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【结 构 式】 
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【分子编号】20594 【品名】2-(3,4-dimethoxyphenyl)acetyl chloride 【CA登记号】 |
【 分 子 式 】C10H11ClO3 【 分 子 量 】214.64824 【元素组成】C 55.96% H 5.17% Cl 16.52% O 22.36% |
合成路线1
该中间体在本合成路线中的序号：(II)3,4-Dimethoxyphenylacetyl chloride (II), obtained by the reaction of SOCl2 with 3,4-dimethoxyphenylacetic acid (I), is reacted with an excess of N-n-propyl-N-n-butylamine (III) in dry DMF to yield the corresponding amide. Following its extraction with ether from an aqueous solution, the amide (IV) is reduced to the corresponding amine (V) by refluxing in dry THF with 1.0 M diborane. The methyl protective groups are removed by refluxing the amine salt for less than 1 h with 56% HI in acetic anhydride. The deprotected amine obtained by neutralizing the hydroiodic salt with aqueous NaHCO3 is then converted to its hydrochloride salt. The final compound is recrystallized from ethanol ether.
| 【1】 Ginos, J.Z.; et al.; Cholinergic effects of molecular segments of apomorphine and dopaminergic effects of N,N-dialkylated dopamines. J Med Chem 1975, 18, 12, 1194. |
| 【2】 Ginos, J.Z.; et al.; New dopaminergic and potential anti-parkinson compounds, N,N-disubstituted beta-(3,4-dihydroxyphenyl)ethylamines. J Med Chem 1978, 21, 2, 160. |
| 【3】 Ginos, J.Z.; Propylbutyldopamine hydrochloride. Drugs Fut 1986, 11, 3, 191. |
| 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) | 24049 | 2-(3,4-dimethoxyphenyl)acetic acid | 93-40-3 | C10H12O4 | 详情 | 详情 |
| (II) | 20594 | 2-(3,4-dimethoxyphenyl)acetyl chloride | C10H11ClO3 | 详情 | 详情 | |
| (III) | 24051 | N-butyl-N-propylamine | 20193-21-9 | C7H17N | 详情 | 详情 |
| (IV) | 24052 | N-butyl-2-(3,4-dimethoxyphenyl)-N-propylacetamide | C17H27NO3 | 详情 | 详情 | |
| (V) | 24053 | N-(3,4-dimethoxyphenethyl)-N-propyl-1-butanamine | C17H29NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The reaction of 3,4-dimethoxyphenylacetic acid (I) with SOCl2 in methylene chloride gives the corresponding acyl chloride (II), which is treated with aminoacetaldehyde dimethylacetal (III) and triethylamine in methylene chloride yielding N-(2,2-diethoxyethyl)-3,4-dimethoxyphenylacetamide (IV). The cyclization of (IV) by means of HCl in acetic acid atfords 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one (V), which is alkylated with 1-bromo-3-chloro propane (VI) by means of potassium tert-butoxide in DMSO to give 3-(3-chloropropyl)-7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one (VII). The reaction of (VII) with N-methyl-2-(3,4-dimethoxyphenyl)ethylamine (VIII) at 100 C affords 7,8-dimethoxy-3-[3-[N-methyl-N-[2-(3,4-dimethoxyphenyl)ethyl]amino]propyl]-1,3-dihydro-2H-3-benzazepin-2-one (IX), which is finally hydrogenated with H2 over Pd/C in acetic acid.
| 【1】 Reiffen, M.; et al. (Dr. Karl Thomae GmbH); Benzazepines, process for their preparation and their application as pharmaceutical preparations. DE 3119874; EP 0065229; GB 2099425; JP 57193462 . |
| 【2】 Reiffen, M. (Dr. Karl Thomae GmbH); Process for the prepaation of benzazepine derivatives. CA 1207764; DD 215541; DE 3242345 . |
| 【3】 Prous, J.; Castaner, J.; Ul-FS-49. Drugs Fut 1985, 10, 8, 639. |
| 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) | 24049 | 2-(3,4-dimethoxyphenyl)acetic acid | 93-40-3 | C10H12O4 | 详情 | 详情 |
| (II) | 20594 | 2-(3,4-dimethoxyphenyl)acetyl chloride | C10H11ClO3 | 详情 | 详情 | |
| (III) | 10331 | 2,2-Diethoxy-1-ethanamine; 2,2-Diethoxyethylamine; Aminoacetaldehyde diethyl acetal | 645-36-3 | C6H15NO2 | 详情 | 详情 |
| (IV) | 24284 | N-(2,2-diethoxyethyl)-2-(3,4-dimethoxyphenyl)acetamide | C16H25NO5 | 详情 | 详情 | |
| (V) | 24285 | 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one | C12H13NO3 | 详情 | 详情 | |
| (VI) | 10358 | 1-Bromo-3-chloropropane | 109-70-6 | C3H6BrCl | 详情 | 详情 |
| (VII) | 18398 | 1-(tert-butyl) 3-ethyl (3R,4R)-4-phenyl-1,3-piperidinedicarboxylate | C19H27NO4 | 详情 | 详情 | |
