Morpholine → 3-{[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]amino}-N-({4-(4-morpholinyl)-2-[(trifluoromethyl)oxy]phenyl}methyl)cyclohexanecarboxamide

HRID 1510954Notes

Reaction equation

HRID 1510954 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([CH:12]2[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C:19]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([NH:26][CH3:27])[N:20]=3)[CH2:13]2)=[O:11])=[C:4]([O:28][C:29]([F:32])([F:31])[F:30])[CH:3]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:25][C:23]1[N:22]=[C:21]([NH:26][CH3:27])[N:20]=[C:19]([NH:18][CH:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:10]([NH:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[CH:3][C:4]=3[O:28][C:29]([F:32])([F:31])[F:30])=[O:11])[CH2:13]2)[N:24]=1

Participants

7

Reactant 4

HCID 8083MorpholineHCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 67493268N-({4-bromo-2-[(trifluoromethyl)oxy]phenyl}methyl)-3-{[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]amino}cyclohexanecarboxamide

Product 1

HCID 674936773-{[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]amino}-N-({4-(4-morpholinyl)-2-[(trifluoromethyl)oxy]phenyl}methyl)cyclohexanecarboxamideYield 19%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Procedure

A mixture of N-({4-bromo-2-[(trifluoromethyl)oxy]phenyl}methyl)-3-{[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]amino}cyclohexanecarboxamide (60 mg, 0.116 mmol), morpholine (20.21 mg, 0.232 mmol), Pd2(dba)3 (5.31 mg, 5.80 μmol), BINAP (5.42 mg, 8.70 μmol) and cesium carbonate (76 mg, 0.232 mmol) in 1,4-Dioxane (2 ml) was irradiated via microwave reactor for 20 min at 170° C. The crude reaction mixture was passed through a 2 gram SCX ion-exchange column. The column was flushed with MeOH, then it was flushed with 2N NH3 in MeOH. The NH3 solution was collected and the solvent was evacuated to give a residue which was purified by preparative HPLC, resulting in 3-{[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]amino}-N-({4-(4-morpholinyl)-2-[(trifluoromethyl)oxy]phenyl}methyl)cyclohexanecarboxamide (15 mg, 0.022 mmol, 19%). MS (ES) m/e 524 [M+H]+.

Workup

  1. customwas irradiated via microwave reactor for 20 min at 170° C
  2. customThe crude reaction mixture
  3. customThe column was flushed with MeOH
  4. customit was flushed with 2N NH3 in MeOH
  5. customThe NH3 solution was collected
  6. customthe solvent was evacuated
  7. customto give a residue which
  8. customwas purified by preparative HPLC

Sources & evidence

ORD record
ord-98f7a06cf7b34b1d9026bd8510226f50
Source dataset
uspto-grants-2012_07
Patent number
US08212032B2

Reaction notes

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