Hydrochloric Acid → 7-Bromo-3-(2-chloro-5-fluorophenyl)-1,6-naphthyridine

HRID 468887Notes

Reaction equation

HRID 468887 reaction equation
CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[CH2:15][CH:16]=O.[Br:18][C:19]1[CH:24]=[C:23]([NH:25]C(=O)OC(C)(C)C)[C:22]([CH:33]=O)=[CH:21][N:20]=1.Cl>O1CCOCC1.O.C(OCC)(=O)C>[Br:18][C:19]1[CH:24]=[C:23]2[C:22]([CH:33]=[C:15]([C:9]3[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]=3[Cl:7])[CH:16]=[N:25]2)=[CH:21][N:20]=1

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 23665647Potassium tert-butoxideHCID 552747552-(2-Chloro-5-fluorophenyl)acetaldehydeHCID 86674965tert-Butyl (2-bromo-5-formylpyridin-4-yl)carbamate

Product 1

HCID 866749667-Bromo-3-(2-chloro-5-fluorophenyl)-1,6-naphthyridineYield 30%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent3×

Procedure

To a slurry of potassium tert-butoxide (94 mg, 0.8 mmol) in 1,4-dioxane (1 mL) cooled at 0° C. was added 2-(2-chloro-5-fluorophenyl)acetaldehyde (98 mg, 0.4 mmol) as a solution in 1,4-dioxane (0.6 mL). The reaction mixture was stirred for 10 minutes at this temperature, and then tert-butyl 2-bromo-5-formylpyridin-4-ylcarbamate (60 mg, 0.2 mmol) was added as a solution in dioxane (0.6 mL). The reaction mixture was allowed to warm to room temperature, and after 30 minutes a 5.0M solution of hydrogen chloride in water (0.5 mL) was added and the mixture was heated at 100° C. for 1 hour. The cooled reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 4 g, ISCO, 0-50% ethyl acetate in heptane) to afford the title compound as an off-white solid (20 mg, 30%), which was used in the next step without further purification.

Workup

  1. temperaturethe mixture was heated at 100° C. for 1 hour
  2. customThe cooled reaction mixture
  3. washwashed with water (50 mL)
  4. customThe organic layer was separated
  5. dry with materialdried over sodium sulfate
  6. filtrationfiltered
  7. customevaporated in vacuo
  8. customto afford a residue that
  9. customwas purified by flash chromatography (silica, 4 g, ISCO, 0-50% ethyl acetate in heptane)

Sources & evidence

ORD record
ord-84fcc6721143408589546e34daac356b
Source dataset
uspto-grants-2014_01
Patent number
US08623889B2

Reaction notes

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