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【结 构 式】 
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【分子编号】36640 【品名】N-[(1S,2S)-1-(4-chloro-3-methoxyphenyl)-1,2,3,4-tetrahydro-2-naphthalenyl]-N-(2,2-dimethoxyethyl)-N-methylamine; (1S,2S)-1-(4-chloro-3-methoxyphenyl)-N-(2,2-dimethoxyethyl)-N-methyl-1,2,3,4-tetrahydro-2-naphthalenamine 【CA登记号】 |
【 分 子 式 】C22H28ClNO3 【 分 子 量 】389.92196 【元素组成】C 67.77% H 7.24% Cl 9.09% N 3.59% O 12.31% |
合成路线1
该中间体在本合成路线中的序号：(XXVIII)The bromination of tetraline (XIX) with Br2 in hexane gives trans-1,2-dibromotetraline (XX), which by treatment with H2O and NaHCO3 yields trans-2-bromotetralin-1-ol (XXI) [also obtained by reaction of 1,2-dihydronaphthalene (XXII) with 1,3-dibromo-5,5-dimethylhydantoin (DBDH) and perchloric acid]. The reaction of (XXI) with methylamine affords the intermediate epoxide (XXIII), which without isolation with more methylamine gives trans 1-(methylamino) tetralin-2-ol as a racemic mixture rac-(XXIV). The optical resolution of this mixture with (+)-L-tartaric acid yields the desired enantiomer (R,R)(XXIV), which is condensed with 2-bromoacetaldehyde dimethyl acetal (XXV) by means of K2CO3 in acetonitrile furnishing the chiral tertiary amine (XXVI). The cyclization of (XXVI) with BuLi and TsCl provides the intermediate aziridinium salt (XXVII), which without isolation, is condensed with 4-chloro-3-methoxyphenyl-magnesium bromide (X) in THF to give the chiral tertiary amine (XXVIII). The cyclization of (XXVIII) by means of methanesulfonic acid yields the chiral tetracyclic compound (XXIX), which is hydrogenated by means of BH3/t-Bu-NH2 to afford (6aS,13bR)(VIII). Finally, this compound is demethylated with 48% HBr in acetic acid. The chiral secondary amine (XXVI) can also be obtained as follows: The enantioselective epoxidation of 1,2-dihydronaphthalene (XXII) by means of a chiral manganese catalyst and sodium hypochlorite gives the chiral epoxide (1S,2R)(XXIII), which is cleaved with 2-(methylamino)acetaldehyde dimethylacetal (XXX) at 95 C in a pressure vessel to yield the desired chiral secondary amine (XXVI).
| 【1】 Berger, J.G.; Clader, J.W.; Chang, W.K.; Gold, E.H. (Schering Corp.); Fused benzazepines. EP 0230270; EP 0254737; JP 1988502348; WO 8704430 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11021 | Methanamine; Methylamine | 74-89-5 | CH5N | 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 | |
| (X) | 36324 | methyl 2-chloro-3-[4-[4-(2-chloro-3-methoxy-3-oxopropyl)benzyl]phenyl]propanoate | C21H22Cl2O4 | 详情 | 详情 | |
| (XIX) | 36632 | 1,2,3,4-tetrahydronaphthalene | 119-64-2 | C10H12 | 详情 | 详情 |
| (XX) | 36633 | (1S,2S)-1,2-dibromo-1,2,3,4-tetrahydronaphthalene | C10H10Br2 | 详情 | 详情 | |
| (XXI) | 36634 | (1S,2S)-2-bromo-1,2,3,4-tetrahydro-1-naphthalenol | C10H11BrO | 详情 | 详情 | |
| (XXII) | 36635 | 1,2-dihydronaphthalene | 447-53-0 | C10H10 | 详情 | 详情 |
| (XXIII) | 36636 | (1aR,7bS)-1a,2,3,7b-tetrahydronaphtho[1,2-b]oxirene | C10H10O | 详情 | 详情 | |
| (XXIV) | 36637 | (1R,2R)-1-(methylamino)-1,2,3,4-tetrahydro-2-naphthalenol | C11H15NO | 详情 | 详情 | |
| (XXV) | 13183 | 2-Bromo-1,1-dimethoxyethane; 2-Bromo-1-methoxyethyl methyl ether; Bromoacetaldehyde dimethyl acetal | 7252-83-7 | C4H9BrO2 | 详情 | 详情 |
| (XXVI) | 36638 | (1R,2R)-1-[(2,2-dimethoxyethyl)(methyl)amino]-1,2,3,4-tetrahydro-2-naphthalenol | C15H23NO3 | 详情 | 详情 | |
| (XXVII) | 36639 | n/a | AB | 详情 | 详情 | |
| (XXVIII) | 36640 | N-[(1S,2S)-1-(4-chloro-3-methoxyphenyl)-1,2,3,4-tetrahydro-2-naphthalenyl]-N-(2,2-dimethoxyethyl)-N-methylamine; (1S,2S)-1-(4-chloro-3-methoxyphenyl)-N-(2,2-dimethoxyethyl)-N-methyl-1,2,3,4-tetrahydro-2-naphthalenamine | C22H28ClNO3 | 详情 | 详情 | |
