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【结 构 式】 
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【分子编号】40292 【品名】2-[4-(2-azidoethoxy)-3-methoxyphenyl]-N-[3-(3,4-dimethylphenyl)propyl]acetamide 【CA登记号】 |
【 分 子 式 】C22H28N4O3 【 分 子 量 】396.48948 【元素组成】C 66.65% H 7.12% N 14.13% O 12.11% |
合成路线1
该中间体在本合成路线中的序号：(XII)The condensation of 3,4-dimethylbenzyl chloride (I) with diethyl malonate (II) by means of sodium ethoxide ethanol gives the diethyl 2-(3,4-dimethylbenzyl)malonate (III), which by treatment with aqueous refluxing NaOH and the with refluxing aqueous sulfuric acid yields 3-(3,4-dimethylphenyl)propionic acid (IV). The reaction of (IV) with refluxing SOCl2 affords the corresponding acyl chloride (V), which is treated with ammonia providing the amide (VI). The reduction of (VI) with LiAlH4 in refluxing THF gives 3-(3,4-dimethylphenyl)propylamine (VII), which by condensation with 2-(4-hydroxy-3-methoxyphenyl)acetic acid (VIII) by heating at 150 C yields the corresponding amide (IX). The alkylation of the phenolic group of (IX) with 1,2-dibromoethane (X) and NaH in refluxing THF affords the 2-bromoethoxy derivative (XI), which by treatment with NaN3 and Bu4NBr in refluxing benzene gives the 2-azidoethoxy derivative (XII). Finally, this compound is reduced with H2 over Pd/C in ethyl acetate to afford the target compound.
| 【1】 Lee, J.-C.; Lee, K.-S.; Han, M.-S.; Jung, Y.S.; Choi, J.; Park, N.-S.; Ha, D.-C.; Seong, C.-M.; Lim, H.-J.; Choi, S.W.; Synthesis of homovanillic amide derivatives and their analgesic activity. Arch Pharmacal Res 1996, 19, 3, 246. |
| 【2】 Lim, H.-J.; Park, N.-S.; Choi, J.-K.; Ha, D.-C.; Kim, H.-S.; Lee, B.-Y.; N-Aralkylated 4-(2-aminoethoxy)phenylacetamide derivatives as potent analgesic and antiinflammatory agents. Korean Journal of Medicinal Chemistry 1991, 1, 1, 36. |
| 【3】 Lee, K.S.; Choi, J.K.; Hong, M.S.; Kim, H.S.; Lim, H.J.; Ha, D.C.; Park, N.S. (Korea Research Institute of Chemical Technology); Novel phenylacetamide derivs. and processes for the preparation thereof. EP 0525360; US 5242944 . |
| 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) | 40283 | 4-(chloromethyl)-1,2-dimethylbenzene | 102-46-5 | C9H11Cl | 详情 | 详情 |
| (II) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (III) | 40284 | diethyl 2-(3,4-dimethylbenzyl)malonate | C16H22O4 | 详情 | 详情 | |
| (IV) | 40285 | 3-(3,4-dimethylphenyl)propionic acid | C11H14O2 | 详情 | 详情 | |
| (V) | 40286 | 3-(3,4-dimethylphenyl)propanoyl chloride | C11H13ClO | 详情 | 详情 | |
| (VI) | 40287 | 3-(3,4-dimethylphenyl)propanamide | C11H15NO | 详情 | 详情 | |
| (VII) | 40288 | 3-(3,4-dimethylphenyl)-1-propanamine; 3-(3,4-dimethylphenyl)propylamine | C11H17N | 详情 | 详情 | |
| (VIII) | 40289 | 4-Hydroxy-3-methoxyphenylacetic acid; Homovanillic acid; 2-(4-hydroxy-3-methoxyphenyl)acetic acid | 306-08-1 | C9H10O4 | 详情 | 详情 |
| (IX) | 40290 | N-[3-(3,4-dimethylphenyl)propyl]-2-(4-hydroxy-3-methoxyphenyl)acetamide | C20H25NO3 | 详情 | 详情 | |
