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【结 构 式】 
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【药物名称】Ipidacrine hydrochloride hydrate, Amiridine, NIK-247, Senita 【化学名称】9-Amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinoline hydrochloride monohydrate 【CA登记号】62732-44-9 (anhydrous free base), 90043-86-0 (anhydrous monoHCl salt), 118499-70-0 (monoHCl monohydrate) 【 分 子 式 】C12H19ClN2O 【 分 子 量 】242.75103 |
【开发单位】Nauchno-Issledovatelsky Institut (Originator), Nikken Chemicals (Licensee) 【药理作用】Alzheimer's Dementia, Treatment of , Cognition Disorders, Treatment of, NEUROLOGIC DRUGS, Acetylcholinesterase Inhibitors |
合成路线1
By reaction of 2-aminocyclopent-1-ene-1-carbonitrile (I) with cyclohexanone (II) in presence of polyphosphoric acid in benzene followed by treatment with hydrochloric acid in ethanol.
| 【1】 (Nauchno-Issledovatelsky Institut); 9-Amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta(b)quinoline monohydrate hydrochloride as stimulant of neuro-muscular transmission of smooth muscles. US 4550113 . |
| 【2】 Lavretskaya, E.F.; Upadysheva, A.V.; Znamenskaya, A.P.; Sukhanova, S.A.; Grigorieva, N.D.; Penke, I.K.; Timofeeva, A.K. (Nauchno-Issledovatelsky Institut); Pharmaceutical preparation for learning stimulation and memory improvement. GB 2192129; US 4735953 . |
| 【3】 Graul, A.; Castaner, J.; Prous, J.; NIK-247. Drugs Fut 1994, 19, 4, 343. |
合成路线2
The monohydroxylated metabolite of NIK-247, (+)-9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinolin-8-ol (VI) has been synthesized as follows: The condensation of cyclohexane-1,3-dione (I) with 2-amino-1-cyclopentene-1-carbonitrile (II) by means of PPE gives 2-(3-oxo-1-cyclohexen-1-yl)-1-cyclopentene-1-carbonitrile (III), which is cyclized by means of BF3.Et2O to yield 9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinolin-8-one (IV). The reduction of (IV) with NaBH4 affords the corresponding racemic alcohol (V), which is submitted to optical resolution with (+)-di-p-toluyltartaric acid to give the desired compound (VI).
| 【1】 Inada, H.; Yano, M.; Komatsu, T.; Iwamoto, M.; Suzuki, K.; Okada, K.; Synthesis of estimated metabolites of 9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinoline monohydrochloride monohydrate (NIK-247). I.Synthesis of mono-hydroxylated metabolites. Yakugaku Zasshi 1995, 115, 12, 1016. |
| 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) | 11244 | 1,3-Cyclohexanedione | 504-02-9 | C6H8O2 | 详情 | 详情 |
| (II) | 11242 | 2-Amino-1-cyclopentene-1-carbonitrile | C6H8N2 | 详情 | 详情 | |
| (III) | 11246 | 2-[(3-Oxo-1-cyclohexen-1-yl)amino]-1-cyclopentene-1-carbonitrile | C12H14N2O | 详情 | 详情 | |
| (IV) | 11247 | 9-Amino-1,2,3,5,6,7-hexahydro-8H-cyclopenta[b]quinolin-8-one | C12H14N2O | 详情 | 详情 | |
| (V) | 11248 | 9-Amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinolin-8-ol | C12H16N2O | 详情 | 详情 | |
| (VI) | 63081 | (+)-9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinolin-8-ol | C12H16N2O | 详情 | 详情 |
合成路线3
The monohydroxylated metabolite of NIK-247, (+)-9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinolin-1-ol (XII) has been synthesized as follows: The condensation of cyclopentane-1,3-dione (VIII) with 2-amino-1-cyclohexene-1-carbonitrile (VII) by means of PPE gives 2-(3-oxo-1-cyclopenten-1-yl)-1-cyclohexene-1-carbonitrile (IX), which is cyclized by means of BF3.Et2O to yield 9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinolin-1-one (X). The reduction of (X) with NaBH4 affords the corresponding racemic alcohol (XI), which is submitted to optical resolution with (+)-di-p-toluyltartaric acid to give the desired compound (XII).
