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

HRID 1661105Notes

Reaction equation

HRID 1661105 reaction equation
Cl[CH2:2][C:3]1[N:7]2[N:8]([CH2:28][C:29]3[C:30]([CH3:39])=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=3)[C:9](=[O:27])[C:10]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:6]2=[N:5][N:4]=1.[I-].[Na+].CC(C)=[O:44].O>[OH-].[Na+].CCOC(C)=O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]2[C:6]3[N:7]([C:3]([CH2:2][OH:44])=[N:4][N:5]=3)[N:8]([CH2:28][C:29]3[C:30]([CH3:39])=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=3)[C:9](=[O:27])[C:10]=2[C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)=[CH:13][CH:14]=1

Participants

7

Reactant 4

HCID 180AcetoneHCID 962WaterHCID 5238Sodium IodideHCID 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)benzonitrile

Product 1

HCID 25026694Benzonitrile, 4-[8-(4-chlorophenyl)-5,6-dihydro-3-(hydroxyMethyl)-5-[[2-Methyl-6-(trifluoroMethyl)-3-pyridinyl]Methyl]-6-oxo-1,2,4-triazolo[4,3-b]pyridazin-7-yl]-Yield 51%

Reagents, catalysts & solvents 2

HCID 14798Sodium HydroxideCatalystHCID 8857Ethyl AcetateSolvent

Procedure

To a round bottom flask was added 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 (30 mg, 0.053 mmol), sodium iodide (40 mg, 0.264 mmol) and acetone (2 ml). The reaction was stirred at room temperature for 8 hr. After this time, water (0.3 ml) was added followed by 1 drop of 1N NaOH. The reaction was stirred at room temperature for an additional 14 hrs. The solution was then diluted with EtOAc (25 ml) and washed with water (2×15 ml) and saturated NaCl (15 ml). The organic layer was dried (MgSO4), filtered and concentrated. The crude material was purified using an ISCO automated chromatography system (4 g silica gel, 20%-50% EtOAC/CH2Cl2) to give the product 4-(8-(4-chlorophenyl)-3-(hydroxymethyl)-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 as a white solid (15 mg, 51% yield). HPLC retention time 2.990 min (Method A); LCMS (M+1)=551.0. 1HNMR (CDCl3, 500 Hz) 7.61(2H, d, J=8.25 Hz), 7.52(1H, d, J=7.7 Hz), 7.30-7.37(7H, m), 6.05(2H, s), 4.60(2H, s), 2.78(3H, s); 13CNMR (CDCl3, 500 Hz) 161.00, 158.90, 156.25, 146.20, 144.10, 137.10, 136.80, 132.80, 131.96, 131.74, 129.90, 129.09, 118.00, (m), 113.00, 100.00, 55.10, 49.10, 22.10.

Workup

  1. stirringThe reaction was stirred at room temperature for an additional 14 hrs
  2. washwashed with water (2×15 ml) and saturated NaCl (15 ml)
  3. dry with materialThe organic layer was dried (MgSO4)
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe crude material was purified

Sources & evidence

ORD record
ord-b0aa7bea0d8a4fca996a88c3aef56d0f
Source dataset
uspto-grants-2011_10
Patent number
US08030306B2

Reaction notes

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