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【结 构 式】 
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【药物名称】Troglitazone, GR-92132X, CI-991, CS-045, Romozin, Prelay, Rezulin, Noscal 【化学名称】(±)-5-[4-[(6-Hydroxy-2,5,7,8-tetramethylchroman-2-yl)methoxy]benzyl]thiazolidine-2,4-dione 【CA登记号】97322-87-7 【 分 子 式 】C24H27NO5S 【 分 子 量 】441.55049 |
【开发单位】Sankyo (Originator), GlaxoSmithKline (Licensee), Pfizer (Licensee) 【药理作用】Antidiabetic Drugs, Cerebrovascular Diseases, Treatment of, ENDOCRINE DRUGS, GASTROINTESTINAL DRUGS, Inflammatory Bowel Disease, Agents for, NEUROLOGIC DRUGS, Stroke, Treatment of, Type 2 Diabetes Mellitus, Agents for, EGR1 Expression Enhancers, Insulin Sensitizers, MCP-1 Expression Inhibitors, PPARgamma Agonists, Thiazolidinediones (Glitazones) |
合成路线1
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.
| 【1】 Prous, J.; Castaner, J.; CS-045. Drugs Fut 1989, 14, 9, 846. |
| 【2】 Aizawa, Y.; Yoshioka, T.; Fujita, T.; Kawai, K.; Kanai, T.; 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). J Label Compd Radiopharm 1990, 28, 8, 911. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 10874 | 3-acetyl-2,5,6-trimethylphenyl acetate | C13H16O3 | 详情 | 详情 | |
| (II) | 10875 | 1-Phenoxyacetone; 1-Phenoxy-2-propanone | 621-87-4 | C9H10O2 | 详情 | 详情 |
| (III) | 10876 | 2,5,7,8-tetramethyl-4-oxo-2-(phenoxymethyl)-3,4-dihydro-2H-chromen-6-yl acetate | C22H24O5 | 详情 | 详情 | |
| (IV) | 10877 | 4-hydroxy-2,5,7,8-tetramethyl-2-(phenoxymethyl)-3,4-dihydro-2H-chromen-6-yl acetate | C22H26O5 | 详情 | 详情 | |
| (V) | 10878 | 2,5,7,8-tetramethyl-2-(phenoxymethyl)-2H-chromen-6-yl acetate | C22H24O4 | 详情 | 详情 | |
| (VI) | 10879 | 2,5,7,8-tetramethyl-2-(phenoxymethyl)-3,4-dihydro-2H-chromen-6-yl acetate | C22H26O4 | 详情 | 详情 | |
| (VII) | 10880 | 2,5,7,8-Tetramethyl-2-(phenoxymethyl)-6-chromanol | C20H24O3 | 详情 | 详情 | |
| (VIII) | 10881 | 2-[[4-(Chloromethyl)phenoxy]methyl]-2,5,7,8-tetramethyl-6-chromanol | C21H25ClO3 | 详情 | 详情 | |
| (IX) | 10882 | 2-[[4-(Chloromethyl)phenoxy]methyl]-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromen-6-yl methoxymethyl ether; 2-[[4-(Chloromethyl)phenoxy]methyl]-6-(methoxymethoxy)-2,5,7,8-tetramethylchromane | C23H29ClO4 | 详情 | 详情 | |
| (X) | 10883 | 1,3-Thiazolane-2,4-dione; 2,4-Thiazolidinedione | 2295-31-0 | C3H3NO2S | 详情 | 详情 |
| (X) | 44682 | 1,3-thiazolidine-2,4-dione | C3H3NO2S | 详情 | 详情 | |
| (XI) | 10884 | 5-(4-[[6-(Methoxymethoxy)-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromen-2-yl]methoxy]benzyl)-1,3-thiazolane-2,4-dione | C26H31NO6S | 详情 | 详情 | |
| (XI) | 44683 | 5-(4-[[6-(methoxymethoxy)-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromen-2-yl]methoxy]benzyl)-1,3-thiazolidine-2,4-dione | C26H31NO6S | 详情 | 详情 |
合成路线2
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.
| 【1】 Cossy, J.; et al.; A short synthesis of troglitazone: An antidiabetic drug for treating insulin resistance. Bioorg Med Chem Lett 1999, 9, 24, 3439. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 40477 | (E)-4-bromo-1-methoxy-3-methyl-2-butenyl methyl ether; (E)-4-bromo-1,1-dimethoxy-3-methyl-2-butene | C7H13BrO2 | 详情 | 详情 | |
| (II) | 13433 | 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde | 123-08-0 | C7H6O2 | 详情 | 详情 |
| (III) | 40478 | 4-[[(E)-4,4-dimethoxy-2-methyl-2-butenyl]oxy]benzaldehyde | C14H18O4 | 详情 | 详情 | |
| (IV) | 26357 | 2,3,5-trimethyl-1,4-benzenediol | 700-13-0 | C9H12O2 | 详情 | 详情 |
| (V) | 40479 | 4-[(6-hydroxy-2,5,7,8-tetramethyl-2H-chromen-2-yl)methoxy]benzaldehyde | C21H22O4 | 详情 | 详情 | |
| (VI) | 40480 | 2-[(4-formylphenoxy)methyl]-2,5,7,8-tetramethyl-2H-chromen-6-yl acetate | C23H24O5 | 详情 | 详情 | |
| (VII) | 10883 | 1,3-Thiazolane-2,4-dione; 2,4-Thiazolidinedione | 2295-31-0 | C3H3NO2S | 详情 | 详情 |
| (VIII) | 40481 | 2-([4-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenoxy]methyl)-2,5,7,8-tetramethyl-2H-chromen-6-yl acetate | C26H25NO6S | 详情 | 详情 | |
| (IX) | 40482 | 2-([4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenoxy]methyl)-2,5,7,8-tetramethyl-2H-chromen-6-yl acetate | C26H27NO6S | 详情 | 详情 |