Hydrochloric Acid → 3-[2-Chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-dihydro-2H-imidazo[4,5-b]pyridin-2-one

HRID 1513028Notes

Reaction equation

HRID 1513028 reaction equation
Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1C(O)=O.[Cl:11][C:12]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH2:22][C:23]2[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[C:25]([F:31])[C:24]=2[F:32])=[CH:15][C:13]=1[NH2:14].C[Si](C)(C)[N-:35][Si](C)(C)C.[Li+].Cl.[O:44]1[CH2:48]CCC1>>[Cl:11][C:12]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH2:22][C:23]2[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[C:25]([F:31])[C:24]=2[F:32])=[CH:15][C:13]=1[N:14]1[CH:2]2[NH:10][CH:9]=[CH:8][CH:7]=[C:3]2[NH:35][C:48]1=[O:44]

Participants

6

Reactant 5

HCID 313Hydrochloric AcidHCID 8028Tetrahydrofuran2×HCID 762582-Chloronicotinic acidHCID 2733832Lithium HexamethyldisilazideHCID 593096392-Chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyaniline

Product 1

HCID 685917793-[2-Chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-dihydro-2H-imidazo[4,5-b]pyridin-2-one

Procedure

To a mixture of 2-chloronicotinic acid (0.47 g) and 2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyaniline (0.99 g) in tetrahydrofuran (5 mL) was added lithium hexamethyldisilazide (1.05 mol/L n-hexane solution, 8.57 mL) at −78° C., and the mixture was stirred at the same temperature for 10 minutes. To the reaction mixture was added tetrahydrofuran (4 mL), and the mixture was allowed to warm slowly to room temperature, and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate twice. The extracts were washed with water and brine, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. To the mixture of the residue and triethylamine (1.25 mL) in 1,4-dioxane (10 mL) was added diphenylphosphoryl azide (0.71 mL), and the mixture was stirred at room temperature for 1 hour, and then heated at reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/2−1/4) to give the title compound (0.94 g).

Workup

  1. stirringthe mixture was stirred at room temperature overnight
  2. extractionthe resulting mixture was extracted with ethyl acetate twice
  3. washThe extracts were washed with water and brine
  4. dry with materialdried over anhydrous magnesium sulfate
  5. customthe solvent was removed under reduced pressure
  6. additionTo the mixture of the residue and triethylamine (1.25 mL) in 1,4-dioxane (10 mL)
  7. additionwas added diphenylphosphoryl azide (0.71 mL)
  8. stirringthe mixture was stirred at room temperature for 1 hour
  9. temperatureheated
  10. temperatureat reflux for 2 hours
  11. concentrationThe reaction mixture was concentrated under reduced pressure
  12. customthe residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/2−1/4)

Sources & evidence

ORD record
ord-a54cf02642bc43c3a0edfe89823d3f71
Source dataset
uspto-grants-2012_07
Patent number
US08217069B2

Reaction notes

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