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【结 构 式】 
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【药物名称】Ciloprost, Iloprost, E-1030, SH-401, ZK-36374, Ventavis, Endoprost, Ilom閐ine, Ilomedin 【化学名称】5(E)-[(1S,5S,6R,7R)-7-Hydroxy-6-[(3S,4RS)-3-hydroxy-4-methyl-1(E)-octen-6-ynyl]bicyclo[3.3.0]octan-3-ylidene]pentanoic acid 【CA登记号】73873-87-7（Chiral），78919-13-8 【 分 子 式 】C22H32O4 【 分 子 量 】360.49794 |
【开发单位】Schering AG (Orphan Drug), Berlex (Originator), Schering AG (Originator), CoTherix (Licensee), Eisai (Licensee), Italfarmaco (Licensee) 【药理作用】CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Peripheral Vascular Disease, Treatment of, Pulmonary Hypertension, Treatment of, Raynaud's Phenomenon, Treatment for , Treatment of Peripheral Obstructive Vascular Disease, Prostacyclin Analogs |
合成路线1
| 【1】 Kramp GJ, Kim M, Gail. H-J, et aL 2005. Fully stereocontrolled total syntheses of the proetacyclin analogues 16S-iloprost and 16S-3-oxa-iloprost by a common route, using alkenylcopper-aroalke conjugate addition, asymmetric olefiMoon, and allylic alkylation. J Am Chem Soc, 127(50): 17910~17920 |
| 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) | 66462 | tert-butyldimethyl(((3R,4R,E)-4-methyl-1-(tri-tert-butylstannyl)oct-1-en-6-yn-3-yl)oxy)silane | C27H54OSiSn | 详情 | 详情 | |
| (II) | 66463 | (Z)-1-((3a'S,6a'R)-5,5-dimethyl-3',3a',4',6a'-tetrahydro-1'H-spiro[[1,3]dioxane-2,2'-pentalen]-5'-yl)-2-tosyldiazene | C20H26N2O4S | 详情 | 详情 | |
| (III) | 66464 | (E)-N'-((3a'R,4'S,6a'S)-4'-((3R,4S,E)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)-5,5-dimethyltetrahydro-1'H-spiro[[1,3]dioxane-2,2'-pentalen]-5'(3'H)-ylidene)-4-methylbenzenesulfonohydrazide | C35H54N2O5SSi | 详情 | 详情 | |
| (IV) | 66465 | (E)-N'-((3a'R,4'S,6a'S)-4'-((3R,4S,E)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)-5,5-dimethyltetrahydro-1'H-spiro[[1,3]dioxane-2,2'-pentalen]-5'(3'H)-ylidene)-4-methylbenzenesulfonohydrazide | C35H52O4Si | 详情 | 详情 | |
| (V) | 66466 | (3a'R,4'S,6a'S)-4'-((3R,4S,E)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)-5,5-dimethyltetrahydro-1'H-spiro[[1,3]dioxane-2,2'-pentalen]-5'(3'H)-one | C28H46O4Si | 详情 | 详情 | |
| (VI) | 66467 | (3a'R,4'S,5'S,6a'S)-4'-((3R,4S,E)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)-5,5-dimethylhexahydro-1'H-spiro[[1,3]dioxane-2,2'-pentalen]-5'-ol | C28H48O4Si | 详情 | 详情 | |
| (VII) | 66468 | tert-butyl(((3a'R,4'S,6a'S)-4'-((3R,4S,E)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)-5,5-dimethylhexahydro-1'H-spiro[[1,3]dioxane-2,2'-pentalen]-5'-yl)oxy)dimethylsilane | C34H62O4Si2 | 详情 | 详情 | |
| (VIII) | 66469 | (3aR,4S,5S,6aS)-5-((tert-butyldimethylsilyl)oxy)-4-((3R,4S,E)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)hexahydropentalen-2(1H)-one | C29H52O3Si2 | 详情 | 详情 | |
| (IX) | 66470 | (1R)-2-(2-phenylpropan-2-yl)cyclohexyl 2-(dimethoxyphosphoryl)acetate | C19H29O5P | 详情 | 详情 | |
| (X) | 66471 | (E)-(1R)-2-(2-phenylpropan-2-yl)cyclohexyl 2-((3aR,4S,5S,6aR)-5-((tert-butyldimethylsilyl)oxy)-4-((3R,4S,E)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)hexahydropentalen-2(1H)-ylidene)acetate | C46H74OSi2 | 详情 | 详情 | |
| (XI) | 66472 | (E)-2-((3aR,4S,5S,6aR)-5-((tert-butyldimethylsilyl)oxy)-4-((3R,4S,E)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)hexahydropentalen-2(1H)-ylidene)ethanol | C31H56O3Si2 | 详情 | 详情 | |
| (XII) | 66473 | (E)-2-((3aR,4S,5S,6aR)-5-((tert-butyldimethylsilyl)oxy)-4-((3R,4S,E)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)hexahydropentalen-2(1H)-ylidene)ethyl acetate | C33H58O4Si2 | 详情 | 详情 | |
| (XIII) | 66474 | tert-butyl(((E)-5-((3aR,4S,5S,6aR)-5-((tert-butyldimethylsilyl)oxy)-4-((3R,4S,E)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)hexahydropentalen-2(1H)-ylidene)pentyl)oxy)dimethylsilane | C40H76O3Si3 | 详情 | 详情 | |
