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【结 构 式】 
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【分子编号】59562 【品名】(3aR,4R,5R,6aS)-5-hydroxy-4-[(3R)-3-hydroxy-5-phenylpentyl]hexahydro-2H-cyclopenta[b]furan-2-one 【CA登记号】 |
【 分 子 式 】C18H24O4 【 分 子 量 】304.38616 【元素组成】C 71.03% H 7.95% O 21.03% |
合成路线1
该中间体在本合成路线中的序号：(XIII)The title compound was prepared starting from the known bicyclic lactone (VI). Oxidation of the primary alcohol function of (VI) to the corresponding aldehyde (VII) was accomplished by either following the Pfitzner-Moffat method or by means of Dess-Martin perodinane reagent. Aldehyde (VII) was then converted to enone (IX) by Wittig reaction with the phosphonium salt (VIII) or, in a related method, by Wadsworth-Emmons condensation of (VII) with phosphonate (IV). Stereoselective reduction of enone (IX) with either L-selectride or (-)-B-chlorodiisopinocampheylborane produced the (15S)-allylic alcohol (X) as the major diastereoisomer, which was isolated by flash chromatography. Then, catalytic hydrogenation of the double bond of (X) gave the saturated alcohol (XI). Reduction of the lactone function employing DIBAL led to the protected lactol (XII). Subsequent removal of the phenylbenzoyl group of (XII) with K2CO3 in methanol furnished dihydroxy lactol (XIII). In a variation of this sequence, the phenylbenzoyl group of (XI) was first removed by methanolysis, and the resultant dihydroxy lactone (XIV) was then reduced with DIBAL to lactol (XIII).
| 【1】 Gutman, A.; Nisnevich, G.; Etinger, M.; Zaltzman, I.; Judovich, L.; Pertsikov, B.; A new process for the preparation of latanoprost. WO 0155101 . |
| 【2】 Kovács, G.; Hermecz, I.; Szabó, T.; Ivanics, J.; Ivanics, J.; Dalmadi, G.; Bahram, R. (Chinoin Pharmaceutical and Chemical Works Co., Ltd.); Chemical process. WO 9300329 . |
| 【3】 Resul, B.; et al.; Phenyl-substituted prostaglandins: Potent and selective antiglaucoma agents. J Med Chem 1993, 36, 2, 243. |
| 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) | 59558 | dimethyl 2-oxo-4-phenylbutylphosphonate | C12H17O4P | 详情 | 详情 | |
| (VI) | 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 |
| (VII) | 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 | |
| (VIII) | 59560 | (2-oxo-4-phenylbutyl)(triphenyl)phosphonium iodide | C28H26IOP | 详情 | 详情 | |
| (IX) | 43180 | (3aR,4R,5R,6aS)-2-oxo-4-[(E)-3-oxo-5-phenyl-1-pentenyl]hexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate | C31H28O5 | 详情 | 详情 | |
| (X) | 43182 | (3aR,4R,5R,6aS)-4-[(E,3S)-3-hydroxy-5-phenyl-1-pentenyl]-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate | C31H30O5 | 详情 | 详情 | |
| (XI) | 59561 | (3aR,4R,5R,6aS)-4-[(3R)-3-hydroxy-5-phenylpentyl]-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate | C31H32O5 | 详情 | 详情 | |
| (XII) | 59564 | (3aR,4R,5R,6aS)-2-hydroxy-4-[(3R)-3-hydroxy-5-phenylpentyl]hexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate | C31H34O5 | 详情 | 详情 | |