| (X) | 10252 | 1,2-Dibromoethane; Ethylene dibromide | 106-93-4 | C2H4Br2 | 详情 | 详情 |
| (XI) | 40291 | 2-[4-(2-bromoethoxy)-3-methoxyphenyl]-N-[3-(3,4-dimethylphenyl)propyl]acetamide | C22H28BrNO3 | 详情 | 详情 | |
| (XII) | 40292 | 2-[4-(2-azidoethoxy)-3-methoxyphenyl]-N-[3-(3,4-dimethylphenyl)propyl]acetamide | C22H28N4O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)The 2-chloroethylation of ethyl homovanillate (I) with 1-bromo-2-chloroethane and K2CO3 in acetone gives ethyl 2-[4-(2-chloroethoxy)-3-methoxyphenyl]acetate (II), which is treated with sodium azide in toluene followed by hydrolysis with aqueous NaOH in MeOH, yielding 2-[4-(2-azidoethoxy)-3-methoxyphenyl]acetic acid (IV). The reaction of (IV) with SOCl2 and Et3N affords the acyl chloride (V). The reaction of 3-iodo-o-xylene (VI) and acrylonitrile under the Heck reaction conditions [Pd(OAc)2, tri-o-tolylphosphine and Et3N in MeCN] gives an isomeric mixture of 3-(3,4-dimethyl-phenyl)-2-propenenitrile (VII), which is hydrogenated with Pd/C followed by Raney-Ni to provide 3-(3,4-dimethylphenyl)propylamine (IX). The coupling reaction between the acyl chloride (V) and amine (IX) with Et3N in CH2Cl2 gives the amide (X). Finally, Pd/C catalyzed hydrogenation of this compound affords 2-[4-(2-aminoethoxy)-3-methoxyphenyl]-N-[3-(3,4-dimethylphenyl)propyl]acetamide.
| 【1】 Lee, C.W.; Park, N.S.; Seong, C.M.; Jung, Y.S.; Baek, G.H.; Cho, S.J.; Synthesis of 3-arylpropylamine derivatives from aryl halides using Heck reaction. Bull Korean Chem Soc 1999, 20, 232-236. |
| 【2】 Park, N.S.; Kim, W.B.; Kim, S.H.; Seong, C.M.; Jung, Y.S.; DA-5018. Drugs Fut 2000, 25, 11, 1131. |
| 【3】 Lee, K.S.; Choi, J.K.; Hong, M.S.; Kim, H.S.; Lim, H.J.; Ha, D.C.; Park, N.S. (Korea Research Institute of Chemical Technology); Novel phenylacetamide derivs. and processes for the preparation thereof. EP 0525360; US 5242944 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10847 | Acrylonitrile | 107-13-1 | C3H3N | 详情 | 详情 | |
| (I) | 41693 | ethyl 2-(4-hydroxy-3-methoxyphenyl)acetate | C11H14O4 | 详情 | 详情 | |
| (II) | 41694 | ethyl 2-[4-(2-chloroethoxy)-3-methoxyphenyl]acetate | C13H17ClO4 | 详情 | 详情 | |
| (III) | 41695 | ethyl 2-[4-(2-azidoethoxy)-3-methoxyphenyl]acetate | C13H17N3O4 | 详情 | 详情 | |
| (IV) | 41696 | 2-[4-(2-azidoethoxy)-3-methoxyphenyl]acetic acid | C11H13N3O4 | 详情 | 详情 | |
| (V) | 41697 | 2-[4-(2-azidoethoxy)-3-methoxyphenyl]acetyl chloride | C11H12ClN3O3 | 详情 | 详情 | |
| (VI) | 41698 | 4-iodo-1,2-dimethylbenzene | 31599-61-8 | C8H9I | 详情 | 详情 |
| (VII) | 41699 | (E)-3-(3,4-dimethylphenyl)-2-propenenitrile | C11H11N | 详情 | 详情 | |
| (VIII) | 41700 | 3-(3,4-dimethylphenyl)propanenitrile | C11H13N | 详情 | 详情 | |
| (IX) | 40288 | 3-(3,4-dimethylphenyl)-1-propanamine; 3-(3,4-dimethylphenyl)propylamine | C11H17N | 详情 | 详情 | |
| (X) | 40292 | 2-[4-(2-azidoethoxy)-3-methoxyphenyl]-N-[3-(3,4-dimethylphenyl)propyl]acetamide | C22H28N4O3 | 详情 | 详情 |