| (XXIX) | 36641 | (3aS,9bR)-12-chloro-3-methyl-3a,4,5,9b-tetrahydro-3H-naphtho[1,2-a][3]benzazepin-11-yl methyl ether; (3aS,9bR)-12-chloro-11-methoxy-3-methyl-3a,4,5,9b-tetrahydro-3H-naphtho[1,2-a][3]benzazepine | C20H20ClNO | 详情 | 详情 | |
| (XXX) | 36650 | 2,2-dimethoxy-N-methyl-1-ethanamine;1,1-Dimethoxy-2-(methylamino)-ethane;Methylaminoacetaldehyde dimethyl acetal;N-(2,2-dimethoxyethyl)-N-methylamine | 122-07-6 | C5H13NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXXVIII)The reaction of L-homophenylalanine (XXXIX) with methyl chloroformate, NaHCO3 and NaOH gives N-(methoxycarbonyl)-L-homophenylalanine (XXXI), which is treated with SOCl2 yielding the acyl chloride (XXXII). The cyclization of (XXXII) by means of AlCl3 in dichloromethane affords the chiral tetralone (XXXIII), which is condensed with the aryllithium (or arylmagnesium bromide) (XXXIV) to give the intermediate alcohol (XXXV). Elimination of the OH group of (XXXV) by means of Et3SiH and TFA yields the carbamate (XXXVI) as a 3.6:1 mixture of cis- and trans-isomers, which is reduced with LiAlH4 in refluxing THF providing the secondary amine (XXXVII). The alkylation of (XXXVII) with 2-bromoacetaldehyde dimethylacetal (XXV) by means of KF/Al2O3 in refluxing acetonitrile affords the tertiary amine (XXXVIII), also as a mixture of cis- and trans-isomers. The 1:3 trans/cis ratio of isomers in (XXXVIII) is improved up to 50:1 by treatment with t-BuOK in DMSO/DMF providing the desired trans(1R,2S)-isomer (XXVIII) already reported.
| 【1】 Draper, R.W.; et al.; Novel stereoselective syntheses of the fused benzazepine dopamine D1 antagonist (6aS,13bR)-11-chloro-6,6a,7,8,9,13b-hexahydro-7-methyl-5-H-benzo[d]naphth[2,1-b]azepin-12-ol (Sch 39166): 2. L-homophenylalanine-based syntheses. Org Process Res Dev 1998, 2, 3, 186. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 | |
| (XXXIVb) | 36624 | bromo(4-chloro-3-methoxyphenyl)magnesium | C7H6BrClMgO | 详情 | 详情 | |
| (XXXIVa) | 36646 | (4-chloro-3-methoxyphenyl)lithium | C7H6ClLiO | 详情 | 详情 | |
| (XXV) | 13183 | 2-Bromo-1,1-dimethoxyethane; 2-Bromo-1-methoxyethyl methyl ether; Bromoacetaldehyde dimethyl acetal | 7252-83-7 | C4H9BrO2 | 详情 | 详情 |
| (XXVIII) | 63422 | (2S)-1-(4-chloro-3-methoxyphenyl)-N-(2,2-dimethoxyethyl)-N-methyl-1,2,3,4-tetrahydro-2-naphthalenamine; N-[(2S)-1-(4-chloro-3-methoxyphenyl)-1,2,3,4-tetrahydro-2-naphthalenyl]-N-(2,2-dimethoxyethyl)-N-methylamine | C22H28ClNO3 | 详情 | 详情 | |
| (XXXI) | 36643 | (2S)-2-[(methoxycarbonyl)amino]-4-phenylbutyric acid | C12H15NO4 | 详情 | 详情 | |
| (XXXII) | 36644 | methyl (1S)-1-(chlorocarbonyl)-3-phenylpropylcarbamate | C12H14ClNO3 | 详情 | 详情 | |
| (XXXIII) | 36645 | methyl (2S)-1-oxo-1,2,3,4-tetrahydro-2-naphthalenylcarbamate | C12H13NO3 | 详情 | 详情 | |
| (XXXV) | 36647 | methyl (1R,2S)-1-(4-chloro-3-methoxyphenyl)-1-hydroxy-1,2,3,4-tetrahydro-2-naphthalenylcarbamate | C19H20ClNO4 | 详情 | 详情 | |
| (XXXVI) | 36648 | methyl (2S)-1-(4-chloro-3-methoxyphenyl)-1,2,3,4-tetrahydro-2-naphthalenylcarbamate | C19H20ClNO3 | 详情 | 详情 | |
| (XXXVII) | 36649 | (2S)-1-(4-chloro-3-methoxyphenyl)-N-methyl-1,2,3,4-tetrahydro-2-naphthalenamine; N-[(2S)-1-(4-chloro-3-methoxyphenyl)-1,2,3,4-tetrahydro-2-naphthalenyl]-N-methylamine | C18H20ClNO | 详情 | 详情 | |
| (XXXVIII) | 36640 | N-[(1S,2S)-1-(4-chloro-3-methoxyphenyl)-1,2,3,4-tetrahydro-2-naphthalenyl]-N-(2,2-dimethoxyethyl)-N-methylamine; (1S,2S)-1-(4-chloro-3-methoxyphenyl)-N-(2,2-dimethoxyethyl)-N-methyl-1,2,3,4-tetrahydro-2-naphthalenamine | C22H28ClNO3 | 详情 | 详情 | |
| (XXXIX) | 36642 | (2S)-2-amino-4-phenylbutyric acid | 943-73-7 | C10H13NO2 | 详情 | 详情 |