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【结 构 式】 
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【药物名称】LY-367265 【化学名称】1-[2-[4-(6-Fluoro-1H-indol-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]ethyl]-5,6-dihydro-1H,4H-[1,2,5]thiadiazolo[4,3,2-ij]quinoline 2,2-dioxide 【CA登记号】210751-39-6, 210751-40-9 (phosphate (1:1) salt) 【 分 子 式 】C24H25FN4O2S 【 分 子 量 】452.55485 |
【开发单位】Lilly (Originator) 【药理作用】Antidepressants, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, 5-HT2A Antagonists, Serotonine Transporter (SERT) Inhibitors |
合成路线1
The indole intermediate (V) has been obtained as follows: The reaction of 4-fluoro-2-nitrotoluene (I) with dimethylformamide dimethylacetal afforded enamine (II). Reductive cyclization of (II) by hydrogenation over Pd/C produced 6-fluoroindole (III). Subsequent condensation of indole (III) with piperidone monohydrate (IV) in the presence of KOH furnished the intermediate indolyl tetrahydropyridine (V).
| 【1】 Fairhurst, J. (Eli Lilly and Company); Substd. 4-(6-fluoro-(1H)-indol-3-yl)-1,2,3,6-tetrahydropyridine for the treatment of CNS-disorders. EP 0854146; WO 9831686 . |
| 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) | 48011 | 4-fluoro-1-methyl-2-nitrobenzene | 446-10-6 | C7H6FNO2 | 详情 | 详情 |
| (II) | 48012 | N-[(E)-2-(4-fluoro-2-nitrophenyl)ethenyl]-N,N-dimethylamine; (E)-2-(4-fluoro-2-nitrophenyl)-N,N-dimethyl-1-ethenamine | C10H11FN2O2 | 详情 | 详情 | |
| (III) | 48013 | 6-Fluoroindole; 6-Fluoro-1H-indole | 399-51-9 | C8H6FN | 详情 | 详情 |
| (IV) | 18178 | 4,4-piperidinediol | 73390-11-1 | C5H11NO2 | 详情 | 详情 |
| (V) | 18014 | tert-butyl 4-[2-[2-([[(2S)-2-[[(2-bromo-4-methylphenyl)sulfonyl]amino]-3-(tert-butoxy)-3-oxopropyl]amino]carbonyl)-4-oxo-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl]ethyl]-1-piperidinecarboxylate | C34H49BrN6O8S | 详情 | 详情 |
合成路线2
8-Amino-1,2,3,4-tetrahydroquinoline (VII) was obtained by catalytic hydrogenation of 8-nitroquinoline (VI) over PtO2. Condensation of (VII) with sulfamide in diglyme at 160 C gave rise to the tricyclic system (VIII), which was further alkylated with 1-bromo-2-chloroethane in the presence of NaH to yield chloride (IX). Finally, condensation between tetrahydropyridine (V) and chloride (IX) afforded the title compound.
| 【1】 Fairhurst, J. (Eli Lilly and Company); Substd. 4-(6-fluoro-(1H)-indol-3-yl)-1,2,3,6-tetrahydropyridine for the treatment of CNS-disorders. EP 0854146; WO 9831686 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 48014 | 6-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole | C13H13FN2 | 详情 | 详情 | |
| (VI) | 48015 | 8-nitroquinoline | 607-35-2 | C9H6N2O2 | 详情 | 详情 |
| (VII) | 48016 | 1,2,3,4-tetrahydro-8-quinolinamine; 1,2,3,4-tetrahydro-8-quinolinylamine | 54012-92-9 | C9H12N2 | 详情 | 详情 |
| (VIII) | 48017 | 5,6-dihydro-4H-2lambda(6)-[1,2,5]thiadiazolo[4,3,2-ij]quinoline-2,2(1H)-dione | C9H10N2O2S | 详情 | 详情 | |
| (IX) | 48018 | 1-(2-chloroethyl)-5,6-dihydro-4H-2lambda(6)-[1,2,5]thiadiazolo[4,3,2-ij]quinoline-2,2(1H)-dione | C11H13ClN2O2S | 详情 | 详情 |