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【结 构 式】 
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【药物名称】 【化学名称】1-[3-[3,3-Bis(4-methylphenyl)-2,5-dioxopyrrolidin-1-yl]propyl]-4-(2-methylphenyl)piperidine-4-carbonitrile 【CA登记号】 【 分 子 式 】C34H37N3O2 【 分 子 量 】519.69289 |
【开发单位】Merck & Co. (Originator) 【药理作用】Benign Prostatic Hyperplasia Therapy, RENAL-UROLOGIC DRUGS, alpha1A-Adrenoceptor Antagonists |
合成路线1
The intermediate piperidine (IV) was prepared by bis-alkylation of o-methylphenylacetonitrile (I) with N-Boc-bis(2-chloroethyl)amine (II), followed by deprotection of the resulting N-Boc-piperidine (III) with HCl in EtOAc.
| 【1】 Newton, R.C.; Freidinger, R.M.; Price, R.A.; Chang, R.S.L.; Patane, M.A.; DiPardo, R.M.; Di Salvo, J.; Broten, T.P.; Ransom, R.W.; Bock, M.G.; Cyclic imides as potent and selective alpha-1A adrenergic receptor antagonists. Bioorg Med Chem Lett 2001, 11, 14, 1959. |
| 【2】 Bell, M.G.; DiPardo, R.M.; Crowell, T.A.; et al.; Cyclic imides as potent and selective alpha-1A adrenergic receptor antagonists. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 298. |
| 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) | 43938 | 2-(2-methylphenyl)acetonitrile | C9H9N | 详情 | 详情 | |
| (II) | 43939 | tert-butyl bis(2-chloroethyl)carbamate | C9H17Cl2NO2 | 详情 | 详情 | |
| (III) | 43940 | tert-butyl 4-cyano-4-(2-methylphenyl)-1-piperidinecarboxylate | C18H24N2O2 | 详情 | 详情 | |
| (IV) | 43941 | 4-(2-methylphenyl)-4-piperidinecarbonitrile | C13H16N2 | 详情 | 详情 |
合成路线2
Di-tolylacetic acid (V) was converted into the benzyl ester (VI) using benzyl bromide and K2CO3 in DMF. Subsequent alpha-alkylation of ester (VI) with ethyl bromoacetate provided diester (VII). The benzyl ester group of (VII) was then removed by hydrogenolysis over Pd/C. Condensation of the resulting mono-acid (VIII) with 3-bromopropylamine (IX) in the presence of EDC and HOBt furnished the N-(bromopropyl)succinimide (X). This was finally condensed with piperidine (IV) to provide the title compound.
| 【1】 Newton, R.C.; Freidinger, R.M.; Price, R.A.; Chang, R.S.L.; Patane, M.A.; DiPardo, R.M.; Di Salvo, J.; Broten, T.P.; Ransom, R.W.; Bock, M.G.; Cyclic imides as potent and selective alpha-1A adrenergic receptor antagonists. Bioorg Med Chem Lett 2001, 11, 14, 1959. |
| 【2】 Bell, M.G.; DiPardo, R.M.; Crowell, T.A.; et al.; Cyclic imides as potent and selective alpha-1A adrenergic receptor antagonists. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 298. |
| 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) | 43941 | 4-(2-methylphenyl)-4-piperidinecarbonitrile | C13H16N2 | 详情 | 详情 | |
| (V) | 43942 | 2,2-bis(4-methylphenyl)acetic acid | C16H16O2 | 详情 | 详情 | |
| (VI) | 43943 | benzyl 2,2-bis(4-methylphenyl)acetate | C23H22O2 | 详情 | 详情 | |
| (VII) | 43944 | 1-benzyl 4-ethyl 2,2-bis(4-methylphenyl)succinate | C27H28O4 | 详情 | 详情 | |
| (VIII) | 43945 | 4-ethoxy-2,2-bis(4-methylphenyl)-4-oxobutyric acid | C20H22O4 | 详情 | 详情 | |
| (IX) | 25449 | 3-bromo-1-propanamine; 3-bromopropylamine | 18370-81-5 | C3H8BrN | 详情 | 详情 |
| (X) | 43946 | 1-(3-bromopropyl)-3,3-bis(4-methylphenyl)-2,5-pyrrolidinedione | C21H22BrNO2 | 详情 | 详情 |