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【结 构 式】 
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【分子编号】29762 【品名】sodium 5-(triphenylphosphoranylidene)pentanoate 【CA登记号】 |
【 分 子 式 】C23H22NaO2P 【 分 子 量 】384.39001 【元素组成】C 71.87% H 5.77% Na 5.98% O 8.32% P 8.06% |
合成路线1
该中间体在本合成路线中的序号：(B)Treatment of the optically pure lactone (I) with lithium dimethyl methylphosphonate in tetrahydrofuran gives hemiacetal (II), which is oxidized to the diketone (III) using Jones' reagent in acetone. Then in the key step, compound (III) cyclizes to enone (IV) using potassium carbonate and 18-crown-6 in warm toluene. Lithium dimethyl cuprate addition to enone (IV) in ether gives ketone (V), which is converted to acid (VI) (a 1:1 mixture of E and Z olefins at C-5) using (4-carboxybutyl)triphenylphosphorane in dimethyl sulfoxide. Cleavage of the alcohol-protecting groups in (VI) with an acetic acid-water-tetrahydrofuran mixture followed by chromatography to remove the 5-E isomer affords 9-methylcarbacyclin (VII). Finally, treatment of (VII) with calcium oxide in tetrahydrofuran gives U-61431F (ciprostene calcium).
| 【1】 Aristoff, P.A.; Harrison, A.W.; Johnson, P.D.; Synthesis of 9-subtituted cabacyclin analogues. J Org Chem 1983, 48, 5341. |
| 【2】 Aristoff, P.A.; Practical synthesis of 6a-carbaprostaglandin I2. J Org Chem 1981, 46, 1954. |
| 【3】 Aristoff, P.A. (Pharmacia Corp.); Composition and process. US 4420632 . |
| 【4】 Aistoff, P.A.; Ciprostene Calcium. Drugs Fut 1985, 10, 11, 900. |
| 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) | 29720 | [(dimethoxyphosphoryl)methyl]lithium | C3H8LiO3P | 详情 | 详情 | |
| (B) | 29762 | sodium 5-(triphenylphosphoranylidene)pentanoate | C23H22NaO2P | 详情 | 详情 | |
| (I) | 29757 | (3aR,4S,5R,6aS)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-4-[(E,3S)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]hexahydro-2H-cyclopenta[b]furan-2-one | C27H44O6 | 详情 | 详情 | |
| (II) | 29758 | dimethyl ((3aR,4S,5R,6aS)-2-hydroxy-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-4-[(E,3S)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]hexahydro-2H-cyclopenta[b]furan-2-yl)methylphosphonate | C30H53O9P | 详情 | 详情 | |
| (III) | 29759 | dimethyl 2-oxo-3-((4R,5R)-2-oxo-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-4-[(E,3S)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]tetrahydro-3-furanyl)propylphosphonate | C29H49O10P | 详情 | 详情 | |
| (IV) | 29760 | (3aR,4R,5R)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-4-[(E,3S)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]-3a,4,5,6-tetrahydro-2(3H)-pentalenone | C28H44O5 | 详情 | 详情 | |
| (V) | 29761 | (3aR,5R,6R,6aR)-3a-methyl-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-6-[(E,3S)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]hexahydro-2(1H)-pentalenone | C29H48O5 | 详情 | 详情 | |
| (VI) | 29763 | 5-[(3aR,5R,6R,6aR)-3a-methyl-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-6-[(E,3S)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]hexahydro-2(1H)-pentalenylidene]pentanoic acid | C34H56O6 | 详情 | 详情 | |
| (VII) | 29764 | 5-[(3aS,5R,6R,6aR)-5-hydroxy-6-[(E,3S)-3-hydroxy-1-octenyl]-3a-methylhexahydro-2(1H)-pentalenylidene]pentanoic acid | C22H36O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)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 |