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【结 构 式】 
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【分子编号】32049 【品名】methyl 6-hydroxy-7-[(1R,2S,3R,5S)-5-hydroxy-2-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-4-heptynoate 【CA登记号】 |
【 分 子 式 】C35H50O9 【 分 子 量 】614.7766 【元素组成】C 68.38% H 8.2% O 23.42% |
合成路线1
该中间体在本合成路线中的序号：(XIII)The reaction of phenol (I) with ethyl bromoacetate (II) by means of NaH in dimethoxyethane gives ethyl phenoxyacetate (III), which is condensed with dimethyl methylphosphonate (IV) by means of n-butyllithium in THF to afford dimethyl 2-oxo-3-phenoxypropylphosphonate (V). The Wittig condensation of (V) with (2'alpha-hydroxy-4'alpha-p-phenylbenzoyloxy-5'beta-ormylcyclopent-1'alpha-yl)acetic acid 1,2'-lactone (VI) by means of NaH in dimethoxyethane yields the ketonic lactone (VII), which is reduced with aluminum isopropoxide in refluxing toluene to give the hydroxy lactone (VIII). The hydrolysis of the protecting group of (VIII) with K2CO3 in methanol yields the dihydroxy lactone (IX), which is then protected with dihydropyran affording the bis(tetrahydropyranyloxy) compound (X). The reduction of the lactone group of (X) with diisobutylaluminum hydride in toluene yields the protected hemiacetal (XI), which is condensed with 4-pentinoic acid (XII) by means of LiCH3 in HMPT affording 6,9alpha-dihy-droxy-11alpha,15alpha-bistetrahydropyranyloxy-16-phenoxy-17,18,19,20-tetranorprost-4-yn-13-trans-enoic acid methyl ester (XIII) resulting from the methylation with CH2N2 of the acid intermediate.
| 【1】 Van Horn, A.R.; Garay, G.; Edwards, J.A. (Syntex (USA), Inc.); (dl)-16-Phenoxy- and 16-substituted phenoxy-9-keto prostatrienoic acid derivatives and processes for the production thereof. DE 2927715; EP 0008003; ES 482330; FR 2430939; GB 2025413; US 4178457 . |
| 【2】 Muchowski, J.M.; Fried, J.H. (Syntex (USA), Inc.); 16-Phenoxy and 16-substituted phenoxy-prostatrienoic acid derivatives. DE 2627910; ES 449162; FR 2315263; US 3985791 . |
| 【3】 Blancafort, P.; Castaner, J.; Serradell, M.N.; Hillier, K.; RS-84,135. Drugs Fut 1982, 7, 11, 812. |
| 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) | 23540 | Phenol | 108-95-2 | C6H6O | 详情 | 详情 |
| (II) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (III) | 32040 | ethyl 2-phenoxyacetate | 2555-49-9 | C10H12O3 | 详情 | 详情 |
| (IV) | 13607 | dimethyl methylphosphonate | 756-79-6 | C3H9O3P | 详情 | 详情 |
| (V) | 32041 | dimethyl 2-oxo-3-phenoxypropylphosphonate | 40665-68-7 | C11H15O5P | 详情 | 详情 |
| (VI) | 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 | |
| (VII) | 32043 | (3aR,4R,5R,6aS)-2-oxo-4-[(E)-3-oxo-4-phenoxy-1-butenyl]hexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate | C30H26O6 | 详情 | 详情 | |
| (VIII) | 32044 | (3aR,4R,5R,6aS)-4-[(E,3R)-3-hydroxy-4-phenoxy-1-butenyl]-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate | C30H28O6 | 详情 | 详情 | |
| (IX) | 32045 | (3aR,4R,5R,6aS)-5-hydroxy-4-[(E,3R)-3-hydroxy-4-phenoxy-1-butenyl]hexahydro-2H-cyclopenta[b]furan-2-one | C17H20O5 | 详情 | 详情 | |
| (X) | 32046 | (3aR,4S,5R,6aS)-4-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2H-cyclopenta[b]furan-2-one | C29H40O7 | 详情 | 详情 | |
| (XI) | 32047 | (3aR,4S,5R,6aS)-4-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2H-cyclopenta[b]furan-2-ol | C29H42O7 | 详情 | 详情 | |
| (XII) | 32048 | 4-pentynoic acid | 6089-09-4 | C5H6O2 | 详情 | 详情 |
| (XIII) | 32049 | methyl 6-hydroxy-7-[(1R,2S,3R,5S)-5-hydroxy-2-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-4-heptynoate | C35H50O9 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIII)The acetylation of (XIII) with acetic anhydride and triethylamine in methylene chloride yields the diacetoxy-bistetra-hydropyranyloxy acetylenic compound (XlV), which by a treatment with Cu2Br2-LiCH3 in ether is converted into 16-phenoxy-9alpha-acetoxy-11alpha,15alpha-bistetrahydropyranyloxy-17,18,19,20-tetranorprosta-4,5,13-trans-trienoic acid methyl ester (XV). Elimination of the tetrahydropyranyl groups with acetic acid in water gives the corresponding dihydroxy compound (XVI), which is fully deprotected with K2CO3 in methanol yielding 9alpha,11alpha,15alpha-trihydroxy-16-phenoxy-17,18,19,20-tetranorprosta-4,5,13-trans-trienoic acid (XVII). The methylation of (XVII) with diazomethane affords the corresponding methyl ester (XVIII), which by treatment with tert-butyldimethylsilyl chloride (XIX) in DMF is converted into the corresponding 11,15-bis(silyloxy) compound (XX). The oxidation of (XX) with CrO3 - pyridine in CH2Cl2 affords 9-oxo-16-phenoxy-11alpha,15alpha-bis(tert-butyldimethylsilyloxy)-17,18,19,20-tetranorprosta-4,5,13-trans-trienoic acid methyl ester (XXI), which is deprotected with aqueous acetic acid giving the free keto ester (XXII). Finally, this ester is hydrolyzed by treatment with pancreatic lipase.
