto silica gel
  3. customchromatographed (40 g silica cartridge, 0-100% ethyl acetate/petroleum benzine 40-60° C.)
  4. customto give a residue which
  5. customwas triturated with petroleum benzine 40-60° C.

Sources & evidence

ORD record
ord-aedcdccc52b848df99e08e80f1653891
Source dataset
uspto-grants-2016_08
Patent number
US09421205B2

Reaction notes

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