Isopropyl iodide → 3-[4-(benzyloxy)phenyl]-6-chloro-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

HRID 1044273

Reaction equation

HRID 1044273 reaction equation
Cl[C:2]1[C:7]([NH:8][C:9](=[O:15])OC(C)(C)C)=[CH:6][C:5]([Cl:16])=[CH:4][N:3]=1.Cl.[CH2:18]([O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH3:33][C:34]1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2[C:35]1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+].IC(C)C.[H-].[Na+].[Cl-].[Cl-].[Ca+2]>C1(C)C=CC=CC=1.CN(C=O)C.CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(O)C>[CH2:18]([O:25][C:26]1[CH:27]=[CH:28][C:29]([N:30]2[C:2]3=[N:3][CH:4]=[C:5]([Cl:16])[CH:6]=[C:7]3[N:8]([CH:34]([CH3:35])[CH3:33])[C:9]2=[O:15])=[CH:31][CH:32]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1

Participants

13

Reactant 7

HCID 6362Isopropyl iodideHCID 24758Sodium hydrideHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 27238314-Benzyloxyaniline hydrochlorideHCID 5284359Calcium ChlorideHCID 23676156Sodium t-butoxideHCID 86660673Tert-butyl 2,5-dichloropyridin-3-ylcarbamate

Product 1

HCID 585775533-[4-(benzyloxy)phenyl]-6-chloro-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-oneYield 62.4%

Reagents, catalysts & solvents 5

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 887MethanolSolventHCID 1140TolueneSolventHCID 3776IsopropanolSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

Di-tert-butyl dicarbonate (17.05 mL) was added to a solution of 2,5-dichloropyridin-3-amine (11.4 g) and NaHMDS (81 mL) in THF (dry) (200 mL) at 0° C. The mixture was stirred at 0° C. under a dry atmosphere for 1 h. The mixture was neutralized with 1N HCl at 0° C. and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-20% EtOAc in hexane) to give tert-butyl 2,5-dichloropyridin-3-ylcarbamate (15.6 g) as colorless oil. The mixture of tert-butyl 2,5-dichloropyridin-3-ylcarbamate (7.5 g), 4-benzyloxyaniline hydrochloride (10.08 g), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (1.319 g), Pd2(dba)3 (1.044 g) and sodium tert-butoxide (6.57 g) in toluene (160 mL)-2-propanol (40.0 mL) was stirred at 100° C. under Ar overnight. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-100% EtOAc in hexane) to give intermediate. To the intermediate in DMF (100 mL) were added 2-iodopropane (5.69 mL) and NaH (2.280 g), and the mixture was stirred at room temperature under a dry atmosphere (CaCl2 tube) for 1 h. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-50% EtOAc in hexane) to give 3-[4-(benzyloxy)phenyl]-6-chloro-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (560 mg) as a colorless solid.

Workup

  1. concentrationThe reaction mixture was concentrated in vacuo
  2. customThe residue was purified by column chromatography (silica gel, eluted with 0%-100% EtOAc in hexane)
  3. customto give intermediate
  4. concentrationconcentrated in vacuo
  5. customThe residue was purified by column chromatography (NH silica gel, eluted with 0%-50% EtOAc in hexane)

Sources & evidence

ORD record
ord-14e28e2c01f4488db9fca6b077e0fa35
Source dataset
uspto-grants-2013_10
Patent number
US08563575B2

Linked notes

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