Phosphorus oxychloride → (S)-4-(3-(1-(benzyloxy)ethyl)-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 1661110Notes

Reaction equation

HRID 1661110 reaction equation
[CH2:1]([O:8][C@@H:9]([CH3:48])[C:10]([NH:12][NH:13][C:14]1[C:19]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[C:18]([C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=2)[C:17](=[O:35])[N:16]([CH2:36][C:37]2[C:38]([CH3:47])=[N:39][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:41][CH:42]=2)[N:15]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH2:1]([O:8][C@H:9]([C:10]1[N:15]2[N:16]([CH2:36][C:37]3[C:38]([CH3:47])=[N:39][C:40]([C:43]([F:44])([F:45])[F:46])=[CH:41][CH:42]=3)[C:17](=[O:35])[C:18]([C:27]3[CH:28]=[CH:29][C:30]([C:33]#[N:34])=[CH:31][CH:32]=3)=[C:19]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[C:14]2=[N:13][N:12]=1)[CH3:48])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

4

Reactant 2

HCID 24813Phosphorus oxychlorideHCID 67129291(S)-2-(benzyloxy)-N'-(4-(4-chlorophenyl)-5-(4-cyanophenyl)-1-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-1,6-dihydropyridazin-3-yl)propanehydrazide

Product 1

HCID 67128877(S)-4-(3-(1-(benzyloxy)ethyl)-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 44%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
120 °C

Procedure

To a round bottom flask was added (S)-2-(benzyloxy)-N′-(4-(4-chlorophenyl)-5-(4-cyanophenyl)-1-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-1,6-dihydropyridazin-3-yl)propanehydrazide (70 mg, 0.140 mmol) and toluene (3 ml). The reaction was heated to 120° C. Then POCl3(0.3 ml) was added and the reaction was stirred at 120° C. for additional 3 hr. After this time, the solution was cooled to rt and concentrated. The residue was diluted with EtOAc (30 ml) and washed with NaHCO3(sat, 20 ml), water (20 ml) and saturated NaCl (20 ml). The organic solution was dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (4 g silica gel) eluting with a gradient of 20%-50% EtOAc/Hex to give product (S)-4-(3-(1-(benzyloxy)ethyl)-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 as a white solid (40 mg, 44% yield).

Workup

  1. temperatureAfter this time, the solution was cooled to rt
  2. concentrationconcentrated
  3. additionThe residue was diluted with EtOAc (30 ml)
  4. washwashed with NaHCO3(sat, 20 ml), water (20 ml) and saturated NaCl (20 ml)
  5. dry with materialThe organic solution was dried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe crude product was purified by silica gel column chromatography (4 g silica gel)
  9. washeluting with a gradient of 20%-50% EtOAc/Hex

Sources & evidence

ORD record
ord-ab69a2dc59a24edb8b39314bbb5f72fe
Source dataset
uspto-grants-2011_10
Patent number
US08030306B2

Reaction notes

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