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【结 构 式】 
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【分子编号】32046 【品名】(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 【CA登记号】 |
【 分 子 式 】C29H40O7 【 分 子 量 】500.6324 【元素组成】C 69.58% H 8.05% O 22.37% |
合成路线1
该中间体在本合成路线中的序号：(I)The reduction of L-pyroglutamic acid (I) with NaBH4 gives 5(S)-(hydroxymethyl)pyrrolidin-2-one (II), which is cyclized with benzaldehyde (III) by means of p-toluenesulfonic acid yielding the perhydropyrrolooxazolone (IV). The alkylation of (IV) with 2-cyclohexenyl bromide (V) and LDA in THF affords the corresponding cyclohexenyl derivative (VI), which is reduced with LiAlH4 in THF to give 1-benzyl-3(S)-(2-cyclohexenyl)-5(S)-(hydroxymethyl)pyrrolidine (VII). Elimination of the benzyl protecting group of (VII) with H2 over Pd/C yields the pyrrolidine (VIII), which is reprotected with benzyl chloroformate and K2CO3 to afford the carbamate (IX). The oxidation of the carbinol group of (IX) with Jones reagent or oxygen and platinum black gives the protected proline (X), which is finally deprotected with H2 over Pd/C providing the desired intermediate trans-4-cyclohexyl-L-proline (XI).
| 【1】 Thottathil, J.K.; et al.; Conversion of L-pyroglutamic acid to 4-alkyl substituted L-prolines. The synthesis of trans-4-cyclohexyl L-proline. J Org Chem 1986, 51, 16, 3140. |
| 【2】 Thottathil, J.K. (Bristol-Myers Squibb Co.); Process and intermediates for preparing trans-4-substd.-S-prolines. EP 0183390; US 4588819 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 | |
| (I) | 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 | |
| (II) | 38560 | (5S)-5-(hydroxymethyl)-2-pyrrolidinone | 17342-08-4 | C5H9NO2 | 详情 | 详情 |
| (III) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (IV) | 38561 | (3R,7aS)-3-phenyltetrahydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one | 103201-79-2 | C12H13NO2 | 详情 | 详情 |
| (V) | 30800 | 3-bromo-1-cyclohexene | 1521-51-3 | C6H9Br | 详情 | 详情 |
| (VI) | 38562 | (3R,6S,7aS)-6-[(1S)-2-cyclohexen-1-yl]-3-phenyltetrahydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one | C18H21NO2 | 详情 | 详情 | |
| (VII) | 38563 | [(2S,4S)-1-benzyl-4-[(1S)-2-cyclohexen-1-yl]pyrrolidinyl]methanol | C18H25NO | 详情 | 详情 | |
| (VIII) | 38564 | [(2S,4S)-4-cyclohexylpyrrolidinyl]methanol; trans-4-cyhexyl-L-Proline | 90657-55-9 | C11H21NO | 详情 | 详情 |
| (IX) | 38565 | benzyl (2S,4S)-4-cyclohexyl-2-(hydroxymethyl)-1-pyrrolidinecarboxylate | C19H27NO3 | 详情 | 详情 | |
| (X) | 38566 | (2S,4S)-1-[(benzyloxy)carbonyl]-4-cyclohexyl-2-pyrrolidinecarboxylic acid | C19H25NO4 | 详情 | 详情 | |
| (XI) | 38567 | (2S,4S)-4-cyclohexyl-2-pyrrolidinecarboxylic acid | C11H19NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)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3
该中间体在本合成路线中的序号：(X)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4
该中间体在本合成路线中的序号：(X)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 |