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【结 构 式】 
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【药物名称】NSC-712392, LB-42908 【化学名称】1-[1-[1-(1,3-Benzodioxol-5-ylmethyl)-1H-imidazol-5-ylmethyl]-4-(1-naphthyl)-1H-pyrrol-3-yl]-1-(4-methyl-1-piperazinyl)methanone 【CA登记号】226927-89-5 【 分 子 式 】C32H31N5O3 【 分 子 量 】533.63557 |
【开发单位】LG Chem (Originator) 【药理作用】ONCOLYTIC DRUGS, Farnesyl Transferase Inhibitors, Inhibitors of Signal Transduction Pathways |
合成路线1
The condensation of piperonylamine (I) with dihydroxyacetone dimer (II) in the presence of potassium thiocyanate produced the mercaptoimidazole (III), which was desulfurized upon treatment with nitric acid and sodium nitrite. The resulting (hydroxymethyl)imidazole (IV) was then converted to the corresponding chloride (V) employing thionyl chloride in chloroform.
| 【1】 Lee, J.; Lee, H.; Shin, Y.; et al.; Synthesis and structure-activity relationships of 1-(1(3)H-imidazole-5(4)-yl)-methylpyrroles as farnesyl protein transferase inhibitors (FTPI). 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 210. |
| 【2】 Lee, J.H.; Yoo, J.K.; Koh, J.S.; Choi, T.S.; Shin, Y.S.; Kim, K.H.; Jung, W.H.; Kim, J.H.; Lee, S.H.; Ahn, I.A.; Ro, S.G.; Lee, H.I.; Kim, H.S.; Chung, H.H.; Jeong, S.W.; Kwak, T.H. (LG Chem Ltd.); Imidazole derivs. having an inhibitory activity for farnesyl transferase and process for preparation thereof. WO 9928315 . |
| 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) | 33669 | 1,3-benzodioxol-5-ylmethylamine; 1,3-benzodioxol-5-ylmethanamine; 3,4-Methylendioxybenzylamine | 2620-50-0 | C8H9NO2 | 详情 | 详情 |
| (II) | 20067 | 2,5-bis(hydroxymethyl)-1,4-dioxane-2,5-diol | 89727-88-8 | C6H12O6 | 详情 | 详情 |
| (III) | 33670 | [1-(1,3-benzodioxol-5-ylmethyl)-2-sulfanyl-1H-imidazol-5-yl]methanol | C12H12N2O3S | 详情 | 详情 | |
| (IV) | 33671 | [1-(1,3-benzodioxol-5-ylmethyl)-1H-imidazol-5-yl]methanol | C12H12N2O3 | 详情 | 详情 | |
| (V) | 33672 | 1-(1,3-benzodioxol-5-ylmethyl)-5-(chloromethyl)-1H-imidazole | C12H11ClN2O2 | 详情 | 详情 |
合成路线2
Horner-Emmons condensation of 1-naphthaldehyde (VI) with triethyl phosphonoacetate (VII) using DBU as the base afforded naphthylacrylate (VIII). This was reacted with tosylmethylisocyanide and potassium tert-butoxide to produce pyrrole (IX). Hydrolysis of the ester group of (IX) with KOH gave rise to the carboxylic acid (X), which was coupled with N-methylpiperazine (XI) employing EDC and HOBt or, alternatively, by previous conversion to the corresponding acid chloride with SOCl2. The resulting amide (XII) was finally alkylated at the pyrrole N atom with chloride (V) in the presence of NaH.
| 【1】 Lee, J.; Lee, H.; Shin, Y.; et al.; Synthesis and structure-activity relationships of 1-(1(3)H-imidazole-5(4)-yl)-methylpyrroles as farnesyl protein transferase inhibitors (FTPI). 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 210. |
| 【2】 Lee, J.H.; Yoo, J.K.; Koh, J.S.; Choi, T.S.; Shin, Y.S.; Kim, K.H.; Jung, W.H.; Kim, J.H.; Lee, S.H.; Ahn, I.A.; Ro, S.G.; Lee, H.I.; Kim, H.S.; Chung, H.H.; Jeong, S.W.; Kwak, T.H. (LG Chem Ltd.); Imidazole derivs. having an inhibitory activity for farnesyl transferase and process for preparation thereof. WO 9928315 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 33672 | 1-(1,3-benzodioxol-5-ylmethyl)-5-(chloromethyl)-1H-imidazole | C12H11ClN2O2 | 详情 | 详情 | |
| (VI) | 12314 | 1-Naphthaldehyde | 66-77-3 | C11H8O | 详情 | 详情 |
| (VII) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (VIII) | 25405 | ethyl (E)-3-(1-naphthyl)-2-propenoate | C15H14O2 | 详情 | 详情 | |
| (IX) | 33673 | ethyl 4-(1-naphthyl)-1H-pyrrole-3-carboxylate | C17H15NO2 | 详情 | 详情 | |
| (X) | 33674 | 4-(1-naphthyl)-1H-pyrrole-3-carboxylic acid | C15H11NO2 | 详情 | 详情 | |
| (XI) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
| (XII) | 33675 | (4-methyl-1-piperazinyl)[4-(1-naphthyl)-1H-pyrrol-3-yl]methanone | C20H21N3O | 详情 | 详情 |