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【结 构 式】 
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【分子编号】56989 【品名】(3aR,4R,5R,6aS)-2-oxo-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-4-carbaldehyde 【CA登记号】 |
【 分 子 式 】C13H18O5 【 分 子 量 】254.28292 【元素组成】C 61.41% H 7.13% O 31.46% |
合成路线1
该中间体在本合成路线中的序号：(II)In an alternative method, oxidation of the lactone alcohol (I) using DMSO in the presence of SO3-pyridine complex gives aldehyde (II). Horner-Emmons condensation of aldehyde (II) with phosphonate (III) affords enone (IV). Stereoselective reduction of (IV) with LiAlH4 in the presence of (S)-BINOL provides the (S)-alcohol (V), which is further protected with dihydropyran in the presence of p-toluenesulfonic acid to yield the bis-tetrahydropyranyl ether (VI). Lactone ring opening in (VI) under reductive conditions leads to diol (VII). Selective mesylation of the primary alcohol of (VII), followed by protection of the secondary hydroxyl with chlorotrimethylsilane produces the intermediate mesylate (VIII), which is then displaced with potassium thioacetate to yield the thioacetate ester (IX).
| 【1】 Maruyama, T.; et al.; Design and synthesis of a selective EP4-receptor agonist. Part 4: Practical synthesis and biological evaluation of a novel highly selective EP4-receptor agonist. Bioorg Med Chem 2002, 10, 7, 2103. |
| 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) | 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 | |
| (II) | 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 | |
| (III) | 56990 | dimethyl 3-[3-(methoxymethyl)phenyl]-2-oxopropylphosphonate | C13H19O5P | 详情 | 详情 | |
| (IV) | 56991 | (3aR,4R,5R,6aS)-4-{(E)-4-[3-(methoxymethyl)phenyl]-3-oxo-1-butenyl}-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one | C24H30O6 | 详情 | 详情 | |
| (V) | 56992 | (3aR,4R,5R,6aS)-4-{(E,3S)-3-hydroxy-4-[3-(methoxymethyl)phenyl]-1-butenyl}-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one | C24H32O6 | 详情 | 详情 | |
| (VI) | 56993 | (3aR,4R,5R,6aS)-4-[(E,3S)-4-[3-(methoxymethyl)phenyl]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one | C29H40O7 | 详情 | 详情 | |
| (VII) | 56994 | (1S,2R,3R,4R)-2-(2-hydroxyethyl)-3-[(E,3S)-4-[3-(methoxymethyl)phenyl]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-4-(tetrahydro-2H-pyran-2-yloxy)cyclopentanol | C29H44O7 | 详情 | 详情 | |
| (VIII) | 56995 | 2-{(1R,2R,3R,5S)-2-[(E,3S)-4-[3-(methoxymethyl)phenyl]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-3-(tetrahydro-2H-pyran-2-yloxy)-5-[(trimethylsilyl)oxy]cyclopentyl}ethyl methanesulfonate | C33H54O9SSi | 详情 | 详情 | |
| (IX) | 56996 | S-(2-{(1R,2R,3R,5S)-2-[(E,3S)-4-[3-(methoxymethyl)phenyl]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-3-(tetrahydro-2H-pyran-2-yloxy)-5-[(trimethylsilyl)oxy]cyclopentyl}ethyl) ethanethioate | C34H54O7SSi | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)Oxidation of the lactone alcohol (I) using DMSO in the presence of SO3-pyridine complex gives aldehyde (II). Horner-Emmons condensation of aldehyde (II) with phosphonate (III) affords enone (IV). Stereoselective reduction of (IV) with LiAlH4 in the presence of (S)-BINOL provides the (S)-alcohol (V), which is further protected with dihydropyran in the presence of p-toluenesulfonic acid to yield the bis-tetrahydropyranyl ether (VI). Lactone ring opening in (VI) under reductive conditions leads to diol (VII). Selective mesylation of the primary alcohol of (VII), followed by protection of the secondary hydroxyl with chlorotrimethylsilane produces the intermediate mesylate (VIII), which is then displaced with potassium thioacetate to yield the thioacetate ester (IX).
| 【1】 Maruyama, T.; et al.; Design and synthesis of a selective EP4-receptor agonist. Part 4: Practical synthesis and biological evaluation of a novel highly selective EP4-receptor agonist. Bioorg Med Chem 2002, 10, 7, 2103. |
| 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) | 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 | |
| (II) | 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 | |
| (III) | 56990 | dimethyl 3-[3-(methoxymethyl)phenyl]-2-oxopropylphosphonate | C13H19O5P | 详情 | 详情 | |
| (IV) | 56991 | (3aR,4R,5R,6aS)-4-{(E)-4-[3-(methoxymethyl)phenyl]-3-oxo-1-butenyl}-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one | C24H30O6 | 详情 | 详情 | |
| (V) | 56992 | (3aR,4R,5R,6aS)-4-{(E,3S)-3-hydroxy-4-[3-(methoxymethyl)phenyl]-1-butenyl}-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one | C24H32O6 | 详情 | 详情 | |
| (VI) | 56993 | (3aR,4R,5R,6aS)-4-[(E,3S)-4-[3-(methoxymethyl)phenyl]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one | C29H40O7 | 详情 | 详情 | |
| (VII) | 56994 | (1S,2R,3R,4R)-2-(2-hydroxyethyl)-3-[(E,3S)-4-[3-(methoxymethyl)phenyl]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-4-(tetrahydro-2H-pyran-2-yloxy)cyclopentanol | C29H44O7 | 详情 | 详情 | |
| (VIII) | 56995 | 2-{(1R,2R,3R,5S)-2-[(E,3S)-4-[3-(methoxymethyl)phenyl]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-3-(tetrahydro-2H-pyran-2-yloxy)-5-[(trimethylsilyl)oxy]cyclopentyl}ethyl methanesulfonate | C33H54O9SSi | 详情 | 详情 | |
| (IX) | 56996 | S-(2-{(1R,2R,3R,5S)-2-[(E,3S)-4-[3-(methoxymethyl)phenyl]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-3-(tetrahydro-2H-pyran-2-yloxy)-5-[(trimethylsilyl)oxy]cyclopentyl}ethyl) ethanethioate | C34H54O7SSi | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)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 |