|
【结 构 式】 
|
【药物名称】Naxaprostene, CG-4305 【化学名称】[2E,3aalpha,4alpha(1E,3R*),5beta,6aalpha]-3-[[4-(3-Cyclohexyl-3-hydroxy-1-propenyl)hexahydro-5-hydroxy-2(1H)-pentalenylidene]methyl]benzoic acid 【CA登记号】87269-59-8, 89955-40-8 (racemate) 【 分 子 式 】C25H32O4 【 分 子 量 】396.53139 |
【开发单位】Grünenthal (Originator) 【药理作用】Antiplatelet Therapy, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Prostaglandins |
合成路线1
Monoketal (I) is acylated with dimethylcarbonate to (II), reduced with NaBH4 to give (III) and protected with tert-butyldimethylsilylchloride to give (IV). After selective reduction of the ester function of (IV) with DIBAH, the resulting aldehyde (V) undergoes a Wittig-Horner-reaction with dimethyl 2-oxo-2-cyclohexylethylphosphonate to give (VI), which is subsequently reduced with NaBH4. After separation of the epimeric alcohols by silica flash chromatography, (VII) is deprotected with a AcOH/THF/water mixture. Wittig reaction of 3-methoxycarbonylphenylmethylene-triphenylphosphorane with (VIII) gives a mixture of E/Z-isomers, which is separated by preparative HPLC. Ester hydrolysis with KOH and acidification of the E-isomer gives naxaprostene (IX), R = H.
| 【1】 Stezowski, J.J.; Flohé, L.; Böhlke, H.; The crystal structure of CG 4305, a biologically active prostacyclin analogue with exceptional chemical and metabolic stability. J Chem Soc Chem Commun 1983, 1315-6. |
| 【2】 Bohlke, H.; Loschen, G.; Michel, G.; Muller, B. (Grunenthal GmbH); New cis-bicyclo[3.3.0]octane derivs., medicines containing them and processes for the preparation of these compds. and medicines. DE 3146278 . |
| 【3】 Flohé, L.; Böhlke, H.; Frankus, E.; et al.; Designing prostacylin analogues. Arzneim-Forsch Drug Res 1983, 33, 9, 1240-8. |
| 【4】 Winter, W.; NAXAPROSTENE. Drugs Fut 1990, 15, 3, 233. |
| 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) | 11311 | Perhydropentalene-2,5-dione mono ethyleneketal | C10H14O3 | 详情 | 详情 | |
| (II) | 11312 | (3'aS,4'R,6'aS)-5'-Oxoperhydrospiro[1,3-dioxolane-2,2'-pentalen]-4'-ylcarboxylic acid methyl ester | C12H16O5 | 详情 | 详情 | |
| (III) | 11313 | (3'aS,4'R,5'R,6'aR)-5'-Hydroxyperhydrospiro[1,3-dioxolane-2,2'-pentalen]-4'-ylcarboxylic acid methyl ester | C12H18O5 | 详情 | 详情 | |
| (IV) | 11314 | (3'aS,4'R,5'R,6'aR)-5'-(tert-Butyldimethylsilyloxy)perhydrospiro[1,3-dioxolane-2,2'-pentalen]-4'-ylcarboxylic acid methyl ester | C18H32O5Si | 详情 | 详情 | |
| (V) | 11315 | (3'aS,4'R,5'R,6'aR)-5'-(tert-Butyldimethylsilyloxy)perhydrospiro[1,3-dioxolane-2,2'-pentalen]-4'-ylcarbaldehyde | C17H30O4Si | 详情 | 详情 | |
| (VI) | 11316 | (3'aS,4'R,5'R,6'aR)-3-[5'-(tert-Butyldimethylsilyloxy)perhydrospiro[1,3-dioxolane-2,2'-pentalen]-4'-yl]-1-cyclohexyl-2(E)-propen-1-one | C25H42O4Si | 详情 | 详情 | |
| (VII) | 11317 | (3'aS,4'R,5'R,6'aR)-3-[5'-(tert-Butyldimethylsilyloxy)perhydrospiro[1,3-dioxolane-2,2'-pentalen]-4'-yl]-1-cyclohexyl-2(E)-propen-1(S)-ol | C25H44O4Si | 详情 | 详情 | |
| (VIII) | 11318 | (3aS,4S,5R,6aR)-4-[(E,3S)-3-Cyclohexyl-3-hydroxy-1-propenyl]-5-hydroxyhexahydro-2(1H)-pentalenone | C17H26O3 | 详情 | 详情 |