Phosphorus oxychloride → 4-(3-(Chloromethyl)-8-(4-chlorophenyl)-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 1661104Notes

Reaction equation

HRID 1661104 reaction equation
[Cl:1][CH2:2][C:3]([NH:5][NH:6][C:7]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:11]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)[C:10](=[O:28])[N:9]([CH2:29][C:30]2[C:31]([CH3:40])=[N:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=2)[N:8]=1)=O.O=P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]1[N:8]2[N:9]([CH2:29][C:30]3[C:31]([CH3:40])=[N:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=3)[C:10](=[O:28])[C:11]([C:20]3[CH:21]=[CH:22][C:23]([C:26]#[N:27])=[CH:24][CH:25]=3)=[C:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[C:7]2=[N:6][N:5]=1

Participants

4

Reactant 2

HCID 24813Phosphorus oxychlorideHCID 671288852-chloro-N'-(4-(4-chlorophenyl)-5-(4-cyanophenyl)-1-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-1,6-dihydropyridazin-3-yl)acetohydrazide

Product 1

HCID 671286434-(3-(Chloromethyl)-8-(4-chlorophenyl)-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 54.2%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
120 °C

Procedure

To a round bottom flask was added 2-chloro-N′-(4-(4-chlorophenyl)-5-(4-cyanophenyl)-1-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-1,6-dihydropyridazin-3-yl)acetohydrazide (400 mg, 0.681 mmol) and toluene (10 ml). The mixture was heated at 120° C. for 5 min. After this time, POCl3(1.5 ml) was added and the reaction was stirred at 120° C. for an additional 6 hr. The reaction mixture was then cooled to room temperature and concentrated to dryness under reduced pressure. The resulting residue was dissolved in EtOAc (50 ml) and washed with saturated NaHCO3(20 ml), water (20 ml), and saturated NaCl (20 ml). The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified using an ISCO automated chromatography system (12 g silica gel, 20%-40% EtOAc/Hex) to give the product 4-(3-(chloromethyl)-8-(4-chlorophenyl)-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 (210 mg) as an off-white solid (54% yield). HPLC retention time 3.148 min (Method A); LCMS (M+1)=569.0.

Workup

  1. temperatureThe reaction mixture was then cooled to room temperature
  2. concentrationconcentrated to dryness under reduced pressure
  3. dissolutionThe resulting residue was dissolved in EtOAc (50 ml)
  4. washwashed with saturated NaHCO3(20 ml), water (20 ml), and saturated NaCl (20 ml)
  5. dry with materialThe organic layer was dried (MgSO4)
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe residue was purified

Sources & evidence

ORD record
ord-ea73cad33f5b44dc9b46d585a1c7945a
Source dataset
uspto-grants-2011_10
Patent number
US08030306B2

Reaction notes

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