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【结 构 式】 
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【药物名称】AL-6598 【化学名称】(5Z,9R,11R,15R)-9-Chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanorprosta-5-enoic acid isopropyl ester 【CA登记号】170291-06-2 【 分 子 式 】C23H39ClO5 【 分 子 量 】431.01728 |
【开发单位】Alcon (Originator) 【药理作用】Antiglaucoma Agents, OCULAR MEDICATIONS, Ophthalmic Drugs, Prostaglandins, Prostanoid DP Agonists |
合成路线1
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).
| 【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
Alkylation of the allylic alcohol (IX) with tert-butyl bromoacetate (X) under phase-transfer conditions afforded ester (XI), which was then subjected to titanium isopropoxide-mediated transesterification to the corresponding isopropyl ester (XII). Conversion of secondary alcohol (XII) into chloride (XIV) was performed via the mesylate (XIII), which was then treated with tetrabutylammonium chloride in hot toluene. Finally, acidic cleavage of the tetrahydropyranyl ether groups of (XIV) led to the title compound.
| 【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 |
|---|---|---|---|---|---|---|
| (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 | |
| (X) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
| (XI) | 56288 | tert-butyl 2-({(Z)-4-[(1R,2R,3R,5S)-2-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-2-butenyl}oxy)acetate | C34H58O8 | 详情 | 详情 | |
| (XII) | 56291 | isopropyl 2-({(Z)-4-[(1R,2R,3R,5S)-2-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-2-butenyl}oxy)acetate | C33H56O8 | 详情 | 详情 | |
| (XIII) | 56292 | isopropyl 2-({(Z)-4-[(1R,2R,3R,5S)-2-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-5-[(methylsulfonyl)oxy]-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-2-butenyl}oxy)acetate | C34H58O10S | 详情 | 详情 | |
| (XIV) | 56293 | isopropyl 2-({(Z)-4-[(1R,2R,3R,5R)-5-chloro-2-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-2-butenyl}oxy)acetate | C33H55ClO7 | 详情 | 详情 |
合成路线3
In a different route, hydrogenation of (R)-3-chloro-1-phenyl-1-propanol (XV) over Rh/Al2O3 gave the cyclohexyl carbinol (XVI), which was protected as the ethoxyethyl ether (XVII) by treatment with ethyl vinyl ether in the presence of pyridinium tosylate. Lithiation of chloride (XVII), followed by exchange with lithium (2-thienyl)cyanocuprate, generated the organocuprate reagent (XVIII), which produced a conjugate addition to enone (XIX) to afford the methylene ketone (XX). Protecting group exchange in (XX) was effected by acidic cleavage of the ethoxyethyl group, followed by silylation with t-butyldimethylsilyl triflate, yielding the bis-silylated compound (XXI). The Z-vinylstannane reagent (XXII) was subjected to a stereospecific transmetalation with Me2Cu(CN)Li2 and the resulting cuprate underwent conjugate addition to enone (XXI) yielding adduct (XXIII). Reduction of ketone (XXIII) with L-Selectride®, followed by acidic cleavage of the ethoxyethyl group, provided diol (XXIV). Alkylation of (XXIV) with tert-butyl bromoacetate (X), followed by transterification as above, furnished the isopropyl ester (XXV). The remaining hydroxyl group of (XXV) was subsequently exchanged by a chloride (XXVI) via the corresponding mesylate. Finally, desilylation of (XXVI) with HF in THF gave rise to the title compound.
| 【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 |
|---|---|---|---|---|---|---|
| (X) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
| (XV) | 37782 | (1R)-3-chloro-1-phenyl-1-propanol | C9H11ClO | 详情 | 详情 | |
| (XVI) | 56294 | (1R)-3-chloro-1-cyclohexyl-1-propanol | C9H17ClO | 详情 | 详情 | |
| (XVII) | 56295 | (1R)-3-chloro-1-cyclohexylpropyl 2-ethoxyethyl ether; 1-[(1R)-3-chloro-1-(2-ethoxyethoxy)propyl]cyclohexane | C13H25ClO2 | 详情 | 详情 | |
| (XVIII) | 56296 | {[(3R)-3-cyclohexyl-3-(2-ethoxyethoxy)propyl]cuprio}lithium | C13H25CuLiO2 | 详情 | 详情 | |
| (XIX) | 56297 | (4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-[(diethylamino)methyl]-2-cyclopenten-1-one | C16H31NO2Si | 详情 | 详情 | |
| (XX) | 56298 | (3R,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-[(3R)-3-cyclohexyl-3-(2-ethoxyethoxy)propyl]-2-methylenecyclopentanone | C25H46O4Si | 详情 | 详情 | |
| (XXI) | 56299 | (3R,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-((3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-cyclohexylpropyl)-2-methylenecyclopentanone | C27H52O3Si2 | 详情 | 详情 | |
| (XXII) | 56300 | 2-ethoxyethyl (Z)-3-(tributylstannyl)-2-propenyl ether; tributyl[(Z)-3-(2-ethoxyethoxy)-1-propenyl]stannane | C19H40O2Sn | 详情 | 详情 | |
| (XXIII) | 56301 | (2R,3R,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-((3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-cyclohexylpropyl)-2-[(Z)-4-(2-ethoxyethoxy)-2-butenyl]cyclopentanone | C34H66O5Si2 | 详情 | 详情 | |
| (XXIV) | 56302 | (1S,2R,3R,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-((3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-cyclohexylpropyl)-2-[(Z)-4-hydroxy-2-butenyl]cyclopentanol | C30H60O4Si2 | 详情 | 详情 | |
| (XXV) | 56303 | isopropyl 2-({(Z)-4-[(1R,2R,3R,5S)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-((3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-cyclohexylpropyl)-5-hydroxycyclopentyl]-2-butenyl}oxy)acetate | C35H68O6Si2 | 详情 | 详情 | |
| (XXVI) | 56304 | isopropyl 2-({(Z)-4-[(1R,2R,3R,5R)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-((3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-cyclohexylpropyl)-5-chlorocyclopentyl]-2-butenyl}oxy)acetate | C35H67ClO5Si2 | 详情 | 详情 |