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【结 构 式】 
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【药物名称】S-3483 【化学名称】(1S,3R,4R,5R)-1-[2(S)-(4-Chlorophenyl)-(1R)-cyclopropylmethoxy]-3,4-dihydroxy-5-[3-(4-hydroxyphenyl)-2(E)-propenoyloxy]cyclohexane-1-carboxylic acid 【CA登记号】 【 分 子 式 】C26H27ClO8 【 分 子 量 】502.95329 |
【开发单位】Hoechst Marion Roussel 【药理作用】ENDOCRINE DRUGS, ANTIDIABETIC DRUGS |
合成路线1
Reaction of quinic acid (I) with boiling cyclohexanone (II) and a trace of H2SO4 under azeotropical removal of water gave lactone-ketal (III). Subsequent alkylation with bromide (IV) and NaH in DMF at r.t. provided ether (V), which was hydrolyzed with NaOH in aqueous dioxan to produce the sodium carboxylate (VI). Protected 4-hydroxycinnamic acid (VII) was converted to the imidazolide (VIII) on treatment with carbonyl diimidazole (CDI) in DMF, and this was subsequently condensed with (VI) in the presence of NaH in DMF to afford ester (IX). Finally, deprotection of acetal and silylethoxymethyl groups with HCl in aqueous dioxan at r.t. provided the target compound.
| 【1】 Hemmerle, H.; Schindler, P.; Herling, A. (Aventis SA); Derivs. of substd. cyclohexane, their process of preparation and their application for the treatment of diseases. EP 0587088; JP 1994211736; US 5463062 . |
| 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) | 11524 | D-Quinic acid; D-(-)-Chinic acid; D-(-)-Quinic acid; (3R,5R)-1,3,4,5-Tetrahydroxycyclohexanecarboxylic acid | 77-95-2 | C7H12O6 | 详情 | 详情 |
| (II) | 11059 | Cyclohexanone | 108-94-1 | C6H10O | 详情 | 详情 |
| (III) | 18750 | (3'aR,4'R,7'S,8'aR)-7'-Hydroxyspiro[cyclohexane-1,2'-[4,7]methanoperhydro[1,3]dioxolo[4,5-c]oxepin]-6'-one | C13H18O5 | 详情 | 详情 | |
| (IV) | 18751 | 1-[(1S,2R)-2-(bromomethyl)cyclopropyl]-4-chlorobenzene | C10H10BrCl | 详情 | 详情 | |
| (V) | 18752 | (3'aR,4'R,7'S,8'aR)-7'-[2(S)-(4-Chlorophenyl)cycloprop-1(R)-ylmethoxy]spiro[cyclohexane-1,2'-[4,7]methanoperhydro[1,3]dioxolo[4,5-c]oxepin]-6'-one | C23H27ClO5 | 详情 | 详情 | |
| (VI) | 18753 | (3'aR,5'S,7'R,7'aR)-5'-[2(S)-(4-Chlorophenyl)cycloprop-1(R)-ylmethoxy]-7'-hydroxyspiro[cyclohexane-1,2'-perhydro[1,3]benzodioxole]-5-carboxylic acid sodium salt | C23H28ClNaO6 | 详情 | 详情 | |
| (VII) | 18754 | (E)-3-(4-[[2-(trimethylsilyl)ethoxy]methoxy]phenyl)-2-propenoic acid | C15H22O4Si | 详情 | 详情 | |
| (VIII) | 18755 | (E)-1-(1H-imidazol-1-yl)-3-(4-[[2-(trimethylsilyl)ethoxy]methoxy]phenyl)-2-propen-1-one | C18H24N2O3Si | 详情 | 详情 | |
| (IX) | 18756 | (3'aR,5'S,7'R,7'aR)-5'-[2(S)-(4-Chlorophenyl)cycloprop-1(R)-ylmethoxy]-7'-[3-[4-[2-(trimethylsilyloxy)ethoxymethoxy]phenyl]-2(E)-propeneoyloxy]spiro[cyclohexane-1,2'-perhydro[1,3]benzodioxole]-5-carboxylic acid | C38H49ClO9Si | 详情 | 详情 |