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【结 构 式】 
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【药物名称】Centperazine, 67/255 【化学名称】3-Ethyl-8-methyl-1,3,8-triazabicyclo[4.4.0]decan-2-one 【CA登记号】25143-13-9, 31969-02-5 (monoHCl) 【 分 子 式 】C10H19N3O 【 分 子 量 】197.28243 |
【开发单位】Central Drug Research Institute (Originator) 【药理作用】ANTIINFECTIVE THERAPY, Treatment of Helminthic Diseases |
合成路线1
A new synthesis of centperazine has been reported: The cyclization of N,N'-dibenzylethylenediamine (I) with 2,3-dibromopropionitrile (II) by means of triethylamine in refluxing toluene gives 2-(1,4-dibenzylpiperazin-2-yl)acetonitrile (III), which is reduced with H2 over RaNi in methanol to yield the corresponding ethylamine (IV). Acylation of (IV) with ethyl chloroformate (V) and triethylamine in dichloromethane affords the corresponding carbamate (VI), which is debenzylated by hydrogenation with H2 over Pd/C in acetic acid, giving N-[2-(2-piperazinyl)ethyl]carbamic acid ethyl ester (VII). The cyclization of (VII) by means of sodium ethoxide in hot ethanol yields perhydropyrazino[1,2-c]pyrimidin-6-one (VIII), which is methylated with formaldehyde-formic acid to the 2-methyl derivative (IX). Finally, this compound is ethylated with ethyl iodide, tetrabutylammonium bromide and KOH in THF.
| 【1】 Chatterjee, S.K.; Sahu, D.P.; Sengupta, S.; A convenient synthesis of centperazine, an antifilarial candidate drug. Liebigs Ann Chem 1993, 4, 4, 437. |
| 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) | 18340 | N(1),N(2)-dibenzyl-1,2-ethanediamine; N-benzyl-N-[2-(benzylamino)ethyl]amine; N,N-Dibenzylethylendiamine | 140-28-3 | C16H20N2 | 详情 | 详情 |
| (II) | 10364 | 3,4-dibromobutanenitrile | C4H5Br2N | 详情 | 详情 | |
| (III) | 10365 | 2-(1,4-Dibenzyl-2-piperazinyl)acetonitrile | C20H23N3 | 详情 | 详情 | |
| (IV) | 10366 | 2-(1,4-Dibenzyl-2-piperazinyl)ethylamine; 2-(1,4-Dibenzyl-2-piperazinyl)-1-ethanamine | C20H27N3 | 详情 | 详情 | |
| (VI) | 10367 | ethyl N-[2-(1,4-dibenzyl-2-piperazinyl)ethyl]carbamate | C23H31N3O2 | 详情 | 详情 | |
| (VII) | 10368 | ethyl N-[2-(2-piperazinyl)ethyl]carbamate | C9H19N3O2 | 详情 | 详情 | |
| (VIII) | 10369 | Octahydro-6H-pyrazino[1,2-c]pyrimidin-6-one | C7H13N3O | 详情 | 详情 | |
| (IX) | 10370 | 2-Methyloctahydro-6H-pyrazino[1,2-c]pyrimidin-6-one | C8H15N3O | 详情 | 详情 |
合成路线2
Condensation of dimethyl aspartate (II) with benzyloxy carbonyl sarcosine (I) using DCI gave dimethyl benzyloxycarbonyl sarcosylaspartate (III). Removal of benzyloxycarbonyl function from (III) by catalytic hydrogenation or HBr-AcOH followed by cyclization, effected by storage over P2O5 in vacuo for 48 h, gave methyl (1-methyl-2,5-dioxopiperazin-3-yl)acetate (IV). When (IV) was reacted with ethylamine in a sealed tube for 36 h, it yielded N-ethyl-2-(1-methyl-2,5,dioxopiperazin-3-yl)acetamide (V). The compound (V) was reduced with LiAlH4 to give 1-methyl-3-(2-ethylamino)ethylpiperazine (VI). When (VI) was condensed with ethyl chloroformate (A) at pH 3-3.5, a mixture of monocarbamates (VIIa, VIIb) were obtained. Cyclization of the monocarbamates (VIIa, VIIb) were effected by treatment with sodium ethoxide to afford 3-ethyl-8-methyl-1,3,8-triazabicyclo[4.4.0]decan-2-one (centperazine). When (VI) was reacted with ethyl chloroformate (A) in the presence of NaOC2H5 or Et3N, the dicarbamate (VIII) was formed.
| 【1】 Saxena, R.; et al.; Studies in potential filaricides. 5. 3-Ethyl-8-methyl-1,3,8-triazabicyclo[4.4.0]decan-2-one, a new antifilarial agent. J Med Chem 1971, 14, 10, 929. |
| 【2】 Arya, V.P.; Centperazine. Drugs Fut 1980, 5, 5, 229. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 12229 | (2R,3S)-5,5-Dimethoxy-3-(phenylselanyl)-1,2-pentanediol | C13H20O4Se | 详情 | 详情 | |
| (VIIa) | 39052 | ethyl ethyl[2-(4-methyl-2-piperazinyl)ethyl]carbamate | C12H25N3O2 | 详情 | 详情 | |
| (VIIb) | 39053 | ethyl 2-[2-(ethylamino)ethyl]-4-methyl-1-piperazinecarboxylate | C12H25N3O2 | 详情 | 详情 | |
| (I) | 39046 | (benzyloxy)carbonyl(methyl)carbamic acid | C10H11NO4 | 详情 | 详情 | |
| (II) | 39047 | dimethyl 2-aminosuccinate | C6H11NO4 | 详情 | 详情 | |
| (III) | 39048 | dimethyl 2-([2-[[(benzyloxy)carbonyl](methyl)amino]acetyl]amino)succinate | C17H22N2O7 | 详情 | 详情 | |
| (IV) | 39049 | methyl 2-(4-methyl-3,6-dioxo-2-piperazinyl)acetate | C8H12N2O4 | 详情 | 详情 | |
| (V) | 39050 | N-ethyl-2-(4-methyl-3,6-dioxo-2-piperazinyl)acetamide | C9H15N3O3 | 详情 | 详情 | |
| (VI) | 39051 | N-ethyl-2-(4-methyl-2-piperazinyl)-1-ethanamine; N-ethyl-N-[2-(4-methyl-2-piperazinyl)ethyl]amine | C9H21N3 | 详情 | 详情 | |
| (VIII) | 39054 | ethyl 2-[2-[(ethoxycarbonyl)(ethyl)amino]ethyl]-4-methyl-1-piperazinecarboxylate | C15H29N3O4 | 详情 | 详情 |