|
【结 构 式】 
|
【药物名称】 【化学名称】(-)-trans-N,N'-(1,8-Octanediyl)bis[4-(4-chlorophenyl)-1-methylpiperidine-3-carboxamide] 【CA登记号】 【 分 子 式 】C34H48Cl2N4O2 【 分 子 量 】615.69326 |
【开发单位】Georgetown University (Originator), UT Medical Branch at Galveston (Originator) 【药理作用】Antidepressants, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, 5-HT Reuptake Inhibitors |
合成路线1
Addition of 4-chlorophenylmagnesium bromide (II) to arecoline (I) in Et2O at -10 C afforded the corresponding 4-arylpiperidine-3-carboxylate as a mixture of trans (III) and cis (IV) isomers. After chromatographic isolation of the racemic cis isomer (IV), resolution employing dibenzoyl-D-tartaric acid furnished the dextro enantiomer (cis)(+)-(IV). Its epimerization in the presence of NaOMe produced a 1:5.6 mixture of cis/trans isomers, from which the major compound (-)-(trans)(III) was isolated by flash chromatography. Acid hydrolysis of its methyl ester group provided carboxylic acid (V), that was further converted to acid chloride (VI) using oxalyl chloride (1,2). Finally, coupling of (VI) with 1,8-octanediamine (VII) gave the title diamide.
| 【1】 Tamiz, A.P.; Johnson, K.M.; Wang, C.Z.; Kozikowski, A.P.; Zhang, J.; Zhang, M.; Application of the bivalent ligand approach to the design of novel dimeric serotonin reuptake inhibitors. J Am Chem Soc 2000, 122, 22, 5393. |
| 【2】 Tamiz, A.P.; Araldi, G.L.; Kozikowski, A.P. (Georgetown University); Monomeric and dimeric heterocycles, and therapeutic uses thereof. WO 0020390 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (rac)-(III) | 41630 | (rac)-methyl (3S*,4R*)-4-(4-chlorophenyl)-1-methyl-3-piperidinecarboxylate | n/a | C14H18ClNO2 | 详情 | 详情 |
| (rac)-(IV) | 41631 | (rac)-methyl (3R*,4R*)-4-(4-chlorophenyl)-1-methyl-3-piperidinecarboxylate | C14H18ClNO2 | 详情 | 详情 | |
| (+)-(IV) | 41632 | (+)-methyl (3R,4R)-4-(4-chlorophenyl)-1-methyl-3-piperidinecarboxylate | C14H18ClNO2 | 详情 | 详情 | |
| (-)-(III) | 41633 | (-)-methyl (3S,4R)-4-(4-chlorophenyl)-1-methyl-3-piperidinecarboxylate | C14H18ClNO2 | 详情 | 详情 | |
| (I) | 25127 | bromo(4-chlorophenyl)magnesium | 873-77-8 | C6H4BrClMg | 详情 | 详情 |
| (I) | 38648 | methyl 1-methyl-1,2,5,6-tetrahydro-3-pyridinecarboxylate | C8H13NO2 | 详情 | 详情 | |
| (V) | 41634 | (3S,4R)-4-(4-chlorophenyl)-1-methyl-3-piperidinecarboxylic acid | C13H16ClNO2 | 详情 | 详情 | |
| (VI) | 41635 | (3S,4R)-4-(4-chlorophenyl)-1-methyl-3-piperidinecarbonyl chloride | C13H15Cl2NO | 详情 | 详情 | |
| (VII) | 20965 | 1,8-octanediamine; 8-aminooctylamine | 373-44-4 | C8H20N2 | 详情 | 详情 |