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【结 构 式】 
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【分子编号】11312 【品名】(3'aS,4'R,6'aS)-5'-Oxoperhydrospiro[1,3-dioxolane-2,2'-pentalen]-4'-ylcarboxylic acid methyl ester 【CA登记号】 |
【 分 子 式 】C12H16O5 【 分 子 量 】240.25604 【元素组成】C 59.99% H 6.71% O 33.3% |
合成路线1
该中间体在本合成路线中的序号：(IVa)The decarboxylative hydrolysis of 2,4-dimethoxycarbonyl-3-(3-phenylpropyl)cyclopentanone (XIV) with HCl in acetic acid gives 4-carboxy-3-(3-phenylpropyl)cyclopentanone (XV), which by reaction with oxalyl chloride (B) is converted into the corresponding acyl chloride (XVI). The Arndt-Eistert carbon homologation in (XVI) with diazomethane and silver benzoate (C) in methanol affords 4-(methoxycarbonylmethyl)-4-(3-phenylpropyl)cyclopentanone (XVIIa), which is dehydrogenated by the sequence of reactions: N-bromosuccinimide and sodium selenofenolate (D) [to obtain intermediates (XVIIb) and (XVIIc), respectively], followed by reaction with hydrogen peroxide to give 4-(methoxycarbonylmethyl)-3-(3-phenylallyl)cyclopentanone (XVIIIa). Oxidation of (XVIIIa) first with osmium tetroxide and then with Jones reagent (CrO3) [to obtain intermediates (XVIIIb) and (XVIIIc), respectively], followed by methylation of (XVIIIc) with CH2N2 affords 3,4-di(methoxycarbonylmethyl)cyclopentanone (XIX), which is ketalized in the usual way to the ketal (XX). Finally, this compound is submitted to a Dieckmann condensation with sodium methoxide in DMS to yield the protected ketoester (IVa), the methyl ester analogue of the compound (IV) obtained in scheme 09083302a. This compound can then be used instead of (IV) in scheme 09083302a.
| 【1】 Sakai, K.; Kojima, K.; Synthetic studies of prostanoids. XVII. Total synthesis of 9(O)-methanoprostacyclin and its isomers. Tetrahedron Lett 1978, 39, 3743-46. |
| 【2】 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 |
| (IVa) | 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 | |
| (XVIIa) | 24518 | methyl 2-[(1S,2S)-4-oxo-2-(3-phenylpropyl)cyclopentyl]acetate | C17H22O3 | 详情 | 详情 | |
| (XVIIIa) | 24519 | methyl 2-[(1S,2S)-4-oxo-2-[(E)-3-phenyl-2-propenyl]cyclopentyl]acetate | C17H20O3 | 详情 | 详情 | |
| (B) | 29841 | Oxalyl chloride; 2-Chloro-2-oxoacetyl chloride | 79-37-8 | C2Cl2O2 | 详情 | 详情 |
| (XVIIb) | 37510 | methyl 2-[(1S,2S)-2-(3-bromo-3-phenylpropyl)-4-oxocyclopentyl]acetate | C17H21BrO3 | 详情 | 详情 | |
| (D) | 37511 | sodium benzeneselenolate | C6H5NaSe | 详情 | 详情 | |
| (XVIIc) | 37512 | methyl 2-[(1S,2S)-4-oxo-2-[3-phenyl-3-(phenylselanyl)propyl]cyclopentyl]acetate | C23H26O3Se | 详情 | 详情 | |
| (XVIIIb) | 37513 | methyl 2-[(1S,2S)-4-oxo-2-(2-oxoethyl)cyclopentyl]acetate | C10H14O4 | 详情 | 详情 | |
| (XVIIIc) | 37514 | 2-[(1R,2S)-2-(2-methoxy-2-oxoethyl)-4-oxocyclopentyl]acetic acid | C10H14O5 | 详情 | 详情 | |
| (XIV) | 37506 | dimethyl (1R,2R,3S)-4-oxo-2-(3-phenylpropyl)-1,3-cyclopentanedicarboxylate | C18H22O5 | 详情 | 详情 | |
| (XV) | 37507 | (1R,2S)-4-oxo-2-(3-phenylpropyl)cyclopentanecarboxylic acid | C15H18O3 | 详情 | 详情 | |
| (XVI) | 37508 | (1R,2S)-4-oxo-2-(3-phenylpropyl)cyclopentanecarbonyl chloride | C15H17ClO2 | 详情 | 详情 | |
| (XIX) | 24520 | methyl 2-[(1R,2S)-2-(2-methoxy-2-oxoethyl)-4-oxocyclopentyl]acetate | C11H16O5 | 详情 | 详情 | |
| (XX) | 24521 | methyl 2-[(7R,8S)-8-(2-methoxy-2-oxoethyl)-1,4-dioxaspiro[4.4]non-7-yl]acetate | C13H20O6 | 详情 | 详情 | |
| (C) | 37509 | silver(1+) benzoate | 532-31-0 | C7H5AgO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)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 |
