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【结 构 式】 
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【药物名称】Rolipram, ME-3167, ZK-62711, Adeo 【化学名称】4-[3-(Cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidinone 【CA登记号】61413-54-5 【 分 子 式 】C16H21NO3 【 分 子 量 】275.35067 |
【开发单位】Schering AG (Originator) 【药理作用】Cerebrovascular Diseases, Treatment of, Chronic Obstructive Pulmonary Diseases (COPD), Treatment of, NEUROLOGIC DRUGS, RESPIRATORY DRUGS, Phosphodiesterase IV Inhibitors |
合成路线1
The enantioselective synthesis of the (R)-enantiomer of rolipram, which is the most active, has been published: The reaction of 3-benzyloxy-4-methoxybenzaldehyde (I) with nitromethane by means of ammonium acetate in refluxing acetic acid gives 3-benzyloxy-4-methoxy-beta-nitrostyrene (II), which is condensed with the chiral oxazolidinone (R)-3-acetyl-4-benzyl-2-oxazolidinone (III) by means of sodium bis(trimethylsilyl)amine in THF yielding 4(R)-benzyl-3-[3(R)-(3-benzyloxy-4-methoxyphenyl)-4-nitrobutyryl]-2-oxa zolidinone (IV). Hydrogenation of (IV) with H2 over Raney Ni in ethanol - ethyl acetate affords 4(R)-(3-hydroxy-4-methoxyphenyl)-2-pyrrolidinone (VI) through the intermediate benzyl ether (V). Finally, compound (VI) is etherified with cyclopentyl bromide (VII) by means of NaH in refluxing THF.
| 【1】 Schmiechen, R.; Mulzer, J.; Zuhse, R.; Enantioselective synthesis of the antidepressant rolipram by Michael addition to a nitroolefin. Angew Chem. Int Ed Engl 1992, 31, 7, 870. |
| 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) | 10966 | 3-(Benzyloxy)-4-methoxybenzaldehyde; 3-Benzyloxy-4-methoxybenzaldehyde | 6346-05-0 | C15H14O3 | 详情 | 详情 |
| (II) | 10967 | trans-3-Benzyloxy-4-methoxy-beta-nitrostyrene; Benzyl 2-methoxy-5-[(E)-2-nitroethenyl]phenyl ether; 2-(Benzyloxy)-1-methoxy-4-[(E)-2-nitroethenyl]benzene | 63909-29-5 | C16H15NO4 | 详情 | 详情 |
| (III) | 10968 | (4R)-3-Acetyl-4-benzyl-1,3-oxazolidin-2-one; (R)-(-)-3-Acetyl-4-benzyl-2-oxazolidinone | 184363-65-3 | C12H13NO3 | 详情 | 详情 |
| (IV) | 10969 | (4R)-4-Benzyl-3-[(3S)-3-[3-(benzyloxy)-4-methoxyphenyl]-4-nitrobutanoyl]-1,3-oxazolidin-2-one | C28H28N2O7 | 详情 | 详情 | |
| (V) | 10970 | (4R)-4-[3-(Benzyloxy)-4-methoxyphenyl]-2-pyrrolidinone | C18H19NO3 | 详情 | 详情 | |
| (VI) | 10971 | (4R)-4-(3-Hydroxy-4-methoxyphenyl)tetrahydro-2H-pyrrol-2-one | C11H13NO3 | 详情 | 详情 | |
| (VII) | 10972 | 1-Bromocyclopentane; Cyclopentyl bromide | 137-43-9 | C5H9Br | 详情 | 详情 |
合成路线2
A new synthesis for (-)-(R)-rolipram has been described: The cyclization of (S)-2-hydroxy-1-phenylethylamine (I) with 3-formylpropionic acid (II), or the reductocyclization of N-[2-hydroxy-1(S)-phenylethyl]succinimide (III) with NaBH4, yields the bicyclic amine (IV), which is treated with benzyl chloroformate and phenylselenyl bromide to afford the bicyclic ketoester (V). The stereocontrolled arylation of (V) with 4-bromo-2-(cyclopentyloxy)anisole by means of tert-butyllithium in THF gives the arylated ketoester (VII), which is decarboxylated with ammonium formate and Pd/C in methanol to the bicyclic pyrrolidone (VIII). The ring cleavage of (VIII) with Ca metal in liquid ammonia affords the hydroxypyrrolidone (IX), which is finally reduced with sodium cyanoborohydride in THF-methanol.