| (XIII) | 59562 | (3aR,4R,5R,6aS)-5-hydroxy-4-[(3R)-3-hydroxy-5-phenylpentyl]hexahydro-2H-cyclopenta[b]furan-2-one | C18H24O4 | 详情 | 详情 | |
| (XIV) | 59563 | (3aR,4R,5R,6aS)-4-[(3R)-3-hydroxy-5-phenylpentyl]hexahydro-2H-cyclopenta[b]furan-2,5-diol | C18H26O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIV)In an alternative method, the aldehyde lactone (XXIII) was subjected to Wadsworth-Emmons reaction with phosphonate (IV) to afford enone (XXIV). Stereoselective ketone reduction, followed by catalytic hydrogenation of the resultant allylic alcohol (XXV), provided (XXVI). Both the benzoate ester and the lactone groups of (XXIV) were hydrolyzed by KOH, yielding trihydroxy acid (XXVII), which was further cyclized to lactone (XIV) in boiling toluene. The hydroxyl groups of (XIV) were then protected with ethyl vinyl ether in the presence of trichloroacetic acid to produce the bis-acetal (XXVIII). Reduction of the lactone function of (XXVIII) to the corresponding lactol (XXIX), followed by Wittig reaction with the phosphorane generated from phosphonium salt (XV) and potassium t-butoxide, furnished olefin (XXX). After acidic hydrolysis of the acetal protecting groups of (XXX), the carboxylate function was converted to the corresponding isopropyl ester by treatment with 2-iodopropane and cesium carbonate.
| 【1】 Henegar, K.E. (Pharmacia Corp.); Process and intermediates to prepare latanoprost. WO 0187816 . |
| 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) | 59558 | dimethyl 2-oxo-4-phenylbutylphosphonate | C12H17O4P | 详情 | 详情 | |
| (XIV) | 59562 | (3aR,4R,5R,6aS)-5-hydroxy-4-[(3R)-3-hydroxy-5-phenylpentyl]hexahydro-2H-cyclopenta[b]furan-2-one | C18H24O4 | 详情 | 详情 | |
| (XV) | 13616 | (4-Carboxybutyl)triphenylphosphonium bromide | 17814-85-6 | C23H24BrO2P | 详情 | 详情 |
| (XXIII) | 25585 | ethyl 5-(aminocarbonyl)-4-(benzylamino)-3-methyl-3,6-dihydro-1(2H)-pyridinecarboxylate | C17H23N3O3 | 详情 | 详情 | |
| (XXIV) | 59578 | (1S,2S,3aR,6aS)-5-methylene-1-[(1E)-3-phenethyl-1,3-butadienyl]-2-(2-phenyl-2-propenyl)octahydropentalene | C30H34 | 详情 | 详情 | |
| (XXV) | 59572 | (3aR,4R,5R,6aS)-4-[(E,3S)-3-hydroxy-5-phenyl-1-pentenyl]-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate | C25H26O5 | 详情 | 详情 | |
| (XXVI) | 59573 | (3aR,4R,5R,6aS)-4-[(3R)-3-hydroxy-5-phenylpentyl]-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate | C25H28O5 | 详情 | 详情 | |
| (XXVII) | 59574 | 2-{(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl}acetic acid | C18H26O5 | 详情 | 详情 | |
| (XXVIII) | 59575 | (3aR,4R,5R,6aS)-5-(1-ethoxyethoxy)-4-[(3R)-3-(1-ethoxyethoxy)-5-phenylpentyl]hexahydro-2H-cyclopenta[b]furan-2-one | C26H40O6 | 详情 | 详情 | |
| (XXIX) | 59576 | (3aR,4R,5R,6aS)-5-(1-ethoxyethoxy)-4-[(3R)-3-(1-ethoxyethoxy)-5-phenylpentyl]hexahydro-2H-cyclopenta[b]furan-2-ol | C26H42O6 | 详情 | 详情 | |
| (XXX) | 59577 | (Z)-7-{(1R,2R,3R,5S)-3-(1-ethoxyethoxy)-2-[(3R)-3-(1-ethoxyethoxy)-5-phenylpentyl]-5-hydroxycyclopentyl}-5-heptenoic acid | C31H50O7 | 详情 | 详情 |