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【结 构 式】 
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【药物名称】R-96544 【化学名称】2(R)-[2-[2-[2-(3-Methoxyphenyl)ethyl]phenoxy]ethyl]-1-methylpyrrolidin-4(R)-ol hydrochloride 【CA登记号】167144-79-8 【 分 子 式 】C22H30ClNO3 【 分 子 量 】391.9423 |
【开发单位】Sankyo (Originator) 【药理作用】Antiplatelet Therapy, CARDIOVASCULAR DRUGS, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Peripheral Vascular Disease, Treatment of, Treatment of Peripheral Obstructive Vascular Disease, 5-HT2A Antagonists |
合成路线1
Synthesis of intermediate (VIII): Condensation of salicyl alcohol (I) with benzyl bromide (II) by means of KOtBu in DMF gives 2-benzyloxybenzyl alcohol (III), which is converted into chloride (IV) by reaction with SOCl2 in THF. Treatment of derivative (IV) with PPh3 in refluxing toluene furnishes triphenylphosphonium chloride (V), which is condensed with aldehyde (VI) by means of DBU in acetonitrile to afford benzyloxystilbene derivative (VII). Finally, intermediate (VIII) is obtained by hydrogenation of (VII) over Pd/C in EtOH.
| 【1】 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 |
|---|---|---|---|---|---|---|
| (I) | 42341 | 2-(hydroxymethyl)phenol | 90-01-7 | C7H8O2 | 详情 | 详情 |
| (II) | 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 |
| (III) | 42342 | [2-(benzyloxy)phenyl]methanol | C14H14O2 | 详情 | 详情 | |
| (IV) | 42343 | benzyl 2-(chloromethyl)phenyl ether; 1-(benzyloxy)-2-(chloromethyl)benzene | C14H13ClO | 详情 | 详情 | |
| (V) | 42344 | [2-(benzyloxy)benzyl](triphenyl)phosphonium chloride | C32H28ClOP | 详情 | 详情 | |
| (VI) | 20589 | 3-methoxybenzaldehyde; m-Anisaldehyde | 591-31-1 | C8H8O2 | 详情 | 详情 |
| (VII) | 42345 | 1-(benzyloxy)-2-[(E)-2-(3-methoxyphenyl)ethenyl]benzene; benzyl 2-[(E)-2-(3-methoxyphenyl)ethenyl]phenyl ether | C22H20O2 | 详情 | 详情 | |
| (VIII) | 13604 | 2-(3-Methoxyphenethyl)phenol | C15H16O2 | 详情 | 详情 |
合成路线2
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 |