Troglitazone, GR-92132X, CI-991, CS-045, Romozin, Prelay, Rezulin, Noscal

合成路线:A new synthesis of [14C]-labeled CS-045 has been reported:The condensation of 5-acetoxy-2-hydroxy-3,4,6-trimethylacetophenone (I) with phenoxyacetone (II) by means of morpholine and p-toluenesulfonic acid in refluxing benzene gives 6-acetoxy-2,5,7,8-tetramethyl-2-(phenoxymethyl)-3,4-dihydro-2H-benzo[b]pyran-4-one (III),which is reduced with NaBH4 in methanol to the corresponding carbinol (IV).The dehydration of (IV) by means of p-toluenesulfonic acid in refluxing benzene affords 2-acetoxy-2,5,7,8-tetramethyl-2-(phenoxymethyl)-2H-benzo[b]pyran (V),which is hydrogenated with H2 over Pd/C in methanol to give the corresponding 3,4-dihydro derivative (VI).The hydrolysis of (VI) with NaOH in methanol yields the corresponding phenol (VII),which is chloromethylated with paraformaldehyde and dry HCl in dioxane to afford 2-[4-(chloromethyl)phenoxymethyl]-2,5,7,8-tetramethyl-3,4-dihydro-2H-benzo[b]pyran-6-ol (VIII).The protection of (VIII) with chloromethyl methyl ether by means of potassium tert-butoxide in THF gives the corresponding 6-(methoxymethoxy) derivative (IX),which is condensed with [5-14C]-thiazolidine-2,4-dione (X) by means of butyllithium in THF-HMPT to yield 5-[4-[6-(methoxymethoxy)-2,5,7,8-tetramethyl-3,4-dihydro-2H-benzo[b]pyran-2-ylmethoxy]benzyl]-[5-14C]-thiazolidine-2,4-dione (XI).Finally,this compound is deprotected with concentrated HCl in ethylene glycol monomethyl ether at 130 C.

参考文献标题:Studies on hindered phenols.III.Synthesis of (?-5-[4-(6-hydroxy-2,5,7,8 -tetramethyl-chroman-2-yl-methoxy)benzyl]-5-14C-thiazolidine-2,4-dione (14C-labelled CS-045)
文献作者:Aizawa,Y.; Yoshioka,T.; Fujita,T.; Kawai,K.; Kanai,T.
参考来源:J Label Compd Radiopharm 1990,28(8),911


合成路线:A new short synthesis of troglitazone has been described:Condensation of the bromoacetal (I) with 4-hydroxybenzaldehyde (II) by means of K2CO3 and NaI in refluxing acetone gives the unsaturated ether (III),which is cyclized with trimethylhydroquinone (IV) by means of bis(trifluoromethylsulfonyl)imide in dichloromethane to yield the 6-hydroxybenzopyran (V).Acylation of (V) with acetic anhydride and DMAP in THF affords the expected acetoxybenzopyran (VI),which is condensed with thiazolidine-2,4-dione (VII) by means of piperidine in toluene to provide the 6-benzylidene-thiazolidine (VIII).The hydrogenation of (VIII) with H2 over Pd/C in methanol gives the corresponding benzyl derivative (IX),which is finally deacetylated with AcOH/HCl/water (3:1:1) in MeOH.
参考文献标题:A short synthesis of troglitazone: An antidiabetic drug for treating insulin resistance
文献作者:Cossy,J.; Menciu,C.; Rakotoarisoa,H.; Kahn,P.H.; Desmurs,J.R.
参考来源:Bioorg Med Chem Lett 1999,9(24),3439


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