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【结 构 式】 
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【分子编号】26177 【品名】(5-methoxy-5-oxopentyl)(triphenyl)phosphonium bromide 【CA登记号】 |
【 分 子 式 】C24H26BrO2P 【 分 子 量 】457.347002 【元素组成】C 63.03% H 5.73% Br 17.47% O 7% P 6.77% |
合成路线1
该中间体在本合成路线中的序号：(II)The Wittig condensation of the bicyclic lactol (I) with 4-(methoxycarbonyl)butyl triphenylphosphonium bromide (II) by means of sodium methylsulfinyl carbanide in DMSO and simultaneous dehydrobromination gives the bis(tetrahydropyranyl) derivative (III), which is finally deprotected by a treatment with oxalic acid in refluxing acetone.
| 【1】 Gandolfi, C.; Pellegata, R.; Ceserani, R.; Usardi, M.M. (Pharmacia Corp.); Omega-nor-cycloalkyl-13,14-dehydroprostaglandins. DE 2539116; FR 2285866; FR 2378757; GB 1483880; JP 51125044; JP 58135858; US 4035415; US 4361577 . |
| 【2】 Castaner, J.; Serradell, M.N.; de Angelis, L.; Alfaprostol. Drugs Fut 1985, 10, 1, 9. |
| 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) | 29030 | (4S,5R)-4-[(Z,3R)-2-bromo-5-cyclohexyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-pentenyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2H-cyclopenta[b]furan-2-ol | C30H49BrO6 | 详情 | 详情 | |
| (II) | 26177 | (5-methoxy-5-oxopentyl)(triphenyl)phosphonium bromide | C24H26BrO2P | 详情 | 详情 | |
| (III) | 29031 | methyl (Z)-7-[(1R,2S,3R,5S)-2-[(3S)-5-cyclohexyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-pentynyl]-5-hydroxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-5-heptenoate | C36H58O7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)Title compound was prepared by Wittig condensation of benzophenone (I) with the phosphorane derived from (4-methoxycarbonylbutyl)triphenyl phosphonium bromide (II) and sodium hexamethyldisilazide at -78 C.
| 【1】 Hejchman, E.; Casimiro-Garcia, A.; Cushman, M.; et al.; New alkenyldiarylmethanes with enhanced potencies as anti-HIV agents which act as non-nucleoside reverse transcriptase inhibitors. J Med Chem 1998, 41, 12, 2076. |
| 【2】 Rice, W.G.; Casimiro-Garcia, A.; Cushman, M.S. (Purdue Research Foundation; US Department of Health & Human Services); Alkenyldiarylmethane non-nucleoside HIV-1 reverse transcriptase inhibitors. WO 9936384 . |
合成路线3
该中间体在本合成路线中的序号：(XXII)Oxidation of the (-)-Corey's lactone (XIV) with Collins reagent (CrO3 and pyridine) gives aldehyde (XV), which is condensed with phosphonate (IV) by means of thallium ethoxide in benzene to yield the unsaturated difluoroketolactone (XVI). Hydrogenation of compound (XVI) with H2 over Pd/C in ethyl acetate affords the saturated analogue (XVII), which is reduced with NaBH4 in methanol/THF to provide the hydroxylactone (XVIII), which is then protected at the hydroxy group with TBDMS-Cl and imidazole to give the silyl ether (XIX). Hydrolysis of the ester group of compound (XIX) in basic medium, followed by reaction with dihydropyran yields the tetrahydropyranyl ether (XX), which is reduced with DIBAL to afford the lactol (XXI). Condensation of lactol (XXI) with 4-(methoxycarbonyl)butyl triphenylphosphonium bromide (XXII) provides the unsaturated methyl ester (XXIII), which is desilylated by means of TBAF in THF to give the diol (XXIV). Finally, hydrolysis of the ester group of compound (XXIV) with NaOH in methanol yields the already described intermediate prostaglandin F2a derivative (X).
| 【1】 Ueno, R.; Ueno, R.; Kato, I.; Oda, T. (Ueno Fine Chemicals Industry, Ltd.); Prostaglandins E and anti-ulcers containing same. EP 0284180; JP 1989052753; US 5166174; US 5225439; US 5284858; US 5380709; US 5428062; US 5886034; US 6265440 . |
| 【2】 Sorbera, L.A., Castaner, J., Mealy, N.E.; Lubiprostone. Drugs Fut 2004, 29 (4): 336. |
| 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) | 65189 | dimethyl 3,3-difluoro-2-oxoheptylphosphonate | C9H17F2O4P | 详情 | 详情 | |
| (X) | 65194 | (Z)-7-[(1R,2R,3R,5S)-2-(4,4-difluoro-3-hydroxyoctyl)-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-5-heptenoic acid | C25H42F2O6 | 详情 | 详情 | |
| (XIV) | 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 |
| (XV) | 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 | |
| (XVI) | 65198 | (3aR,4R,5R,6aS)-4-[(E)-4,4-difluoro-3-oxo-1-octenyl]-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate | C28H28F2O5 | 详情 | 详情 | |
| (XVII) | 65199 | (3aR,4R,5R,6aS)-4-(4,4-difluoro-3-oxooctyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate | C28H30F2O5 | 详情 | 详情 | |
| (XVIII) | 65200 | (3aR,4R,5R,6aS)-4-(4,4-difluoro-3-hydroxyoctyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate | C28H32F2O5 | 详情 | 详情 | |
| (XIX) | 65201 | (3aR,4R,5R,6aS)-4-(3-{[tert-butyl(dimethyl)silyl]oxy}-4,4-difluorooctyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate | C34H46F2O5Si | 详情 | 详情 | |
| (XX) | 65202 | (3aR,4R,5R,6aS)-4-(3-{[tert-butyl(dimethyl)silyl]oxy}-4,4-difluorooctyl)-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one | C26H46F2O5Si | 详情 | 详情 | |
| (XXI) | 65203 | (3aR,4R,5R,6aS)-4-(3-{[tert-butyl(dimethyl)silyl]oxy}-4,4-difluorooctyl)-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-ol | C26H48F2O5Si | 详情 | 详情 | |
| (XXII) | 26177 | (5-methoxy-5-oxopentyl)(triphenyl)phosphonium bromide | C24H26BrO2P | 详情 | 详情 | |
| (XXIII) | 65204 | methyl (Z)-7-[(1R,2R,3R,5S)-2-(3-{[tert-butyl(dimethyl)silyl]oxy}-4,4-difluorooctyl)-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-5-heptenoate | C32H58F2O6Si | 详情 | 详情 | |
| (XXIV) | 65205 | methyl (Z)-7-[(1R,2R,3R,5S)-2-(4,4-difluoro-3-hydroxyoctyl)-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-5-heptenoate | C26H44F2O6 | 详情 | 详情 |