Diethyl Ether → HCID 86675723, compound

HRID 1473094Notes

Reaction equation

HRID 1473094 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.C(OCC)C.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1.CCN(CC)CC>[Cl-].[Cl-].[Zn+2].ClCCCl.CC(O)(C)C>[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]([N:25]3[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[N:7]=1

Participants

8

Reactant 4

HCID 3283Diethyl EtherHCID 8471TriethylamineHCID 27827742,4-Dichloro-5-(trifluoromethyl)pyrimidineHCID 12050749Carbamic acid, N-[1-(4-aminophenyl)-4-piperidinyl]-, 1,1-dimethylethyl ester

Product 1

HCID 86675723HCID 86675723, compound

Reagents, catalysts & solvents 3

HCID 3007855ZincchlorideCatalystHCID 111,2-DichloroethaneSolvent3×HCID 6386tert-ButanolSolvent3×

Conditions

Temperature
0 °C

Procedure

2,4-Dichloro-5-(trifluoromethyl)pyrimidine (0.551 g, 2.54 mmol) was stirred in a 1:1 t-BuOH:1,2-dichloroethane mixture (30 mL) at 0° C. A 1.0 M ZnCl2 solution in diethyl ether (2.903 mL, 2.903 mmol) was added cautiously over 10 minutes, after addition the reaction was left stirring at 0° C. for 30 minutes. A solution of tert-butyl (1-(4-aminophenyl)piperidin-4-yl)carbamate (I75) (0.705 g, 2.42 mmol) in 1:1 t-BuOH:1,2-dichloroethane (15 mL) was added drop-wise over 15 minutes at 0° C., a solution of NEt3 (0.405 mL, 2.903 mmol) in 1:1 t-BuOH:1,2-dichloroethane (15 mL) was added drop-wise over 15 minutes and the reaction was allowed to warm to room temperature and was stirred for 18 hours. The organic solvents were evaporated in vacuo and the crude oily solid was suspended in water (200 mL), the suspension was sonicated for 30 minutes and the product was separated by filtration, the solid was washed with water (10×20 mL) and dried under a high vacuum. The material was further purified by silica gel chromatography using a gradient of 0-50% ethyl acetate in petroleum benzine 40-60° C. to give the title compound (I76) (0.730 g, 64%) as a yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 10.41 (s, 1H), 8.71 (s, 1H), 7.46 (d, J=7.7 Hz, 2H), 6.92 (d, J=8.9 Hz, 2H), 6.84 (d, J=7.1 Hz, 1H), 3.60 (d, J=12.4 Hz, 2H), 2.69 (t, J=10.9 Hz, 2H), 1.78 (d, J=10.9 Hz, 2H), 1.54-1.34 (m, 11H). LCMS Method C: rt 6.36 min; m/z 474.1 [M+H]+.

Workup

  1. customat 0° C
  2. additionafter addition the reaction
  3. waitwas left
  4. temperatureto warm to room temperature
  5. stirringwas stirred for 18 hours
  6. customThe organic solvents were evaporated in vacuo
  7. customthe suspension was sonicated for 30 minutes
  8. customthe product was separated by filtration
  9. washthe solid was washed with water (10×20 mL)
  10. customdried under a high vacuum
  11. customThe material was further purified by silica gel chromatography
  12. customa gradient of 0-50% ethyl acetate in petroleum benzine 40-60° C.

Sources & evidence

ORD record
ord-e9a0059c75eb49b588b64878bd7ed994
Source dataset
uspto-grants-2015_04
Patent number
US09012461B2

Reaction notes

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