Levoglucosan → Canagliflozin

HRID 520850

Reaction equation

HRID 520850 reaction equation
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

Participants

9

Reactant 6

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

Product 1

HCID 24812758CanagliflozinYield 42%

Reagents, catalysts & solvents 2

HCID 73012-MethyltetrahydrofuranSolventHCID 7519AnisoleSolvent

Procedure

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.

Workup

  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

Sources & evidence

ORD record
ord-332bc69448c4424397fb4152f1f98397
Source dataset
uspto-grants-2016_05
Patent number
US09328100B2

Linked notes

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