Hydrochloric Acid → (4-(3-chloropyrazin-2-yloxy)phenyl)(1H-benzo[d]imidazol-2-yl)methanone

HRID 555792

Reaction equation

HRID 555792 reaction equation
[C:1]1([NH2:8])[C:2]([NH2:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH:9](OCC)(OCC)OCC.C1(S(O)(=O)=O)C=CC=CC=1.[Cl:29][C:30]1[C:31]([O:36][C:37]2[CH:47]=[CH:46][C:40]([C:41]([O:43]CC)=O)=[CH:39][CH:38]=2)=[N:32][CH:33]=[CH:34][N:35]=1.[Li+].CC([N-]C(C)C)C.Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.C1COCC1.C(OCC)(=O)C>[NH:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=[C:9]1[C:41]([C:40]1[CH:39]=[CH:38][C:37]([O:36][C:31]2[C:30]([Cl:29])=[N:35][CH:34]=[CH:33][N:32]=2)=[CH:47][CH:46]=1)=[O:43]

Participants

11

Reactant 7

HCID 313Hydrochloric AcidHCID 7243O-PhenylenediamineHCID 7371Benzenesulfonic AcidHCID 14798Sodium HydroxideHCID 31214Ethyl orthoformateHCID 2724682Lithium diisopropylamideHCID 45031059Ethyl 4-[(3-chloropyrazin-2-yl)oxy]benzoate

Product 1

HCID 46207940(4-(3-chloropyrazin-2-yloxy)phenyl)(1H-benzo[d]imidazol-2-yl)methanone

Reagents, catalysts & solvents 3

HCID 1140TolueneSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

A solution of benzene-1,2-diamine (1.5 g, 14 mmol), triethyl orthoformate (5.7 mL, 37 mmol), and benzenesulfonic acid (0.075 g, 0.47 mmol) in toluene (15 mL) was heated to reflux for 4 h and then slowly distilled to remove half of the solvent. The mixture was then cooled to RT and neutralized with diisopropyl amine, followed by addition of a solution of ethyl 4-(3-chloropyrazin-2-yloxy)benzoate (4.3 g, 15 mmol) in THF (15 mL). The mixture was cooled to −78° C. and 1.2 equiv of LDA (9.2 mL, 17 mmol) was added. After aging at −78° C. for 1.5 h, the mixture was warmed to RT after 1.5 h and then 2N HCl was added and the mixture was agitated for 30 min. Following that, the mixture was adjusted to pH 9 with 1N NaOH. Ethyl acetate was added and the layers were separated, the aqueous was extracted with ethyl acetate (3×), and the combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. Upon treatment with MeOH, a yellow solid crashed out which was filtered and collected to give (1H-benzo[d]imidazol-2-yl)(4-(3-chloropyrazin-2-yloxy)phenyl)methanone.

Workup

  1. temperatureto reflux for 4 h
  2. distillationslowly distilled
  3. customto remove half of the solvent
  4. temperatureThe mixture was cooled to −78° C.
  5. temperaturethe mixture was warmed to RT after 1.5 h
  6. customthe layers were separated
  7. extractionthe aqueous was extracted with ethyl acetate (3×)
  8. washthe combined organics were washed with brine
  9. dry with materialdried over Na2SO4
  10. filtrationfiltered
  11. concentrationconcentrated
  12. filtrationwas filtered
  13. customcollected

Sources & evidence

ORD record
ord-377fce8bcbc243d483d3f6e5c2289810
Source dataset
uspto-grants-2011_11
Patent number
US08053438B2

Linked notes

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