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【结 构 式】 
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【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 |