Phosphorus oxychloride → HCID 57977978, compound

HRID 1865828Notes

Reaction equation

HRID 1865828 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH:33][NH:34][C:35](=O)[CH2:36][CH3:37])=[N:10][N:11]([CH2:21][C:22]3[C:23]([CH3:32])=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=3)[C:12](=[O:20])[C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[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:35]([CH2:36][CH3:37])=[N:34][N:33]=3)[N:11]([CH2:21][C:22]3[C:23]([CH3:32])=[N:24][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:26][CH:27]=3)[C:12](=[O:20])[C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1

Participants

4

Reactant 2

HCID 24813Phosphorus oxychlorideHCID 57978015HCID 57978015, compound

Product 1

HCID 57977978HCID 57977978, compoundYield 64%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
130 °C

Procedure

To a round bottom flask was added N′-(4-(4-chlorophenyl)-1-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-5-(pyridin-4-yl)-1,6-dihydropyridazin-3-yl)propionohydrazide (130 mg, 0.239 mmol) and toluene (5 ml). The reaction was heated at 130° C. and stirred at this temperature for 1 hr. After this time, POCl3 (1.3 ml) was added and the reaction was stirred at 130° C. for additional 4 hrs. The reaction mixture was then cooled to rt and concentrated under reduced pressure. The residue was dissolved in EtOAc (30 ml). The resulting solution was poured into a separatory funnel and wash with 0.5N NaOH (10 ml), water (15 ml) and 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 65%-100% EtOAc/Hex to give product 8-(4-chlorophenyl)-3-ethyl-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-7-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6(5H)-one (80 mg) as off-white solid in 64% yield. HPLC retention time (method A) 2.110 min; LCMS (M+H)=525.2; 1HNMR (CDCl3, 500 Hz): 8.59 (2H, d, J=4.4 Hz), 7.56 (1H, d, J=7.7 Hz), 7.44, (1H, d, J=7.7 Hz), 7.3417 (4H, m), 7.18 (2H, d, J=4.4 Hz), 5.64 (2H, s), 2.82 (2H, q), 2.79 (3H, s), 1.46 (3H, t). 13C-NMR (CDCl3, 500 Hz) 158.3, 154.4, 148.9, 144.0, 140.8, 138.2, 136.2, 133.3, 131.8, 131.6, 129.0, 128.8, 126.8, 125.8, 118.3, 49.1, 22.4, 20.8, 12.3.

Workup

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

Sources & evidence

ORD record
ord-e48632e4bdb24f798ed1490a235d18f1
Source dataset
uspto-grants-2009_12
Patent number
US07629342B2

Reaction notes

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