1,3-Dichloroacetone → Mubritinib

HRID 352081

Reaktionsgleichung

Reaktionsgleichung von HRID 352081
[F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([NH2:13])=[O:12])=[CH:5][CH:4]=1.Cl[CH2:17][C:18]([CH2:20]Cl)=O.[OH-].[K+].[N:24]1([CH2:29][CH2:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=2)[CH:28]=[CH:27][N:26]=[N:25]1>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.S(=O)(=O)(O)O.CO.O.C1COCC1>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[C:11]2[O:12][CH:17]=[C:18]([CH2:20][O:39][C:36]3[CH:35]=[CH:34][C:33]([CH2:32][CH2:31][CH2:30][CH2:29][N:24]4[CH:28]=[CH:27][N:26]=[N:25]4)=[CH:38][CH:37]=3)[N:13]=2)=[CH:7][CH:8]=1

Komponenten

11

Edukt 4

HCID 107931,3-DichloroacetoneHCID 14797Potassium HydroxideHCID 57090144-(Trifluoromethyl)cinnamamideHCID 121094944-(4-[1,2,3]Triazol-1-yl-butyl)phenol

Produkt 1

HCID 6444692MubritinibAusbeute 86 %

Reagenzien, Katalysatoren, Lösungsmittel 6

HCID 1118Sulfuric AcidKatalysatorHCID 74236Tetrabutylammonium BromideKatalysatorHCID 887MethanolLösungsmittelHCID 962WaterLösungsmittelHCID 1140TolueneLösungsmittel2×HCID 8028TetrahydrofuranLösungsmittel

Versuchsvorschrift

(E)-3-(4-(Trifluoromethyl)phenyl)-2-propenamide (4.00 g, 18.59 mmol) and 1,3-dichloroacetone (3.54 g, 27.89 mmol) were added to toluene (14 ml) and the mixture was subjected to refluxing azeotropic dehydration using a Dean-Stark tube for 3 hours. A solution of sulfuric acid (91 mg) in toluene (1 ml) was added at the same temperature and the mixture was further subjected to refluxing azeotropic dehydration for 3.5 hours. The reaction mixture was concentrated under reduced pressure, and THF (20 ml) and tetra(n-butyl) ammonium bromide (428 mg, 1.328 mmol) were added to the residue. 30% Aqueous potassium hydroxide solution (12.42 g, 66.4 mmol) was added dropwise at 20-30° C. and the mixture was stirred at the same temperature for 15 min. 4-[4-(1H-1,2,3-Triazol-1-yl)butyl]phenol (2.89 g, 13.28 mmol) was added and the mixture was refluxed under stirring for 2 hours. Water (13.4 ml) and methanol (20 ml) were added dropwise at the same temperature. After allowing to cool to room temperature and stirring, the mixture was stirred at the same temperature for 1 hour. The precipitated crystals were collected by filtration, washed with cold-methanol (40 ml) and dried under reduced pressure to give 1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole (5.35 g, 11.42 mmol, yield 86%).

Aufarbeitung

  1. temperatureto refluxing azeotropic dehydration
  2. customfor 3 hours
  3. temperatureto refluxing azeotropic dehydration for 3.5 hours
  4. additionwere added to the residue
  5. temperaturethe mixture was refluxed
  6. stirringunder stirring for 2 hours
  7. stirringstirring
  8. stirringthe mixture was stirred at the same temperature for 1 hour
  9. filtrationThe precipitated crystals were collected by filtration
  10. washwashed with cold-methanol (40 ml)
  11. customdried under reduced pressure

Quellen und Nachweise

ORD-Eintrag
ord-766109aca46e44f78c7d4237cb507b56
Quelldatensatz
uspto-grants-2004_06
Patentnummer
US06743924B2

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