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【结 构 式】 
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【分子编号】56996 【品名】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 【CA登记号】 |
【 分 子 式 】C34H54O7SSi 【 分 子 量 】634.95006 【元素组成】C 64.32% H 8.57% O 17.64% S 5.05% Si 4.42% |
合成路线1
该中间体在本合成路线中的序号：(IX)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：(IX)Methanolysis of the thioacetate and silyl ether groups of (IX), with concomitant S-alkylation by methyl 4-iodobutyrate (X) lead to thioether (XI). The deprotected alcohol function of (XI) is then oxidized to ketone (XII) under modified Swern conditions. Subsequent acidic hydrolysis of the tetrahydropyranyl ether groups of (XII) provide diol (XIII). Finally, hydrolysis of ester (XIII) to the target carboxylic acid is performed employing pig liver esterase.
| 【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 |
|---|---|---|---|---|---|---|
| (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 | |
| (X) | 13816 | Methyl 4-iodobutyrate; Methyl 4-iodobutanoate | 14273-85-9 | C5H9IO2 | 详情 | 详情 |
| (XI) | 56997 | methyl 4-({2-[(1R,2R,3R,5S)-5-hydroxy-2-[(E,3S)-4-[3-(methoxymethyl)phenyl]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]ethyl}sulfanyl)butanoate | C34H52O8S | 详情 | 详情 | |
| (XII) | 56998 | methyl 4-({2-[(1R,2R,3R)-2-[(E,3S)-4-[3-(methoxymethyl)phenyl]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-5-oxo-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]ethyl}sulfanyl)butanoate | C34H50O8S | 详情 | 详情 | |
| (XIII) | 56987 | methyl 4-{[2-((1R,2R,3R)-3-hydroxy-2-{(E,3S)-3-hydroxy-4-[3-(methoxymethyl)phenyl]-1-butenyl}-5-oxocyclopentyl)ethyl]sulfanyl}butanoate | C24H34O6S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)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4
该中间体在本合成路线中的序号：(IX)Methanolysis of the thioacetate and silyl ether groups of (IX), with concomitant S-alkylation by methyl 4-iodobutyrate (X) lead to thioether (XI). The deprotected alcohol function of (XI) is then oxidized to ketone (XII) under modified Swern conditions. Finally, acidic hydrolysis of the tetrahydropyranyl ether groups of (XII) provide the title diol.
| 【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 |
|---|---|---|---|---|---|---|
| (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 | |
| (X) | 13816 | Methyl 4-iodobutyrate; Methyl 4-iodobutanoate | 14273-85-9 | C5H9IO2 | 详情 | 详情 |
| (XI) | 56997 | methyl 4-({2-[(1R,2R,3R,5S)-5-hydroxy-2-[(E,3S)-4-[3-(methoxymethyl)phenyl]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]ethyl}sulfanyl)butanoate | C34H52O8S | 详情 | 详情 | |
| (XII) | 56998 | methyl 4-({2-[(1R,2R,3R)-2-[(E,3S)-4-[3-(methoxymethyl)phenyl]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-5-oxo-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]ethyl}sulfanyl)butanoate | C34H50O8S | 详情 | 详情 |