| 【1】 Meyers, A.I.; Snyder, L.; The synthesis of aracemic 4-substituted pyrrolidinones and 3-substituted pyrrolidines. An asymmetric synthesis of (-)-rolipram. J Org Chem 1993, 58, 1, 36. |
| 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) | 10973 | (2S)-2-Amino-2-phenyl-1-ethanol; (S)-2-Hydroxy-1-phenylethylamine; (S)-(+)-2-Phenylglycinol; (S)-2-Amino-2-phenyl-1-ethanol | 20989-17-7 | C8H11NO | 详情 | 详情 |
| (II) | 10974 | Succinic semialdehyde; 4-Oxobutyric acid | 692-29-5 | C4H6O3 | 详情 | 详情 |
| (III) | 10975 | 1-[(1S)-2-Hydroxy-1-phenylethyl]dihydro-1H-pyrrole-2,5-dione | C12H13NO3 | 详情 | 详情 | |
| (IV) | 10976 | (3S,7aR)-3-Phenyltetrahydropyrrolo[2,1-b][1,3]oxazol-5(6H)-one | C12H13NO2 | 详情 | 详情 | |
| (V) | 10977 | benzyl (3S,7aR)-5-oxo-3-phenyl-2,3,5,7a-tetrahydropyrrolo[2,1-b][1,3]oxazole-6-carboxylate | C20H17NO4 | 详情 | 详情 | |
| (VI) | 10978 | 4-Bromo-2-(cyclopentyloxy)-1-methoxybenzene; 4-Bromo-2-(cyclopentyloxy)phenyl methyl ether | C12H15BrO2 | 详情 | 详情 | |
| (VII) | 10979 | benzyl (3S,6S,7R,7aR)-7-[3-(cyclopentyloxy)-4-methoxyphenyl]-5-oxo-3-phenylhexahydropyrrolo[2,1-b][1,3]oxazole-6-carboxylate | C32H33NO6 | 详情 | 详情 | |
| (VIII) | 10980 | (3S,7R,7aR)-7-[3-(Cyclopentyloxy)-4-methoxyphenyl]-3-phenyltetrahydropyrrolo[2,1-b][1,3]oxazol-5(6H)-one | C24H27NO4 | 详情 | 详情 | |
| (IX) | 10981 | (4S,5S)-4-[3-(Cyclopentyloxy)-4-methoxyphenyl]-5-hydroxytetrahydro-2H-pyrrol-2-one | C16H21NO4 | 详情 | 详情 |
合成路线3
This compound can be obtained by three related ways: 1) The condensation of 3-cyclopentyloxy-4-methoxybenzaldehyde (I) with diethyl malonate (II) by means of piperidine in refluxing acetic acid gives diethyl 3-cyclopentyloxy-4-methoxybenzylidenemalonate (III), which is treated with nitromethane and tetramethylguanidine (TMG) yielding diethyl 2-[1-(3-cyclopentyloxy-4-methoxyphenyl)-2-nitroethyl]malonate (IV). The reductocyclization of (IV) with H2 over Raney Ni in hot methanol gives ethyl 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylat (V). Finally, this compound is hydrolyzed and decarboxylated. 2) The reaction of malonate (III) with KCN in ethanol at 60 C gives ethyl 3-cyano-3-(3-cyclopentyloxy-4-methoxyphenyl)propionate (VI), which is reduced with H2 over PtO2 in acetic acid yielding ethyl 4-amino-3-(3-cyclopentyloxy-4-methoxyphenyl)butanoate (VII). Finally, this compound is hydrolyzed and cyclized. 3) The reaction of malonate (III) with KNC in refluxing ethanol gives 3-cyano-3-(3-cyclopentyloxy-4-methoxy)propanoic acid (VIII), which is reduced with H2 over PtO2 as before yielding 4-amino-3-(3-cyclopentyloxy-4-methoxyphenyl)butanoic acid (IX). Finally, this compound is cyclized.
| 【1】 Huth, A.; Schmiechen, R.; Kehr, W.; Palenschat, D.; Paschelke, G.; Wachtel, H. (Schering AG); 4-(Polyalkoxyphenyl)-2-pyrrolidones (II).. BE 846335; ES 451518; FR 2324299; GB 1563398; US 4153713 . |
| 【2】 Crossland, J.; Prous, J.; Castaner, J.; ROLIPRAM < Rec INN; USAN >. Drugs Fut 1988, 13, 1, 38. |
| 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) | 16510 | 3-(cyclopentyloxy)-4-methoxybenzaldehyde | C13H16O3 | 详情 | 详情 | |
| (II) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (III) | 21586 | diethyl 2-[3-(cyclopentyloxy)-4-methoxybenzylidene]malonate | C20H26O6 | 详情 | 详情 | |
| (IV) | 21587 | diethyl 2-[1-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-nitroethyl]malonate | C21H29NO8 | 详情 | 详情 | |
| (V) | 21588 | ethyl 4-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-oxo-3-pyrrolidinecarboxylate | C19H25NO5 | 详情 | 详情 | |
| (VI) | 21589 | ethyl 3-cyano-3-[3-(cyclopentyloxy)-4-methoxyphenyl]propanoate | C18H23NO4 | 详情 | 详情 | |
| (VII) | 21590 | ethyl 4-amino-3-[3-(cyclopentyloxy)-4-methoxyphenyl]butanoate | C18H27NO4 | 详情 | 详情 | |
| (VIII) | 21591 | 3-cyano-3-[3-(cyclopentyloxy)-4-methoxyphenyl]propionic acid | C16H19NO4 | 详情 | 详情 | |
| (IX) | 21592 | 4-amino-3-[3-(cyclopentyloxy)-4-methoxyphenyl]butyric acid | C16H23NO4 | 详情 | 详情 |