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【结 构 式】 
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【分子编号】18938 【品名】2-(3,4-dimethoxyphenyl)-N-methyl-1-ethanamine; N-(3,4-dimethoxyphenethyl)-N-methylamine 【CA登记号】3490-06-0 |
【 分 子 式 】C11H17NO2 【 分 子 量 】195.26152 【元素组成】C 67.66% H 8.78% N 7.17% O 16.39% |
合成路线1
该中间体在本合成路线中的序号：(III)The bromination of labeled acetophenone (I) with Br2 and AlCl3 gives phenacyl bromide (II), which is condensed with N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methylamine (III), yielding the 2-aminoacetophenone (IV). The reduction of (IV) with NaBH4 affords the secondary alcohol (V), which is finally cyclized by means of H2SO4 and trifluoroacetic acid to provide the target 3-benzazepine.
| 【1】 Hieble, J.P.; Wilson III, J.W.; Weinstock, J.; The chemistry and pharmacology of 3-benzazepines derivatives. Drugs Fut 1985, 10, 8, 645. |
| 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) | 10317 | Acetophenone | 98-86-2 | C8H8O | 详情 | 详情 |
| (I) | 44572 | acetophenone | C8H8O | 详情 | 详情 | |
| (II) | 10315 | 2-Bromo-1-phenyl-ethanone; 2-Bromo-1-phenyl-1-ethanone | 70-11-1 | C8H7BrO | 详情 | 详情 |
| (II) | 44573 | 2-bromo-1-phenyl-1-ethanone | C8H7BrO | 详情 | 详情 | |
| (III) | 18938 | 2-(3,4-dimethoxyphenyl)-N-methyl-1-ethanamine; N-(3,4-dimethoxyphenethyl)-N-methylamine | 3490-06-0 | C11H17NO2 | 详情 | 详情 |
| (IV) | 44047 | 2-[(3,4-dimethoxyphenethyl)(methyl)amino]-1-phenyl-1-ethanone | C19H23NO3 | 详情 | 详情 | |
| (IV) | 44574 | 2-[(3,4-dimethoxyphenethyl)(methyl)amino]-1-phenyl-1-ethanone | C19H23NO3 | 详情 | 详情 | |
| (V) | 44048 | 2-[(3,4-dimethoxyphenethyl)(methyl)amino]-1-phenyl-1-ethanol | C19H25NO3 | 详情 | 详情 | |
| (V) | 44575 | 2-[(3,4-dimethoxyphenethyl)(methyl)amino]-1-phenyl-1-ethanol | C19H25NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)Gallopamil is obtained by condensing 2-(3,4,5-trimethoxypheny)-3-methylbutyronitrile (I) with N-(3-chloropropyl)-N-(2-(3,4-dimethoxyphenyl)ethyl]-N-methylamine (II) in the presence of bases. Compound (I) can be prepared by reaction of 3,4,5-trimethoxyphenylacetonitrile (III) with isopropyl chloride (IV) by means of NaNH2. Compound (II) is formed from 1-bromo-3-chloropropane (V) and N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methylamine (VI).
| 【1】 Dengel, F. (Knoll AG); Verfahren zur herstellung basisch substituerter phenylacetonitrile. DE 1154810; DE 1158083 . |
| 【2】 Mannhold, R.; Gallopamil Hydrochloride. Drugs Fut 1984, 9, 2, 108. |
| 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) | 29985 | 3-methyl-2-(3,4,5-trimethoxyphenyl)butanenitrile | C14H19NO3 | 详情 | 详情 | |
| (II) | 29986 | 3-chloro-N-(3,4-dimethoxyphenethyl)-N-methyl-1-propanamine; N-(3-chloropropyl)-N-(3,4-dimethoxyphenethyl)-N-methylamine | C14H22ClNO2 | 详情 | 详情 | |
| (III) | 29983 | 2-(3,4,5-trimethoxyphenyl)acetonitrile | 13338-63-1 | C11H13NO3 | 详情 | 详情 |
| (IV) | 29984 | 2-chloropropane | 75-29-6 | C3H7Cl | 详情 | 详情 |
| (V) | 10358 | 1-Bromo-3-chloropropane | 109-70-6 | C3H6BrCl | 详情 | 详情 |
| (VI) | 18938 | 2-(3,4-dimethoxyphenyl)-N-methyl-1-ethanamine; N-(3,4-dimethoxyphenethyl)-N-methylamine | 3490-06-0 | C11H17NO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)This compound has been obtained by two similar ways: 1) The alkylation of 4-hydroxyphenyl(2-isopropylindolizin-1-yl)sulfone (I) 1,3-dibromopropane (II) by means of K2CO3 in DMF gives 4-(3-bromopropoxy)phenyl(2-isopropylindolizin-1-yl)sulfone (III), which is finally condensed with N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methylamine. 2) By direct condensation of sulfone (I) with the tertiary amine N-(3-chloropropyl)-N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methylamine.
