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【结 构 式】 
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【药物名称】 【化学名称】1-(3-Chlorophenyl)-4-[1-[4'-(trifluoromethyl)biphenyl-4-ylmethyl]-1H-imidazol-5-ylmethyl]piperazin-2-one 【CA登记号】 【 分 子 式 】C28H24ClF3N4O 【 分 子 量 】524.97788 |
【开发单位】Merck & Co. (Originator) 【药理作用】ONCOLYTIC DRUGS, Farnesyl Transferase Inhibitors, Geranylgeranyl Transferase Inhibitors, Inhibitors of Signal Transduction Pathways |
合成路线1
3-Chloroaniline (I) was acylated with chloroacetyl chloride (II) in isopropyl acetate. The resulting chloroacetanilide (III) was condensed with ethanolamine (IV) to yield the (hydroxyethyl)glycinamide (V). Cyclization of (V) to produce the piperazinone (VI) was then effected by treatment with di-tert-butyl azodicarboxylate and tributylphosphine.
| 【1】 Williams, T.M. (Merck & Co., Inc.); Biaryl inhibitors of prenyl-protein transferase. WO 0075135 . |
| 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) | 25239 | 3-chloroaniline; 3-chlorophenylamine | 108-42-9 | C6H6ClN | 详情 | 详情 |
| (II) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (III) | 47290 | 2-chloro-N-(3-chlorophenyl)acetamide | C8H7Cl2NO | 详情 | 详情 | |
| (IV) | 10259 | Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol | 141-43-5 | C2H7NO | 详情 | 详情 |
| (V) | 47291 | N-(3-chlorophenyl)-2-[(2-hydroxyethyl)amino]acetamide | C10H13ClN2O2 | 详情 | 详情 | |
| (VI) | 47289 | 1-(3-chlorophenyl)-2-piperazinone | C10H11ClN2O | 详情 | 详情 |
合成路线2
The mercaptoimidazole (IX) was prepared by condensation between 4-bromobenzylamine (VII), 1,3-dihydroxyacetone (VIII) and potassium thiocyanate. Oxidative desulfuration of (IX) with hydrogen peroxide in acidic medium yielded imidazole (X). The biphenyl derivative (XII) was obtained by Suzuki coupling of aryl bromide (X) with 4-(trifluoromethyl)benzeneboronic acid (XI). Subsequent oxidation of the alcohol group of (XII) under Swern conditions gave aldehyde (XIII). Finally, reductive coupling of aldehyde (XIII) with piperazinone (VI) in the presence of sodium triacetoxyborohydride furnished the title compound.
| 【2】 Williams, T.M. (Merck & Co., Inc.); Biaryl inhibitors of prenyl-protein transferase. WO 0075135 . |
| 【1】 Kohl, N.E.; Nguyen, D.N.; Lobell, R.B.; Williams, T.M.; Heimbrook, D.C.; Buser, C.A.; Huber, H.E.; Stump, C.A.; Graham, S.L.; Potent inhibitors of farnesyltransferase and geranylgeranyltransferase. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 56. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 47289 | 1-(3-chlorophenyl)-2-piperazinone | C10H11ClN2O | 详情 | 详情 | |
| (VII) | 15869 | 4-bromobenzylamine; (4-bromophenyl)methanamine | 26177-44-6 | C7H8BrN | 详情 | 详情 |
| (VIII) | 14575 | Dihydroxyacetone; 1,3-dihydroxyacetone | 96-26-4 | C3H6O3 | 详情 | 详情 |
| (IX) | 48637 | [1-(4-bromobenzyl)-2-sulfanyl-1H-imidazol-5-yl]methanol | C11H11BrN2OS | 详情 | 详情 | |
| (X) | 48638 | [1-(4-bromobenzyl)-1H-imidazol-5-yl]methanol | C11H11BrN2O | 详情 | 详情 | |
| (XI) | 48639 | 4-(Trifluoromethyl)phenylboronic acid | C7H6BF3O2 | 详情 | 详情 | |
| (XII) | 48640 | (1-[[4'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazol-5-yl)methanol | C18H15F3N2O | 详情 | 详情 | |
| (XIII) | 48641 | 1-[[4'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-carbaldehyde | C18H13F3N2O | 详情 | 详情 |