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【结 构 式】 
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【药物名称】Ecopipam, Sch-39166 【化学名称】(-)-(6aS,13bR)-11-Chloro-12-hydroxy-7-methyl-6,6a,7,8,9,13b-hexahydro-5H-benzo[d]naphtho[2,1-d]azepine 【CA登记号】112108-01-7, 190133-94-9 (HCl), 112108-00-6 (trans-isomer), 112107-92-3 (undefined stereoch.) 【 分 子 式 】C19H20ClNO 【 分 子 量 】313.83035 |
【开发单位】Schering-Plough (Originator) 【药理作用】Antiobesity Drugs, METABOLIC DRUGS, Treatment of Cocaine Dependency, Treatment of Nutritional Disorders, TREATMENT OF POISONING, DRUG ABUSE & DEPENDENCY, Treatment of Substance Dependency, Dopamine D1 Antagonists, Dopamine D5 Antagonists |
合成路线1
Acylation of the chiral aminodiol (I) with acid chloride (II) gave amide (III), which was reduced to amine (IV) by means of NaBH4 and AcOH. Cyclization of (IV) using HF and BF3 then produced benzazepine (V). Reductive N-methylation of (V) was accomplished by the Eschweiler-Clarke procedure using formaldehyde and formic acid. The resulting aminoalcohol (VI) was converted to mesylate (VII) and subsequently treated with NaCN in DMSO to generate nitrile (VIII). Acid hydrolysis of the nitrile (VIII) to the corresponding carboxylic acid (IX), followed by treatment with SOCl2 afforded acid chloride (X), which was cyclized in the presence of AlCl3 to produce the tetracyclic system (XI). The ketone function of (XI) was then reduced to (XII) using BH3 and trifluoroacetic acid. Further demethylation of the methyl ether of (XII) with either BBr3 or AlCl3 yielded the title compound.
| 【1】 Wu, G.; et al.; Amino diol based asymetric syntheses of a fused benzazepine as a selective D1 dopamine receptor. Org Process Res Dev 1997, 1, 5, 359. |
| 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) | 31768 | (1S,2S)-2-amino-1-phenyl-1,3-propanediol | 28143-91-1 | C9H13NO2 | 详情 | 详情 |
| (II) | 31769 | 2-(3-chloro-4-methoxyphenyl)acetyl chloride | C9H8Cl2O2 | 详情 | 详情 | |
| (III) | 31770 | 2-(3-chloro-4-methoxyphenyl)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]acetamide | C18H20ClNO4 | 详情 | 详情 | |
| (IV) | 31771 | (1S,2S)-2-[(3-chloro-4-methoxyphenethyl)amino]-1-phenyl-1,3-propanediol | C18H22ClNO3 | 详情 | 详情 | |
| (V) | 31772 | [(1R,2R)-7-chloro-8-methoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-yl]methanol | C18H20ClNO2 | 详情 | 详情 | |
| (VI) | 31773 | [(1R,2R)-7-chloro-8-methoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-yl]methanol | C19H22ClNO2 | 详情 | 详情 | |
| (VII) | 31774 | (4R,5R)-8-chloro-3-methyl-4-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)-5-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl methyl ether; (1R,2R)-7-chloro-8-methoxy-3-methyl-2-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine | C22H28ClNO2S | 详情 | 详情 | |
| (VIII) | 31775 | 2-[(1R,2S)-7-chloro-8-methoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-yl]acetonitrile | C20H21ClN2O | 详情 | 详情 | |
| (IX) | 31776 | 2-[(1R,2S)-7-chloro-8-methoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-yl]acetic acid | C20H22ClNO3 | 详情 | 详情 | |
| (X) | 31777 | 2-[(1R,2S)-7-chloro-8-methoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-yl]acetyl chloride | C20H21Cl2NO2 | 详情 | 详情 | |
| (XI) | 31778 | (3aS,9bS)-12-chloro-11-methoxy-3-methyl-1,2,3,3a,4,9b-hexahydro-5H-naphtho[1,2-a][3]benzazepin-5-one | C20H20ClNO2 | 详情 | 详情 | |
| (XII) | 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2
Alternatively, nitrile (VIII) was converted to ester (XIII) upon treatment with H2SO4 and MeOH. Ester reduction employing lithium borohydride afforded alcohol (XIV). This was chlorinated with PCl5 and then cyclized and demethylated using AlCl3.
