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【结 构 式】 
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【分子编号】43182 【品名】(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 【CA登记号】 |
【 分 子 式 】C31H30O5 【 分 子 量 】482.5762 【元素组成】C 77.16% H 6.27% O 16.58% |
合成路线1
该中间体在本合成路线中的序号：(Vb)The oxidation of protected hydroxymethyl lactone (I) with DCC/DMSO gives the aldehyde (II), which is condensed with phosphorane (III) to yield the pentenone (IV). The reduction of (IV) with NaBH4 in methanol affords the pentenol (Va-b), which is further reduced with DIBAL to provide the lactol (VIa-d). The condensation of (VIa-d) with phosphorane (VII) by means of KOtBu gives the trihydroxyheptenoic acid (VIIIa-b), which is esterified with isopropyl iodide (A) and DBU, yielding the isopropyl ester (IXa-b). Finally, this compound is selectively oxidized with DDQ to afford the target compound.
| 【1】 Stjernschantz, J.; Resul, B.; Phenyl substituted prostaglandin analogs for glaucoma treatment. Drugs Fut 1992, 17, 8, 691. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IXa) | 19369 | 2-iodopropane | 75-30-9 | C3H7I | 详情 | 详情 |
| (Va) | 43181 | (3aR,4R,5R,6aS)-4-[(E,3R)-3-hydroxy-5-phenyl-1-pentenyl]-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate | C31H30O5 | 详情 | 详情 | |
| (Vb) | 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 | |
| (VIa) | 43183 | (2R,3aR,4R,5R,6aS)-4-[(E,3R)-3-hydroxy-5-phenyl-1-pentenyl]hexahydro-2H-cyclopenta[b]furan-2,5-diol | C18H24O4 | 详情 | 详情 | |
| (VIb) | 43184 | (2S,3aR,4R,5R,6aS)-4-[(E,3R)-3-hydroxy-5-phenyl-1-pentenyl]hexahydro-2H-cyclopenta[b]furan-2,5-diol | C18H24O4 | 详情 | 详情 | |
| (VIc) | 43185 | (2R,3aR,4R,5R,6aS)-4-[(E,3S)-3-hydroxy-5-phenyl-1-pentenyl]hexahydro-2H-cyclopenta[b]furan-2,5-diol | C18H24O4 | 详情 | 详情 | |
| (VId) | 43186 | (2S,3aR,4R,5R,6aS)-4-[(E,3S)-3-hydroxy-5-phenyl-1-pentenyl]hexahydro-2H-cyclopenta[b]furan-2,5-diol | C18H24O4 | 详情 | 详情 | |
| (VIIIa) | 43187 | (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3R)-3-hydroxy-5-phenyl-1-pentenyl]cyclopentyl]-5-heptenoic acid | C23H32O5 | 详情 | 详情 | |
| (VIIIb) | 43188 | (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3S)-3-hydroxy-5-phenyl-1-pentenyl]cyclopentyl]-5-heptenoic acid | 38344-08-0 | C23H32O5 | 详情 | 详情 |
| (IXb) | 43189 | isopropyl (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3R)-3-hydroxy-5-phenyl-1-pentenyl]cyclopentyl]-5-heptenoate | C26H38O5 | 详情 | 详情 | |
| (I) | 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 |
| (II) | 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 | |
| (III) | 43179 | 4-phenyl-1-(triphenylphosphoranylidene)-2-butanone | C28H25OP | 详情 | 详情 | |
| (IV) | 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 | |
| (VII) | 37805 | methyl (4R,5S)-5-isopropyl-2-phenyl-4,5-dihydro-1,3-oxazole-4-carboxylate | C14H17NO3 | 详情 | 详情 | |
| (X) | 43190 | isopropyl (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3S)-3-hydroxy-5-phenyl-1-pentenyl]cyclopentyl]-5-heptenoate | C26H38O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)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3
该中间体在本合成路线中的序号：(X)A closely related strategy using tetrahydropyranyl protection has been reported. Protection of the allylic alcohol (X) with dihydropyran in the presence of p-toluenesulfonic acid yielded the tetrahydropyranyl ether (XVII). Catalytic hydrogenation of (XVII) gave rise to (XVIII), which was further reduced to lactol (XIX) employing DIBAL in cold toluene. After methanolysis of the phenylbenzoyl group of (XIX), the resultant lactol (XX) was subjected to Wittig condensation with the phosphonium reagent (XV), yielding olefin (XXI). After conversion of acid (XXI) to the corresponding isopropyl ester(XXII), the tetrahydropyranyl group was removed by means of pyridinium tosylate in MeOH.
| 【1】 Gutman, A.; Nisnevich, G.; Etinger, M.; Zaltzman, I.; Judovich, L.; Pertsikov, B.; A new process for the preparation of latanoprost. WO 0155101 . |
| 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) | 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 | |
| (XV) | 13616 | (4-Carboxybutyl)triphenylphosphonium bromide | 17814-85-6 | C23H24BrO2P | 详情 | 详情 |
| (XVII) | 59566 | (3aR,4R,5R,6aS)-2-oxo-4-[(E,3S)-5-phenyl-3-(tetrahydro-2H-pyran-2-yloxy)-1-pentenyl]hexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate | C36H38O6 | 详情 | 详情 | |
| (XVIII) | 59567 | (3aR,4R,5R,6aS)-2-oxo-4-[(3R)-5-phenyl-3-(tetrahydro-2H-pyran-2-yloxy)pentyl]hexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate | C36H40O6 | 详情 | 详情 | |
| (XIX) | 59568 | (3aR,4R,5R,6aS)-2-hydroxy-4-[(3R)-5-phenyl-3-(tetrahydro-2H-pyran-2-yloxy)pentyl]hexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate | C36H42O6 | 详情 | 详情 | |
| (XX) | 59569 | (3aR,4R,5R,6aS)-4-[(3R)-5-phenyl-3-(tetrahydro-2H-pyran-2-yloxy)pentyl]hexahydro-2H-cyclopenta[b]furan-2,5-diol | C23H34O5 | 详情 | 详情 | |
| (XXI) | 59570 | (Z)-7-{(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-5-phenyl-3-(tetrahydro-2H-pyran-2-yloxy)pentyl]cyclopentyl}-5-heptenoic acid | C28H42O6 | 详情 | 详情 | |
| (XXII) | 59571 | isopropyl (Z)-7-{(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-5-phenyl-3-(tetrahydro-2H-pyran-2-yloxy)pentyl]cyclopentyl}-5-heptenoate | C31H48O6 | 详情 | 详情 |