| (XIV) | 66475 | (E)-5-((3aR,4S,5S,6aR)-5-((tert-butyldimethylsilyl)oxy)-4-((3R,4S,E)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)hexahydropentalen-2(1H)-ylidene)pentan-1-ol | C34H62O3Si2 | 详情 | 详情 |
合成路线2
Reaction of the lactone (I) with lithium ethyl acetate followed by acid catalyzed dehydration and hydrolysis of the ester group with K2CO3 in methanol affords the hydroxy compound (II), which gives after Collins oxidation, treatment with 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and reduction with NaBH4, the ketoester (III). Dealkoxy carbonylation with DABCO in toluene, benzoylation and removal of the silyl group with acetic acid in THF-water yield the ketone (IV). Ketalization of the ketone (IV) with ethylene glycol, Collins oxidation and condensation of the resulting aldehyde with the sodium salt of the phosphonate (V) afford the enone (VI). Reduction of (VI) with NaBH4 in methanol, cleavage of the ketal function with acetic acid-H2O and subsequent tetrahydropyranylation lead to the ketone (VII). Wittig condensation of the ketone (VII) with (VIII) and NaH in DMSO affords after chromatographic separation the acid (IX), which is finally deprotected to (X) (ZK-36374) by treatment with acetic acid in THF-water mixture.
| 【1】 Skuballa, W.; Raduechel, B.; Vorbrueggen, H.; Mannesmann, G.; Losert, W.; Casals, J. (Schering AG); Novel prostacyclin derivatives and a process for the preparation thereof.. DE 2845770; ES 485199; US 4692464 . |
| 【2】 Vorbruggen, H.; Schillinger, E.; Ciloprost. Drugs Fut 1981, 6, 11, 676. |
| 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 |
| (IIIa) | 32254 | ethyl (1R,3aS,4S,5R,6aS)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-hydroxy-2-oxooctahydro-1-pentalenecarboxylate | C18H32O5Si | 详情 | 详情 | |
| (IIIb) | 32255 | (3aS,4S,5R,6aS)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-hydroxy-1-methylhexahydro-2(1H)-pentalenone | C18H32O5Si | 详情 | 详情 | |
| (VIa) | 32257 | Benzoic acid (1S,2R,3aR,6aS)-5,5-(ethylenedioxy)-1-(4(S)-methyl-3-oxo-1(E)-octen-6-yn-1-yl)octahydropentalen-2-yl ester | C26H30O5 | 详情 | 详情 | |
| (VIb) | 32258 | Benzoic acid (1S,2R,3aR,6aS)-5,5-(ethylenedioxy)-1-(4(R)-methyl-3-oxo-1(E)-octen-6-yn-1-yl)octahydropentalen-2-yl ester | C26H30O5 | 详情 | 详情 | |
| (VIIa) | 32259 | (3aS,4S,5R,6aR)-4-[(E,3S,4S)-4-methyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octen-6-ynyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenone | C29H44O5 | 详情 | 详情 | |
| (VIIb) | 32260 | (3aS,4S,5R,6aR)-4-[(E,3S,4R)-4-methyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octen-6-ynyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenone | C29H44O5 | 详情 | 详情 | |
| (IXa) | 32261 | 5-[(3aS,4S,5R,6aR)-4-[(E,3S,4S)-4-methyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octen-6-ynyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenylidene]pentanoic acid | C34H52O6 | 详情 | 详情 | |
| (IXb) | 32262 | 5-[(3aS,4S,5R,6aR)-4-[(E,3S,4R)-4-methyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octen-6-ynyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenylidene]pentanoic acid | C34H52O6 | 详情 | 详情 | |
| (I) | 32252 | (3aR,4S,5R,6aS)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate | C21H30O5Si | 详情 | 详情 | |
| (II) | 32253 | ethyl 2-[(3aR,4S,5R,6aS)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-hydroxyhexahydro-2H-cyclopenta[b]furan-2-ylidene]acetate | C18H32O5Si | 详情 | 详情 | |
| (IV) | 32256 | (1S,2R,3aR,6aS)-1-(hydroxymethyl)-5-oxooctahydro-2-pentalenyl benzoate | C16H18O4 | 详情 | 详情 | |
| (V) | 24482 | dimethyl 3-methyl-2-oxo-5-heptynylphosphonate | C10H17O4P | 详情 | 详情 | |
| (VIII) | 29762 | sodium 5-(triphenylphosphoranylidene)pentanoate | C23H22NaO2P | 详情 | 详情 |