合成路线3
该中间体在本合成路线中的序号：(VII)The decarboxylative hydrolysis ot 2beta,4alpha-di(methoxycarbonyl)-3alpha-(3-phenylpropyl)cyclopentanone (I) with HCl in refluxing acetic acid gives 3alpha-(3-phenylpropyl)cyclopentanone-4alpha-carboxylic acid methyl ester (II), which by successive reactions with oxalyl chloride in refluxing benzene, with diazomethane in ether, and with silver benzoate and triethylamine in methanol, is converted to 3alpha-(3-phenylpropyl)cyclopentanone-4alpha-acetic acid methyl ester (III). The dehydrogenation of (III) by reaction with N-bromosuccinimide and sodium selenobenzene in benzene and THF affords 3alpha-(3-phenyl-2-propenyl)cyclopentanone-4alpha-acetic acid methyl ester (IV), which is oxidized with sodium methaperiodate and Jones reagent, and methylated with diazomethane to give cyclopentanone 3alpha,4alpha-di(acetic acid) dimethyl ester (V). The reaction of (V) with ethyl eneglycol and p-toluenesulfonic acid yields the corresponding ketal (VI), which is submitted to a cyclization with sodium methoxide in hot methanol - DMSO to afford 7,7-ethylenedioxybicyclo[3.3.0] octan-3-one-4beta-carboxylic acid methyl ester (VII). The reduction of (VII) with NaBH4 in methanol gives the corresponding hydroxyester (VIII), which is protected with dihydropyran and p-toluenesulfonic acid to the corresponding tetrahydropyranyloxy compound (IX). The reduction of (IX) with LiAlH4 in ether affords the methanol derivative (X), which is oxidized with CrO3 - pyridine to the aldehyde (XI). The Wittig condensation of (XI) with dimethyl 2-oxo-4R,8-dimethyl-7-nonenylphosphonate (XII) by means of NaH in THF affords the dienic ketone (XIII).
| 【1】 Kojima, K.; Sakai, K.; Kobayashi, S. (Sankyo Co., Ltd.); Protacyclin compounds. DE 2900352; FR 2414039; GB 2012265; JP 54095552 . |
| 【2】 Prous, J.; Castaner, J.; CS-570. Drugs Fut 1986, 11, 11, 918. |
| 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) | 24516 | methyl (1R,2S,3R)-3-acetyl-4-oxo-2-(3-phenylpropyl)cyclopentanecarboxylate | C18H22O4 | 详情 | 详情 | |
| (II) | 24517 | methyl (1R,2S)-4-oxo-2-(3-phenylpropyl)cyclopentanecarboxylate | C16H20O3 | 详情 | 详情 | |
| (III) | 24518 | methyl 2-[(1S,2S)-4-oxo-2-(3-phenylpropyl)cyclopentyl]acetate | C17H22O3 | 详情 | 详情 | |
| (IV) | 24519 | methyl 2-[(1S,2S)-4-oxo-2-[(E)-3-phenyl-2-propenyl]cyclopentyl]acetate | C17H20O3 | 详情 | 详情 | |
| (V) | 24520 | methyl 2-[(1R,2S)-2-(2-methoxy-2-oxoethyl)-4-oxocyclopentyl]acetate | C11H16O5 | 详情 | 详情 | |
| (VI) | 24521 | methyl 2-[(7R,8S)-8-(2-methoxy-2-oxoethyl)-1,4-dioxaspiro[4.4]non-7-yl]acetate | C13H20O6 | 详情 | 详情 | |
| (VII) | 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 | |
| (VIII) | 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 | |
| (IX) | 24524 | (1'R,2'R,3'aR,6'aS)-2'-(Tetrahydropyranyloxy)spiro[1,3-dioxolane-2,5'-perhydropentalene]-1'-carboxylic acid | C17H26O6 | 详情 | 详情 | |
| (X) | 24525 | (1'R,2'R,3'aR,6'aS)-2'-(Tetrahydropyranyloxy)spiro[1,3-dioxolane-2,5'-perhydropentalene]-1'-methanol | C16H26O5 | 详情 | 详情 | |
| (XI) | 24526 | (1'R,2'R,3'aR,6'aS)-2'-(Tetrahydropyranyloxy)spiro[1,3-dioxolane-2,5'-perhydropentalene]-1'-carbaldehyde | C12H18O3 | 详情 | 详情 | |
| (XII) | 63310 | dimethyl (4R)-4,8-dimethyl-2-oxo-7-nonenylphosphonate | C13H25O4P | 详情 | 详情 | |
| (XIII) | 24527 | 5(R),9-Dimethyl-1-[(2'(R),3'a(R),6'a(S))-2'-(tetrahydropyranyloxy)spiro[1,3-dioxolane-2,5'-perhydropentalen]-1-yl]deca-1(E),8-dien-3-one | C27H42O5 | 详情 | 详情 |