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【结 构 式】 
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【药物名称】SB-269652 【化学名称】trans-N-[4-[2-(7-Cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-1H-indole-2-carboxamide 【CA登记号】215802-15-6 【 分 子 式 】C27H30N4O 【 分 子 量 】426.56635 |
【开发单位】GlaxoSmithKline (Originator) 【药理作用】Antipsychotic Drugs, PSYCHOPHARMACOLOGIC DRUGS, Dopamine D3 Antagonists |
合成路线1
Tetrahydroisoquinoline (II) was prepared by intramolecular cyclization of N-trifluoroacetyl 4-bromophenethylamine (I) with paraformaldehyde in acetic/ sulfuric acid. Displacement of the bromine atom of (II) with CuCN in boiling N-methyl-2-pyrrolidinone produced nitrile (III). The trifluoroacetyl group og (III) was then removed by means of K2CO3 in aqueous methanol, yielding the intermediate isoquinoline (IV).
| 【1】 Stokker, G.E.; Preparation of 1,2,3,4-tetrahydroisoquinolines lacking electron donating groups - an intramolecular cyclization complementary to the Pictet-Spengler reaction. Tetrahedron Lett 1996, 37, 31, 5453. |
| 【2】 Branch, C.L.; Stemp, G.; Johnson, C.N. (SmithKline Beecham plc); Tetrahydroisoquinoline derivs. as modulators of dopamine D3 receptors. EP 0983244; WO 9850364 . |
| 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) | 33023 | N-(4-bromophenethyl)-2,2,2-trifluoroacetamide | C10H9BrF3NO | 详情 | 详情 | |
| (II) | 33024 | 1-[7-bromo-3,4-dihydro-2(1H)-isoquinolinyl]-2,2,2-trifluoro-1-ethanone | C11H9BrF3NO | 详情 | 详情 | |
| (III) | 33025 | 2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro-7-isoquinolinecarbonitrile | C12H9F3N2O | 详情 | 详情 | |
| (IV) | 33026 | 1,2,3,4-tetrahydro-7-isoquinolinecarbonitrile | C10H10N2 | 详情 | 详情 |
合成路线2
Swern oxidation of hydroxy ketal (V) led to aldehyde (VI), which was reductively condensed with tetrahydroquinoline (IV) in the presence of sodium triacetoxyborohydride to produce the N-alkylated quinoline (VII). Acid hydrolysis of the ethylene ketal of (VII) afforded the corresponding ketone (VIII). Subsequent reductive amination of (VIII) with ammonium acetate in the presence of sodium borohydride furnished the primary amine (IXa-b) as a mixture of cis and trans isomers. Coupling of (IXa-b) with indole-2-carboxylic acid (X) employing EDC and HOBt yielded the corresponding amide as a mixture of geometric isomers. The target trans isomer was finally isolated by chromatography on silica gel.
| 【1】 Branch, C.L.; Stemp, G.; Johnson, C.N. (SmithKline Beecham plc); Tetrahydroisoquinoline derivs. as modulators of dopamine D3 receptors. EP 0983244; WO 9850364 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IXa) | 33031 | 2-[2-(4-aminocyclohexyl)ethyl]-1,2,3,4-tetrahydro-7-isoquinolinecarbonitrile | C18H25N3 | 详情 | 详情 | |
| (IXb) | 33032 | 2-[2-(4-aminocyclohexyl)ethyl]-1,2,3,4-tetrahydro-7-isoquinolinecarbonitrile | C18H25N3 | 详情 | 详情 | |
| (IV) | 33026 | 1,2,3,4-tetrahydro-7-isoquinolinecarbonitrile | C10H10N2 | 详情 | 详情 | |
| (V) | 33027 | 2-(1,4-dioxaspiro[4.5]dec-8-yl)-1-ethanol | C10H18O3 | 详情 | 详情 | |
| (VI) | 33028 | 2-(1,4-dioxaspiro[4.5]dec-8-yl)acetaldehyde | C10H16O3 | 详情 | 详情 | |
| (VII) | 33029 | 2-[2-(1,4-dioxaspiro[4.5]dec-8-yl)ethyl]-1,2,3,4-tetrahydro-7-isoquinolinecarbonitrile | C20H26N2O2 | 详情 | 详情 | |
| (VIII) | 33030 | 2-[2-(4-oxocyclohexyl)ethyl]-1,2,3,4-tetrahydro-7-isoquinolinecarbonitrile | C18H22N2O | 详情 | 详情 | |
| (X) | 25226 | 1H-Indole-2-carboxylic acid; Indole-2-carboxylic acid | 1477-50-5 | C9H7NO2 | 详情 | 详情 |
合成路线3
An alternative procedure started from trans-4-aminocyclohexylacetic acid hydrogen sulfate (XI), which was esterified with methanol and sulfuric acid to give aminoester (XII). Protection of the amino group of (XII) as the tert-butyl carbamate (XIII), followed by ester reduction with DIBAL gave rise to aldehyde (XIV). Reductive condensation of (XIV) with tetrahydroisoquinoline (IV) provided (XV). The Boc group of (XV) was then cleaved with trifluoroacetic acid to furnish the trans amine (XVI). This was finally converted to the target compound by coupling with indole-2-carboxylic acid (X) as above.
| 【1】 Stokker, G.E.; Preparation of 1,2,3,4-tetrahydroisoquinolines lacking electron donating groups - an intramolecular cyclization complementary to the Pictet-Spengler reaction. Tetrahedron Lett 1996, 37, 31, 5453. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 33026 | 1,2,3,4-tetrahydro-7-isoquinolinecarbonitrile | C10H10N2 | 详情 | 详情 | |
| (X) | 25226 | 1H-Indole-2-carboxylic acid; Indole-2-carboxylic acid | 1477-50-5 | C9H7NO2 | 详情 | 详情 |
| (XI) | 33033 | 2-(4-aminocyclohexyl)acetic acid | C8H15NO2 | 详情 | 详情 | |
| (XII) | 33034 | methyl 2-(4-aminocyclohexyl)acetate | C9H17NO2 | 详情 | 详情 | |
| (XIII) | 33035 | methyl 2-[4-[(tert-butoxycarbonyl)amino]cyclohexyl]acetate | C14H25NO4 | 详情 | 详情 | |
| (XIV) | 33036 | tert-butyl 4-(2-oxoethyl)cyclohexylcarbamate | C13H23NO3 | 详情 | 详情 | |
| (XV) | 33037 | tert-butyl 4-[2-[7-cyano-3,4-dihydro-2(1H)-isoquinolinyl]ethyl]cyclohexylcarbamate | C23H33N3O2 | 详情 | 详情 | |
| (XVI) | 33038 | 2-[2-(4-aminocyclohexyl)ethyl]-1,2,3,4-tetrahydro-7-isoquinolinecarbonitrile | C18H25N3 | 详情 | 详情 |