Triethylamine → 1,1-Dimethylethyl (2S)-4-({4-[{[6-(4,4-difluoro-1-piperidinyl)-3-pyridinyl]carbonyl}(methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate

HRID 644762Notes

Reaction equation

HRID 644762 reaction equation
Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]([CH3:32])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]3)=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1.[F:33][C:34]1([F:40])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(N(CC)CC)C>C(#N)C>[F:33][C:34]1([F:40])[CH2:39][CH2:38][N:37]([C:2]2[N:7]=[CH:6][C:5]([C:8]([N:10]([CH3:32])[C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]4)=[CH:13][CH:12]=3)=[O:9])=[CH:4][CH:3]=2)[CH2:36][CH2:35]1

Participants

5

Reactant 3

HCID 8471Triethylamine2×HCID 27583524,4-Difluoropiperidine2×HCID 592622181,1-Dimethylethyl (2S)-4-({4-[[(6-bromo-3-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate

Product 1

HCID 592622121,1-Dimethylethyl (2S)-4-({4-[{[6-(4,4-difluoro-1-piperidinyl)-3-pyridinyl]carbonyl}(methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
150 °C

Procedure

A mixture of 1,1-dimethylethyl (2S)-4-({4-[[(6-bromo-3-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate (D108) (0.050 g, 0.0993 mmol), 4,4-difluoropiperidine (0.141 g, 0.894 mmol) and triethylamine (0.138 mL, 0.993 mmol) in acetonitrile (4 mL) was heated in a microwave at 150° C. for 12 h. Further portions of 4,4-difluoropiperidine (4 eq.) and triethylamine (5 eq.) were added and the reaction heated at 150° C. for 1 h. The reaction mixture was concentrated and the residue dissolved in DCM/water. The aqueous layer was further extracted with DCM (×3) and the combined organics were dried (Na2SO4) and concentrated to give a yellow gum which was purified by column chromatography. Elution with 0-100% EtOAc/hexane gave a colourless gum which was a mixture (˜9:1) of the title compound and unreacted D109 (0.0485 g). MS (ES): MH+ 544.2.

Workup

  1. temperaturethe reaction heated at 150° C. for 1 h
  2. concentrationThe reaction mixture was concentrated
  3. dissolutionthe residue dissolved in DCM/water
  4. extractionThe aqueous layer was further extracted with DCM (×3)
  5. dry with materialthe combined organics were dried (Na2SO4)
  6. concentrationconcentrated
  7. customto give a yellow gum which
  8. customwas purified by column chromatography
  9. washElution with 0-100% EtOAc/hexane
  10. customgave a colourless gum which

Sources & evidence

ORD record
ord-42901e5787ef4931b3277ffdffc44e12
Source dataset
uspto-grants-2010_04
Patent number
US07700599B2

Reaction notes

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