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Diisopropylethylamine → 4-((4-Chlorobenzyl)oxy)-1-(2-((1RS,2RS)-2-fluorocyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

HRID 2202958
Notes
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Reaction equation

HRID 2202958 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:10][C:9]2=[O:23])=[CH:4][C:3]=1[NH:24][CH3:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:50][C@H:51]1[CH2:53][C@H:52]1[C:54](O)=O.C(N(CC)C(C)C)(C)C.[Cl-].[Cl-].[Ca+2]>CN(C=O)C>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][O:14][C:11]2[CH:12]=[CH:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]4[N:1]=[C:54]([CH:52]5[CH2:53][CH:51]5[F:50])[N:24]([CH3:25])[C:3]=4[CH:4]=3)[C:9](=[O:23])[CH:10]=2)=[CH:21][CH:20]=1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 5

HCID 81531DiisopropylethylamineHCID 5284359Calcium ChlorideHCID 9793716cis-2-Fluorocyclopropanecarboxylic acidHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 896902584-(4-Chlorobenzyloxy)-1-(4-amino-3-(methylamino)phenyl)pyridin-2(1h)-one

Product 1

HCID 1213862314-((4-Chlorobenzyl)oxy)-1-(2-((1RS,2RS)-2-fluorocyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-oneYield 15.8%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
90 °C

Procedure

A mixture of 1-(4-amino-3-(methylamino)phenyl)-4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (200 mg), HATU (224 mg), cis-2-fluoro-cyclopropanecarboxylic acid (100 mg), N,N-diisopropylethylamine (288 μl) and DMF (4 ml) was stirred at room temperature under a dry atmosphere (CaCl2 tube) for 1 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was dissolved in AcOH (4.0 ml) and stirred at 90° C. for 1 h. After AcOH was evaporated, the residue was purified by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was recrystallized from EtOH to give the title compound (37.6 mg) as an off-white solid.

Workup

  1. customThe mixture was quenched with water
  2. extractionextracted with EtOAc
  3. customThe organic layer was separated
  4. washwashed with water and brine
  5. dry with materialdried over MgSO4
  6. concentrationconcentrated in vacuo
  7. dissolutionThe residue was dissolved in AcOH (4.0 ml)
  8. customAfter AcOH was evaporated
  9. customthe residue was purified by NH silica gel column chromatography (hexane/EtOAc)
  10. customThe resulting solid was recrystallized from EtOH

Sources & evidence

ORD record
ord-63131c222d624cf2ad747ea227d03590
Source dataset
uspto-grants-2016_06
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09365540B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes