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【结 构 式】 
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【分子编号】40285 【品名】3-(3,4-dimethylphenyl)propionic acid 【CA登记号】 |
【 分 子 式 】C11H14O2 【 分 子 量 】178.23096 【元素组成】C 74.13% H 7.92% O 17.95% |
合成路线1
该中间体在本合成路线中的序号：(IV)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：(III)Knoevenagel condensation of 3,4-dimethylbenzaldehyde (I) with malonic acid in the presence of piperidine afforded dimethylcinnamic acid (II), which was reduced to the saturated acid (III) by catalytic hydrogenation. Conversion of (III) to the corresponding acid chloride, followed by Friedel-Crafts cyclization, gave rise to the 1-indanone (IV). This was isomerized to the desired 2-indanone (VII) by the sequence of ketone reduction, followed by acidic dehydration of the resulting alcohol to give indene (V), which was converted to epoxide (VI) and then Lewis-acid promoted rearrangement to the 2-indanone (VII). Condensation of ketone (VII) with benzylamine and subsequent addition of trimethylsilyl cyanide to the resulting imine furnished amino nitrile (VIII). After reduction of (VIII) to the diamine (IX) with LiAlH4, the N-benzyl group was removed by transfer hydrogenolysis, yielding (X). Condensation of diamine (X) with formamidine acetate produced the target imidazoline, which was finally isolated as the fumarate salt.
| 【1】 Lacoste, J.-M.; Verbeuren, T.J.; Cordi, A.; Descombes, J.-J.; Couchay, C.; Spiro[(1,3-diazacyclopent-1-ene)-5,2'-(5',6'-dimethylindane)]: A new alpha-adrenergic partial agonist. Two synthetic approaches. 16th Int Symp Med Chem (Sept 18 2000, Bologna) 2000, Abst PA-83. |
| 【2】 Cordi, A.; Lacoste, J.-M.; Laubie, M.; Verbeuren, T.; Descombes, J.-J. (ADIR et Cie.); Benzospiroalkene derivs., process for their preparation and pharmaceutical compsns. containing them. CA 2128359; EP 0635497; FR 2709306; JP 1995304753; US 5436261 . |
| 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) | 46036 | 3,4-dimethylbenzaldehyde | 5973-71-7 | C9H10O | 详情 | 详情 |
| (II) | 46037 | (Z)-3-(3,4-dimethylphenyl)-2-propenoic acid | C11H12O2 | 详情 | 详情 | |
| (III) | 40285 | 3-(3,4-dimethylphenyl)propionic acid | C11H14O2 | 详情 | 详情 | |
| (IV) | 46038 | 5,6-dimethyl-1-indanone | C11H12O | 详情 | 详情 | |
| (V) | 46039 | 5,6-dimethyl-1H-indene | C11H12 | 详情 | 详情 | |
| (VI) | 46040 | 3,4-dimethyl-6,6a-dihydro-1aH-indeno[1,2-b]oxirene | C11H12O | 详情 | 详情 | |
| (VII) | 46041 | 5,6-dimethyl-1,3-dihydro-2H-inden-2-one | C11H12O | 详情 | 详情 | |
| (VIII) | 46042 | 2-(benzylamino)-5,6-dimethyl-2-indanecarbonitrile | C19H20N2 | 详情 | 详情 | |
| (IX) | 46043 | N-[2-(aminomethyl)-5,6-dimethyl-2,3-dihydro-1H-inden-2-yl]-N-benzylamine; 2-(aminomethyl)-N-benzyl-5,6-dimethyl-2-indanamine | C19H24N2 | 详情 | 详情 | |
| (X) | 46044 | 2-(aminomethyl)-5,6-dimethyl-2-indanamine; (2-amino-5,6-dimethyl-2,3-dihydro-1H-inden-2-yl)methylamine | C12H18N2 | 详情 | 详情 |