5-Bromo-1-methyl-1H-imidazole → HCID 86716088, compound

HRID 627522Notes

Reaction equation

HRID 627522 reaction equation
Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.C([Mg]Cl)(C)C.[Li+].[Cl-].[Cl:15][C:16]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:24]([Cl:32])[C:23]2[C:18](=[C:19]([F:35])[CH:20]=[C:21]([CH:33]=[O:34])[CH:22]=2)[N:17]=1>C(Cl)Cl.O=[Mn]=O>[Cl:15][C:16]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:24]([Cl:32])[C:23]2[C:18](=[C:19]([F:35])[CH:20]=[C:21]([C:33]([C:2]3[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=3)=[O:34])[CH:22]=2)[N:17]=1

Participants

6

Reactant 3

HCID 15152585-Bromo-1-methyl-1H-imidazoleHCID 86716087HCID 86716087, compound2×HCID 178461733HCID 178461733, compound

Product 1

HCID 86716088HCID 86716088, compound

Reagents, catalysts & solvents 2

HCID 14801Manganese dioxideCatalystHCID 6344DichloromethaneSolvent2×

Procedure

A solution of 5-bromo-1-methyl-1H-imidazole (95.7 mg, 0.594 mmol) in DCM (0.6 mL) was stirred on an ice bath while iPrMgCl—LiCl (0.495 mL, 1.2 M in THF, 0.593 mmol) was added dropwise over 2.5 min under argon. After 15 min stirring at room temperature, the Grignard solution was added dropwise over 2.5 min to a slurry of 2,4-dichloro-8-fluoro-3-phenylquinoline-6-carbaldehyde (140 mg, 0.436 mmol, Intermediate 46, step b) in LaCl3-2LiCl (0.779 mL, 0.56 M in THF, 0.436 mmol) on an ice bath. The red-colored reaction was removed from the ice bath immediately following Grignard addition, and after 15 min stirring under ambient conditions, the reaction was partitioned with DCM (5 mL) and 1M NaHCO3 (0.6 mL). The mixture was filtered and the filter cake washed with 3 mL DCM. The combined clear yellow filtrates were dried (Na2SO4), filtered, and concentrated, and the crude secondary alcohol was dissolved in DCM (2 mL), treated with MnO2 (379 mg, 4.36 mmol), and stirred at 40° C. for 2 hours. The reaction was then diluted with DCM (4 mL) and filtered, and the clear yellow filtrate was concentrated and flash chromatographed with a 5% acetone/heptane to 100% acetone gradient to yield the title compound as a white solid.

Workup

  1. additionwas added dropwise over 2.5 min under argon
  2. customThe red-colored reaction
  3. customwas removed from the ice bath immediately following Grignard addition
  4. stirringafter 15 min stirring under ambient conditions
  5. customthe reaction was partitioned with DCM (5 mL) and 1M NaHCO3 (0.6 mL)
  6. filtrationThe mixture was filtered
  7. washthe filter cake washed with 3 mL DCM
  8. dry with materialThe combined clear yellow filtrates were dried (Na2SO4)
  9. filtrationfiltered
  10. concentrationconcentrated
  11. dissolutionthe crude secondary alcohol was dissolved in DCM (2 mL)
  12. stirringstirred at 40° C. for 2 hours
  13. filtrationfiltered
  14. concentrationthe clear yellow filtrate was concentrated
  15. customflash chromatographed with a 5% acetone/heptane to 100% acetone gradient

Sources & evidence

ORD record
ord-5e77cdc56c62448abb79f387cd48b28f
Source dataset
uspto-grants-2016_04
Patent number
US09309222B2

Reaction notes

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