| (VIII) | 24899 | 3-(3-chloropropyl)-7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one | C15H18ClNO3 | 详情 | 详情 | |
| (IX) | 24901 | 3-[3-[(3,4-dimethoxyphenethyl)(methyl)amino]propyl]-7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one | C26H34N2O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)3,4-Dimethoxyphenylacetic acid (I) is dissotved in anhydrous chloroform free of ethanol and thionyl chloride is added. When the reaction is complete (4 h) and the solvent evaporated, the oily residue is distilled under reduced presaure (10 mm) and the fraction distilled at 170-2 C is collected. The pure 3,4-dimethoxyphenylacetic acid chloride is thus obtained with 81% yield (II). 2-(3,4-Dimethoxyphenyl)ethylamine is dissolved in anhydrous chloroform and anhydrous triethylamine is added to the solution. 3,4-Dimethoxyphenylacetyl chloride is added to the cooled solution, refluxed for 8 h, washed with diluted HCl, with water, the organic phase is dried over anhydrous sodium sulfate and the solvent is evaporated under reduced pressure. The final solid is recrystallized from absolute ethanol. The pure N-[2-(3,4-dimethoxyphenyl)ethyl]-3,4-dimethoxyphenylacetamide is obtained with a yield of 84% (III). The amide is reduced according to the method of Umino et al. (Tetrahedron Lett 1976; 763). The N-bis(3,4-dimethoxyphenylethyl)amine obtained (IV) is then dissolved in methanol and CH2O is added. The mixture is boiled under stirring, cooled, and NaBH4 is added in small portions. After evaporation under reduced pressure the residue is dissolved in water acidified with hydrochloric acid, cooled and made definitely alkaline with 4N sodium hydroxide. The alkaline solution is extracted with dichloromethane, the organic phase is isotated, washed and dried over Na2SO4. After filtration the solvent is evaporated under reduced pressure. The residue is crystallized twice from n-hexane, thus obtaining a pure base with a 62% yield. N,N-Bis[2-(3,4-dimethoxyphenyl)ethyl]methylamine hydrochloride (YS-035) is then prepared.
| 【1】 Quadro, G.; Cahn, J. (SIR International SA; Yason Srl); Compounds having calcium blocking activity. BE 0897244; CA 431900; CH 3684839; DE 33247277; ES 524353; GB 2216213; IT 20838; IT 22339; JP 83125363; NL 832451; ZA 834975 . |
| 【2】 Quadro, G.; YS-035. Drugs Fut 1985, 10, 12, 1000. |
| 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) | 24049 | 2-(3,4-dimethoxyphenyl)acetic acid | 93-40-3 | C10H12O4 | 详情 | 详情 |
| (II) | 20594 | 2-(3,4-dimethoxyphenyl)acetyl chloride | C10H11ClO3 | 详情 | 详情 | |
| (III) | 10098 | 2-(3,4-Dimethoxyphenyl)-1-ethanamine; 3,4-Dimethoxyphenethylamine; 2-(3,4-Dimethoxyphenyl)ethylamine | 120-20-7 | C10H15NO2 | 详情 | 详情 |
| (IV) | 29858 | N-(3,4-dimethoxyphenethyl)-2-(3,4-dimethoxyphenyl)acetamide | C20H25NO5 | 详情 | 详情 | |
| (V) | 29859 | N,N-bis(3,4-dimethoxyphenethyl)amine; N-(3,4-dimethoxyphenethyl)-2-(3,4-dimethoxyphenyl)-1-ethanamine | C20H27NO4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)The condensation of ethyl 2-(aminomethyl)-2-(3,4-dimethoxyphenyl)acetate (I) with 3,4-dimethoxyphenylacetyl chloride (II) by means of NaOH in hot toluene gives ethyl 2-(3,4-dimethoxyphenyl)-3-(3,4-dimethoxyphenylacetamido)propionate (III), which is cyclized by means of Cl3PO in refluxing acetonitrile yielding ethyl 1-(3,4 dimethoxybenzyl)-6,7-dimethoxy-3,4-dihydroisoquinoline-4-carboxylate (IV). Aromatization of (IV) with sulfur at 150 C affords the corresponding isoquinoline derivative (V), which is reduced with sodium bis(2 methoxyethoxy)aluminum hydride in THF to give1-(3,4-dimethoxybenzyl)-6,7-dimethoxyisoquinoline-4-methanol (VI). The reaction of (VI) with SOCl2 in dichloromethane affords 4-(chloromethyl)-6,7-dimethoxy-1-(3,4-dimethoxybenzyl)isoquinoline (VII), which is finally condensed with 1-(2-methoxyphenyl)piperazine (VIII) by means of triethyl amine in hot DMSO.
