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【结 构 式】 
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【药物名称】ORG-25935 【化学名称】cis-N-(6-Methoxy-1-phenyl-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-N-methylglycine hydrochloride 【CA登记号】258887-13-7 ((+)-(R*,S*)-isomer), 258886-37-2 (diastereomer), 258886-39-4 (diastereomer) 【 分 子 式 】C21H26ClNO3 【 分 子 量 】375.89927 |
【开发单位】Organon (Originator) 【药理作用】Antipsychotic Drugs, PSYCHOPHARMACOLOGIC DRUGS, GlyT-1 Inhibitors |
合成路线1
Conjugate addition of methyl acrylate (II) to 3-methoxybenzaldehyde (I) under reversion of reactivity conditions in the presence of KCN produced the keto ester (III). The Wolff-Kishner reduction of the keto group caused simultaneous ester hydrolysis, yielding acid (IV), which was further cyclized to the tetralone (V) employing hot polyphosphoric acid. Mannich reaction of ketone (V) with N-benzyl methylamine and paraformaldehyde furnished amino ketone (VI). To this was added phenylmagnesium bromide (VII), yielding amino alcohol (VIII), which was subsequently dehydrated to (IX) by means of trifluoroacetic acid. Catalytic hydrogenation of the olefin double bond of (IX) with simultaneous N-benzyl group hydrogenolysis gave the secondary amine (X). This was then alkylated with ethyl bromoacetate, producing the substituted glycine ester (XI), which was finally hydrolyzed by means of LiOH.
| 【1】 Jaap, D.R.; Gilfillan, R.; Gibson, S.G.; Thorn, S.N. (Akzo Nobel N.V.); Aminomethylcarboxylic acid derivs.. EP 1100769; WO 0007978 . |
| 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) | 14156 | methyl acrylate | 96-33-3 | C4H6O2 | 详情 | 详情 |
| (III) | 51352 | methyl 4-(3-methoxyphenyl)-4-oxobutanoate | C12H14O4 | 详情 | 详情 | |
| (IV) | 51353 | 4-(3-methoxyphenyl)butyric acid | C11H14O3 | 详情 | 详情 | |
| (V) | 17594 | 6-methoxy-3,4-dihydro-1(2H)-naphthalenone; 6-Methoxytetralone; 6-Methoxy-1-tetralone; 3,4-dihydro-6-methoxy-1(2H)-naphthalenone | 1078-19-9 | C11H12O2 | 详情 | 详情 |
| (VI) | 51354 | 2-[[benzyl(methyl)amino]methyl]-6-methoxy-3,4-dihydro-1(2H)-naphthalenone | C20H23NO2 | 详情 | 详情 | |
| (VII) | 17616 | bromo(phenyl)magnesium; Phenyl Magnesium Bromide | 100-58-3 | C6H5BrMg | 详情 | 详情 |
| (VIII) | 51355 | 2-[[benzyl(methyl)amino]methyl]-6-methoxy-1-phenyl-1,2,3,4-tetrahydro-1-naphthalenol | C26H29NO2 | 详情 | 详情 | |
| (IX) | 51356 | N-benzyl(6-methoxy-1-phenyl-3,4-dihydro-2-naphthalenyl)-N-methylmethanamine; N-benzyl-N-[(6-methoxy-1-phenyl-3,4-dihydro-2-naphthalenyl)methyl]-N-methylamine | C26H27NO | 详情 | 详情 | |
| (X) | 51357 | [(1S,2R)-6-methoxy-1-phenyl-1,2,3,4-tetrahydro-2-naphthalenyl]-N-methylmethanamine; N-[[(1S,2R)-6-methoxy-1-phenyl-1,2,3,4-tetrahydro-2-naphthalenyl]methyl]-N-methylamine | C19H23NO | 详情 | 详情 | |
| (XI) | 51358 | ethyl 2-[[[(1S,2R)-6-methoxy-1-phenyl-1,2,3,4-tetrahydro-2-naphthalenyl]methyl](methyl)amino]acetate | C23H29NO3 | 详情 | 详情 |