| 【1】 Inada, H.; Yano, M.; Komatsu, T.; Iwamoto, M.; Suzuki, K.; Okada, K.; Synthesis of estimated metabolites of 9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinoline monohydrochloride monohydrate (NIK-247). I.Synthesis of mono-hydroxylated metabolites. Yakugaku Zasshi 1995, 115, 12, 1016. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 11250 | 2-Amino-1-cyclohexene-1-carbonitrile | C7H10N2 | 详情 | 详情 | |
| (VIII) | 11251 | 1,3-Cyclopentanedione | 3859-41-4 | C5H6O2 | 详情 | 详情 |
| (IX) | 11252 | 2-[(3-Oxo-1-cyclopenten-1-yl)amino]-1-cyclohexene-1-carbonitrile | C12H14N2O | 详情 | 详情 | |
| (X) | 11253 | 9-Amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinolin-1-one | C12H14N2O | 详情 | 详情 | |
| (XI) | 11254 | 9-Amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinolin-1-ol | C12H16N2O | 详情 | 详情 | |
| (XII) | 63082 | (+)9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinolin-1-ol | C12H16N2O | 详情 | 详情 |
合成路线4
The synthesis of two dihydroxylated metabolites of NIK-247 has been reported: Two diastereomeric isomers 9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinoline-1,8-diol (VI) and (VII) have been synthesized as follows. The oxidation of 2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinolin-9-amine (I) with CrO3.H2SO4 gives 9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinoline-1,8-dione (II), which is selectively reduced with 1 equivalent of NaBH4 yielding a mixture of the two hydroxyketones (III) and (IV), separated by crystallization. The optical resolution of (III) with (-)-di-p-toluyltartaric acid affords the pre (+)-isomer (V), which is further reduced with NaBH4 to afford a diastereomeric mixture of the 1,8-diols (VI) and (VII), which is separated by HPLC over Chiracel OG in n-hexane ethanol (9:1).
| 【1】 Komatsu, T.; Yano, M.; Iwamoto, M.; Kobayashi, M.; Suzuki, K.; Synthesis of estimated metabolites of 9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinoline monohydrochloride monohydrate (NIK-247). II. Synthesis of dihydroxylated metabolites. Yakugaku Zasshi 1995, 115, 12, 1022. |
| 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) | 11256 | 2,3,5,6,7,8-Hexahydro-1H-cyclopenta[b]quinolin-9-amine; 2,3,5,6,7,8-Hexahydro-1H-cyclopenta[b]quinolin-9-ylamine | C12H16N2 | 详情 | 详情 | |
| (II) | 11257 | 9-Amino-2,3,6,7-tetrahydro-1H-cyclopenta[b]quinoline-1,8(5H)-dione | C12H12N2O2 | 详情 | 详情 | |
| (III) | 11258 | 9-Amino-8-hydroxy-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinolin-1-one | C12H14N2O2 | 详情 | 详情 | |
| (IV) | 11259 | 9-Amino-1-hydroxy-1,2,3,5,6,7-hexahydro-8H-cyclopenta[b]quinolin-8-one | C12H14N2O2 | 详情 | 详情 | |
| (V) | 63083 | (+)9-amino-8-hydroxy-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinolin-1-one | C12H14N2O2 | 详情 | 详情 | |
| (VI) | 11261 | 9-Amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinoline-1,8-diol | C12H16N2O2 | 详情 | 详情 | |
| (VII) | 63084 | 9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinoline-1,8-diol | C12H16N2O2 | 详情 | 详情 |