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【结 构 式】 
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【分子编号】47641 【品名】(2S,4R)-4-hydroxy-2-[2-[2-(3-methoxyphenethyl)phenoxy]ethyl]-1-pyrrolidinecarboxylic acid 【CA登记号】 |
【 分 子 式 】C22H27NO5 【 分 子 量 】385.46012 【元素组成】C 68.55% H 7.06% N 3.63% O 20.75% |
合成路线1
该中间体在本合成路线中的序号：(XVIII)Synthesis of EN 212779: Deprotection and esterification of pyrrolidine (IX) by first treatment with HCl (gas) in EtOH followed by reaction with ethyl chloroformate (X) and Et3N in acetone/H2O yields carbamate (XI), which is then reduced with LiBH4 in THF to give carbinol (XII). Conversion of alcohol (XII) into cyano derivative (XIII) is then accomplished by first tosylation with p-toluenesulfonic anhydride (Ts2O) and Et3N in dichloromethane followed by reaction with NaCN in DMF. Acidic ethanolysis of nitrile (XIII) by means of HCl in EtOH furnishes ethyl ester (XIV), which is reduced with LiAlH4 in THF to provide ethanol derivative (XV). Treatment of alcohol (XV) with Ts2O and Et3N in dichloromethane affords tosylate (XVI), which is converted into derivative (XVII) by condensation with intermediate (VIII) by means of KOtBu in dimethylacetamide (DMA). Debenzylation of (XVII) by hydrogenation over Pd/C in EtOH yields alcohol (XVIII), which is finally reduced with LiAlH4 in THF and hydrolyzed with HCl in dioxane to give the desired compound. Alternatively, the final product can be obtained by condensation of bromo derivative (XIX) with intermediate (VIII) by means of KOtBu in dimethylacetamide (DMA), furnishing compound (XX), which is finally reduced with LiAlH4 in THF and hydrolyzed with HCl.
| 【3】 Fujimoto, K.; Tanaka, N.; Asai, F.; Ito, T.; Koike, H. (Sankyo Co., Ltd.); Phenoxyalkylamines, -pyrrolidines and -piperidines for the treatment and prevention of circulatory diseases and psychosis. EP 0600717; JP 1994234736; JP 1994306025; US 5556864 . |
| 【1】 Ogawa, T.; Sugidachi, A.; Goto, R.; Asai, T.; Tanaka, S.; Ito, R.; Hayakawa, M.; Fujimoto, K.; 2-(omega-Phenylalkyl)phenoxy)alkylamines III: Synthesis and selective serotonin-2 receptor binding (2). Chem Pharm Bull 2000, 48, 11, 1729. |
| 【2】 Tanaka, N.; et al.; Antiplatelets with 5-HT2 receptor antagonistic action - Synthesis and structure-activity relationships of [2-(omega-phenylalkyl)phenoxy]alkylamines. 18th Symp Med Chem (Nov 25 1998, Kyoto) 1998, Abst 2-P-01. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 13604 | 2-(3-Methoxyphenethyl)phenol | C15H16O2 | 详情 | 详情 | |
| (IX) | 19059 | (2R,4S)-4-(benzyloxy)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid | 54631-81-1 | C17H23NO5 | 详情 | 详情 |
| (X) | 11229 | 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate | 541-41-3 | C3H5ClO2 | 详情 | 详情 |