| 【1】 Gubin, J.; et al.; A novel class of calcium-entry blockers: The 1-[[4-(aminoalkoxy)phenyl]sulfonyl]indolizines. J Med Chem 1992, 35, 6, 981. |
| 【2】 Gubin, J.; et al.; Novel heterocyclic analogues of the new potent class of calcium entry blockers: 1-[[4-(Aminoalkoxy)phenyl]sulfonyl]indolizines. J Med Chem 1993, 36, 10, 1425. |
| 【3】 Chatelain, P.; Gubin, J.; Aminoalkoxybenzenesulfonyl heterocyclic compounds, a novel class of calcium channel antagonists. Structure-activity relationship with a focus on fantofarone, SR 33557. Drugs Fut 1993, 18, 9, 817. |
| 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) | 41267 | 4-[(2-isopropyl-1-indolizinyl)sulfonyl]phenol | C17H17NO3S | 详情 | 详情 | |
| (II) | 12581 | 1,3-Dibromopropane | 109-64-8 | C3H6Br2 | 详情 | 详情 |
| (III) | 41268 | 4-(3-bromopropoxy)phenyl 2-isopropyl-1-indolizinyl sulfone; 1-[[4-(3-bromopropoxy)phenyl]sulfonyl]-2-isopropylindolizine | C20H22BrNO3S | 详情 | 详情 | |
| (IV) | 29986 | 3-chloro-N-(3,4-dimethoxyphenethyl)-N-methyl-1-propanamine; N-(3-chloropropyl)-N-(3,4-dimethoxyphenethyl)-N-methylamine | C14H22ClNO2 | 详情 | 详情 | |
| (V) | 18938 | 2-(3,4-dimethoxyphenyl)-N-methyl-1-ethanamine; N-(3,4-dimethoxyphenethyl)-N-methylamine | 3490-06-0 | C11H17NO2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)The condensation of N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methylamine (I) with 2-bromo-1-tetralone (II) by means of K2CO3 in DMF gives the tertiary amine (III), which is reduced with NaBH4 in ethanol to the hydroxyamine (IV). The cyclization of (IV) by means of methanesulfonic acid yields a mixture of cis and trans tetracyclic compounds that is separated by chromatography. The desired trans isomer (V) is monodemethylated by means of EtS-Na in DMF affording a mixture of 11-methoxy,12-hydroxy and 12-methoxy-11-hydroxy compounds that is separated by crystallization. The desired 12-methoxy-11-hydroxy compound (VI) is dehydroxylated by means of 5-chloro-1-phenyltetrazole (CPT) and NaH in hot DMF giving the 12-methoxy compound (VII), which is chlorinated with SO2Cl2 in dichloromethane to afford the racemic 11-chloro-12-methoxy compound rac-(VIII). Optical resolution of rac-(VIII) with (+)-di-p-toluoyl-D-tartaric acid [(+)-DPT] gives (-)(6aS,13bR)(VIII), which is finally demethylated to the target compound with 48% HBr in refluxing acetic acid.
