5-Bromo-2-methylpyridine → HCID 86716091, compound

HRID 627525Notes

Reaction equation

HRID 627525 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[Li+].[Cl-].[Cl:16][C:17]1[C:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:25]([Cl:33])[C:24]2[C:19](=[C:20]([CH3:36])[CH:21]=[C:22]([CH:34]=[O:35])[CH:23]=2)[N:18]=1>C(Cl)Cl.C(Cl)Cl.CO.O=[Mn]=O>[Cl:16][C:17]1[C:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:25]([Cl:33])[C:24]2[C:19](=[C:20]([CH3:36])[CH:21]=[C:22]([C:34]([C:2]3[CH:7]=[N:6][C:5]([CH3:8])=[CH:4][CH:3]=3)=[O:35])[CH:23]=2)[N:18]=1

Participants

7

Reactant 3

HCID 12010205-Bromo-2-methylpyridineHCID 86716090HCID 86716090, compound2×HCID 178461733HCID 178461733, compound

Product 1

HCID 86716091HCID 86716091, compound

Reagents, catalysts & solvents 3

HCID 14801Manganese dioxideCatalystHCID 6344DichloromethaneSolventHCID 21226129Dichloromethane methanolSolvent

Procedure

A solution of 5-bromo-2-methylpyridine (380 mg, 2.21 mmol) in DCM (2.2 mL) was stirred on an ice bath while iPrMgCl—LiCl (1.84 mL, 1.2 M in THF, 2.21 mmol) was added dropwise over 1-2 min under argon. After 30 min stirring at room temperature, the dark brown Grignard solution was added dropwise over 1-2 min to a slurry of 2,4-dichloro-8-methyl-3-phenylquinoline-6-carbaldehyde (460 mg, 1.46 mmol, Intermediate 47, step b) in LaCl3-2LiCl (2.60 mL, 0.56 M in THF, 1.46 mmol) on an ice bath under argon. The homogeneous reddish-amber reaction was removed from the ice bath immediately following Grignard addition and stirred at room temperature overnight. The resulting homogeneous brown amber solution was diluted with 9:1 DCM/MeOH (14 mL) and 5 M NH4Cl (0.72 mL), shaken with Celite® and filtered, and the filter cake was washed with 9:1 DCM/MeOH (1×5 mL). The combined clear amber filtrates were dried (Na2SO4), filtered, and concentrated repeatedly from DCM. The residue was taken up in DCM (15 mL) and the resulting slurry was stirred with MnO2 (1.27 g, 14.5 mmol) under air (capped) at 40° C. for 32 hours. The reaction was diluted with 9:1 DCM/MeOH (10 mL) and Celite®, and filtered on a bed of Celite®. The filtrate was concentrated and flash chromatographed with a DCM to 30% EtOAc/DCM gradient to provide the title compound as a colorless film.

Workup

  1. additionwas added dropwise over 1-2 min under argon
  2. customThe homogeneous reddish-amber reaction
  3. customwas removed from the ice bath immediately following Grignard addition
  4. stirringstirred at room temperature overnight
  5. additionThe resulting homogeneous brown amber solution was diluted with 9:1 DCM/MeOH (14 mL) and 5 M NH4Cl (0.72 mL)
  6. stirringshaken with Celite®
  7. filtrationfiltered
  8. washthe filter cake was washed with 9:1 DCM/MeOH (1×5 mL)
  9. dry with materialThe combined clear amber filtrates were dried (Na2SO4)
  10. filtrationfiltered
  11. concentrationconcentrated repeatedly from DCM
  12. filtrationfiltered on a bed of Celite®
  13. concentrationThe filtrate was concentrated
  14. customflash chromatographed with a DCM to 30% EtOAc/DCM gradient

Sources & evidence

ORD record
ord-ca7c9ed682cc41bc862858ea199c4309
Source dataset
uspto-grants-2016_04
Patent number
US09309222B2

Reaction notes

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