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【结 构 式】 
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【分子编号】52931 【品名】isopropyl (Z)-7-[(1R,2R,3R,5S)-5-hydroxy-2-[(E)-4-[2-iodo-5-(trifluoromethyl)phenoxy]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-5-heptenoate 【CA登记号】 |
【 分 子 式 】C36H50F3IO8 【 分 子 量 】794.6878796 【元素组成】C 54.41% H 6.34% F 7.17% I 15.97% O 16.11% |
合成路线1
该中间体在本合成路线中的序号：(XIV)The alkylation of 2-iodo-5-(trifluoromethyl)phenol (I) with ethyl 2-bromoacetate (II) and K2CO3 in acetone gives the phenyl ether (III), which is condensed with the phosphonate (IV) by means of BuLi in THF to yield the ketophosphonate (V). The condensation of the Corey aldehyde (VI) with phosphonate (V) by means of ClLi and TEA in THF affords the ketonic intermediate (VII), which is reduced with (-)-chlorodiisopinocampheylborane [(-)-DIPCl] in THF to produce C-15 hydroxy epimer predominantly with the desired stereochemistry (VIII).The hydrolysis of the benzoate group of (VIII) with K2CO3 in methanol gives the dihydroxylactone (IX), which is protected with DHP and Ts-OH in dichloromethane to yield the bis-tetrahydropyranyl ether (X). The lactone group of (X) is reduced with DIBAL in THF to yield the lactol (XI), which is submitted to a Wittig condensation with 4-carboxybutyltriphenylphosphonium bromide (XII) by means of tBu-OK in THF to afford the carboxylic acid (XIII). The esterification of (XIII) with isopropyl iodide and DBU in acetone affords the isopropyl ester (XIV), which is deprotected (elimination of the THP protecting groups) with HCl in methanol/water and purified by chromatography (elimination of the unwanted C15-epimer) to afford the precursor (XV). Finally the iodine atom of (XV) is eliminated by hydrogenation with hydrogen over Pd/C in ethyl acetate.
| 【1】 Selliah, R.; et al.; Synthesis of [phenyl-2-H-3]-travoprost: Isopropyl ester prodrug of a selective prostaglandin FP receptor agonist. J Label Compd Radiopharm 2001, 44, 3, 173. |
| 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) | 52922 | 2-iodo-5-(trifluoromethyl)phenol | C7H4F3IO | 详情 | 详情 | |
| (II) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (III) | 52923 | ethyl 2-[2-iodo-5-(trifluoromethyl)phenoxy]acetate | n/a | C11H10F3IO3 | 详情 | 详情 |
| (IV) | 13607 | dimethyl methylphosphonate | 756-79-6 | C3H9O3P | 详情 | 详情 |
| (V) | 52924 | dimethyl 3-[2-iodo-5-(trifluoromethyl)phenoxy]-2-oxopropylphosphonate | C12H13F3IO5P | 详情 | 详情 | |
| (VI) | 33585 | (8R,9S,10R,13S,14S)-13-ethyl-11-methylene-3-(1-pyrrolidinyl)-1,2,7,8,9,10,11,12,13,14,15,16-dodecahydro-17H-cyclopenta[a]phenanthren-17-one | C24H33NO | 详情 | 详情 | |
| (VII) | 52925 | (3aR,4R,5R,6aS)-4-{(E)-4-[2-iodo-5-(trifluoromethyl)phenoxy]-3-oxo-1-butenyl}-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate | C25H20F3IO6 | 详情 | 详情 | |
| (VIII) | 52926 | (3aR,4R,5R,6aS)-4-{(E)-3-hydroxy-4-[2-iodo-5-(trifluoromethyl)phenoxy]-1-butenyl}-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate | C25H22F3IO6 | 详情 | 详情 | |
| (IX) | 52927 | (3aR,4R,5R,6aS)-5-hydroxy-4-{(E)-3-hydroxy-4-[2-iodo-5-(trifluoromethyl)phenoxy]-1-butenyl}hexahydro-2H-cyclopenta[b]furan-2-one | C18H18F3IO5 | 详情 | 详情 | |
| (X) | 52928 | (3aR,4R,5R,6aS)-4-[(E)-4-[2-iodo-5-(trifluoromethyl)phenoxy]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one | C28H34F3IO7 | 详情 | 详情 | |
| (XI) | 52929 | (3aR,4R,5R,6aS)-4-[(E)-4-[2-iodo-5-(trifluoromethyl)phenoxy]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-ol | C28H36F3IO7 | 详情 | 详情 | |
| (XII) | 13616 | (4-Carboxybutyl)triphenylphosphonium bromide | 17814-85-6 | C23H24BrO2P | 详情 | 详情 |
| (XIII) | 52930 | (Z)-7-[(1R,2R,3R,5S)-5-hydroxy-2-[(E)-4-[2-iodo-5-(trifluoromethyl)phenoxy]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-5-heptenoic acid | C33H44F3IO8 | 详情 | 详情 | |
| (XIV) | 52931 | isopropyl (Z)-7-[(1R,2R,3R,5S)-5-hydroxy-2-[(E)-4-[2-iodo-5-(trifluoromethyl)phenoxy]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-5-heptenoate | C36H50F3IO8 | 详情 | 详情 | |
