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【结 构 式】 
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【药物名称】SB-277011-A, SB-277011 【化学名称】trans-N-[4-[2-(6-Cyano-1,2,3,4-tetrahydro-2-isoquinolinyl)ethyl]cyclohexyl]quinoline-4-carboxamide 【CA登记号】 【 分 子 式 】C28H30N4O 【 分 子 量 】438.5775 |
【开发单位】GlaxoSmithKline (Originator) 【药理作用】Antipsychotic Drugs, PSYCHOPHARMACOLOGIC DRUGS, Dopamine D3 Antagonists |
合成路线1
Esterification of trans-4-aminocyclohexylacetic acid (I), followed by protection of the resulting amino ester (II) with di-tert-butyl dicarbonate, afforded carbamate (III). Ester (III) reduction using DIBAL then gave aldehyde (IV) (1,2). 6-Cyano-1,2,3,4-tetrahydroisoquinoline (VII) was prepared by acylation of 6-bromotetrahydroisoquinoline (V) with trifluoroacetic anhydride to give amide (VI). Bromide displacement in (VI) with CuCN in NMP, followed by hydrolysis of the trifluoroacetamido group, furnished (VII) (1). Reductive condensation between amine (VII) and aldehyde (IV) in the presence of NaBH(OAc)3 gave adduct (VIII). The Boc protecting group of (VIII) was then removed by treatment with trifluoroacetic acid, yielding amine (IX). This was finally coupled with 4-quinolinecarboxylic acid (X) by means of EDC and HOBt.
| 【2】 Branch, C.L.; Stemp, G.; Johnson, C.N. (SmithKline Beecham plc); Tetrahydroisoquinoline derivs. as modulators of dopamine D3 receptors. EP 0983244; WO 9850364 . |
| 【1】 Branch, C.L.; Stemp, G.; Ashmeade, T.; et al.; Design and synthesis of trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarboxamide (SB-277011): A potent and selective dopamine D3 receptor antagonist with high oral bioavailability and CNS penetration in the rat. J Med Chem 2000, 43, 9, 1878. |
| 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) | 33033 | 2-(4-aminocyclohexyl)acetic acid | C8H15NO2 | 详情 | 详情 | |
| (II) | 33034 | methyl 2-(4-aminocyclohexyl)acetate | C9H17NO2 | 详情 | 详情 | |
| (III) | 33035 | methyl 2-[4-[(tert-butoxycarbonyl)amino]cyclohexyl]acetate | C14H25NO4 | 详情 | 详情 | |
| (IV) | 33036 | tert-butyl 4-(2-oxoethyl)cyclohexylcarbamate | C13H23NO3 | 详情 | 详情 | |
| (V) | 45796 | 6-bromo-1,2,3,4-tetrahydroisoquinoline | C9H10BrN | 详情 | 详情 | |
| (VI) | 45797 | 1-[6-bromo-3,4-dihydro-2(1H)-isoquinolinyl]-2,2,2-trifluoro-1-ethanone | C11H9BrF3NO | 详情 | 详情 | |
| (VII) | 45798 | 1,2,3,4-tetrahydro-6-isoquinolinecarbonitrile | C10H10N2 | 详情 | 详情 | |
| (VIII) | 45799 | tert-butyl 4-[2-[6-cyano-3,4-dihydro-2(1H)-isoquinolinyl]ethyl]cyclohexylcarbamate | C23H33N3O2 | 详情 | 详情 | |
| (IX) | 45800 | 2-[2-(4-aminocyclohexyl)ethyl]-1,2,3,4-tetrahydro-6-isoquinolinecarbonitrile | C18H25N3 | 详情 | 详情 | |
| (X) | 45801 | 4-quinolinecarboxylic acid | 486-74-8 | C10H7NO2 | 详情 | 详情 |