|
【结 构 式】 
|
【分子编号】32042 【品名】(3aR,4R,5R,6aS)-4-formyl-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate 【CA登记号】 |
【 分 子 式 】C21H18O5 【 分 子 量 】350.37092 【元素组成】C 71.99% H 5.18% O 22.83% |
合成路线1
该中间体在本合成路线中的序号：(IV)The condensation of methyl phenoxyacetate (I) with dimethyl methylphosphonate (II) by means of butyllithium in THF gives dimethyl 2-oxo-3-phenoxypropylphosphanate (III), which by a Wittig condensation with 2-[3alpha-(p-phenylbenzoyloxy)-5alpha-hydroxy-2beta-formylcyclopentan-1alpha-yl]acetic acid gamma-lactone (IV) by means of butyllithium in hexane yields the keto lactone (V). This compound is reduced with zinc borohydride in dimethoxyethane affording the hydroxylactone (VI), which is hydrolyzed with K2CO3 in methanol giving the dihydroxylactone (VII). The hydroxyl groups of (VII) are protected with dihydropyrane as usual giving (VIII), which is reduced with diisobutylaluminitim hydride in toluene yielding the hemiacetal (IX).
| 【1】 Castaner, J.; Wescott, A.L.; Sulprostone. Drugs Fut 1978, 3, 1, 59. |
| 【2】 Beil, W.; Hoeppener, A.; Wolff, H.J.; Beil, H.; Substituted 16,17,18,19,20-pentanorprostaglandins. DE 2355540; ES 433046; ES 433047; FR 2205335; GB 1456512; JP 49093342; JP 52053841 . |
| 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) | 39696 | methyl 2-phenoxyacetate | 2065-23-8 | C9H10O3 | 详情 | 详情 |
| (II) | 39697 | dimethyl methylphosphonite | 20278-51-7 | C3H9O2P | 详情 | 详情 |
| (III) | 39698 | dimethyl 2-oxo-3-phenoxypropylphosphonite | C11H15O4P | 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) | 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 | |
| (VI) | 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 | |
| (VII) | 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 | |
| (VIII) | 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 | |
| (IX) | 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 |
合成路线2
该中间体在本合成路线中的序号：(VI)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3
该中间体在本合成路线中的序号：(II)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4
该中间体在本合成路线中的序号：(VII)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5
该中间体在本合成路线中的序号：(IV)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 |
合成路线6
该中间体在本合成路线中的序号：(VI)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 |
合成路线7
该中间体在本合成路线中的序号：(XV)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 |