Dimethylformamide → HCID 16004839, compound

HRID 2101332Notes

Reaction equation

HRID 2101332 reaction equation
Cl[C:2]1[C:7]([CH2:8][N:9]2[C:30](=[O:31])[N:12]3[CH:13]=[CH:14][C:15]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)=[C:16]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[C:11]3=[N:10]2)=[CH:6][CH:5]=[C:4]([C:32]([F:35])([F:34])[F:33])[N:3]=1.[CH3:36][N:37](C=O)C>O.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.[Fe+2].[C-]#N.[Zn+2].[C-]#N>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:15]2[CH:14]=[CH:13][N:12]3[C:30](=[O:31])[N:9]([CH2:8][C:7]4[C:2]([C:36]#[N:37])=[N:3][C:4]([C:32]([F:34])([F:33])[F:35])=[CH:5][CH:6]=4)[N:10]=[C:11]3[C:16]=2[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:24][CH:25]=1

Participants

6

Reactant 2

HCID 6228DimethylformamideHCID 160048102-((2-chloro-6-(trifluoromethyl)pyridin-3-yl)methyl)-7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one

Product 1

HCID 16004839HCID 16004839, compoundYield 69%

Reagents, catalysts & solvents 3

HCID 11186Zinc cyanide (Zn(CN)2)CatalystHCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)CatalystHCID 962WaterSolvent

Conditions

Temperature
90 °C

Procedure

Into a 25 mL flame-dried three necked flask equipped with a condenser under argon was placed 2-((2-chloro-6-(trifluoromethyl)pyridin-3-yl)methyl)-7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (250 mg, 0.484 mmol), Pd(dba)3 (44 mg, 0.048 mmol) and dppf (107 mg, 0.194 mmol). The reaction apparatus was purged with argon, and anhydrous DMF (1.5 mL, degassed by bubbling with argon) was added. The resulting suspension was stirred in a pre-heated oil bath at 90° C. To the resulting clear brownish solution, a suspension of zinc cyanide (85.3 mg, 0.73 mmol) in anhydrous DMF (1.5 mL) was added in five portions over 5 min. The reaction mixture was then stirred at 90° C. for 3 h. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc (30 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 (12 g) eluted with a gradient of EtOAc (50-100%) in hexanes to afford 170 mg (69%) of the title compound as a brown foam. A portion of the product was further purified using preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 50% to 100% B over 20 min (A=0.1% trifluoroacetic acid, 90% water, 10% methanol and B=0.1% trifluoroacetic acid, 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 was dissolved in EtOAc, washed with saturated aqueous NaHCO3 once, water twice, then saturated aqueous NaCl, dried over Na2SO4 and evaporated. The residue was dissolved in acetonitrile, frozen and lyophilized to afford the title compound as a yellow powder. HPLC/MS: retention time=2.82 min, [M+H]+=507.1.

Workup

  1. customInto a 25 mL flame-dried three necked flask
  2. customequipped with a condenser under argon
  3. customThe reaction apparatus was purged with argon, and anhydrous DMF (1.5 mL, degassed by bubbling with argon)
  4. additionwas added
  5. additionwas added in five portions over 5 min
  6. stirringThe reaction mixture was then stirred at 90° C. for 3 h
  7. temperatureAfter cooling to room temperature
  8. extractionextracted with EtOAc (30 mL×2)
  9. washThe combined EtOAc extracts were washed with saturated aqueous NaCl
  10. dry with materialdried over Na2SO4
  11. filtrationfiltered
  12. concentrationconcentrated under reduced pressure
  13. customThe crude product was purified
  14. washeluted with a gradient of EtOAc (50-100%) in hexanes

Sources & evidence

ORD record
ord-fef18effb47041ef95203a5b0eeba3dc
Source dataset
uspto-grants-2009_08
Patent number
US07572808B2

Reaction notes

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