4-Amino-2-methylpyridine → HCID 86712024, compound

HRID 1051383Notes

Reaction equation

HRID 1051383 reaction equation
[CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[N:25][C:24](F)=[CH:23]2>C1COCC1>[Br:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[N:25][C:24]([NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)=[CH:23]2

Participants

5

Reactant 3

HCID 7286704-Amino-2-methylpyridine2×HCID 2733832Lithium HexamethyldisilazideHCID 584882946-Bromo-3-fluoroisoquinoline

Product 1

HCID 86712024HCID 86712024, compoundYield 28.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A dry 40 mL scintillation vial equipped with a screw cap with a teflon insert was cooled under nitrogen, equipped with a stir bar and charged with 2-methylpyridine-4-amine (263 mg, 3.32 mmol) and anhydrous THF (27 mL) and maintained under a N2 atmosphere. LiHMDS was added as a solid (0.925 g, 5.53 mmol). The reaction mixture was stirred at RT under nitrogen for 5 min. To the mixture was added 6-bromo-3-fluoro isoquinoline (500 mg, 2.21 mmol), the vial was flushed with N2, tightly capped and placed in a pre-heated oil bath at 85° C. After 4 h at 85° C., additional 2-methylpyridine-4-amine (96 mg, total: 359 mg, 3.32 mmol) and LiHMDSi (185 mg, total: 1.11 g, 6.64 mmol) were added, and the reaction was heated an additional 2 h at 85° C. The reaction was cooled, and the THF was removed in vacuo. The crude reaction mixture was partitioned between water and DCM containing 10% MeOH. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was absorbed onto Celite® and purified by SiO2 chromatography eluting with a MeOH/DCM gradient (0 to 10% MeOH) to afford 196 mg (28%) of 6-bromo-N-(2-methylpyridin-4-yl)isoquinolin-3-amine (94) as a yellow solid, which was used in the next step without further purification.

Workup

  1. customA dry 40 mL scintillation vial equipped with a screw
  2. temperaturewas cooled under nitrogen
  3. customequipped with a stir bar
  4. temperaturemaintained under a N2 atmosphere
  5. customthe vial was flushed with N2
  6. customtightly capped
  7. customplaced in a pre-heated oil bath at 85° C
  8. waitAfter 4 h at 85° C.
  9. temperaturethe reaction was heated an additional 2 h at 85° C
  10. temperatureThe reaction was cooled
  11. customthe THF was removed in vacuo
  12. customThe crude reaction mixture
  13. customwas partitioned between water and DCM containing 10% MeOH
  14. washThe organic layer was washed with brine
  15. dry with materialdried (Na2SO4)
  16. filtrationfiltered
  17. concentrationconcentrated
  18. customThe crude residue was absorbed onto Celite®
  19. custompurified by SiO2 chromatography
  20. washeluting with a MeOH/DCM gradient (0 to 10% MeOH)

Sources & evidence

ORD record
ord-7233834036d945ea8845ff942aa51555
Source dataset
uspto-grants-2016_07
Patent number
US09388171B2

Reaction notes

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