Water → 6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]oxazole

HRID 1848035Notes

Reaction equation

HRID 1848035 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:14][C:15]1[CH:25]=[CH:24][C:18]2[N:19]=[C:20]([S:22][CH3:23])[O:21][C:17]=2[CH:16]=1.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:14][C:15]3[CH:25]=[CH:24][C:18]4[N:19]=[C:20]([S:22][CH3:23])[O:21][C:17]=4[CH:16]=3)[C:5]2=[N:6][CH:7]=1

Participants

6

Reactant 4

HCID 962WaterHCID 24758Sodium hydrideHCID 9115786-Bromo-4H-imidazo[4,5-b]pyridineHCID 866810166-(Chloromethyl)-2-(methylthio)benzo[d]oxazole

Product 1

HCID 866810486-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]oxazoleYield 48.1%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
0 °C

Procedure

To a stirred solution of 6-bromo-3H-imidazo[4,5-b]pyridine (506 mg, 2.55 mmol) from Step 1 of this Example in anhydrous DMF (10 mL) at 0° C. was added in one portion sodium hydride (60% dispersion in mineral oil, 107 mg, 2.68 mmol), and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added a solution of 6-(chloromethyl)-2-(methylthio)benzo[d]oxazole (600 mg, 2.81 mmol) from Step 3 of Example 56 in DMF (2 mL). The mixture was allowed to warm to rt, then stirred for a further 15 h. To the reaction mixture was added water and the mixture was extracted with EtOAc. The organic layer was separated and the aq layer extracted with additional EtOAc. The combined organic layers were washed with water then brine. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 100% DCM, followed by 1% MeOH in DCM to afford 6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]oxazole (460 mg, 48%) as a white solid. The regiochemistry of the alkylation was determined by 2-dimensional nuclear Overhauser effect (NOE) experiment. 1H NMR (300 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.48 (d, J=1.9 Hz, 1H), 8.40 (d, J=1.9 Hz, 1H), 7.68 (s, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 5.59 (s, 2H), 2.73 (s, 3H). LCMS (ESI) m/z 375 and 377 (M+H)+.

Workup

  1. customat 0° C.
  2. temperatureto warm to rt
  3. stirringstirred for a further 15 h
  4. extractionthe mixture was extracted with EtOAc
  5. customThe organic layer was separated
  6. extractionthe aq layer extracted with additional EtOAc
  7. washThe combined organic layers were washed with water
  8. customThe organic layer was separated
  9. dry with materialdried over MgSO4
  10. filtrationfiltered
  11. concentrationconcentrated under reduced pressure
  12. customThe residue was purified by silica gel flash chromatography
  13. washeluting with 100% DCM

Sources & evidence

ORD record
ord-4b6eb43d9ea5442ebe9362add4c10994
Source dataset
uspto-grants-2015_02
Patent number
US08952058B2

Reaction notes

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