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【结 构 式】

【分子编号】67973

【品名】4-amino-5-fluoro-3-(6-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)quinolin-2(1H)-one

【CA登记号】405169-16-6

【 分 子 式 】C21H21FN6O

【 分 子 量 】392.436

【元素组成】C 64.27% H 5.39% F 4.84% N 21.41% O 4.08%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(IX)

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
Extended Information