Hydrogen Peroxide → Di-tert-butyl (8-(4-chlorophenyl)-7-(4-cyanophenyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl phosphate

HRID 1661112Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1661112
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([C:35]([CH2:38][OH:39])=[N:36][N:37]=3)[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:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.C(N(CC)[P:43]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])C.N1C=NC=N1.OO.[O-:63]S([O-])=O.[Na+].[Na+]>ClCCCl>[P:43]([O:39][CH2:38][C:35]1[N:10]2[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]([C:14]3[CH:15]=[CH:16][C:17]([C:18]#[N:19])=[CH:20][CH:21]=3)=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:9]2=[N:37][N:36]=1)([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])([O:49][C:50]([CH3:51])([CH3:52])[CH3:53])=[O:63]

Komponenten

7

Edukt 5

HCID 784Hydrogen PeroxideHCID 92571H-1,2,4-TriazoleHCID 24437Sodium SulfiteHCID 4251849Di-tert-butyl diethylphosphoramiditeHCID 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]-

Produkt 1

HCID 86638628Di-tert-butyl (8-(4-chlorophenyl)-7-(4-cyanophenyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl phosphate

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 111,2-DichloroethaneLösungsmittel

Reaktionsbedingungen

Temperatur
60 °C

Versuchsvorschrift

To a round bottom flask was added 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 (25 mg, 0.0454 mmol), di-tert-butyl diethylphosphoramidite (34 mg, 0.136 mmol), 1,2,4-triazole (9.5 mg, 0.136 mmol) and 1,2-dichloroethane (3 ml). The reaction was stirred at 60° C. for 24 hr. After this time the reaction was cooled to rt. H2O2(7 N, 0.5 ml) was then added and the reaction was stirred at rt for 60 min. Na2SO3 (10%, 1 ml) was added and the reaction was stirred at rt for an additional 30 min. After this time, the reaction mixture was concentrated. The residue was diluted with EtOAc (50 ml) and the resulting solution was washed with water (25 ml) and saturated NaCl (25 ml). The organic layer was dried over MgSO4, filtered and concentrated. The crude intermediate was purified by silica gel column chromatography (4 g silica gel) eluting with a gradient of 0-50% EtOAc/Hex to give di-tert-butyl (8-(4-chlorophenyl)-7-(4-cyanophenyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl phosphate as clear oil. To this purified intermediate was added CH2Cl2(2 ml) and TFA (0.5 ml). The reaction was stirred at rt for 10 min. After this time the solution was concentrated. The crude product was purified by preparative HPLC eluting with water/MeOH to give the product (28 mg). The product was then dissolved in water (1 ml) and 1N NaOH (1N, 0.0445 mmol) was added. The resulting solution was concentrated on a lyophilizer to give the title compound, sodium (8-(4-chlorophenyl)-7-(4-cyanophenyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl hydrogenphosphate, as a white solid (29 mg, 94%).

Aufarbeitung

  1. temperatureAfter this time the reaction was cooled to rt
  2. stirringthe reaction was stirred at rt for 60 min
  3. stirringthe reaction was stirred at rt for an additional 30 min
  4. concentrationAfter this time, the reaction mixture was concentrated
  5. additionThe residue was diluted with EtOAc (50 ml)
  6. washthe resulting solution was washed with water (25 ml) and saturated NaCl (25 ml)
  7. dry with materialThe organic layer was dried over MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe crude intermediate was purified by silica gel column chromatography (4 g silica gel)
  11. washeluting with a gradient of 0-50% EtOAc/Hex

Quellen und Nachweise

ORD-Eintrag
ord-9f85856d37684d7b923fb5efc98dff46
Quelldatensatz
uspto-grants-2011_10
Patentnummer
US08030306B2

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