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【结 构 式】 
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【分子编号】13857 【品名】5-Amino-2-fluorobenzonitrile; 2-Amino-6-fluorobenzonitrile 【CA登记号】77326-36-4 |
【 分 子 式 】C7H5FN2 【 分 子 量 】136.1285832 【元素组成】C 61.76% H 3.7% F 13.96% N 20.58% |
合成路线1
该中间体在本合成路线中的序号：(I)By cyclization of 2-amino-6-fluorobenzonitrile (I) with bicyclo[3.1.1]heptan-2-one (II) by means of ZnCl2 at 110-20 C.
| 【1】 Kawakami, H.; Ohuchi, R.; Kitano, M.; Ono, K. (Sumitomo Pharmaceuticals Co., Ltd.); Quinoline derivs. EP 0268871; JP 1988225358; JP 1988239271; JP 1989000073 . |
| 【2】 Prous, J.; Castaner, J.; SM-10888. Drugs Fut 1991, 16, 1, 33. |
合成路线2
该中间体在本合成路线中的序号：(V)The synthesis of [9-14C]-SM-10888 has been described: The carboxylation of 1,3-difluorobenzene (I) with labeled CO2 by means of butyllithium in THF gives 2,6-difluorobenzoic acid (II), which by reaction first with SOCl2 and then with NH4OH yields the corresponding amide (III). The reaction of (III) with SOCl2 in hot DMF affords the nitrile (IV), which by reaction with ammonia in ethanol at 135 C gives 2-amino-6-fluorobenzonitrile (VI). Finally, this compound is cyclized with bicyclo[3.3.1]heptan-2-one (VI) by means of ZnCl2 at 105 C in nitrobenzene.
| 【1】 Nishioka, K.; Kamada, T.; Kanamaru, H.; 14C-Labeling of a tetrahydroacridine, a novel CNS-selective cholinesterase inhibitor14C-Labeling of a tetrahydroacridine, a novel CNS-selective cholinesterase inhibitor. J Label Compd Radiopharm 1992, 31, 7, 553. |
| 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) | 13095 | m-Difluorobenzene; 1,3-Difluorobenzene | 372-18-9 | C6H4F2 | 详情 | 详情 |
| (II) | 13860 | 2,6-Difluorobenzoic acid | 385-00-2 | C7H4F2O2 | 详情 | 详情 |
| (II) | 45183 | 2,6-difluorobenzoic acid | C7H4F2O2 | 详情 | 详情 | |
| (III) | 13861 | 2,6-Difluorobenzamide | 18063-03-1 | C7H5F2NO | 详情 | 详情 |
| (III) | 45184 | 2,6-difluorobenzamide | C7H5F2NO | 详情 | 详情 | |
| (IV) | 13862 | (14C)-2,6-Difluorobenzonitrile | C7H3F2N | 详情 | 详情 | |
| (IV) | 45185 | 2,6-difluorobenzonitrile | C7H3F2N | 详情 | 详情 | |
| (V) | 13857 | 5-Amino-2-fluorobenzonitrile; 2-Amino-6-fluorobenzonitrile | 77326-36-4 | C7H5FN2 | 详情 | 详情 |
| (V) | 45186 | 2-amino-6-fluorobenzonitrile | C7H5FN2 | 详情 | 详情 | |
| (VI) | 13858 | Bicyclo[3.1.1]heptan-2-one | C7H10O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)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 |