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【结 构 式】 
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【分子编号】65194 【品名】(Z)-7-[(1R,2R,3R,5S)-2-(4,4-difluoro-3-hydroxyoctyl)-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-5-heptenoic acid 【CA登记号】 |
【 分 子 式 】C25H42F2O6 【 分 子 量 】476.6016864 【元素组成】C 63% H 8.88% F 7.97% O 20.14% |
合成路线1
该中间体在本合成路线中的序号：(X)Desilylation of commercial Corey's lactone (I) with TBAF in THF gives carbinol (II), which is oxidized by means of (COCl)2 and DMSO in dichloromethane to yield the carbaldehyde (III). Condensation of compound (III) with phosphonate (IV) by means of thallium ethoxide in dichloromethane affords the unsaturated difluoroketone (V), which is reduced with H2 over Pd/C in ethyl acetate to afford the saturated ketone (VI). Reduction of ketone (VI) with NaBH4 in methanol provides the secondary alcohol (VII), which is further reduced with diisobutylaluminum hydride in toluene to give the lactol (VIII). Condensation of lactol (VIII) with 4-carboxybutyl triphenylphosphonium bromide (IX) by means of t-BuOK in THF yields the prostaglandin F2a derivative (X), which is esterified by means of benzyl bromide and DBU in dichloromethane to afford the benzyl ester (XI). Oxidation of ester (XI) with CrO3 and pyridine in dichloromethane provides the THP-protected prostaglandin E2 derivative (XII), which is treated with AcOH in THF/water to give the prostaglandin E2 benzyl ester derivative (XIII). Finally, this compound is submitted to simultaneous benzyl ester group cleavage and double bond reduction by means of H2 over Pd/C in ethyl acetate.
| 【1】 Ueno, R. (R-Tech Ueno, Ltd.); Promotion of wound-healing with 15-keto-prostaglandin cpds.. EP 0503887; US 5252605 . |
| 【2】 Ueno, R. (R-Tech Ueno, Ltd.); Endothelin antagonist. EP 0978284; US 6197821; WO 9927934 . |
| 【3】 Sorbera, L.A., Castaner, J., Mealy, N.E.; Lubiprostone. Drugs Fut 2004, 29 (4): 336. |
| 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) | 65188 | (3aR,4S,5R,6aS)-5-(tetrahydro-2H-pyran-2-yloxy)-4-{[(trimethylsilyl)oxy]methyl}hexahydro-2H-cyclopenta[b]furan-2-one | C16H28O5Si | 详情 | 详情 | |
| (II) | 56988 | (3aR,4S,5R,6aS)-4-(hydroxymethyl)-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one | C13H20O5 | 详情 | 详情 | |
| (III) | 56989 | (3aR,4R,5R,6aS)-2-oxo-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-4-carbaldehyde | C13H18O5 | 详情 | 详情 | |
| (IV) | 65189 | dimethyl 3,3-difluoro-2-oxoheptylphosphonate | C9H17F2O4P | 详情 | 详情 | |
| (V) | 65190 | (3aR,4R,5R,6aS)-4-[(E)-4,4-difluoro-3-oxo-1-octenyl]-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one | C20H28F2O5 | 详情 | 详情 | |
| (VI) | 65191 | (3aR,4R,5R,6aS)-4-(4,4-difluoro-3-oxooctyl)-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one | C20H30F2O5 | 详情 | 详情 | |
| (VII) | 65192 | (3aR,4R,5R,6aS)-4-(4,4-difluoro-3-hydroxyoctyl)-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one | C20H32F2O5 | 详情 | 详情 | |
| (VIII) | 65193 | (3aR,4R,5R,6aS)-4-(4,4-difluoro-3-hydroxyoctyl)-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-ol | C20H34F2O5 | 详情 | 详情 | |
| (IX) | 13616 | (4-Carboxybutyl)triphenylphosphonium bromide | 17814-85-6 | C23H24BrO2P | 详情 | 详情 |
| (X) | 65194 | (Z)-7-[(1R,2R,3R,5S)-2-(4,4-difluoro-3-hydroxyoctyl)-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-5-heptenoic acid | C25H42F2O6 | 详情 | 详情 | |
| (XI) | 65195 | benzyl (Z)-7-[(1R,2R,3R,5S)-2-(4,4-difluoro-3-hydroxyoctyl)-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-5-heptenoate | C32H48F2O6 | 详情 | 详情 | |
| (XII) | 65196 | benzyl (Z)-7-[(1R,2R,3R)-2-(4,4-difluoro-3-oxooctyl)-5-oxo-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-5-heptenoate | C32H44F2O6 | 详情 | 详情 | |
