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【结 构 式】 
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【分子编号】32121 【品名】dimethyl 2-oxo-3-[3-(trifluoromethyl)phenoxy]propylphosphonate 【CA登记号】 |
【 分 子 式 】C12H14F3O5P 【 分 子 量 】326.2091316 【元素组成】C 44.18% H 4.33% F 17.47% O 24.52% P 9.5% |
合成路线1
该中间体在本合成路线中的序号：(II)The Wittig reaction of 1alpha-acetoxy-2alpha-(6-methoxycarbonyl-hex-2-cis-enyl)-3beta-formyl-4alpha-(2-tetrahydropyranyloxy)cyclopentane (I) and dimethyl 2-oxo-3-(3-trifluoromethylphenoxy)propylphosphonate (II) by means of NaH in hot THF gives 9alpha-acetoxy-11alpha-(2-tetrahydropyranyloxy)-15-oxo-16-(3-trifluoromethylphenoxy)-17,18,19,20-tetranorprosta-5-cis-13-trans-dienoate (III), which is reduced with NaBH4 in methanol yielding the protected trihydroxy compound (IV). The partial hydrolysis of (IV) with K2CO3 in methanol affords the dihydroxytetrahydropyranyloxy compound (V), which by reaction with diphenyldiselenide (A) by means of 17-butyllithium and diisopropylamine in THF is converted into the mixed selenide (VI). The treatment of (VI) with H2O2 in THF-ethyl acetate gives methyl 9alpha,15alpha-dihydroxy-11alpha-(2-tetra)-17,18,19,20-tetranorprosta-2-trans-5-cis-13-trans-trienoate (VII), which is finally treated with HCl in THF-water to eliminate the tetrahydropyranyl group.
| 【1】 Hayashi, M.; et al.; US 4065632 . |
| 【2】 Castaner, J.; Riberos, J.; ONO-995. Drugs Fut 1980, 5, 10, 499. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 39170 | 1,2-diphenyldiselane | 1666-13-3 | C12H10Se2 | 详情 | 详情 |
| (I) | 20983 | methyl (Z)-7-[(1R,2S,3R,5S)-5-(acetoxy)-2-formyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-5-heptenoate | C22H34O7 | 详情 | 详情 | |
| (II) | 32121 | dimethyl 2-oxo-3-[3-(trifluoromethyl)phenoxy]propylphosphonate | C12H14F3O5P | 详情 | 详情 | |
| (III) | 39167 | methyl (Z)-7-[(1R,2S,3R,5S)-5-(acetoxy)-2-[(E)-3-oxo-4-[3-(trifluoromethyl)phenoxy]-1-butenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-5-heptenoate | C32H41F3O8 | 详情 | 详情 | |
| (IV) | 39168 | methyl (Z)-7-[(1R,2S,3R,5S)-5-(acetoxy)-2-[(E,3R)-3-hydroxy-4-[3-(trifluoromethyl)phenoxy]-1-butenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-5-heptenoate | C32H43F3O8 | 详情 | 详情 | |
| (V) | 39169 | methyl (Z)-7-[(1R,2S,3R,5S)-5-hydroxy-2-[(E,3R)-3-hydroxy-4-[3-(trifluoromethyl)phenoxy]-1-butenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-5-heptenoate | C30H41F3O7 | 详情 | 详情 | |
| (VI) | 39171 | methyl (Z)-7-[(1R,2S,3R,5S)-5-hydroxy-2-[(E,3R)-3-hydroxy-4-[3-(trifluoromethyl)phenoxy]-1-butenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-2-(phenylselanyl)-5-heptenoate | C36H45F3O7Se | 详情 | 详情 | |
| (VII) | 39172 | methyl (2E,5Z)-7-[(1R,2S,3R,5S)-5-hydroxy-2-[(E,3R)-3-hydroxy-4-[3-(trifluoromethyl)phenoxy]-1-butenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-2,5-heptadienoate | C30H39F3O7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The reaction of 3-trifluoromethylphenol (XVIII) with ethyl chloroacetate (XIX) by means of NaI and K2CO3 in acetone gives ethyl-(3-trifluoromethylphenoxy)acetate (XX), which is then condensed with dimethyl methylphosphonate (C) by means of butyllithium in THF to afford dimethyl 2-oxo-3-(3-trifluoromethylphenoxy)propylphosphonate (II).
