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

HRID 2202959Notes

Reaction equation

HRID 2202959 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

Participants

7

Reactant 5

HCID 81531DiisopropylethylamineHCID 5284359Calcium ChlorideHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 10103129rac-(1R,2S)-2-fluorocyclopropane-1-carboxylic acidHCID 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 10.8%

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), trans-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 (25.8 mg) as a pale yellow 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-a205f8d83f554a3dbde8083f00d82e2d
Source dataset
uspto-grants-2016_06
Patent number
US09365540B2

Reaction notes

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