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【结 构 式】 
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【分子编号】11311 【品名】Perhydropentalene-2,5-dione mono ethyleneketal 【CA登记号】 |
【 分 子 式 】C10H14O3 【 分 子 量 】182.21936 【元素组成】C 65.92% H 7.74% O 26.34% |
合成路线1
该中间体在本合成路线中的序号：(III)The ketalization of cis-bicyclo[3.3.0]octane-3,7-dione (I) with ethylene glycol (A) and p-toluenesulfonic acid gives the diethyleneketal (II), which by controlled hydrolysis with acetic acid-THF-water is converted into the monoketal (III). Carboxylation of (III) with diethyl carbonate by means of NaH yields the ketoester (IV), which is reduced with sodium borohydride in ethanol to afford the hydroxyester (V). Protection of (V) with dimethyl-tert-butylsilyl chloride gives the silylether (VI), which is reduced with diisobutylaluminum hydride to the alcohol (VII). Oxidation of (VII) with pyridinium chlorochromate affords the aIdehyde (VIII), which by a Wittig reaction with the sodium salt of dimethyl 2-oxoheptylphosphonate (IX) is converted into the enone (X). The reduction of (X) with zinc borohydride yields the protected alcohol (XI), which is deprotected to the corresponding dihydroxyketone (XII) by treatment with acetic acid-THF-water. Finally, this compound is submitted to a Wittig reaction with the sodium salt of 4-carboxybutyltriphenylphosphorane (XIII) in DMS.
| 【1】 Shibasaki, M.; Ikegami, S.; Ueda, J.; New synthetic routes to 9(O)-methanopostacyclin. A highly stable and biologically potent analog of prostacyclin. Tetrahedron Lett 1979, 5, 433-436. |
| 【2】 Magolda, R.L.; Barnette, W.E.; Nicolaou, K.C.; Seitz, S.; Sipio, W.J.; Total synthesis of carboprostacyclin, a stable and biologically active analog of prostacyclin (PGI2). J Chem Soc Chem Commun 1978, 23, 1067-68. |
| 【3】 Castaner, J.; Hillier, K.; Carbacyclin. Drugs Fut 1981, 6, 12, 753. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 |
| (I) | 37496 | tetrahydro-2,5(1H,3H)-pentalenedione | C8H10O2 | 详情 | 详情 | |
| (II) | 37497 | C12H18O4 | 详情 | 详情 | ||
| (III) | 11311 | Perhydropentalene-2,5-dione mono ethyleneketal | C10H14O3 | 详情 | 详情 | |
| (IV) | 37498 | C13H18O5 | 详情 | 详情 | ||
| (V) | 37499 | C13H20O5 | 详情 | 详情 | ||
| (VI) | 37500 | C19H34O5Si | 详情 | 详情 | ||
| (VII) | 37501 | C17H32O4Si | 详情 | 详情 | ||
| (VIII) | 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 | |
| (IX) | 13738 | dimethyl 2-oxoheptylphosphonate; Dimethyl (2-oxoheptyl)phosphonate | 36969-89-8 | C9H19O4P | 详情 | 详情 |
| (X) | 37502 | C24H42O4Si | 详情 | 详情 | ||
| (XI) | 37503 | C24H44O4Si | 详情 | 详情 | ||
| (XII) | 37504 | (3aS,4S,5R,6aR)-5-hydroxy-4-[(E,3S)-3-hydroxy-1-octenyl]hexahydro-2(1H)-pentalenone | C16H26O3 | 详情 | 详情 | |
| (XIII) | 37505 | 5-(triphenylphosphoranylidene)pentanoic acid | C23H23O2P | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)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 |