Sodium Hydroxide → Mubritinib

HRID 352077

Reaktionsgleichung

Reaktionsgleichung von HRID 352077
[OH:1][CH2:2][C:3]1[N:4]=[C:5](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[O:6][CH:7]=1.C(N(C(C)C)CC)(C)C.CS(Cl)(=O)=O.[OH-].[Na+].[N:36]1([CH2:41][CH2:42][CH2:43][CH2:44][C:45]2[CH:50]=[CH:49][C:48](O)=[CH:47][CH:46]=2)[CH:40]=[CH:39][N:38]=[N:37]1>C1COCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CO.O>[F:17][C:16]([F:19])([F:18])[C:13]1[CH:14]=[CH:15][C:10](/[CH:9]=[CH:8]/[C:5]2[O:6][CH:7]=[C:3]([CH2:2][O:1][C:48]3[CH:47]=[CH:46][C:45]([CH2:44][CH2:43][CH2:42][CH2:41][N:36]4[CH:40]=[CH:39][N:38]=[N:37]4)=[CH:50][CH:49]=3)[N:4]=2)=[CH:11][CH:12]=1

Komponenten

10

Edukt 5

HCID 14798Sodium HydroxideHCID 31297Methanesulfonyl chloride2×HCID 81531Diisopropylethylamine2×HCID 121094944-(4-[1,2,3]Triazol-1-yl-butyl)phenolHCID 129928474-(hydroxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole

Produkt 1

HCID 6444692MubritinibAusbeute 89,1 %

Reagenzien, Katalysatoren, Lösungsmittel 4

HCID 74236Tetrabutylammonium BromideKatalysatorHCID 887MethanolLösungsmittelHCID 962WaterLösungsmittelHCID 8028TetrahydrofuranLösungsmittel3×

Versuchsvorschrift

The obtained 4-(hydroxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole (567 g, 2.11 mol) and diisopropylethylamine (340 g, 2.63 mol) were added to THF (3.4 L). A solution of methanesulfonyl chloride (302 g, 2.63 mol) in THF (567 ml) was added dropwise under ice-cooling. The mixture was stirred at the same temperature for 1 hour and diisopropylethylamine (27.3 g, 0.21 mol), methanesulfonyl chloride (24.2 g, 0.21 mol) and THF (57 ml) solution were added. The mixture was stirred under reflux for 1.5 hours. After allowing to cool to room temperature, 15% aqueous sodium hydroxide (1.96 kg, 7.35 mol) was added dropwise. 4-[4-(1H-1,2,3-Triazol-1-yl)butyl]phenol (503 g, 2.32 mol) and tetra(n-butyl) ammonium bromide (68.0 g, 0.21 mol) were added at the same temperature, and the mixture was refluxed for 4 hours under stirring. Water (3.1 L) and methanol (7.4 L) were added dropwise at the same temperature. After allowing to cool to room temperature, the mixture was stirred at the same temperature for 1 hour. The precipitated crystals were collected by filtration, washed with THF/methanol/water (1:1:2) (2.8 L), water (2.8 L) and cold-methanol (2.8 L) 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 (883 g, 1.88 mol, yield 85%).

Aufarbeitung

  1. temperaturecooling
  2. stirringThe mixture was stirred
  3. temperatureunder reflux for 1.5 hours
  4. temperaturethe mixture was refluxed for 4 hours
  5. stirringunder stirring
  6. temperatureto cool to room temperature
  7. stirringthe mixture was stirred at the same temperature for 1 hour
  8. filtrationThe precipitated crystals were collected by filtration
  9. washwashed with THF/methanol/water (1:1:2) (2.8 L), water (2.8 L)
  10. dry with materialcold-methanol (2.8 L) and dried under reduced pressure

Quellen und Nachweise

ORD-Eintrag
ord-252ae74d593c40f89f11f01947237fbe
Quelldatensatz
uspto-grants-2004_06
Patentnummer
US06743924B2

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