Phosphorus oxychloride → 4-(8-(4-Chlorophenyl)-3-ethyl-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-7-yl)benzonitrile

HRID 1865837Notes

Reaction equation

HRID 1865837 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH:35][NH:36][C:37](=O)[CH2:38][CH3:39])=[N:10][N:11]([CH2:23][C:24]3[C:25]([CH3:34])=[N:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=3)[C:12](=[O:22])[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([C:37]([CH2:38][CH3:39])=[N:36][N:35]=3)[N:11]([CH2:23][C:24]3[C:25]([CH3:34])=[N:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=3)[C:12](=[O:22])[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1

Participants

4

Reactant 2

HCID 24813Phosphorus oxychlorideHCID 69026179N'-(4-(4-chlorophenyl)-5-(4-cyanophenyl)-1-((2-methyl-6-(trifluoromethyl)pyridin-3-yl) methyl)-6-oxo-1,6-dihydropyridazin-3-yl)propionohydrazide

Product 1

HCID 119901694-(8-(4-Chlorophenyl)-3-ethyl-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-7-yl)benzonitrileYield 69%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
130 °C

Procedure

To a round bottom flask was added N′-(4-(4-chlorophenyl)-5-(4-cyanophenyl)-1-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-1,6-dihydropyridazin-3-yl)propionohydrazide (45 mg, 0.0794 mmol) and toluene (3 ml). The reaction was heated to 130° C. and stirred at this temperature for 1 hr. After this time, POCl3 (1 ml) was added and the reaction mixture was stirred at 130° C. for additional 4 hrs. The reaction was then cooled to rt and concentrated under reduced pressure. The residue was dissolved in EtOAc (30 ml) and the resulting solution was washed with 0.5N NaOH (10 ml), water (15 ml), saturated aqueous NaCl (10 mL). The organic layer was then slurried with MgSO4 to remove excess water, filtered and concentrated to give the crude product. The crude product was purified using an automated column chromatography system (ISCO, 4 gm silica gel) eluting with a gradient of 65%-100% EtOAc/Hex to give product 4-(8-(4-chlorophenyl)-3-ethyl-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-7-yl)benzonitrile (30 mg) as off-white solid. 69% yield. HPLC retention time (method A) 3.110 min; LCMS (M+H)=549.4. 1HNMR (CDCl3, 500 Hz): 7.49-7.53 (3H, m), 7.35-7.37 (1H, m), 7.22-7.24 (6H, m), 5.57 (2H, s), 2.73 (2H, q), 2.65 (3H, s), 1.38 (3H, t); 13CNMR (CDCl3, 500 Hz) 159.8, 155.7, 148.6, 147.5(q), 143.9, 138.0, 137.1, 136.6, 133.5, 131.9, 131.8, 128.9, 120.8(q), 118.6, 118.2, 112.6, 49.2, 22.2, 20.5, 12.4.

Workup

  1. stirringthe reaction mixture was stirred at 130° C. for additional 4 hrs
  2. temperatureThe reaction was then cooled to rt
  3. concentrationconcentrated under reduced pressure
  4. dissolutionThe residue was dissolved in EtOAc (30 ml)
  5. washthe resulting solution was washed with 0.5N NaOH (10 ml), water (15 ml), saturated aqueous NaCl (10 mL)
  6. customto remove excess water
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customto give the crude product
  10. customThe crude product was purified
  11. washeluting with a gradient of 65%-100% EtOAc/Hex

Sources & evidence

ORD record
ord-a2d2616e5f3046e39e3d888be217d32a
Source dataset
uspto-grants-2009_12
Patent number
US07629342B2

Reaction notes

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