| (XV) | 52932 | isopropyl (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-{(E,3R)-3-hydroxy-4-[2-iodo-5-(trifluoromethyl)phenoxy]-1-butenyl}cyclopentyl)-5-heptenoate | C26H34F3IO6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIV)The alkylation of 2-iodo-5-(trifluoromethyl)phenol (I) with ethyl 2-bromoacetate (II) and K2CO3 in acetone gives the phenyl ether (III), which is condensed with the phosphonate (IV) by means of BuLi in THF to yield the ketophosphonate (V). The condensation of the Corey aldehyde (VI) with phosphonate (V) by means of ClLi and TEA in THF affords the ketonic intermediate (VII), which is reduced with (-)-chlorodiisopinocampheylborane [(-)-DIPCl] in THF to produce C-15 hydroxy epimer (VIII) predominantly with the desired stereochemistry. The hydrolysis of the benzoate group of (VIII) with K2CO3 in methanol gives the dihydroxylactone (IX), which is protected with DHP and Ts-OH in dichloromethane to yield the bis-tetrahydropyranyl ether (X). The lactone group of (X) is reduced with DIBAL in THF to yield the lactol (XI), which is submitted to a Wittig condensation with 4-carboxybutyltriphenylphosphonium bromide (XII) by means of tBu-OK in THF to afford the carboxylic acid (XIII). The esterification of (XIII) with isopropyl iodide and DBU in acetone affords the isopropyl ester (XIV), which is deprotected (elimination of the THP protecting groups) with HCl in methanol/water and purified by chromatography (elimination of the unwanted C15-epimer) to afford the precursor (XV). Finally the iodine atom of (XV) is substituted with tritium by hydrogenation with tritium gas over Pd/C in ethyl acetate.
| 【1】 Selliah, R.; et al.; Synthesis of [phenyl-2-H-3]-travoprost: Isopropyl ester prodrug of a selective prostaglandin FP receptor agonist. J Label Compd Radiopharm 2001, 44, 3, 173. |
| 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) | 52922 | 2-iodo-5-(trifluoromethyl)phenol | C7H4F3IO | 详情 | 详情 | |
| (II) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (III) | 52923 | ethyl 2-[2-iodo-5-(trifluoromethyl)phenoxy]acetate | n/a | C11H10F3IO3 | 详情 | 详情 |
| (IV) | 13607 | dimethyl methylphosphonate | 756-79-6 | C3H9O3P | 详情 | 详情 |
| (V) | 52924 | dimethyl 3-[2-iodo-5-(trifluoromethyl)phenoxy]-2-oxopropylphosphonate | C12H13F3IO5P | 详情 | 详情 | |
| (VI) | 33585 | (8R,9S,10R,13S,14S)-13-ethyl-11-methylene-3-(1-pyrrolidinyl)-1,2,7,8,9,10,11,12,13,14,15,16-dodecahydro-17H-cyclopenta[a]phenanthren-17-one | C24H33NO | 详情 | 详情 | |
| (VII) | 52925 | (3aR,4R,5R,6aS)-4-{(E)-4-[2-iodo-5-(trifluoromethyl)phenoxy]-3-oxo-1-butenyl}-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate | C25H20F3IO6 | 详情 | 详情 | |
| (VIII) | 52926 | (3aR,4R,5R,6aS)-4-{(E)-3-hydroxy-4-[2-iodo-5-(trifluoromethyl)phenoxy]-1-butenyl}-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate | C25H22F3IO6 | 详情 | 详情 | |
| (IX) | 52927 | (3aR,4R,5R,6aS)-5-hydroxy-4-{(E)-3-hydroxy-4-[2-iodo-5-(trifluoromethyl)phenoxy]-1-butenyl}hexahydro-2H-cyclopenta[b]furan-2-one | C18H18F3IO5 | 详情 | 详情 | |
| (X) | 52928 | (3aR,4R,5R,6aS)-4-[(E)-4-[2-iodo-5-(trifluoromethyl)phenoxy]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one | C28H34F3IO7 | 详情 | 详情 | |
| (XI) | 52929 | (3aR,4R,5R,6aS)-4-[(E)-4-[2-iodo-5-(trifluoromethyl)phenoxy]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-ol | C28H36F3IO7 | 详情 | 详情 | |
| (XII) | 13616 | (4-Carboxybutyl)triphenylphosphonium bromide | 17814-85-6 | C23H24BrO2P | 详情 | 详情 |
| (XIII) | 52930 | (Z)-7-[(1R,2R,3R,5S)-5-hydroxy-2-[(E)-4-[2-iodo-5-(trifluoromethyl)phenoxy]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-5-heptenoic acid | C33H44F3IO8 | 详情 | 详情 | |
| (XIV) | 52931 | isopropyl (Z)-7-[(1R,2R,3R,5S)-5-hydroxy-2-[(E)-4-[2-iodo-5-(trifluoromethyl)phenoxy]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-5-heptenoate | C36H50F3IO8 | 详情 | 详情 | |
| (XV) | 52932 | isopropyl (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-{(E,3R)-3-hydroxy-4-[2-iodo-5-(trifluoromethyl)phenoxy]-1-butenyl}cyclopentyl)-5-heptenoate | C26H34F3IO6 | 详情 | 详情 |