| 【1】 Van Horn, A.R.; Garay, G.; Edwards, J.A. (Syntex (USA), Inc.); (dl)-16-Phenoxy- and 16-substituted phenoxy-9-keto prostatrienoic acid derivatives and processes for the production thereof. DE 2927715; EP 0008003; ES 482330; FR 2430939; GB 2025413; US 4178457 . |
| 【2】 Muchowski, J.M.; Fried, J.H. (Syntex (USA), Inc.); 16-Phenoxy and 16-substituted phenoxy-prostatrienoic acid derivatives. DE 2627910; ES 449162; FR 2315263; US 3985791 . |
| 【3】 Blancafort, P.; Castaner, J.; Serradell, M.N.; Hillier, K.; RS-84,135. Drugs Fut 1982, 7, 11, 812. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 32049 | methyl 6-hydroxy-7-[(1R,2S,3R,5S)-5-hydroxy-2-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-4-heptynoate | C35H50O9 | 详情 | 详情 | |
| (XIV) | 32050 | methyl 6-(acetoxy)-7-[(1R,2S,3R,5S)-5-(acetoxy)-2-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-4-heptynoate | C39H54O11 | 详情 | 详情 | |
| (XV) | 32051 | methyl 7-[(1R,2S,3R,5S)-5-(acetoxy)-2-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-4,5-heptadienoate | C37H52O9 | 详情 | 详情 | |
| (XVI) | 32052 | methyl 7-[(1R,2R,3R,5S)-5-(acetoxy)-3-hydroxy-2-[(E,3R)-3-hydroxy-4-phenoxy-1-butenyl]cyclopentyl]-4,5-heptadienoate | C25H32O7 | 详情 | 详情 | |
| (XVII) | 32053 | 7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3R)-3-hydroxy-4-phenoxy-1-butenyl]cyclopentyl]-4,5-heptadienoic acid | C22H28O6 | 详情 | 详情 | |
| (XVIII) | 32054 | methyl 7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3R)-3-hydroxy-4-phenoxy-1-butenyl]cyclopentyl]-4,5-heptadienoate | C23H30O6 | 详情 | 详情 | |
| (XIX) | 32057 | tert-butyl(chloro)dimethylsilane | 18162-48-6 | C6H15ClSi | 详情 | 详情 |
| (XX) | 32055 | methyl 7-[(1R,2R,3R,5S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-((E,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-phenoxy-1-butenyl)-5-hydroxycyclopentyl]-4,5-heptadienoate | C35H58O6Si2 | 详情 | 详情 | |
| (XXI) | 32056 | methyl 7-[(1R,2R,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-((E,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-phenoxy-1-butenyl)-5-oxocyclopentyl]-4,5-heptadienoate | C35H56O6Si2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XIII)The condensation of phenol (I) with ethyl bromoacetate (II) by means of NaH in refluxing dimethoxyethane gives phenoxyacetate (III), which by condensation with dimethyl methylphosphonate (IV) by means of butyllithium in THF is converted into dimethyl 2-oxo-3-phenoxypropylphosphonate (V). The Wittig condensation of (V) with (2'alpha-hydroxy-4'alpha-p-phenylbenzoyloxy)-5'beta-formylcyclopent-1’alpha-yl)acetic acid 1,2'-lactone (VI) by means of NaH in methoxyethane affords the phenoxylactone (VII), which is reduced witl aluminium isopropoxide in refluxing toluene to yield the hydroxylactone (VIII). The hydrolysis of (VIII) with K2CO3 in methanol gives the dihydroxylactone (IX), which is protected with dihydropyran and p-toluenesulfonic acid in methylene chloride giving the bis-tetrahydropyranyloxylactone (X). The reduction of (X) with diisobutylaluminium hydride in toluene yields [2'alpha-hydroxy-4'alpha-tetrahydropyranyloxy-5'beta-(3''alpha-tetrapyranyloxy-4''-phenoxybut-1''-trans-en-1''-yl)cyclopent-1'alpha-yl]acetaldehyde 