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【结 构 式】 
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【分子编号】51586 【品名】4-Methylimidazole; 4-Methyl-1H-imidazole; 4-Methyl Imidazole 【CA登记号】822-36-6 |
【 分 子 式 】C4H6N2 【 分 子 量 】82.10512 【元素组成】C 58.52% H 7.37% N 34.12% |
合成路线1
该中间体在本合成路线中的序号：(V)The previously reported indanyl imidazole (I) was nitrated by means of urea nitrate in sulfuric acid to afford (II). Reduction of the nitro group of (II) to the corresponding aniline (III) was carried out by catalytic hydrogenation over PtO2. Diazotization of (III) with sodium nitrite and fluoroboric acid gave rise to the diazonium fluoroborate (IV), which was then subjected to thermal decomposition to generate the title fluoro derivative.
| 【1】 Sorbera, L.A.; Castaner, J.; Bayes, M.; Fipamezole Hydrochloride. Drugs Fut 2003, 28, 1, 14. |
| 【2】 Karjalainen, A.J.; Virtanen, R.E.; Karjalainen, A.L.; Eloranta, M.M.; Salonen, J.S.; Sipilä, H.T.; Haapalinna, A.S. (Orion Corporation); Substd. imidazole derivs. and their preparation and use. EP 0618906; JP 1995506087; US 5498623; WO 9313074 . |
| 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) | 51582 | 4-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole | C14H16N2 | 详情 | 详情 | |
| (II) | 51583 | 4-(2-ethyl-5-nitro-2,3-dihydro-1H-inden-2-yl)-1H-imidazole | C14H15N3O2 | 详情 | 详情 | |
| (III) | 51584 | 2-ethyl-2-(1H-imidazol-4-yl)-2,3-dihydro-1H-inden-5-ylamine; 2-ethyl-2-(1H-imidazol-4-yl)-5-indanamine | C14H17N3 | 详情 | 详情 | |
| (IV) | 51585 | C14H15BF4N4 | 详情 | 详情 | ||
| (V) | 51586 | 4-Methylimidazole; 4-Methyl-1H-imidazole; 4-Methyl Imidazole | 822-36-6 | C4H6N2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The alkylation of 4-methylimidazole (I) with N-(3-bromopropyl)phthalimide (II) produced a mixture of N-alkylated regioisomers (III) and (IV). After selective derivatization of the undesired 5-methyl isomer (III) with trityl chloride, the 4-methyl derivative was isolated by flash chromatography and subsequently subjected to phthaloyl group hydrazinolysis to yield amine (V). Reductive condensation of amine (V) with benzaldehyde (VI) in the presence of NaBH4 afforded the N-benzyl amine (VII).
| 【1】 Guzi, T.; Taveras, A.G.; Ferreira, J.A.; Desai, J.A.; Wang, J.J.S.; Lalwani, T.; Alvarez, C.; Afonso, A.; Girijavallabhan, V.M.; Mallams, A.K.; Doll, R.J.; Weinstein, J.; Cooper, A.B.; Chao, J.; Rane, D.F.; Aki, C.J.; Kelly, J.M. (Schering Corp.); Tricyclic farnesyl protein transferase inhibitors. EP 1140902; WO 0037459 . |
| 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) | 51586 | 4-Methylimidazole; 4-Methyl-1H-imidazole; 4-Methyl Imidazole | 822-36-6 | C4H6N2 | 详情 | 详情 |
| (II) | 15216 | N-(3-Bromopropyl)phthalimide; 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione | 5460-29-7 | C11H10BrNO2 | 详情 | 详情 |
| (III) | 51587 | 2-[3-(5-methyl-1H-imidazol-1-yl)propyl]-1H-isoindole-1,3(2H)-dione | C15H15N3O2 | 详情 | 详情 | |
| (IV) | 51588 | 2-[3-(4-methyl-1H-imidazol-1-yl)propyl]-1H-isoindole-1,3(2H)-dione | C15H15N3O2 | 详情 | 详情 | |
| (V) | 51589 | 3-(4-methyl-1H-imidazol-1-yl)-1-propanamine; 3-(4-methyl-1H-imidazol-1-yl)propylamine | C7H13N3 | 详情 | 详情 | |
| (VI) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (VII) | 51590 | N-benzyl-3-(4-methyl-1H-imidazol-1-yl)-1-propanamine; N-benzyl-N-[3-(4-methyl-1H-imidazol-1-yl)propyl]amine | C14H19N3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XI)Reduction of (R)-ethyl nipecotate (VII) with LiAlH4 yields 3-piperidinemethanol (VIII), which is further protected as the N-Boc derivative (IX) by using Boc2O. Treatment of the piperidine alcohol (IX) with p-toluenesulfonyl chloride and pyridine leads to tosylate (X). Condensation of the sodium derivative of 4-methylimidazole (XI) with tosylate (X) gives rise to a mixture of regioisomeric N-alkylated imidazoles, which are chromatographically separated after derivatization with trityl chloride. The desired isomer (XII) is then deprotected under acidic conditions, giving piperidine (XIII). Finally, EDC-mediated coupling between piperidine (XIII) and the piperazinecarboxylic acid (VI) furnishes the title amide.
| 【1】 Cooper, A.B.; Girijavallabhan, V.M.; Mallams, A.K.; Doll, R.J.; Kelly, J.M.; Rane, D.F.; Taveras, A.G.; Guzi, T.; Strickland, C.; Chao, J. (Schering Corp.); Farnesyl protein transferase inhibitors. EP 1140904; JP 2002533335; WO 0037458 . |
| 【2】 Cooper, A.B.; Girijavallabhan, V.M.; Mallams, A.K.; Doll, R.J.; Kelly, J.M.; Rane, D.F.; Taveras, A.G.; Guzi, T.; Strickland, C.; Chao, J. (Schering Corp.); Farnesyl protein transferase inhibitors. US 6362188 . |
| 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) | 51595 | (2R)-4-[(11S)-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl]-1-[(cyclohexyloxy)carbonyl]-2-piperazinecarboxylic acid | C26H30ClN3O4 | 详情 | 详情 | |
| (VII) | 12453 | ethyl (3R)hexahydro-3-pyridinecarboxylate | C8H15NO2 | 详情 | 详情 | |
| (VIII) | 57427 | (1S)-2,2-dimethylcyclopropanecarbonyl chloride | C6H9ClO | 详情 | 详情 | |
| (IX) | 35221 | tert-butyl (3S)-3-(hydroxymethyl)-1-piperidinecarboxylate | C11H21NO3 | 详情 | 详情 | |
| (X) | 57428 | ethyl 3-ethyl-2-pentenoate | C9H16O2 | 详情 | 详情 | |
| (XI) | 51586 | 4-Methylimidazole; 4-Methyl-1H-imidazole; 4-Methyl Imidazole | 822-36-6 | C4H6N2 | 详情 | 详情 |
| (XII) | 58429 | tert-butyl (3S)-3-[(4-methyl-1H-imidazol-1-yl)methyl]-1-piperidinecarboxylate | C15H25N3O2 | 详情 | 详情 | |
| (XIII) | 58430 | (3R)-3-[(4-methyl-1H-imidazol-1-yl)methyl]piperidine | C10H17N3 | 详情 | 详情 |