| 【1】 Berger, J.G.; et al.; Synthesis and receptor affinities of some conformationally restricted analogues of the dopamine D1 selective ligand (5R)-8-chloro-2,3,4, 5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol. J Med Chem 1989, 32, 8, 1913-21. |
| 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) | 18938 | 2-(3,4-dimethoxyphenyl)-N-methyl-1-ethanamine; N-(3,4-dimethoxyphenethyl)-N-methylamine | 3490-06-0 | C11H17NO2 | 详情 | 详情 |
| (II) | 20721 | 2-bromo-3,4-dihydro-1(2H)-naphthalenone | C10H9BrO | 详情 | 详情 | |
| (III) | 36619 | 2-[(3,4-dimethoxyphenethyl)(methyl)amino]-3,4-dihydro-1(2H)-naphthalenone | C21H25NO3 | 详情 | 详情 | |
| (IV) | 36620 | 2-[(3,4-dimethoxyphenethyl)(methyl)amino]-1,2,3,4-tetrahydro-1-naphthalenol | C21H27NO3 | 详情 | 详情 | |
| (V) | 36621 | (3aS,9bR)-11-methoxy-3-methyl-2,3,3a,4,5,9b-hexahydro-1H-naphtho[1,2-a][3]benzazepin-12-yl methyl ether; (3aS,9bR)-11,12-dimethoxy-3-methyl-2,3,3a,4,5,9b-hexahydro-1H-naphtho[1,2-a][3]benzazepine | C21H25NO2 | 详情 | 详情 | |
| (VI) | 36622 | (3aS,9bR)-11-methoxy-3-methyl-2,3,3a,4,5,9b-hexahydro-1H-naphtho[1,2-a][3]benzazepin-12-ol | C20H23NO2 | 详情 | 详情 | |
| (VII) | 36623 | (3aS,9bR)-11-methoxy-3-methyl-2,3,3a,4,5,9b-hexahydro-1H-naphtho[1,2-a][3]benzazepine; (3aS,9bR)-3-methyl-2,3,3a,4,5,9b-hexahydro-1H-naphtho[1,2-a][3]benzazepin-11-yl methyl ether | C20H23NO | 详情 | 详情 | |
| (VIII) | 31779 | (3aS,9bR)-12-chloro-11-methoxy-3-methyl-2,3,3a,4,5,9b-hexahydro-1H-naphtho[1,2-a][3]benzazepine; (3aS,9bR)-12-chloro-3-methyl-2,3,3a,4,5,9b-hexahydro-1H-naphtho[1,2-a][3]benzazepin-11-yl methyl ether | C20H22ClNO | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IV)3-Chloropropionyl chloride (II) was condensed with 4-aminoveratrole (I) in the presence of triethylamine to give the chloropropionamide (III). Further alkylation of N-methyl-2-(3,4-dimethoxyphenyl)ethylamine (IV) with (III) in refluxing acetonitrile afforded the aminopropionamide (V), which was subsequently reduced to diamine (VI) with LiAlH4 in boiling THF. Finally, acylation of (VI) with 4-nitrobenzoyl chloride (VII) gave the target amide.
| 【1】 Nadler, G.; Faivre, J.F.; Forest, M.C.; Cheval, B.; Martin, M.; Souchet, M.; Gout, B.; Bril, A.; Synthesis, electrophysiological properties and analysis of structural requirements of a novel class of antiarrhythmic agents with potassium and calcium channel blocking properties. Bioorg Med Chem 1998, 6, 11, 1993. |
| 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) | 18935 | 3,4-dimethoxyphenylamine; 3,4-dimethoxyaniline | 6315-89-5 | C8H11NO2 | 详情 | 详情 |
| (II) | 18936 | 3-chloropropanoyl chloride | 625-36-5 | C3H4Cl2O | 详情 | 详情 |
| (III) | 18937 | 3-chloro-N-(3,4-dimethoxyphenyl)propanamide | C11H14ClNO3 | 详情 | 详情 | |
| (IV) | 18938 | 2-(3,4-dimethoxyphenyl)-N-methyl-1-ethanamine; N-(3,4-dimethoxyphenethyl)-N-methylamine | 3490-06-0 | C11H17NO2 | 详情 | 详情 |
| (V) | 18939 | 3-[(3,4-dimethoxyphenethyl)(methyl)amino]-N-(3,4-dimethoxyphenyl)propanamide | C22H30N2O5 | 详情 | 详情 | |
| (VI) | 18940 | N(1)-(3,4-dimethoxyphenethyl)-N(3)-(3,4-dimethoxyphenyl)-N(1)-methyl-1,3-propanediamine; N-[3-(3,4-dimethoxyanilino)propyl]-N-(3,4-dimethoxyphenethyl)-N-methylamine | C22H32N2O4 | 详情 | 详情 | |
| (VII) | 18941 | p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride | 122-04-3 | C7H4ClNO3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(VII)Pyridazinone (I) was converted to 3,4,5-trichloropyridazine (VIII) on treatment with POCl3. Nucleophylic substitution in (II) with 3-aminopropanol (III) gave, after crystallization, the desired isomer (IV). Hydrolysis of the 3-chloro group of (IV) was carried out with AcOH and AcONa, resulting in the N,O-diacetyl derivative (V). Subsequent reaction of (V) with aqueous HBr provided bromide (VI), which was then treated with N-methyl homoveratrylamine (VII) to furnish the target compound (VIII). This compound was finally isolated as the fumarate salt on treatment with fumaric acid in EtOH (1).