| (XI) | 47634 | diethyl (2S,4R)-4-(benzyloxy)-1,2-pyrrolidinedicarboxylate | C17H23NO5 | 详情 | 详情 | |
| (XII) | 47635 | ethyl (2S,4R)-4-(benzyloxy)-2-(hydroxymethyl)-1-pyrrolidinecarboxylate | C15H21NO4 | 详情 | 详情 | |
| (XIII) | 47636 | ethyl (2R,4R)-4-(benzyloxy)-2-(cyanomethyl)-1-pyrrolidinecarboxylate | C16H20N2O3 | 详情 | 详情 | |
| (XIV) | 47637 | ethyl (2S,4R)-4-(benzyloxy)-2-(2-ethoxy-2-oxoethyl)-1-pyrrolidinecarboxylate | C18H25NO5 | 详情 | 详情 | |
| (XV) | 47638 | ethyl (2R,4R)-4-(benzyloxy)-2-(2-hydroxyethyl)-1-pyrrolidinecarboxylate | C16H23NO4 | 详情 | 详情 | |
| (XVI) | 47639 | ethyl (2R,4R)-4-(benzyloxy)-2-(2-[[(4-methylphenyl)sulfonyl]oxy]ethyl)-1-pyrrolidinecarboxylate | C23H29NO6S | 详情 | 详情 | |
| (XVII) | 47640 | ethyl (2S,4R)-4-(benzyloxy)-2-[2-[2-(3-methoxyphenethyl)phenoxy]ethyl]-1-pyrrolidinecarboxylate | C31H37NO5 | 详情 | 详情 | |
| (XVIII) | 47641 | (2S,4R)-4-hydroxy-2-[2-[2-(3-methoxyphenethyl)phenoxy]ethyl]-1-pyrrolidinecarboxylic acid | C22H27NO5 | 详情 | 详情 | |
| (XIX) | 47643 | octyl (2S,4R)-2-(2-bromoethyl)-4-[[(dimethylamino)carbonyl]oxy]-1-pyrrolidinecarboxylate | C18H33BrN2O4 | 详情 | 详情 | |
| (XX) | 47644 | octyl (2R,4R)-4-[[(dimethylamino)carbonyl]oxy]-2-[2-[2-(3-methoxyphenethyl)phenoxy]ethyl]-1-pyrrolidinecarboxylate | C33H48N2O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVIII)Synthesis of EN 296245: Deprotection and esterification of pyrrolidine (IX) by first treatment with HCl (gas) in EtOH followed by reaction with ethyl chloroformate (X) and Et3N in acetone/H2O, yields carbamate (XI), which is then reduced with LiBH4 in THF to give derivative (XII). Conversion of alcohol (XII) into cyano derivative (XIII) is then accomplished by first tosylation with p-toluenesulfonic anhydride (Ts2O) and Et3N in dichloromethane, followed by reaction with NaCN in DMF. Acidic ethanolysis of nitrile (XIII) by means of HCl in EtOH furnishes ethyl ester (XIV), which is reduced with LiAlH4 in THF to provide derivative (XV). Treatment of alcohol (XV) with Ts2O and Et3N in dichloromethane affords tosylate (XVI), which is converted into derivative (XVII) by condensation with intermediate (VIII) by means of KOtBu in dimethylacetamide (DMA). Debenzylation of (XVII) by hydrogenation over Pd/C in EtOH yields alcohol (XVIII), which is converted into alcohol (XIX) by treatment with LiAlH4 in THF, followed by hydrolysis with HCl in dioxane. Alternatively, derivative (XIX) can be obtained by condensation of bromo derivative (XX) with intermediate (VIII) by means of KOtBu in dimethylacetamide (DMA) to furnish compound (XXI), followed by reduction with LiAlH4 in THF and hydrolysis with HCl. Finally, esterification of (XIX) with lauric anhydride (XXII) by means of DMAP in pyridine yields the target product.
