Benzaldehyde → tert-butyl {1-[4-(5-chloro-2-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]cyclobutyl}carbamate

HRID 2408431Notes

Reaction equation

HRID 2408431 reaction equation
[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[C:5]([N+:27]([O-])=O)=[CH:4][CH:3]=1.[CH:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].[OH-].[Na+].CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>CS(C)=O.CO.C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([C:9]3[CH:14]=[CH:13][C:12]([C:15]4([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:18][CH2:17][CH2:16]4)=[CH:11][CH:10]=3)[C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:27][C:5]2=[CH:4][CH:3]=1

Participants

8

Reactant 5

HCID 240BenzaldehydeHCID 14798Sodium HydroxideHCID 24489Sodium DithioniteHCID 90495Di-tert-butyl dicarbonateHCID 58345132tert-Butyl (1-(4-((6-chloro-3-nitropyridin-2-yl)amino)phenyl)cyclobutyl)carbamate

Product 1

HCID 89309104tert-butyl {1-[4-(5-chloro-2-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]cyclobutyl}carbamateYield 46%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 22036561Dimethyl sulfoxide methanolSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of tert-butyl (1-{4-[(6-chloro-3-nitropyridin-2-yl)amino]phenyl}cyclobutyl)carbamate (1 g, 2.4 mmol) in DMSO/MeOH (4:1, 20 mL), were added benzaldehyde (0.32 mL, 3.2 mmol) and sodium dithionite (2.0 g, 9.5 mmol). The mixture was heated at 100° C. for 22 h and 1M-NaOH was added to the mixture with cooling in an ice bath until the pH becomes 9. The mixture was diluted with THF (50 mL) then Boc2O (1.5 g) was added and mixed stirred for 2 h at rt. The mixture was filtered through celite and the water phase was extracted with ethyl acetate (×2). The combined organic phase was washed with brine and dried over anhydrous Na2SO4. After evaporation, the residue was purified by silica gel column chromatography (hexane/ethyl acetate, 4:1 to 0:100) to give tert-butyl {1-[4-(5-chloro-2-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]cyclobutyl}carbamate (520 mg) as a white solid (46%). To a suspension of tert-butyl {1-[4-(5-chloro-2-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]cyclobutyl}carbamate (50 mg, 0.1 mmol) in toluene/ethanol/saturated NaHCO3 (3/3/0.3 mL), were added 3-(4-morphoryl)phenylboronic acid (65 mg, 0.22 mmol) and Pd(PPh3)4 (12 mg, 0.01 mmol). The mixture was heated at 100° C. for 13.5 h. After evaporation under reduced pressure, the residue was purified by silica gel column chromatography (hexane/ethyl acetate, 4:1 to 0:100) to give the titled compound (69 mg) as a white solid. 1H-NMR (CDCl3) δ: 8.17 (1H, d, J=8.6 Hz), 7.78 (1H, d, J=8.6 Hz), 7.62 (3H, d, J=7.4 Hz), 7.54 (3H, t, J=8.0 Hz), 7.42 (2H, td, J=5.6, 3.2 Hz), 7.40-7.37 (1H, m), 7.36-7.31 (3H, m), 6.94 (1H, dd, J=8.0, 1.7 Hz), 3.89 (4H, t, J=4.6 Hz), 3.22 (4H, t, J=4.9 Hz), 2.65-2.32 (4H, m), 2.20-2.11 (1H, m), 1.93-1.90 (1H, m), 1.47-1.19 (9H, m); LC/MS: 602 [M+H]+.

Workup

  1. temperaturewith cooling in an ice bath until the pH
  2. additionmixed
  3. filtrationThe mixture was filtered through celite
  4. extractionthe water phase was extracted with ethyl acetate (×2)
  5. washThe combined organic phase was washed with brine
  6. dry with materialdried over anhydrous Na2SO4
  7. customAfter evaporation
  8. customthe residue was purified by silica gel column chromatography (hexane/ethyl acetate, 4:1 to 0:100)

Sources & evidence

ORD record
ord-346dcfddb0944a668fa7f99303d75137
Source dataset
uspto-grants-2014_08
Patent number
US08815854B2

Reaction notes

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