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【结 构 式】 
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【分子编号】13604 【品名】2-(3-Methoxyphenethyl)phenol 【CA登记号】 |
【 分 子 式 】C15H16O2 【 分 子 量 】228.29084 【元素组成】C 78.92% H 7.06% O 14.02% |
合成路线1
该中间体在本合成路线中的序号：(II)The reaction of 2-hydroxy-3'-methoxybibenzyl (I) with epichlorohydrin (II) by means of NaH in DMF gives 2-(2,3-epoxypropoxy)-3'-methoxybibenzyl (III), which by reaction with dimethylamine in refluxing THF yields 2-[3-(dimethylamino)-2-hydroxypropoxy]-3'-methoxybibenzyl (IV). Finally, this compound is treated with succinic anhydride (V) in refluxing THF and with HCl in acetone.
| 【1】 Kikumoto, R.; Fukami, H.; Hara, H.; Ninomiya, K.; Sugano, M. (Mitsubishi Chemical Corp.); Pharmaceutically active (3-aminopropoxy)-bibenzyl derivs. EP 0072942 . |
| 【2】 Prous, J.; Castaner, J.; Sarpogrelate Hydrochloride. Drugs Fut 1992, 17, 12, 1093. |
| 【3】 Osakabe, M.; Fukami, H.; Sugano, M.; Kikumoto, R.; Ninomiya, K.; Tamao, Y.; Hara, H.; Syntheses and platelet aggregation inhibitory and antithrombotic properties of [2-[(omega-aminoalkoxy)phenyl]ethyl]benzenes. J Med Chem 1990, 33, 6, 1818. |
| 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) | 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 |
| (II) | 13604 | 2-(3-Methoxyphenethyl)phenol | C15H16O2 | 详情 | 详情 | |
| (III) | 13605 | 2-(3-Methoxyphenethyl)phenyl 2-oxiranylmethyl ether; 2-[[2-(3-Methoxyphenethyl)phenoxy]methyl]oxirane | C18H20O3 | 详情 | 详情 | |
| (IV) | 13606 | 1-(Dimethylamino)-3-[2-(3-methoxyphenethyl)phenoxy]-2-propanol | C20H27NO3 | 详情 | 详情 | |
| (V) | 11291 | Dihydro-2,5-furandione; Succinic anhydride | 108-30-5 | C4H4O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)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3
该中间体在本合成路线中的序号：(VIII)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4
该中间体在本合成路线中的序号：(VIII)Treatment of salicyl alcohol (I) with benzyl bromide (II) in DMF in the presence of KOtBu affords benzyloxybenzyl alcohol (III), which is converted into its chloride form (IV) by means of SOCl2 in THF. Reaction of (IV) with PPh3 in refluxing toluene gives triphenyl phosphonium chloride derivative (V), which is then subjected to a Wittig reaction with aldehyde (VI) to yield olefine (VII). Catalytic hydrogenolysis of (VII) over Pd/C provides phenol derivative (VIII), which is then alkylated by reaction with tosylate (XVI) and KOtBu in dimethylacetamide to yield (XVII). Finally, ethoxycarbonyl derivative (XVII) is reduced by means of LiAlH4 in THF and converted into its hydrochloride form by treatment with HCl in dioxane. Intermediate (XVI) can be prepared as follows: Protection of 2(S)-pyrrolidinemethanol (IX) by reaction with ethyl chloroformate in the presence of Et3N in dichloromethane affords carbamate (XI), which is tosylated by means of Ts2O and Et3N in dichloromethane to yield (XII). One carbon elongation of (XII) by reaction with NaCN in DMF provides (XIII), which is then converted into ester (XIV) by means of H2SO4 in EtOH. Reduction of ester (XIV) with LiAlH4 in THF gives alcohol (XV), which is finally tosylated by reaction with Ts2O and Et3N in dichloromethane.
| 【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 . |
| 【2】 Goto, R.; Hayakawa, M.; Ito, R.; Ogawa, T.; Sugidachi, A.; Tanaka, N.; Asai, F.; Fujimoto, K.; [2-(omega-Phenylalkyl)phenoxy]alkylamines II: Synthesis and selective serotonin-2 receptor binding. Chem Pharm Bull 2000, 48, 2, 245. |
| 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 | |
| (IX) | 21347 | (2S)pyrrolidinylmethanol | 23356-96-9 | C5H11NO | 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) | 42346 | ethyl (2S)-2-(hydroxymethyl)-1-pyrrolidinecarboxylate | C8H15NO3 | 详情 | 详情 | |
| (XII) | 42347 | ethyl (2S)-2-([[(4-methylphenyl)sulfonyl]oxy]methyl)-1-pyrrolidinecarboxylate | C15H21NO5S | 详情 | 详情 | |
| (XIII) | 42348 | ethyl (2S)-2-(cyanomethyl)-1-pyrrolidinecarboxylate | C9H14N2O2 | 详情 | 详情 | |
| (XIV) | 42349 | ethyl (2S)-2-(2-ethoxy-2-oxoethyl)-1-pyrrolidinecarboxylate | C11H19NO4 | 详情 | 详情 | |
| (XV) | 42350 | ethyl (2S)-2-(2-hydroxyethyl)-1-pyrrolidinecarboxylate | C9H17NO3 | 详情 | 详情 | |
| (XVI) | 42351 | ethyl (2S)-2-(2-[[(4-methylphenyl)sulfonyl]oxy]ethyl)-1-pyrrolidinecarboxylate | C16H23NO5S | 详情 | 详情 | |
| (XVII) | 42352 | ethyl (2S)-2-[2-[2-(3-methoxyphenethyl)phenoxy]ethyl]-1-pyrrolidinecarboxylate | C24H31NO4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VIII)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 then 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 then 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6
该中间体在本合成路线中的序号：(VIII)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 |