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【结 构 式】 
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【分子编号】31430 【品名】2-amino-4-(4-methyl-1-piperazinyl)phenylamine; 4-(4-methyl-1-piperazinyl)-1,2-benzenediamine 【CA登记号】54998-08-2 |
【 分 子 式 】C11H18N4 【 分 子 量 】206.29088 【元素组成】C 64.05% H 8.79% N 27.16% |
合成路线1
该中间体在本合成路线中的序号：(IV)Methylation of (hydroxymethyl)benzimidazole (I) at the amino and hydroxyl groups with MeI and NaH provided (II). Subsequent formylation of (II) employing dichloromethyl methyl ether and SnCl4 gave aldehyde (III), which was condensed with the phenylenediamine derivative (IV) in nitrobenzene to produce the bis(benzimidazole) (V). Finally, cleavage of the methyl ethers of (V) with BBr3 in toluene yielded the title compound.
| 【1】 Soderlind, K.-J.; et al.; Bis-benzimidazole anticancer agents: Targeting human tumour helicases. Anti-Cancer Drug Des 1999, 14, 1, 19. |
| 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) | 31428 | (4,7-dimethoxy-1H-benzimidazol-2-yl)methanol | C10H12N2O3 | 详情 | 详情 | |
| (II) | 31429 | 4,7-dimethoxy-2-(methoxymethyl)-1-methyl-1H-benzimidazole; (4,7-dimethoxy-1-methyl-1H-benzimidazol-2-yl)methyl methyl ether | C12H16N2O3 | 详情 | 详情 | |
| (III) | 31431 | 4,7-dimethoxy-2-(methoxymethyl)-1-methyl-1H-benzimidazole-5-carbaldehyde | C13H16N2O4 | 详情 | 详情 | |
| (IV) | 31430 | 2-amino-4-(4-methyl-1-piperazinyl)phenylamine; 4-(4-methyl-1-piperazinyl)-1,2-benzenediamine | 54998-08-2 | C11H18N4 | 详情 | 详情 |
| (V) | 31432 | 4,7-Dimethoxy-2-(methoxymethyl)-1-methyl-5-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-benzimidaole | C24H30N6O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)Reaction of 2,4-difluoronitrobenzene (I) with liquid ammonia gives 5-fluoro-2-nitroaniline (IIa) , which by subsequent displacement of the remaining fluoride group with N-methylpiperazine (III) in the presence of Et3N in NMP at 100 °C provides the piperazinyl aniline (IV) . Alternatively, nitroaniline (IV) can be prepared by condensation of 5-chloro-2-nitroaniline (IIb) with N-methylpiperazine (III) in hot EtOH , ethylene glycol or aqueous NaCl, optionally in the presence of NaOH . Catalytic hydrogenation of nitroaniline (IV) over Pd/C in EtOH at 40-45 °C yields the phenyldiamine (V) , wh ich by condensa t ion with ethyl 3-ethoxy-3-iminopropionate hydrochloride (VI) at reflux produces benzimidazole (VII) . Cyclocondensation of ethyl ester (VII) with 2-amino-6-fluorobenzonitrile (VIII) by means of LiHMDS , KHMDS or t-BuOK in THF or toluene furnishes dovitinib (IX ) , which is finally treated with racemic lactic acid in EtOH/H2O .
| 【1】 Machajewski, T., Shafer, C., McCrea, B. et al. (Novartis Vaccines and Diagnostics, Inc.). Quinolone derivatives. EP 1317442, EP 1650203, EP 1849782, JP 2004509112, US 2002107392, US 6605617, WO 2002022598. |
| 【2】 Harrison, S.D., Shafer, C.M., Pecchi, S. et al. (Novartis Vaccines and Diagnostics, Inc.). Benzimidazole quinolines and uses thereof. EP 1539754, JP 2006503919, JP 2011162563, US 200409235, US 2013018058, WO 2004018419. |
| 【3】 Renhowe, P.A., Pecchi, S., Machajewski, T.D. (Novartis Vaccines and Diagnostics, Inc.). Quinolone derivatives. JP 2005527587, US 2003028018, WO 2003087095. |
| 【4】 Cai, S., Chou, J., Harwood, E., Machajewski, T.D., Ryckman, D., Shang, X., Zhu, S. (Novartis Vaccines and Diagnostics, Inc.). Pharmaceutically acceptable salts of quinolinone compounds having improved pharmaceutical properties. CN 102225926, EP 1699421, JP 2007522098, JP 2011042687, WO 2005046589. |
| 【5】 Renhowe, P.A., Pecchi, S., Shafer, C.M. et al. Design, structure-activity relationships and in vivo characterization of 4-amino-3-benzimidazol-2-ylhydroquinolin-2-ones: A novel class of receptor tyrosine kinase inhibitors. J Med Chem 2009, 52(2): 278-92. |
| 【6】 Calvin, G., Harwood, E., Ryckman, D., Zhu, S. (Novartis AG). Methods for synthesizing heterocyclic compounds. EP 1888556, EP 2465857, JP 2008540675, US 2011046376, US 8222413, WO 2006125130. |
| 【7】 Okhamafe, A., Chou, J., Gullapalli, R., Harwood, E., Ryckman, D., Zhu, S.,Shang, X. (Novartis Corp.). Crystalline and other forms of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one lactic acid salts. CN 102070614, EP 1904480, EP 2266974, EP 2270000, JP 200854289, US 2011178097, US 2012208825, WO 2006127926. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IIa) | 67969 | 5-fluoro-2-nitroaniline | 2369-11-1 | C6H5FN2O2 | 详情 | 详情 |
| (IIb) | 15709 | 5-chloro-2-nitrophenylamine; 5-chloro-2-nitroaniline | 1635-61-6 | C6H5ClN2O2 | 详情 | 详情 |
| (I) | 32036 | 2,4-difluoro-1-nitrobenzene | 446-35-5 | C6H3F2NO2 | 详情 | 详情 |
| (III) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
| (IV) | 67970 | 5-(4-methylpiperazin-1-yl)-2-nitroaniline | C11H16N4O2 | 详情 | 详情 | |
| (V) | 31430 | 2-amino-4-(4-methyl-1-piperazinyl)phenylamine; 4-(4-methyl-1-piperazinyl)-1,2-benzenediamine | 54998-08-2 | C11H18N4 | 详情 | 详情 |
| (VI) | 67971 | ethyl 3-ethoxy-3-iminopropionate hydrochloride | 2318-25-4 | C7H13NO3.HCl | 详情 | 详情 |
| (VII) | 67972 | ethyl 2-(6-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)acetate | C16H22N4O2 | 详情 | 详情 | |
| (VIII) | 13857 | 5-Amino-2-fluorobenzonitrile; 2-Amino-6-fluorobenzonitrile | 77326-36-4 | C7H5FN2 | 详情 | 详情 |
| (IX) | 67973 | 4-amino-5-fluoro-3-(6-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)quinolin-2(1H)-one | 405169-16-6 | C21H21FN6O | 详情 | 详情 |