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

HRID 1848151Notes

Reaction equation

HRID 1848151 reaction equation
[F: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>[F: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 866810166-(Chloromethyl)-2-(methylthio)benzo[d]oxazoleHCID 178505977HCID 178505977, compound

Product 1

HCID 866811226-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]oxazoleYield 61%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
0 °C

Procedure

To a stirred solution of 6-fluoro-3H-imidazo[4,5-b]pyridine (502 mg, 3.66 mmol) from Step 2 of Example 70 in anhydrous DMF (10 mL) at 0° C. was added in one portion sodium hydride (60% dispersion in mineral oil, 220 mg, 5.49 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 (858 mg, 4.03 mmol) from Step 3 of Example 56 in DMF (2 mL). The mixture was allowed to warm to rt and stir for a further 3 h. To the reaction mixture was added water and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed sequentially with water and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 30 to 50% ethyl acetate in petroleum ether to afford 6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]oxazole (698 mg, 61%) 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 8.71 (s, 1H), 8.41 (s, 1H), 8.07 (d, J=6.9 Hz, 1H), 7.68 (s, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.35 (d, J=6.3 Hz, 1H), 5.59 (s, 2H), 2.73 (s, 3H); LCMS (ESI) m/z 315 (M+H)+.

Workup

  1. temperatureto warm to rt
  2. stirringstir for a further 3 h
  3. extractionthe mixture was extracted with ethyl acetate (3×100 mL)
  4. washThe combined organic layers were washed sequentially with water and brine
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customThe residue was purified by silica gel flash chromatography
  9. washeluting with 30 to 50% ethyl acetate in petroleum ether

Sources & evidence

ORD record
ord-22c3cc0984a04281b5c4dd0d741dea49
Source dataset
uspto-grants-2015_02
Patent number
US08952058B2

Reaction notes

Loading…