| 【1】 Bruderer, H.; Kierstead, R.W.; Mullin, J.G. Jr.; Nakamura, K.; O'Brien, J.P.; Sidney, T.; Tateishi, M. (F. Hoffmann-La Roche AG); Substd. isoquinolines. EP 0126480; ES 8601141; JP 1984222478; US 4544657 . |
| 【2】 Castaner, J.; Prous, J.; Elziverine. Drugs Fut 1988, 13, 2, 120. |
| 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) | 21862 | ethyl 3-amino-2-(3,4-dimethoxyphenyl)propanoate | C13H19NO4 | 详情 | 详情 | |
| (II) | 20594 | 2-(3,4-dimethoxyphenyl)acetyl chloride | C10H11ClO3 | 详情 | 详情 | |
| (III) | 21864 | ethyl 2-(3,4-dimethoxyphenyl)-3-[[2-(3,4-dimethoxyphenyl)acetyl]amino]propanoate | C23H29NO7 | 详情 | 详情 | |
| (IV) | 21865 | ethyl 1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-3,4-dihydro-4-isoquinolinecarboxylate | C23H27NO6 | 详情 | 详情 | |
| (V) | 21866 | ethyl 1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-4-isoquinolinecarboxylate | C23H25NO6 | 详情 | 详情 | |
| (VI) | 21867 | [1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-4-isoquinolinyl]methanol | C21H23NO5 | 详情 | 详情 | |
| (VII) | 21868 | 4-(chloromethyl)-1-(3,4-dimethoxybenzyl)-6-methoxy-7-isoquinolinyl methyl ether; 4-(chloromethyl)-1-(3,4-dimethoxybenzyl)-6,7-dimethoxyisoquinoline | C21H22ClNO4 | 详情 | 详情 | |
| (VIII) | 11882 | 1-(2-Methoxyphenyl)piperazine; Methyl 2-piperazinophenyl ether; 1-(2-Methoxyphenyl)-piperazine | 35386-24-4 | C11H16N2O | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VII)The condensation of 3-methoxybenzaldehyde (I) with acetone (II) by means of NaOH gives 1-(3-methoxyphenyl)-1-buten-3-one (III), which is hydrogenated with H2 over Pd/C in methanol yielding 1-(3-methoxyphenyl)-3-butanone (IV). The iodination of (IV) with I2-silver acetate in acetic acid affords 1-(2-iodo-5-methoxyphenyl)-3-butanone (V), which is reductocondensed with methylamine and sodium cyanoborohydride in methanol giving 2-iodo-5-methoxy-N,alpha-dimethylphenylpropanamine (VI). The acylation of (VI) with 3,4-dimethoxyphenylacetyl chloride (VII) by means of triethylamine in dichloromethane yields the corresponding acetamide (VIII), which is reduced with borane-THF complex affording the corresponding tertiary amine (IX), which is finally condensed with phenylacetylene (X) by means of butyllithium in THF.
| 【1】 Carson, J.R. (McNeilab, Inc.); Aralkyl(arylethynyl)aralkyl amines for use as vasodilators and antihypertensives. EP 0146271; ES 8604488; US 4661635 . |
| 【2】 Prous, J.; Castaner, J.; McN-5691. Drugs Fut 1989, 14, 4, 322. |
| 【3】 Carson, J.R.; Almond, H.R.; Brannan, M.D.; et al.; 2-Ethynylbenzenealkanamines. A new class of calcium entry blockers. J Med Chem 1988, 31, 3, 630-6. |
| 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) | 20589 | 3-methoxybenzaldehyde; m-Anisaldehyde | 591-31-1 | C8H8O2 | 详情 | 详情 |
| (II) | 23199 | 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether | 67-64-1 | C3H6O | 详情 | 详情 |
| (III) | 20590 | (E)-4-(3-methoxyphenyl)-3-buten-2-one | C11H12O2 | 详情 | 详情 | |
| (IV) | 20591 | 4-(3-methoxyphenyl)-2-butanone | C11H14O2 | 详情 | 详情 | |
| (V) | 20592 | 4-(2-iodo-5-methoxyphenyl)-2-butanone | C11H13IO2 | 详情 | 详情 | |
| (VI) | 20593 | N-[3-(2-iodo-5-methoxyphenyl)-1-methylpropyl]-N-methylamine; 4-(2-iodo-5-methoxyphenyl)-N-methyl-2-butanamine | C12H18INO | 详情 | 详情 | |
| (VII) | 20594 | 2-(3,4-dimethoxyphenyl)acetyl chloride | C10H11ClO3 | 详情 | 详情 | |
| (VIII) | 20595 | 2-(3,4-dimethoxyphenyl)-N-[3-(2-iodo-5-methoxyphenyl)-1-methylpropyl]-N-methylacetamide | C22H28INO4 | 详情 | 详情 | |
| (IX) | 20596 | N-(3,4-dimethoxyphenethyl)-N-[3-(2-iodo-5-methoxyphenyl)-1-methylpropyl]-N-methylamine; N-(3,4-dimethoxyphenethyl)-4-(2-iodo-5-methoxyphenyl)-N-methyl-2-butanamine | C22H30INO3 | 详情 | 详情 | |
| (X) | 20597 | 1-ethynylbenzene | 536-74-3 | C8H6 | 详情 | 详情 |