| 【1】 Hayashi, M.; et al.; US 4065632 . |
| 【2】 Castaner, J.; Riberos, J.; ONO-995. Drugs Fut 1980, 5, 10, 499. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 32121 | dimethyl 2-oxo-3-[3-(trifluoromethyl)phenoxy]propylphosphonate | C12H14F3O5P | 详情 | 详情 | |
| (XVIII) | 33504 | 3-(trifluoromethyl)phenol | 98-17-9 | C7H5F3O | 详情 | 详情 |
| (XIX) | 16601 | ethyl chloroacetate; ethyl 2-chloroacetate | 105-39-5 | C4H7ClO2 | 详情 | 详情 |
| (XX) | 39185 | ethyl 2-[3-(trifluoromethyl)phenoxy]acetate | C11H11F3O3 | 详情 | 详情 | |
| (C) | 13607 | dimethyl methylphosphonate | 756-79-6 | C3H9O3P | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)The condensation of 2-[3-(trifluoromethyl)phenoxy]acetyl chloride (I) with methylphosphonic acid dimethyl ester (II) by means of BuLi in THF gives 2-oxo-3-[3-(trifluoromethyl)phenoxy]propylphosphonic acid dimethyl ester (III), which is condensed with the known bicyclic aldehyde (IV) by means of BuLi in dimethoxyethane, yielding the unsaturated ketone (V). The reduction of (V) with zinc borohydride in dimethoxyethane affords the unsaturated alcohol (VI), which is treated with K2CO3 to give a diastereomeric mixture of unsaturated diols, resolved by chromatography to yield the chiral unsaturated diol (VII). The protection of (VII) with dihydropyran and TsOH in dichloromethane provides the bis(tetrahydropyranyl) ether (VIII), which by reduction of the lactone ring with diisobutylaluminum hydride in THF gives the lactol (IX). The condensation of (IX) with the phosphonium bromide (X) by means of NaH in DMSO yields the prostenoic acid (XI), which is esterified with isopropyl iodide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in acetone to afford the corresponding isopropyl ester (XII). Finally, this compound is deprotected with acetic acid in hot THF/water.
| 【1】 Klimko, P.G.; Bishop, J.A.; DeSantis, L. Jr.; Sallee, V.L. (Alcon Laboratories, Inc.); Use of cloprostenol, fluprostenol and their analogues for the manufacture of a medicament for the treatment of glaucoma and ocular hypertension. EP 0639563; JP 1995165703; JP 1998182465; US 5665773 . |
| 【2】 Castañer, J.; Sorbera, L.A.; Travoprost. Drugs Fut 2000, 25, 1, 41. |
| 【3】 Bowler, J.; Crossley, N.S. (AstraZeneca plc); Method of inducing luteolysis using 16-aryloxy-17,18,19,20-tetranor-prostanoic acid derivs. US 4321275 . |
| 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) | 32120 | 2-[3-(trifluoromethyl)phenoxy]acetyl chloride | C9H6ClF3O2 | 详情 | 详情 | |
| (II) | 13607 | dimethyl methylphosphonate | 756-79-6 | C3H9O3P | 详情 | 详情 |
| (III) | 32121 | dimethyl 2-oxo-3-[3-(trifluoromethyl)phenoxy]propylphosphonate | C12H14F3O5P | 详情 | 详情 | |
| (IV) | 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 | |
| (V) | 32122 | (3aR,4R,5R,6aS)-2-oxo-4-[(E)-3-oxo-4-[3-(trifluoromethyl)phenoxy]-1-butenyl]hexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate | C31H25F3O6 | 详情 | 详情 | |
| (VI) | 32123 | (3aR,4R,5R,6aS)-4-[(E)-3-hydroxy-4-[3-(trifluoromethyl)phenoxy]-1-butenyl]-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate | C31H27F3O6 | 详情 | 详情 | |
| (VII) | 32124 | (3aR,4R,5R,6aS)-5-hydroxy-4-[(E,3R)-3-hydroxy-4-[3-(trifluoromethyl)phenoxy]-1-butenyl]hexahydro-2H-cyclopenta[b]furan-2-one | C18H19F3O5 | 详情 | 详情 | |
| (VIII) | 32125 | (3aR,4R,5R,6aS)-5-(tetrahydro-2H-pyran-2-yloxy)-4-[(E,3R)-3-(tetrahydro-2H-pyran-2-yloxy)-4-[3-(trifluoromethyl)phenoxy]-1-butenyl]hexahydro-2H-cyclopenta[b]furan-2-one | C28H35F3O7 | 详情 | 详情 | |
| (IX) | 32126 | (3aR,4R,5R,6aS)-5-(tetrahydro-2H-pyran-2-yloxy)-4-[(E,3R)-3-(tetrahydro-2H-pyran-2-yloxy)-4-[3-(trifluoromethyl)phenoxy]-1-butenyl]hexahydro-2H-cyclopenta[b]furan-2-ol | C28H37F3O7 | 详情 | 详情 | |
| (X) | 13616 | (4-Carboxybutyl)triphenylphosphonium bromide | 17814-85-6 | C23H24BrO2P | 详情 | 详情 |
| (XI) | 32128 | (Z)-7-((1R,2R,3R,5S)-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)-2-[(E,3R)-3-(tetrahydro-2H-pyran-2-yloxy)-4-[3-(trifluoromethyl)phenoxy]-1-butenyl]cyclopentyl)-5-heptenoic acid | C33H45F3O8 | 详情 | 详情 | |
| (XII) | 19369 | 2-iodopropane | 75-30-9 | C3H7I | 详情 | 详情 |
| (XIII) | 32129 | isopropyl (Z)-7-((1R,2R,3R,5S)-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)-2-[(E,3R)-3-(tetrahydro-2H-pyran-2-yloxy)-4-[3-(trifluoromethyl)phenoxy]-1-butenyl]cyclopentyl)-5-heptenoate | C36H51F3O8 | 详情 | 详情 |