2-Methoxy-5-(trifluoromethyl)aniline → (2-Chloro-[1,2,4]triazolo[1,5-a]pyridine-8-yl)-(2-methoxy-5-trifluoromethyl-phenyl)-amine

HRID 1890035Notes

Reaction equation

HRID 1890035 reaction equation
Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=1[NH2:24].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([NH:24][C:15]3[CH:16]=[C:17]([C:20]([F:22])([F:23])[F:21])[CH:18]=[CH:19][C:14]=3[O:13][CH3:12])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1

Participants

6

Reactant 3

HCID 6006372-Methoxy-5-(trifluoromethyl)anilineHCID 23676156Sodium t-butoxideHCID 674813708-Bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine

Product 1

HCID 67479006(2-Chloro-[1,2,4]triazolo[1,5-a]pyridine-8-yl)-(2-methoxy-5-trifluoromethyl-phenyl)-amineYield 68%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (0.23 g, 0.99 mmol), 2-methoxy-5-trifluoromethyl-phenylamine (0.226 g, 1.19 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.185 g, 0.2 mmol), dicyclohexyl-(2′-4′-6′-triisopropyl-biphenyl-2-yl)-phosphane (0.19 g, 0.4 mmol), and sodium tert-butoxide (0.29 g, 3.0 mmol) in toluene (10 mL) was degassed with nitrogen for 3 minutes, then heated at 100° C. for 2 hours under argon. The reaction was cooled to room temperature, diluted with dichloromethane, filtered through diatomaceous earth, and concentrated. The residue was diluted with dichloromethane, washed with 10% sodium bicarbonate solution, brine, dried over sodium sulfate and concentrated. The crude product was triturated with ether and dichloromethane to give (2-chloro-[1,2,4]triazolo[1,5-a]pyridine-8-yl)-(2-methoxy-5-trifluoromethyl-phenyl)-amine (0.23 g, 68%). MP=144-146° C. MS=343 (MH)+. 290b) N(8)-(2-Methoxy-5-trifluoromethyl-phenyl)-N(2)-[3-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridine-8-yl)-(2-methoxy-5-trifluoromethyl-phenyl)-amine, 3-(4-methylpiperazin-1-yl)aniline with 2,2′-bis-dicyclohexylphosphanyl-biphenyl as the ligand in a manner analogous to Example 2d (0.005 g, 20%). MP=198-200° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.44 (s, 1H), 8.37 (d, 1H), 7.61 (s, 1H), 7.43 (s, 1H), 7.30 (m, 2H), 7.24 (s, 1H), 7.16 (m, 2H), 7.09 (m, 1H), 6.93 (m, 1H), 6.48 (m, 1H), 3.97 (s, 3H), 3.10 (m, 4H), 2.45 (m, 4H), 2.21 (s, 3H). MS=498 (MH)+.

Workup

  1. customwas degassed with nitrogen for 3 minutes
  2. temperatureThe reaction was cooled to room temperature
  3. additiondiluted with dichloromethane
  4. filtrationfiltered through diatomaceous earth
  5. concentrationconcentrated
  6. additionThe residue was diluted with dichloromethane
  7. washwashed with 10% sodium bicarbonate solution, brine
  8. dry with materialdried over sodium sulfate
  9. concentrationconcentrated
  10. customThe crude product was triturated with ether and dichloromethane

Sources & evidence

ORD record
ord-81f76e1045b84036b79893e23ec73a52
Source dataset
uspto-grants-2013_08
Patent number
US08501936B2

Reaction notes

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