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【结 构 式】

【药物名称】Verubulin;Azixa;MPC-6827;MX-128495;VERUBULIN HYDROCHLORIDE;EP-128495

【化学名称】N-(4-Methoxyphenyl)-N,2-dimethylquinazolin-4-amine hydrochloride

【CA登记号】917369-31-4;827031-83-4 (free base)

【 分 子 式 】C17H17N3O.HCl

【 分 子 量 】315.797

【开发单位】EpiCept Corp. (US); licensed to Myrexis, Inc. (US)

【药理作用】Apoptosis Inducer;Vascular Disrupting Agent;Oncolytic

合成路线1

Amination and cyclization of methyl 2-aminobenzoate (I) with acetonitrile in the presence of HCl at reflux gives 2-methyl-4-quinazolinone (II), which by chlorination by means of POCl3 in the presence of DIEA in refluxing toluene or in the absence at 120 °C yields 4-chloro-2-methylquinazoline (III). Finally, intermediate (III) is condensed with N-(4-methoxyphenyl)-N-methylamine (IV) in the presence of HCl in isopropanol .

1 Sirisoma, N., Pervin, A., Zhang, H. et al. Discovery of N-(4-methoxyphenyl)-N,2- dimethylquinazolin-4-amine, a potent apoptosis induced and efficacious anticancer agent with high blood brain barrier penetration. J Med Chem 2009, 52(8): 2341-51.
2 Jaing, S., Cai, S.X., Pervin, A. et al. (Myrexis, Inc.; EpiCept Corp.). Compounds and therapeutical uses thereof. EP 1660092, JP 2007524637, US 2005137213, US 7618975, WO 2005003100.
3 Cai, S.X., Anderson, M.B., Willardsen, A., Sirisoma, N.S., Zhang, H.,Suzuki, K. (Myriad Genetics, Inc.; EpiCept Corp.). Nitrogen containing bicyclic compounds and therapeutic use thereof EP 1833482, WO 2006074147.
4 Anderson, M.B., Willardsen, J.A., Weiner, W.S. et al. (Myrexis, Inc.). Compounds and therapeutical uses thereof. US 2010069383.
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) 11161 methyl 2-aminobenzoate; Methyl anthranilate 134-20-3 C8H9NO2 详情 详情
(II) 69157 2-methyl-4-quinazolinone;2-Methyl-4-quinazolone;2-Methylquinazolone;3H-2-Methyl-4-oxoquinazoline;4-Hydroxy-2-methylquinazoline;2-Methyl-4-oxoquinazoline;2-Methyl-4(3H)-quinazolone;2-Methyl-4(3H)-quinazolinone;2-Methyl-3H-quinazolin-4-one 1769-24-0 C9H8N2O 详情 详情
(III) 69158 4-chloro-2-methylquinazoline 6484-24-8 C9H7ClN2 详情 详情
(IV) 69159 4-methoxy-N-methylaniline hydrochloride   C8H11NO.HCl 详情 详情

合成路线2

Treatment of 2-aminobenzonitrile (V) with N,N-dimethylacetamide dimethylacetal (VI) at 115 °C yields N’-(2-cyanophenyl)-N,N-dimethylacetamidine (VII), which by cyclization with 4-methoxyaniline (VIII) in AcOH/acetonitrile at 118 °C gives N-(4-methoxyphenyl)- 2-methylquinazolin-4-amine (IX). Finally, the secondary amine group in compound (IX) is methylated by means of NaH in DMF .
Intramolecular cyclization of the acetamidine (II) with 4-methoxy-N-methylaniline (IV) in the presence of AlCl3 in NMP at 200 °C (5).

1 Foucourt, A., Dubouilh-Benard, C., Chosson, E. et al. Microwave-accelerated Dimroth rearrangement for the synthesis of 4-anilino-6-nitroquinazolines. Application to an efficient synthesis of a microtubule destabilizing agent. Tetrahedron 2010, 66(25): 4495.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IV) 69159 4-methoxy-N-methylaniline hydrochloride   C8H11NO.HCl 详情 详情
(V) 19493 2-aminobenzonitrile 1885-29-6 C7H6N2 详情 详情
(VI) 22915 1,1-dimethoxy-N,N-dimethyl-1-ethanamine;N,N-dimethylacetamide dimethylacetal; N-(1,1-dimethoxyethyl)-N,N-dimethylamine 18871-66-4 C6H15NO2 详情 详情
(VIII) 10478 p-Anisidine; 4-Methoxyaniline; 4-Methoxyphenylamine 104-94-9 C7H9NO 详情 详情
(IX) 69161 N-(4-methoxyphenyl)-2-methylquinazolin-4-amine   C16H15N3O 详情 详情
Extended Information