3,4-Dichlorophenyl isocyanate → (3R)-N-(3,4-dichlorophenyl)-4-[(1-ethylpiperidin-3-yl)methyl]-3-methylpiperazine-1-carboxamide

HRID 2371145Notes

Reaction equation

HRID 2371145 reaction equation
[CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10]C(C)(C)C)=O)[CH2:3]1.CC1C=CC(S(O[CH2:26][CH:27]2[CH2:32][CH2:31][CH2:30][N:29]([CH2:33][CH3:34])[CH2:28]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].C(N(C(C)C)CC)(C)C.[Cl:50][C:51]1[CH:52]=[C:53]([N:58]=C=O)[CH:54]=[CH:55][C:56]=1[Cl:57]>C(#N)C.ClCCl>[Cl:50][C:51]1[CH:52]=[C:53]([NH:58][C:8]([N:4]2[CH2:5][CH2:6][N:7]([CH2:26][CH:27]3[CH2:32][CH2:31][CH2:30][N:29]([CH2:33][CH3:34])[CH2:28]3)[C@H:2]([CH3:1])[CH2:3]2)=[O:10])[CH:54]=[CH:55][C:56]=1[Cl:57]

Participants

8

Reactant 5

HCID 76073,4-Dichlorophenyl isocyanateHCID 11430Potassium CarbonateHCID 81531DiisopropylethylamineHCID 2756811(R)-1-Boc-3-methylpiperazineHCID 57656762(1-Ethylpiperidin-3-yl)methyl 4-methylbenzenesulfonate

Product 1

HCID 11531706(3R)-N-(3,4-dichlorophenyl)-4-[(1-ethylpiperidin-3-yl)methyl]-3-methylpiperazine-1-carboxamideYield 67.6%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of tert-butyl (3R)-3-methylpiperazine-1-carboxylate (84 mg) and (1-ethylpiperidin-3-yl)methyl 4-methylbenzenesulfonate (150 mg) in acetonitrile (3 mL) was added potassium carbonate (233 mg). The mixture was heated to 100° C. in the microwave for 2 hours and then evaporated. The residue was purified by silica column chromatography, eluting with a gradient of 0 to 5% 7M NH3/MeOH in dichloromethane. To a solution of the isolated material (50 mg) in methanol (5 mL) was added 4M HCl in dioxane (0.5 mL). The mixture was stirred overnight at room temperature and then evaporated to give a colourless oil. To a mixture of this oil in dichloromethane (10 mL) was added di-iso-propylethylamine (0.11 mL) and 3,4-dichlorophenylisocyanate (35 mg). The mixture was stirred for 15 minutes and then evaporated. The residue was purified using reverse phase HPLC eluting with a mixture of 5-95% acetonitrile in water to give the title compound as a white foam (52 mg, 30%).

Workup

  1. customevaporated
  2. customThe residue was purified by silica column chromatography
  3. washeluting with a gradient of 0 to 5% 7M NH3/MeOH in dichloromethane
  4. additionTo a solution of the isolated material (50 mg) in methanol (5 mL) was added 4M HCl in dioxane (0.5 mL)
  5. customevaporated
  6. customto give a colourless oil
  7. stirringThe mixture was stirred for 15 minutes
  8. customevaporated
  9. customThe residue was purified
  10. washeluting with a mixture of 5-95% acetonitrile in water

Sources & evidence

ORD record
ord-4ccaba3f6b124620ab1d0c550ad9db64
Source dataset
uspto-grants-2014_04
Patent number
US08710224B2

Reaction notes

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