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【结 构 式】

【分子编号】56286

【品名】methyl (Z)-4-{(1R,2R,3R,5S)-2-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-3-(tetrahydro-2H-pyran-2-yloxy)-5-[(triethylsilyl)oxy]cyclopentyl}-2-butenoate

【CA登记号】

【 分 子 式 】C35H62O7Si

【 分 子 量 】622.95858

【元素组成】C 67.48% H 10.03% O 17.98% Si 4.51%
与该中间体有关的原料药合成路线共 2 条
合成路线1合成路线2

合成路线1

该中间体在本合成路线中的序号：(VIII)

The title prostaglandin derivative was synthesized by two methods. The benzoate ester group of the known lactone precursor (I) was removed by methanolysis in the presence of K2CO3 to afford diol (II), which was further protected as the bis-tetrahydropyranyl ether (III). Catalytic hydrogenation of (III) provided the 13,14-dihydro compound (IV). The lactone function of (IV) was then reduced with LiAlH4 to the corresponding open chain diol, which was subsequently protected as the bis-silyl derivative (V). Regioselective Swern oxidation of the silylated primary hydroxyl of (V) furnished aldehyde (VI). This was subjected to Wadsworth-Emmons olefination with phosphonate (VII) in the presence of tris[2-(2-methoxyethoxy)ethyl]amine (TDA-1) as the K+-complexing agent to yield the Z-unsaturated ester (VIII) as the major isomer. Ester group reduction in (VIII) by means of DIBAL, followed by desilylation with tetrabutylammonium fluoride, provided the allylic alcohol (IX).

参考文献 中间体
合成目标
【1】 Hellberg, M.R.; et al.; 3-Oxa-15-cyclohexyl prostaglandin DP receptor agonists as topical antiglaucoma agents. Bioorg Med Chem 2002, 10, 6, 2031.
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) 56280 (3aR,4R,5R,6aS)-4-[(E,3S)-3-cyclohexyl-3-hydroxy-1-propenyl]-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate C23H28O5 详情 详情
(II) 56281 (3aR,4R,5R,6aS)-4-[(E,3S)-3-cyclohexyl-3-hydroxy-1-propenyl]-5-hydroxyhexahydro-2H-cyclopenta[b]furan-2-one C16H24O4 详情 详情
(III) 56282 (3aR,4R,5R,6aS)-4-[(E,3S)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)-1-propenyl]-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one C26H40O6 详情 详情
(IV) 56283 (3aR,4R,5R,6aS)-4-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one C26H42O6 详情 详情
(V) 56284 {(1S,2R,3R,5S)-2-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-3-(tetrahydro-2H-pyran-2-yloxy)-5-[(triethylsilyl)oxy]cyclopentyl}methyl triethylsilyl ether; ({(1S,2R,3R,5S)-2-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-3-(tetrahydro-2H-pyran-2-yloxy)-5-[(triethylsilyl)oxy]cyclopentyl}methoxy)(triethyl)silane C37H72O6Si2 详情 详情
(VI) 56285 (1R,2R,3R,5S)-2-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-3-(tetrahydro-2H-pyran-2-yloxy)-5-[(triethylsilyl)oxy]cyclopentanecarbaldehyde C31H56O6Si 详情 详情
(VII) 41856 methyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate 88738-78-7 C7H9F6O5P 详情 详情
(VIII) 56286 methyl (Z)-4-{(1R,2R,3R,5S)-2-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-3-(tetrahydro-2H-pyran-2-yloxy)-5-[(triethylsilyl)oxy]cyclopentyl}-2-butenoate C35H62O7Si 详情 详情
(IX) 56287 (1S,2R,3R,4R)-3-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-2-[(Z)-4-hydroxy-2-butenyl]-4-(tetrahydro-2H-pyran-2-yloxy)cyclopentanol C28H48O6 详情 详情

合成路线2

该中间体在本合成路线中的序号：(VIII)

The benzoate ester group of the known lactone precursor (I) was removed by methanolysis in the presence of K2CO3 to afford diol (II), which was further protected as the bis-tetrahydropyranyl ether (III). Catalytic hydrogenation of (III) provided the 13,14-dihydro compound (IV). The lactone function of (IV) was then reduced with LiAlH4 to the corresponding open chain diol, which was subsequently protected as the bis-silyl derivative (V). Regioselective Swern oxidation of the silylated primary hydroxyl of (V) furnished aldehyde (VI). This was subjected to Wadsworth-Emmons olefination with phosphonate (VII) in the presence of tris[2-(2-methoxyethoxy)ethyl]amine (TDA-1) as the K+-complexing agent to yield the Z-unsaturated ester (VIII) as the major isomer. Ester group reduction in (VIII) by means of DIBAL, followed by desilylation with tetrabutylammonium fluoride, provided the allylic alcohol (IX).

参考文献 中间体
合成目标
【1】 Hellberg, M.R.; et al.; 3-Oxa-15-cyclohexyl prostaglandin DP receptor agonists as topical antiglaucoma agents. Bioorg Med Chem 2002, 10, 6, 2031.
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) 56280 (3aR,4R,5R,6aS)-4-[(E,3S)-3-cyclohexyl-3-hydroxy-1-propenyl]-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate C23H28O5 详情 详情
(II) 56281 (3aR,4R,5R,6aS)-4-[(E,3S)-3-cyclohexyl-3-hydroxy-1-propenyl]-5-hydroxyhexahydro-2H-cyclopenta[b]furan-2-one C16H24O4 详情 详情
(III) 56282 (3aR,4R,5R,6aS)-4-[(E,3S)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)-1-propenyl]-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one C26H40O6 详情 详情
(IV) 56283 (3aR,4R,5R,6aS)-4-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one C26H42O6 详情 详情
(V) 56284 {(1S,2R,3R,5S)-2-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-3-(tetrahydro-2H-pyran-2-yloxy)-5-[(triethylsilyl)oxy]cyclopentyl}methyl triethylsilyl ether; ({(1S,2R,3R,5S)-2-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-3-(tetrahydro-2H-pyran-2-yloxy)-5-[(triethylsilyl)oxy]cyclopentyl}methoxy)(triethyl)silane C37H72O6Si2 详情 详情
(VI) 56285 (1R,2R,3R,5S)-2-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-3-(tetrahydro-2H-pyran-2-yloxy)-5-[(triethylsilyl)oxy]cyclopentanecarbaldehyde C31H56O6Si 详情 详情
(VII) 41856 methyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate 88738-78-7 C7H9F6O5P 详情 详情
(VIII) 56286 methyl (Z)-4-{(1R,2R,3R,5S)-2-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-3-(tetrahydro-2H-pyran-2-yloxy)-5-[(triethylsilyl)oxy]cyclopentyl}-2-butenoate C35H62O7Si 详情 详情
(IX) 56287 (1S,2R,3R,4R)-3-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-2-[(Z)-4-hydroxy-2-butenyl]-4-(tetrahydro-2H-pyran-2-yloxy)cyclopentanol C28H48O6 详情 详情
Extended Information