| 【1】 Kotay-Nagy, P.; et al.; A new synthesis of EGIS-7229, a potent antiarrhythmic drug-candidate. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.151. |
| 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) | 24570 | 4,5-dichloro-3(2H)-pyridazinone | C4H2Cl2N2O | 详情 | 详情 | |
| (II) | 27529 | 3,4,5-trichloropyridazine | 14161-11-6 | C4HCl3N2 | 详情 | 详情 |
| (III) | 18522 | 3-amino-1-propanol | 156-87-6 | C3H9NO | 详情 | 详情 |
| (IV) | 27530 | 3-[(3,5-dichloro-4-pyridazinyl)amino]-1-propanol | C7H9Cl2N3O | 详情 | 详情 | |
| (V) | 27531 | 3-[acetyl(5-chloro-3-oxo-2,3-dihydro-4-pyridazinyl)amino]propyl acetate | C11H14ClN3O4 | 详情 | 详情 | |
| (VI) | 27532 | 4-[(3-bromopropyl)amino]-5-chloro-3(2H)-pyridazinone | C7H9BrClN3O | 详情 | 详情 | |
| (VII) | 18938 | 2-(3,4-dimethoxyphenyl)-N-methyl-1-ethanamine; N-(3,4-dimethoxyphenethyl)-N-methylamine | 3490-06-0 | C11H17NO2 | 详情 | 详情 |
| (VIII) | 27533 | 5-chloro-4-([3-[(3,4-dimethoxyphenethyl)(methyl)amino]propyl]amino)-3(2H)-pyridazinone | C18H25ClN4O3 | 详情 | 详情 | |
| (IX) | 23808 | Fumaric acid; (E)-2-butenedioic acid | 110-17-8 | C4H4O4 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(III)Alkylation of phenol (I) with 1,2-dibromoethane (II) in the presence of K2CO3 in DMF yielded bromoethyl ether (III), which was further, condensed with amine (IV) to afford tertiary amine (V). The nitro group of (V) was then reduced by either catalytic hydrogenation in the presence of Pd/C or by treatment with SnCl2 in aqueous HCl, and the resulting aniline (VI) was condensed with methanesulfonyl chloride in pyridine to give sulfonamide (VII). Finally, acid hydrolysis of the acetamido group provided the title compound.
| 【1】 Kim, D.-I.; Kim, H.Y.; Kwon, L.S.; Park, S.D.; Jeon, G.H.; Jung, K.Y.; Min, J.K.; Nam, W.H.; Lee, K.; Chung, Y.S.; Tanabe, S.; Kozono, T.; Synthesis and biological activity of KCB-328 and its analogues: Novel class III antiarrhythmic agents with little reverse frequency dependence. Bioorg Med Chem Lett 1999, 9, 1, 85. |
| 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) | 19881 | N-(2-hydroxy-5-nitrophenyl)acetamide | C8H8N2O4 | 详情 | 详情 | |
| (II) | 10252 | 1,2-Dibromoethane; Ethylene dibromide | 106-93-4 | C2H4Br2 | 详情 | 详情 |
| (III) | 18938 | 2-(3,4-dimethoxyphenyl)-N-methyl-1-ethanamine; N-(3,4-dimethoxyphenethyl)-N-methylamine | 3490-06-0 | C11H17NO2 | 详情 | 详情 |
| (III) | 19883 | N-[2-(2-bromoethoxy)-5-nitrophenyl]acetamide | C10H11BrN2O4 | 详情 | 详情 | |
| (V) | 19885 | N-(2-[2-[(3,4-dimethoxyphenethyl)(methyl)amino]ethoxy]-5-nitrophenyl)acetamide | C21H27N3O6 | 详情 | 详情 | |
| (VI) | 19886 | N-(5-amino-2-[2-[(3,4-dimethoxyphenethyl)(methyl)amino]ethoxy]phenyl)acetamide | C21H29N3O4 | 详情 | 详情 | |
| (VII) | 19887 | N-[2-[2-[(3,4-dimethoxyphenethyl)(methyl)amino]ethoxy]-5-[(methylsulfonyl)amino]phenyl]acetamide | C22H31N3O6S | 详情 | 详情 |