| (XIII) | 65197 | benzyl (Z)-7-[(1R,2R,3R)-2-(4,4-difluoro-3-oxooctyl)-3-hydroxy-5-oxocyclopentyl]-5-heptenoate | C27H36F2O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)Oxidation of the (-)-Corey's lactone (XIV) with Collins reagent (CrO3 and pyridine) gives aldehyde (XV), which is condensed with phosphonate (IV) by means of thallium ethoxide in benzene to yield the unsaturated difluoroketolactone (XVI). Hydrogenation of compound (XVI) with H2 over Pd/C in ethyl acetate affords the saturated analogue (XVII), which is reduced with NaBH4 in methanol/THF to provide the hydroxylactone (XVIII), which is then protected at the hydroxy group with TBDMS-Cl and imidazole to give the silyl ether (XIX). Hydrolysis of the ester group of compound (XIX) in basic medium, followed by reaction with dihydropyran yields the tetrahydropyranyl ether (XX), which is reduced with DIBAL to afford the lactol (XXI). Condensation of lactol (XXI) with 4-(methoxycarbonyl)butyl triphenylphosphonium bromide (XXII) provides the unsaturated methyl ester (XXIII), which is desilylated by means of TBAF in THF to give the diol (XXIV). Finally, hydrolysis of the ester group of compound (XXIV) with NaOH in methanol yields the already described intermediate prostaglandin F2a derivative (X).
| 【1】 Ueno, R.; Ueno, R.; Kato, I.; Oda, T. (Ueno Fine Chemicals Industry, Ltd.); Prostaglandins E and anti-ulcers containing same. EP 0284180; JP 1989052753; US 5166174; US 5225439; US 5284858; US 5380709; US 5428062; US 5886034; US 6265440 . |
| 【2】 Sorbera, L.A., Castaner, J., Mealy, N.E.; Lubiprostone. Drugs Fut 2004, 29 (4): 336. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 65189 | dimethyl 3,3-difluoro-2-oxoheptylphosphonate | C9H17F2O4P | 详情 | 详情 | |
| (X) | 65194 | (Z)-7-[(1R,2R,3R,5S)-2-(4,4-difluoro-3-hydroxyoctyl)-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-5-heptenoic acid | C25H42F2O6 | 详情 | 详情 | |
| (XIV) | 43178 | (3aR,4S,5R,6aS)-4-(hydroxymethyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate | 31752-99-5 | C21H20O5 | 详情 | 详情 |
| (XV) | 32042 | (3aR,4R,5R,6aS)-4-formyl-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate | C21H18O5 | 详情 | 详情 | |
| (XVI) | 65198 | (3aR,4R,5R,6aS)-4-[(E)-4,4-difluoro-3-oxo-1-octenyl]-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate | C28H28F2O5 | 详情 | 详情 | |
| (XVII) | 65199 | (3aR,4R,5R,6aS)-4-(4,4-difluoro-3-oxooctyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate | C28H30F2O5 | 详情 | 详情 | |
| (XVIII) | 65200 | (3aR,4R,5R,6aS)-4-(4,4-difluoro-3-hydroxyoctyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate | C28H32F2O5 | 详情 | 详情 | |
| (XIX) | 65201 | (3aR,4R,5R,6aS)-4-(3-{[tert-butyl(dimethyl)silyl]oxy}-4,4-difluorooctyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate | C34H46F2O5Si | 详情 | 详情 | |
| (XX) | 65202 | (3aR,4R,5R,6aS)-4-(3-{[tert-butyl(dimethyl)silyl]oxy}-4,4-difluorooctyl)-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one | C26H46F2O5Si | 详情 | 详情 | |
| (XXI) | 65203 | (3aR,4R,5R,6aS)-4-(3-{[tert-butyl(dimethyl)silyl]oxy}-4,4-difluorooctyl)-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-ol | C26H48F2O5Si | 详情 | 详情 | |
| (XXII) | 26177 | (5-methoxy-5-oxopentyl)(triphenyl)phosphonium bromide | C24H26BrO2P | 详情 | 详情 | |
| (XXIII) | 65204 | methyl (Z)-7-[(1R,2R,3R,5S)-2-(3-{[tert-butyl(dimethyl)silyl]oxy}-4,4-difluorooctyl)-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-5-heptenoate | C32H58F2O6Si | 详情 | 详情 | |
| (XXIV) | 65205 | methyl (Z)-7-[(1R,2R,3R,5S)-2-(4,4-difluoro-3-hydroxyoctyl)-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-5-heptenoate | C26H44F2O6 | 详情 | 详情 |