| 【1】 Wu, G.; et al.; Amino diol based asymetric syntheses of a fused benzazepine as a selective D1 dopamine receptor. Org Process Res Dev 1997, 1, 5, 359. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 31775 | 2-[(1R,2S)-7-chloro-8-methoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-yl]acetonitrile | C20H21ClN2O | 详情 | 详情 | |
| (XIII) | 31780 | methyl 2-[(1R,2S)-7-chloro-8-methoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-yl]acetate | C21H24ClNO3 | 详情 | 详情 | |
| (XIV) | 31781 | 2-[(1R,2S)-7-chloro-8-methoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-yl]-1-ethanol | C20H24ClNO2 | 详情 | 详情 |
合成路线3
In a different approach, starting from the chiral oxazolidine (XV), conversion to the corresponding mesylate and further displacement by NaCN afforded nitrile (XVI). Acid hydrolysis of the oxazolidine (XVI) and esterification with MeOH produced aminoester (XVII). This was acylated with acid chloride (II) to yield a mixture of amide-ester (XVIII) and amide-lactone (XIX). Reduction of this mixture with NaBH4 and AcOH furnished diol (XX), which was cyclized employing BF3 in methanesulfonic acid. The resulting benzazepine (XXI) was reductively methylated under Schweiler-Clarke conditions to give (XIV). Finally, chlorination with PCl5, followed by cyclization and demethylation with AlCl3 provided the title compound.
| 【1】 Wu, G.; et al.; Amino diol based asymetric syntheses of a fused benzazepine as a selective D1 dopamine receptor. Org Process Res Dev 1997, 1, 5, 359. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 31769 | 2-(3-chloro-4-methoxyphenyl)acetyl chloride | C9H8Cl2O2 | 详情 | 详情 | |
| (XIV) | 31781 | 2-[(1R,2S)-7-chloro-8-methoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-yl]-1-ethanol | C20H24ClNO2 | 详情 | 详情 | |
| (XV) | 31782 | [(4S,5S)-2-methyl-5-phenyl-4,5-dihydro-1,3-oxazol-4-yl]methanol | 53732-41-5 | C11H13NO2 | 详情 | 详情 |
| (XVI) | 31783 | 2-[(4S,5S)-2-methyl-5-phenyl-4,5-dihydro-1,3-oxazol-4-yl]acetonitrile | C12H12N2O | 详情 | 详情 | |
| (XVII) | 31784 | methyl (3S,4S)-3-amino-4-hydroxy-4-phenylbutanoate | C11H15NO3 | 详情 | 详情 | |
| (XVIII) | 31785 | methyl (3S,4S)-3-[[2-(3-chloro-4-methoxyphenyl)acetyl]amino]-4-hydroxy-4-phenylbutanoate | C20H22ClNO5 | 详情 | 详情 | |
| (XIX) | 31786 | 2-(3-chloro-4-methoxyphenyl)-N-[(2R,3S)-5-oxo-2-phenyltetrahydro-3-furanyl]acetamide | C19H18ClNO4 | 详情 | 详情 | |
| (XX) | 31787 | (1S,2S)-2-[(3-chloro-4-methoxyphenethyl)amino]-1-phenyl-1,4-butanediol | C19H24ClNO3 | 详情 | 详情 | |
| (XXI) | 31788 | 2-[(1R,2S)-7-chloro-8-methoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-yl]-1-ethanol | C19H22ClNO2 | 详情 | 详情 |
合成路线4
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
The Grignard condensation of 1-tetralone (IX) with 4-chloro-3-methoxyphenylmagnesium bromide (X) in THF followed by a treatment with TsOH gives 4-(4-chloro-3-methoxyphenyl)-1,2-dihydronaphthalene (XI), which is oxidized with oxone and TsOH yielding the 2-tetralone (XII). The condensation of (XII) with 2-aminoacetaldehyde dimethylacetal (XIII) in toluene affords the enamine (XIV), which is reduced with BH3 / t-Bu-NH2 and AcOH in dichloromethane to give a 9:1 mixture of cis (XV) and trans (XVI) isomers that is epimerized with t-BuOK in DMSO/DMF to a 15:85 mixture from which the desired trans-diastereomer (XVI) is isolated. The cyclization of (XVI) with CH3SO3H in dichloromethane affords the tetracyclic compound (XVII), which is hydrogenated with BH3 / t-Bu-NH2 to provide the intermediate (XVIII). Finally, this compound is methylated with formaldehyde and formic acid to obtain the previously reported rac-(VIII) compound.
