1-Hydroxybenzotriazole → [3,5-Difluoro-4-(4-methoxy-benzylamino)-phenyl]-(4-ethyl-piperazin-1-yl)-methanone

HRID 912166Notes

Reaction equation

HRID 912166 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:21])[C:10]=1[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:5]([OH:7])=O.C(N(C(C)C)C(C)C)C.C1C=CC2N(O)N=NC=2C=1.[CH2:41]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[CH3:42]>C(#N)C>[F:21][C:9]1[CH:8]=[C:4]([C:5]([N:46]2[CH2:47][CH2:48][N:43]([CH2:41][CH3:42])[CH2:44][CH2:45]2)=[O:7])[CH:3]=[C:2]([F:1])[C:10]=1[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1

Participants

6

Reactant 4

HCID 757711-Hydroxybenzotriazole2×HCID 791961-EthylpiperazineHCID 81531Diisopropylethylamine2×HCID 59244777HCID 59244777, compound

Product 1

HCID 59244390[3,5-Difluoro-4-(4-methoxy-benzylamino)-phenyl]-(4-ethyl-piperazin-1-yl)-methanoneYield 99%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

To a solution of 3,5-difluoro-4-(4-methoxy-benzylamino)-benzoic acid (9.00 g, 30.7 mmol) obtained in Step B in acetonitrile (150 ml), N-ethyldiisopropylamine (16.0 ml, 92.1 mmol), HOBt (4.15 g, 30.7 mmol) and WSCI (5.88 g, 30.7 mmol) were added, followed by stirring at room temperature for 10 minutes. To this, 1-ethyl-piperazine (4.68 ml, 368 mmol) was added, followed by stirring at room temperature for 62 hours. N-Ethyldiisopropylamine (5.35 ml, 30.7 mmol), HOBt (2.07 g, 15.3 mmol) and WSCI (2.94 g, 15.3 mmol) were added at room temperature, followed by stirring for 22 hours. The solvent was distilled off under reduced pressure, followed by dissolution in ethyl acetate (300 ml), which was washed with saturated aqueous sodium chloride solution (100 ml) and saturated sodium hydrogencarbonate aqueous solution (100 ml). Subsequently, the organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. This was purified by silica gel column chromatography (dichloromethane/methanol=50/1 to 25/1), to obtain the desired compound as a brown oil (11.8 g, 99%).

Workup

  1. stirringby stirring at room temperature for 62 hours
  2. stirringby stirring for 22 hours
  3. distillationThe solvent was distilled off under reduced pressure
  4. dissolutionfollowed by dissolution in ethyl acetate (300 ml)
  5. washwhich was washed with saturated aqueous sodium chloride solution (100 ml) and saturated sodium hydrogencarbonate aqueous solution (100 ml)
  6. dry with materialSubsequently, the organic layer was dried over sodium sulfate
  7. distillationthe solvent was distilled off under reduced pressure
  8. customThis was purified by silica gel column chromatography (dichloromethane/methanol=50/1 to 25/1)

Sources & evidence

ORD record
ord-85b18fc9a55c4c8f98deee654d86dd17
Source dataset
uspto-grants-2011_09
Patent number
US08022205B2

Reaction notes

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