Potassium Carbonate → 5-methyl-7-[2'-(trifluoromethyl)-1,1'-biphenyl-3-yl]-N-(3,4,5-trimethoxyphenyl) imidazo[5,1-f][1,2,4]triazin-2-amine

HRID 2374959Notes

Reaction equation

HRID 2374959 reaction equation
Br[C:2]1[CH:3]=[C:4]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14]([NH:17][C:18]4[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=4)=[N:15]3)=[C:10]([CH3:30])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>ClCCl>[CH3:30][C:10]1[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[C:32]([F:43])([F:42])[F:31])[CH:7]=[CH:6][CH:5]=2)[N:16]2[C:11]=1[CH:12]=[N:13][C:14]([NH:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=1)=[N:15]2

Participants

6

Reactant 4

HCID 11430Potassium CarbonateHCID 312751,4-DioxaneHCID 27343872-(Trifluoromethyl)benzeneboronic acidHCID 112135557-(3-bromophenyl)-5-methyl-N-(3,4,5-trimethoxyphenyl)-imidazo[5,1-f][1,2,4]triazin-2-amine

Product 1

HCID 113071655-methyl-7-[2'-(trifluoromethyl)-1,1'-biphenyl-3-yl]-N-(3,4,5-trimethoxyphenyl) imidazo[5,1-f][1,2,4]triazin-2-amineYield 27.1%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
150 °C

Procedure

To a mixture of 7-(3-bromophenyl)-5-methyl-N-(3,4,5-trimethoxyphenyl)-imidazo[5,1-f][1,2,4]triazin-2-amine (Example 9) (50 mg, 0.106 mmol), 2-trifluoromethylphenyl boronic acid (30.3 mg, 0.159 mmol), potassium carbonate (44.1 mg, 0.318 mmol), and Combiphos catalyst POPd1 ((dihydrogen di-κ-chlorotetrakis(di-tert-butylphosphinito-κP)dipalladate(2-)) (5.0 mg, 0.005 mmol) was added 1,4-dioxane (1.8 mL) and distilled water (0.2 mL). In a sealed reaction vessel, the mixture was heated with microwave radiation at 150° C. for a total time of 1 hour. After cooling to room temperature, poured reaction mixture into dichloromethane (50 mL) and washed with distilled water (3×25 mL) and brine (1×25 mL). Dried over MgSO4, filtered and removed solent under reduced pressure to give a gold oil. Dissolved oil in dichloromethane and added silica gel (200 mg). Following evaporation of the volatiles under reduced pressure, the pre-adsorbed solids were loaded into a solid loading cartridge and subjected to a gradient elution using ethyl acetate:hexanes (20:80 to 70:30) using a RediSep silica gel cartridge (4.2 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to give 5-methyl-7-[2′-(trifluoromethyl)-1,1′-biphenyl-3-yl]-N-(3,4,5-trimethoxyphenyl) imidazo[5,1-f][1,2,4]triazin-2-amine (0.0154 g) as a yellow solid. 1H NMR (DMSO-d6): δ9.63 (s, 1H), 9.26 (s, 1H), 8.59 (d, J=7.90 Hz, 1H), 8.14 (s, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.71 (dd, J=7.9, 7.1 Hz, 1H), 7.62 (dd, J=7.3, 7.5 Hz, 1H), 7.54 (dd, J=7.7, 7.9 Hz, 1H), 7.45 (d, J=6.6 Hz, 1H), 7.39 (d, J=7.1 Hz, 1H), 7.05 (s, 2H), 3.67 (s, 6H), 3.61 (s, 3H), 2.51 (s, 3H). MS m/z 536 (M+1).

Workup

  1. distillationdistilled water (0.2 mL)
  2. customIn a sealed reaction vessel
  3. temperatureAfter cooling to room temperature
  4. additionpoured
  5. washwashed with distilled water (3×25 mL) and brine (1×25 mL)
  6. dry with materialDried over MgSO4
  7. filtrationfiltered
  8. customremoved solent under reduced pressure
  9. customto give a gold oil
  10. additionadded silica gel (200 mg)
  11. customevaporation of the volatiles under reduced pressure
  12. washsubjected to a gradient elution
  13. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-b384e26adba24079b0a69947f58a73ae
Source dataset
uspto-grants-2008_12
Patent number
US07462614B2

Reaction notes

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