Luseogliflozin (hydrate)

Luseogliflozin (hydrate) Chemische Eigenschaften,Einsatz,Produktion Methoden

• Beschreibung

  Luseogliflozin hydrate, which is an SGLT2 inhibitor approved in Japan in March 2014 for the treatment of type 2 diabetes, was discovered by Taisho Pharmaceutical and jointly developed and marketed with Novartis as Lusefi®. Luseogliflozin selectively binds and inhibits human SGLT2 with a Ki of 1.10 nM and IC50 value of 2.26 nM.

• Synthese

  The most likely synthetic route capable of producing luseogliflozin on process scale has been reported by Taisho. Commercially available 4-methoxy- 2-methyl-benzoic acid (160) was brominated in the presence of a catalytic amount of iron powder, generating a 1:1 mixture of 3- and 5-bromo derivatives which were separable by recrystallization from methanol to provide the desired regioisomer 161 in 34% yield. Next, benzoic acid 161 was treated with oxalyl chloride to give the corresponding acyl chloride 162, which underwent a Friedel¨C Crafts reaction with ethoxybenzene (163) to afford 164 in 82% yield for the two step sequence. The dibenzylic ketone 164 was reduced using triethylsilane and boron trifluoride to give aglycon 165 in 99% yield. The Grignard reagent prepared from bromide 165 was then alkylated with thiolactone 166 (prepared from 5- thio-D-glucose penta-O-acetate (169) as illustrated in Scheme 27) to give rise to hemithioacetal 167 in 75% yield. This compound underwent stereoselective reduction to provide thioglycoside 168 in 77% yield. Hydrogenation of 168 resulted in global debenzylation to provide the desired product luseogliflozin (XIX) in 81% yield.
  The preparation of key thiolactone 166 started from 5-thio-Dglucose penta-O-acetate (169) ; 169 could be prepared by eight steps from commercially available Dglucurono- 3,6-lactone. The anomeric acetyl group of 169 was selectively removed by hydrazine and acetic acid at room temperature giving compound 170 in 70% yield. Subsequently, the anomeric hydroxyl group of 170 was protected with tetrahydropyran. Then, all acetyl groups of 171 were removed by Zempl¨|n deacetylation, and the resulting hydroxyl groups of 172 were further protected by benzyl groups using benzylbromide with sodium hydride to generate 173. The tetrahydropyranyl group of 173 was removed using pyridinium p-toluenesulfonate (PPTS), followed by DMSO oxidation to provide 166 in 82% yield, by way of 174.

  

Luseogliflozin (hydrate) Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

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