1,2-hemiacetal (XI), which is condensed with 4-pentynoate (XII) by means of methyllithium and diisopropylamine in ether to afford the acetylenic prostaglandin derivative (XIII). The acetylation of (XIII) with acetic anhydride - triethylamine and dimethylaminopyridine in methylene chloride gives the diacetoxy compound (XIV), which by treatment with Cu2I2 and methyllithium in ether is converted into the cumulenic prostaglandin (XV). The elimination of the tetrahydropyran groups with acetic acid yields the dihydroxy-acetoxy ester (XVI), which is fully hydrolyzed with K2ClO3 in MeOH affording 8R-9alpha,11alpha,15alpha-trihydroxy-16-phenoxy-17,18,19,20-tetranorprosta-4,5,13-trans-trienoic acid (XVII). Finally this compound is methylated with diazomethane in ether
| 【1】 Serradell, M.N.; Castaner, J.; Adaikan, P.G.; Kottegoda, S.R.; Fenprostalene. Drugs Fut 1984, 9, 11, 817. |
| 【2】 Muchowski, J.M.; et al. (Syntex (USA) Inc.); US 3985791 . |
| 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) | 23540 | Phenol | 108-95-2 | C6H6O | 详情 | 详情 |
| (II) | 10640 | (1S,3R,4S,7S,8S,10R,13S)-7-(benzyloxy)-13-[[tert-butyl(dimethyl)silyl]oxy]-1,2,5-trihydroxy-8,12,15,15-tetramethyl-9-oxo-4-[(phenylsulfanyl)methyl]tricyclo[9.3.1.0(3,8)]pentadec-11-en-10-yl acetate | C41H58O8SSi | 详情 | 详情 | |
| (III) | 32040 | ethyl 2-phenoxyacetate | 2555-49-9 | C10H12O3 | 详情 | 详情 |
| (IV) | 13607 | dimethyl methylphosphonate | 756-79-6 | C3H9O3P | 详情 | 详情 |
| (V) | 32041 | dimethyl 2-oxo-3-phenoxypropylphosphonate | 40665-68-7 | C11H15O5P | 详情 | 详情 |
| (VI) | 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 | |
| (VII) | 32043 | (3aR,4R,5R,6aS)-2-oxo-4-[(E)-3-oxo-4-phenoxy-1-butenyl]hexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate | C30H26O6 | 详情 | 详情 | |
| (VIII) | 32044 | (3aR,4R,5R,6aS)-4-[(E,3R)-3-hydroxy-4-phenoxy-1-butenyl]-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate | C30H28O6 | 详情 | 详情 | |
| (IX) | 32045 | (3aR,4R,5R,6aS)-5-hydroxy-4-[(E,3R)-3-hydroxy-4-phenoxy-1-butenyl]hexahydro-2H-cyclopenta[b]furan-2-one | C17H20O5 | 详情 | 详情 | |
| (X) | 32046 | (3aR,4S,5R,6aS)-4-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2H-cyclopenta[b]furan-2-one | C29H40O7 | 详情 | 详情 | |
| (XI) | 32047 | (3aR,4S,5R,6aS)-4-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2H-cyclopenta[b]furan-2-ol | C29H42O7 | 详情 | 详情 | |
| (XII) | 51633 | methyl 4-pentynoate | C6H8O2 | 详情 | 详情 | |
| (XIII) | 32049 | methyl 6-hydroxy-7-[(1R,2S,3R,5S)-5-hydroxy-2-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-4-heptynoate | C35H50O9 | 详情 | 详情 | |
| (XIV) | 32050 | methyl 6-(acetoxy)-7-[(1R,2S,3R,5S)-5-(acetoxy)-2-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-4-heptynoate | C39H54O11 | 详情 | 详情 | |
| (XV) | 32051 | methyl 7-[(1R,2S,3R,5S)-5-(acetoxy)-2-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-4,5-heptadienoate | C37H52O9 | 详情 | 详情 | |
| (XVI) | 32052 | methyl 7-[(1R,2R,3R,5S)-5-(acetoxy)-3-hydroxy-2-[(E,3R)-3-hydroxy-4-phenoxy-1-butenyl]cyclopentyl]-4,5-heptadienoate | C25H32O7 | 详情 | 详情 | |
| (XVII) | 32053 | 7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3R)-3-hydroxy-4-phenoxy-1-butenyl]cyclopentyl]-4,5-heptadienoic acid | C22H28O6 | 详情 | 详情 |