Diethyl Ether → tert-Butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-ethylphenyl)piperidine-1-carboxylate

HRID 705763Notes

Reaction equation

HRID 705763 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.CCOCC.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[CH:21][C:20]=1[CH2:38][CH3:39].C(N(CC)CC)C>[Cl-].[Zn+2].[Cl-].CC(O)(C)C.ClCCCl>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:29][CH2:30]3)=[CH:21][C:20]=2[CH2:38][CH3:39])[N:7]=1

Participants

8

Reactant 4

HCID 3283Diethyl EtherHCID 8471TriethylamineHCID 27827742,4-Dichloro-5-(trifluoromethyl)pyrimidineHCID 866758434-(4-Amino-3-ethyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 86675844tert-Butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-ethylphenyl)piperidine-1-carboxylateYield 84%

Reagents, catalysts & solvents 3

HCID 3007855ZincchlorideCatalystHCID 111,2-DichloroethaneSolvent2×HCID 6386tert-ButanolSolvent3×

Procedure

A solution of 2,4-dichloro-5-(trifluromethyl)pyrimidine (166 mg, 0.766 mmol) in 1:1 DCE:t-BuOH (5 mL) was stirred at 0° C. under nitrogen. 1.0 M Zinc(II) chloride in ether (0.77 mL, 0.77 mmol) was added and the mixture stirred for one hour. tert-Butyl 4-(4-amino-3-ethylphenyl)piperidine-1-carboxylate (I40) (212 mg, 0.70 mmol) in 1:1 DCE:t-BuOH (5 mL) was added dropwise, and after 30 minutes triethylamine (146 μL, 1.05 mmol) in 1:1 DOE:t-BuOH (5 mL) was added and the mixture allowed to slowly come to room temperature. After 18 hours the mixture was concentrated, and chromatography (12 g silica cartridge, 0-50% ethyl acetateicyclohexane) gave the title compound (I41) (283 mg, 84% yield) as a pale pink solid; 1H NMR (400 MHz, CDCl3) δ 8.51 (d, J=0.6 Hz, 1H), 7.60 (d, J=8.3 Hz, 1H), 7.15-7.07 (m, 3H), 4.25 (s, 2H), 2.80 (t, J=12.1 Hz, 2H), 2.69-2.59 (m, 3H), 1.83 (d, J=12.9 Hz, 2H), 1.69-1.59 (m, 2H), 1.49 (s, 9H), 1.23 (t, J=7.6 Hz, 3H), LCMS Method C: rt. 6.94 min; m/z 429.1 [M-tBu+2H]+, 385.1 [M-Boc+2H]+; m/z 483.1 [M−H]−.

Workup

  1. customto slowly come to room temperature
  2. concentrationAfter 18 hours the mixture was concentrated

Sources & evidence

ORD record
ord-08d982f49a82485080b6041c61f76b87
Source dataset
uspto-grants-2015_11
Patent number
US09174946B2

Reaction notes

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