| 【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 . |
| 【2】 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): 1. Aziridinium salt based syntheses. Org Process Res Dev 1998, 2, 3, 175. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (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 | |
| (IX) | 20720 | 3,4-dihydro-1(2H)-naphthalenone | 529-34-0 | C10H10O | 详情 | 详情 |
| (X) | 36624 | bromo(4-chloro-3-methoxyphenyl)magnesium | C7H6BrClMgO | 详情 | 详情 | |
| (XI) | 36625 | 4-(4-chloro-3-methoxyphenyl)-1,2-dihydronaphthalene; 2-chloro-5-(3,4-dihydro-1-naphthalenyl)phenyl methyl ether | C17H15ClO | 详情 | 详情 | |
| (XII) | 36626 | 1-(4-chloro-3-methoxyphenyl)-3,4-dihydro-2(1H)-naphthalenone | C17H15ClO2 | 详情 | 详情 | |
| (XIII) | 34158 | aminoacetaldehyde dimethylacetal; 2,2-dimethoxy-1-ethanamine; 2,2-dimethoxyethylamine | 22483-09-6 | C4H11NO2 | 详情 | 详情 |
| (XIV) | 36627 | N-[1-(4-chloro-3-methoxyphenyl)-3,4-dihydro-2-naphthalenyl]-N-(2,2-dimethoxyethyl)amine; 1-(4-chloro-3-methoxyphenyl)-N-(2,2-dimethoxyethyl)-3,4-dihydro-2-naphthalenamine | C21H24ClNO3 | 详情 | 详情 | |
| (XV) | 36628 | N-[(1R,2S)-1-(4-chloro-3-methoxyphenyl)-1,2,3,4-tetrahydro-2-naphthalenyl]-N-(2,2-dimethoxyethyl)amine; (1R,2S)-1-(4-chloro-3-methoxyphenyl)-N-(2,2-dimethoxyethyl)-1,2,3,4-tetrahydro-2-naphthalenamine | C21H26ClNO3 | 详情 | 详情 | |
| (XVI) | 36629 | (1S,2S)-1-(4-chloro-3-methoxyphenyl)-N-(2,2-dimethoxyethyl)-1,2,3,4-tetrahydro-2-naphthalenamine; N-[(1S,2S)-1-(4-chloro-3-methoxyphenyl)-1,2,3,4-tetrahydro-2-naphthalenyl]-N-(2,2-dimethoxyethyl)amine | C21H26ClNO3 | 详情 | 详情 | |
| (XVII) | 36630 | (3aS,9bR)-12-chloro-3a,4,5,9b-tetrahydro-3H-naphtho[1,2-a][3]benzazepin-11-yl methyl ether; (3aS,9bR)-12-chloro-11-methoxy-3a,4,5,9b-tetrahydro-3H-naphtho[1,2-a][3]benzazepine | C19H18ClNO | 详情 | 详情 | |
| (XVIII) | 36631 | (3aS,9bR)-12-chloro-2,3,3a,4,5,9b-hexahydro-1H-naphtho[1,2-a][3]benzazepin-11-yl methyl ether; (3aS,9bR)-12-chloro-11-methoxy-2,3,3a,4,5,9b-hexahydro-1H-naphtho[1,2-a][3]benzazepine | C19H20ClNO | 详情 | 详情 |
合成路线6
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7
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 |