| 【1】 Ogawa, T.; Sugidachi, A.; Goto, R.; Asai, T.; Tanaka, S.; Ito, R.; Hayakawa, M.; Fujimoto, K.; 2-(omega-Phenylalkyl)phenoxy)alkylamines III: Synthesis and selective serotonin-2 receptor binding (2). Chem Pharm Bull 2000, 48, 11, 1729. |
| 【2】 Tanaka, N.; et al.; Antiplatelets with 5-HT2 receptor antagonistic action - Synthesis and structure-activity relationships of [2-(omega-phenylalkyl)phenoxy]alkylamines. 18th Symp Med Chem (Nov 25 1998, Kyoto) 1998, Abst 2-P-01. |
| 【4】 Asai, F.; Fujimoto, K. (Sankyo Co., Ltd.); Compsn. containing diarylalkane deriv. as the active ingredient for treating or preventing pancreatitis. JP 1998212232; WO 9823271 . |
| 【3】 Fujimoto, K.; Tanaka, N.; Asai, F.; Ito, T.; Koike, H. (Sankyo Co., Ltd.); Phenoxyalkylamines, -pyrrolidines and -piperidines for the treatment and prevention of circulatory diseases and psychosis. EP 0600717; JP 1994234736; JP 1994306025; US 5556864 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 13604 | 2-(3-Methoxyphenethyl)phenol | C15H16O2 | 详情 | 详情 | |
| (IX) | 19059 | (2R,4S)-4-(benzyloxy)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid | 54631-81-1 | C17H23NO5 | 详情 | 详情 |
| (X) | 11229 | 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate | 541-41-3 | C3H5ClO2 | 详情 | 详情 |
| (XI) | 47634 | diethyl (2S,4R)-4-(benzyloxy)-1,2-pyrrolidinedicarboxylate | C17H23NO5 | 详情 | 详情 | |
| (XII) | 47635 | ethyl (2S,4R)-4-(benzyloxy)-2-(hydroxymethyl)-1-pyrrolidinecarboxylate | C15H21NO4 | 详情 | 详情 | |
| (XIII) | 47636 | ethyl (2R,4R)-4-(benzyloxy)-2-(cyanomethyl)-1-pyrrolidinecarboxylate | C16H20N2O3 | 详情 | 详情 | |
| (XIV) | 47637 | ethyl (2S,4R)-4-(benzyloxy)-2-(2-ethoxy-2-oxoethyl)-1-pyrrolidinecarboxylate | C18H25NO5 | 详情 | 详情 | |
| (XV) | 47638 | ethyl (2R,4R)-4-(benzyloxy)-2-(2-hydroxyethyl)-1-pyrrolidinecarboxylate | C16H23NO4 | 详情 | 详情 | |
| (XVI) | 47639 | ethyl (2R,4R)-4-(benzyloxy)-2-(2-[[(4-methylphenyl)sulfonyl]oxy]ethyl)-1-pyrrolidinecarboxylate | C23H29NO6S | 详情 | 详情 | |
| (XVII) | 47640 | ethyl (2S,4R)-4-(benzyloxy)-2-[2-[2-(3-methoxyphenethyl)phenoxy]ethyl]-1-pyrrolidinecarboxylate | C31H37NO5 | 详情 | 详情 | |
| (XVIII) | 47641 | (2S,4R)-4-hydroxy-2-[2-[2-(3-methoxyphenethyl)phenoxy]ethyl]-1-pyrrolidinecarboxylic acid | C22H27NO5 | 详情 | 详情 | |
| (XIX) | 47642 | (3R,5S)-5-[2-[2-(3-methoxyphenethyl)phenoxy]ethyl]-1-methyl-3-pyrrolidinol | C22H29NO3 | 详情 | 详情 | |
| (XX) | 47643 | octyl (2S,4R)-2-(2-bromoethyl)-4-[[(dimethylamino)carbonyl]oxy]-1-pyrrolidinecarboxylate | C18H33BrN2O4 | 详情 | 详情 | |
| (XXI) | 47644 | octyl (2R,4R)-4-[[(dimethylamino)carbonyl]oxy]-2-[2-[2-(3-methoxyphenethyl)phenoxy]ethyl]-1-pyrrolidinecarboxylate | C33H48N2O6 | 详情 | 详情 | |
| (XXII) | 47645 | dodecanoic anhydride | C24H46O3 | 详情 | 详情 |