Dichloromethane → 4-(2-((2-Methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-oxo-8-phenyl-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)benzonitrile

HRID 2101296Notes

Reaction equation

HRID 2101296 reaction equation
Br[C:2]1[C:3]2[N:4]([C:16](=[O:31])[N:17]([CH2:19][C:20]3[C:21]([CH3:30])=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=3)[N:18]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[C:32]1(B(O)O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1COCC1>[CH3:30][C:21]1[C:20]([CH2:19][N:17]2[C:16](=[O:31])[N:4]3[CH:5]=[CH:6][C:7]([C:8]4[CH:9]=[CH:10][C:11]([C:12]#[N:13])=[CH:14][CH:15]=4)=[C:2]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:3]3=[N:18]2)=[CH:25][CH:24]=[C:23]([C:26]([F:27])([F:29])[F:28])[N:22]=1

Participants

7

Reactant 4

HCID 6344DichloromethaneHCID 62657Potassium Phosphate, TribasicHCID 66827Phenylboronic AcidHCID 690563694-(8-Bromo-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)benzonitrile

Product 1

HCID 160049094-(2-((2-Methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-oxo-8-phenyl-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)benzonitrileYield 90%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
90 °C

Procedure

Into a flame-dried reaction vessel under argon was placed 4-(8-bromo-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)benzonitrile (49 mg, 0.1 mmol), phenylboronic acid (37 mg, 0.3 mmol), K3PO4 (64 mg, 0.3 mmol), Pd(dppf)Cl2.CH2Cl2 (8.0 mg, 0.01 mmol) and anhydrous THF (1.5 mL). The suspension was degassed with argon bubbling, and the reaction vessel was sealed and stirred at 90° C. for 4.5 h. Analysis by HPLC/MS indicated the reaction was not complete. Additional palladium catalyst (3 mg) and THF (0.5 mL) was added, and the suspension was degassed again. The reaction mixture was stirred at 90° C. for 16 h more. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water. The EtOAc layer was washed with water, then saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (12 g) eluted with a gradient of EtOAc (0-70%) in hexanes to afford the desired product (90% 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 19.5 mg of the title compound as a light yellow powder. HPLC/MS: retention time=3.69 min, [M+H]+=486.7.

Workup

  1. customInto a flame-dried reaction vessel under argon
  2. customThe suspension was degassed with argon bubbling
  3. customthe reaction vessel was sealed
  4. additionAdditional palladium catalyst (3 mg) and THF (0.5 mL) was added
  5. customthe suspension was degassed again
  6. stirringThe reaction mixture was stirred at 90° C. for 16 h more
  7. temperatureAfter cooling to room temperature
  8. customthe reaction mixture was partitioned between EtOAc and water
  9. washThe EtOAc layer was washed with water
  10. dry with materialsaturated aqueous NaCl, dried over Na2SO4
  11. filtrationfiltered
  12. concentrationconcentrated under reduced pressure
  13. customThe crude product was purified
  14. washeluted with a gradient of EtOAc (0-70%) in hexanes

Sources & evidence

ORD record
ord-732c4e68d41c47628a878cf0afa13d91
Source dataset
uspto-grants-2009_08
Patent number
US07572808B2

Reaction notes

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