4-Chloro-6-methyl-1,3,5-triazin-2-amine → 4-(5-Chloro-2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine

HRID 1621935Notes

Reaction equation

HRID 1621935 reaction equation
Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[Cl:10][C:11]1[CH:12]=[C:13](B(O)O)[C:14]([F:17])=[N:15][CH:16]=1.C([O-])(=O)C.[K+]>CCO.O>[Cl:10][C:11]1[CH:12]=[C:13]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[N:3]=2)[C:14]([F:17])=[N:15][CH:16]=1

Participants

6

Reactant 3

HCID 305914-Chloro-6-methyl-1,3,5-triazin-2-amineHCID 517044Potassium AcetateHCID 249017795-Chloro-2-fluoropyridine-3-boronic Acid

Product 1

HCID 666118184-(5-Chloro-2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amineYield 56.3%

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 962WaterSolvent

Conditions

Temperature
100 °C

Procedure

To a 20 mL microwave reaction tube was added 4-chloro-6-methyl-1,3,5-triazin-2-amine (Example 9, 1.00 g, 6.94 mmol), 5-chloro-2-fluoropyridin-3-ylboronic acid (Combi-Blocks, 1.62 g, 9.22 mmol), potassium acetate (Aldrich, 2.07 g, 21.1 mmol) and Am-Phos (Aldrich, 0.247 g, 0.349 mmol) in EtOH (12 mL) and water (1.2 mL). The mixture was degassed by bubbling argon through for 5 min. The tube was heated in an microwave reactor (Biotage) at 100° C. for 20 min. The reaction mixture was partitioned between water (100 mL) and 25% IPA in chloroform with 1% NH4OH (60 mL). The aqueous phase was extracted with 25% IPA in chloroform with 1% NH4OH (2×50 mL). The combined organic phases were washed with saturated aqueous sodium chloride (40 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. Adding DCM to the residue resulted in precipitate formation. The solid was collected via filtration and washed with MeOH to afford 4-(5-chloro-2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.937 g) as a light yellow powder. The filtrate and the wash were combined and concentrated, then purified by column chromatography (eluent: iPrOH (w/10% NH4OH) in CHCl3 0.25% to 6.25%) followed by washing with MeOH to afford additional product (0.149 g) as a white solid. The total yield is 1.08 g (65%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.54 (dd, J=8.02, 2.74 Hz, 1H) 8.46-8.51 (m, 1H) 7.73 (s, 2H) 2.37 (s, 3H). m/z (ESI, positive ion) m/z: 240.1 (M+H)+.

Workup

  1. customThe mixture was degassed
  2. customby bubbling argon through for 5 min
  3. customThe reaction mixture was partitioned between water (100 mL) and 25% IPA in chloroform with 1% NH4OH (60 mL)
  4. extractionThe aqueous phase was extracted with 25% IPA in chloroform with 1% NH4OH (2×50 mL)
  5. washThe combined organic phases were washed with saturated aqueous sodium chloride (40 mL)
  6. dry with materialThe organic phase was dried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customAdding DCM to the residue resulted in precipitate formation
  10. filtrationThe solid was collected via filtration
  11. washwashed with MeOH

Sources & evidence

ORD record
ord-6c5863c972464c5687b112b1e44a1a1f
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

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