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【结 构 式】 
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【分子编号】24049 【品名】2-(3,4-dimethoxyphenyl)acetic acid 【CA登记号】93-40-3 |
【 分 子 式 】C10H12O4 【 分 子 量 】196.20288 【元素组成】C 61.22% H 6.16% O 32.62% |
合成路线1
该中间体在本合成路线中的序号：(I)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：(VI)The enantioselective condensation of 4-(tert-butyldimethylsilyloxy)benzaldehyde (I) with nitromethane (II), catalyzed by the chiral Zn ligand complex (III) in THF gives the (R)-2-nitroethanol derivative (IV), which is reduced with H2 over Pd/C in ethanol to yield the 2-aminoethanol derivative (V). The condensation of (V) with carboxylic acid (VI) by means of 2,2-dimethylpropanoyl chloride and DIEA in THF affords the corresponding amide (VII), which is reduced with LiAlH4 in Et2O to yield the protected hydroxyamine (VIII). Finally, this compound is desilylated by means of HCl and KF in MeOH to furnish the target tetrahydroxyamine derivative.
| 【1】 Ito, H.; Bremeyer, N.; Trost, B.M.; Yeh, V.S.C.; Effect of ligand structure on the zinc-catalyzed Henry reaction. Asymmetric syntheses of (-)-denopamine and (-)-arbutamine. Org Lett 2002, 4, 16, 2621. |
| 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) | 57897 | 4-{[tert-butyl(dimethyl)silyl]oxy}benzaldehyde | C13H20O2Si | 详情 | 详情 | |
| (II) | 39563 | nitromethane | 75-52-5 | CH3NO2 | 详情 | 详情 |
| (III) | 57893 | C64H60O3Zn2 | 详情 | 详情 | ||
| (IV) | 57898 | (1R)-1-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-2-nitro-1-ethanol | C14H23NO4Si | 详情 | 详情 | |
| (V) | 57899 | (1R)-2-amino-1-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-ethanol | C14H25NO2Si | 详情 | 详情 | |
| (VI) | 24049 | 2-(3,4-dimethoxyphenyl)acetic acid | 93-40-3 | C10H12O4 | 详情 | 详情 |
| (VII) | 57900 | N-[(2R)-2-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-2-hydroxyethyl]-2-(3,4-dimethoxyphenyl)acetamide | C24H35NO5Si | 详情 | 详情 | |
| (VIII) | 57901 | (1R)-1-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-2-[(3,4-dimethoxyphenethyl)amino]-1-ethanol | C24H37NO4Si | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)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4
该中间体在本合成路线中的序号：(I)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5
该中间体在本合成路线中的序号：(I)The condensation of 3,4-dimethoxyphenyacetic acid (I) with 2-aminoacetaldehyde diethylacetal (II) by means of 1,1'-carbonyldiimidazole (CDI) in CHCl3 gives N-(2,2-diethoxyethyl)-3,4-dimelhoxyphenylacetamide (III), which is cyclized by means of 48% aqueous HBr yielding 1,3-dihydro-7,8-dimethoxy-2H-3-benzazepin-2-one (IV). The reaction of (IV) with triethyloxonium tetrafluoroborate (V) in methylene chloride affords 2-ethoxy-7,8-dimethoxy-1H-3-benzazepine (VI), which is finally treated with ammonium chloride in refluxing methanol.
| 【1】 Paget, C.J. Jr.; Ruffolo, R.R. Jr. (Eli Lilly and Company); Benzazepine derivs.. EP 0116444; ES 8602681; ES 8801215; GB 2134519 . |
| 【2】 Prous, J.; Castaner, J.; LY-127210. Drugs Fut 1986, 11, 9, 748. |
| 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) | 10331 | 2,2-Diethoxy-1-ethanamine; 2,2-Diethoxyethylamine; Aminoacetaldehyde diethyl acetal | 645-36-3 | C6H15NO2 | 详情 | 详情 |
| (III) | 24284 | N-(2,2-diethoxyethyl)-2-(3,4-dimethoxyphenyl)acetamide | C16H25NO5 | 详情 | 详情 | |
| (IV) | 24285 | 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one | C12H13NO3 | 详情 | 详情 | |
| (VI) | 24287 | 2-ethoxy-7,8-dimethoxy-1H-3-benzazepine | C14H17NO3 | 详情 | 详情 |