Levoglucosan → Canagliflozin

HRID 520850

Reaktionsgleichung

Reaktionsgleichung von HRID 520850
Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([CH:20]=1)[CH2:7][C:8]1[S:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:11][CH:12]=1.C([Li])CCC.[Cl-].C([Al+]CC(C)C)C(C)C.[C@@H:37]12[O:47][CH2:46][C@@H:44]([O:45]1)[C@@H:42]([OH:43])[C@H:40]([OH:41])[C@H:38]2[OH:39].[H-].C([Al+]CC(C)C)C(C)C.[Al]>CC1CCCO1.C1(OC)C=CC=CC=1>[CH3:21][C:5]1[CH:4]=[CH:3][C:2]([C@@H:37]2[O:45][C@H:44]([CH2:46][OH:47])[C@@H:42]([OH:43])[C@H:40]([OH:41])[C@H:38]2[OH:39])=[CH:20][C:6]=1[CH2:7][C:8]1[S:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:11][CH:12]=1

Komponenten

9

Edukt 6

HCID 2724705LevoglucosanHCID 5359268AluminumHCID 16686353Diisobutyl aluminium chlorideHCID 21225700DiisobutylaluminumhydrideHCID 469304322-(5-Bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiopheneHCID 178418339Butyllithium

Produkt 1

HCID 24812758CanagliflozinAusbeute 42 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 73012-MethyltetrahydrofuranLösungsmittelHCID 7519AnisoleLösungsmittel

Versuchsvorschrift

To a solution of 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene (796 mg, 2.2 mmol) in 2-methyltetrahydrofuran (20 mL) was added dropwise n-butyl lithium (1.63 mL, 2.6 mmol, 1.6 M in hexane) at −76° C. and was then stirred for 30 min. Diisobutylaluminum chloride (4.4 mL, 3.5 mmol, 0.8 M in n-heptane) was added and the mixture was stirred for 1 hour and then warmed to ambient temperature and was stirred overnight. To a suspension of 1,6-anhydro-β-D-glucopyranose (648 mg, 4.0 mmol) in anisole (10 mL) at 0° C. was added dropwise diisobutylaluminum hydride (12 mL, 12 mmol, 1.0 M in toluene) and was then stirred at ambient temperature overnight. This solution was then added to the above prepared aluminum mixture via syringe. The mixture was distilled (external bath temperature was 158° C.) to remove the low-boiling solvents. To the remaining mixture was added anisole (10 mL) and the mixture was heated (external bath temperature was 158° C.) for 22 hours at which time HPLC assay analysis indicated a 42% yield of 1-C-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-β-D-glucopyranoside.

Aufarbeitung

  1. stirringthe mixture was stirred for 1 hour
  2. stirringwas stirred overnight
  3. stirringwas then stirred at ambient temperature overnight
  4. additionThis solution was then added to the
  5. distillationThe mixture was distilled (external bath temperature was 158° C.)
  6. customto remove the low-boiling solvents
  7. additionTo the remaining mixture was added anisole (10 mL)
  8. temperaturethe mixture was heated (external bath temperature was 158° C.) for 22 hours at which time HPLC assay analysis

Quellen und Nachweise

ORD-Eintrag
ord-332bc69448c4424397fb4152f1f98397
Quelldatensatz
uspto-grants-2016_05
Patentnummer
US09328100B2

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