Phosphorus oxychloride → Benzonitrile, 4-[8-(4-chlorophenyl)-5,6-dihydro-3-(MethoxyMethyl)-5-[[2-Methyl-6-(trifluoroMethyl)-3-pyridinyl]Methyl]-6-oxo-1,2,4-triazolo[4,3-b]pyridazin-7-yl]-

HRID 1661102Notes

Reaction equation

HRID 1661102 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][O:39][CH3:40])=[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][O:39][CH3:40])=[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 67128631N'-(4-(4-chlorophenyl)-5-(4-cyanophenyl)-1-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-1,6-dihydropyridazin-3-yl)-2-methoxyacetohydrazide

Product 1

HCID 25026885Benzonitrile, 4-[8-(4-chlorophenyl)-5,6-dihydro-3-(MethoxyMethyl)-5-[[2-Methyl-6-(trifluoroMethyl)-3-pyridinyl]Methyl]-6-oxo-1,2,4-triazolo[4,3-b]pyridazin-7-yl]-Yield 73%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
120 °C

Procedure

N′-(4-(4-chlorophenyl)-5-(4-cyanophenyl)-1-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-1,6-dihydropyridazin-3-yl) -2-methoxyacetohydrazide (780 mg, 1.338 mmol) was dissolved in toluene (25 ml) and was heated at 120° C. for 15 min. After this time, POCl3(5 ml) was added and the reaction was stirred at 120° C. for an additional 2 hr. The reaction mixture was then cooled to room temperature and concentrated 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 system (80 g silica gel, 20%-80% EtOAc/Hex) to give the product 4-(8-(4-chlorophenyl)-3-(methoxymethyl)-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 (550 mg) as an off-white solid (73% yield). HPLC retention time 3.085 min (Method A); LCMS (M+H)=565.0. 1HNMR (CD3CN, 500 Hz) 7.67(1H, d, J=7.7Hz), 7.63(2H, d, J=8.8 Hz), 7.58(1H, d, J=7.75), 7.35-7.37(6H, m), 5.81(2H, s), 4.40(2H, s), 3.24(3H, s), 2.65(3H, s); 13CNMR (CD3CN, 500 Hz) 160.24, 157.25, 146.50(m), 146.00, 144.71, 139.15, 137.77, 135.93, 134.84, 134.25, 132.92, 132.64, 131.38, 129.26, 122.90(m), 119.25, 112.66, 65.06, 58.28, 50.01, 22.19.

Workup

  1. temperatureThe reaction mixture was then cooled to room temperature
  2. concentrationconcentrated 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-1defc5d2358f40e894894bba61deb39d
Source dataset
uspto-grants-2011_10
Patent number
US08030306B2

Reaction notes

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