Potassium Phosphate, Tribasic → 6-(2-chlorophenyl)-7-(4-chlorophenyl)-5-methyl-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one

HRID 2101392Notes

Reaction equation

HRID 2101392 reaction equation
Br[C:2]1[C:3]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[CH:4][C:5]2[N:6]([C:9](=[O:23])[N:10]([CH2:12][C:13]3[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=3)[N:11]=2)[C:7]=1[CH3:8].[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>>[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:2]1[C:3]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)=[CH:4][C:5]2[N:6]([C:9](=[O:23])[N:10]([CH2:12][C:13]3[CH:14]=[N:15][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:17][CH:18]=3)[N:11]=2)[C:7]=1[CH3:8]

Participants

5

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 27343222-Chlorophenylboronic acidHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 577994276-bromo-7-(4-chlorophenyl)-5-methyl-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one

Product 1

HCID 577993616-(2-chlorophenyl)-7-(4-chlorophenyl)-5-methyl-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-oneYield 86%

Conditions

Temperature
95 °C

Procedure

Into a flame-dried 25 mL round bottom flask was placed 6-bromo-7-(4-chlorophenyl)-5-methyl-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (25 mg, 0.05 mmol), 2-chlorophenylboronic acid (16 mg, 0.1 mmol), K3PO4 (43 mg, 0.2 mmol), Pd(dba)3 (4.6 mg, 0.005 mmol), and S-Phos (dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine, 4.2 mg, 0.01 mmol). The reaction flask was purged with argon three times before toluene (1 mL) was added. The reaction mixture was stirred at 95° C. for 16 h. Analysis by HPLC/MS indicated the starting 6-bromo-7-(4-chlorophenyl)-5-methyl-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one had been consumed. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (15 mL×2). The combined EtOAc extracts were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (4 g) eluted with a gradient of EtOAc (30-70%) in hexanes to afford the desired product (86% pure). The product was further purified by preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 70% to 100% B over 10 min (A=90% water, 10% methanol and B=90% methanol, 10% water) with flow rate at 20 mL/min and UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The residue obtained was dissolved in acetonitrile, frozen and lyophilized to afford 10 mg (40%) of the title compound as a light yellow powder. HPLC/MS: retention time=4.13 min, [M+H]+=529.3.

Workup

  1. customInto a flame-dried 25 mL round bottom flask was placed
  2. customThe reaction flask was purged with argon three times before toluene (1 mL)
  3. additionwas added
  4. customhad been consumed
  5. temperatureAfter cooling to room temperature
  6. customthe reaction mixture was partitioned between EtOAc and water
  7. extractionThe aqueous layer was extracted with EtOAc (15 mL×2)
  8. washThe combined EtOAc extracts were washed with saturated aqueous NaCl
  9. dry with materialdried over Na2SO4
  10. filtrationfiltered
  11. concentrationconcentrated under reduced pressure
  12. customThe crude product was purified
  13. washeluted with a gradient of EtOAc (30-70%) in hexanes

Sources & evidence

ORD record
ord-781bd4adb84e48a7985d5800e67a1d9e
Source dataset
uspto-grants-2009_08
Patent number
US07572808B2

Reaction notes

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