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【结 构 式】 
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【药物名称】BIBW-2992, Tovok 【化学名称】N-[4-(3-Chloro-4-fluorophenylamino)-7-[tetrahydrofuran-3(S)-yloxy]quinazolin-6-yl]-4-(dimethylamino)-2-butenamide 【CA登记号】439081-18-2 【 分 子 式 】C24H25CIFN5O3 【 分 子 量 】485.9383 |
【开发单位】Boehringer Ingelheim (DE). 【药理作用】Dual EGFR/HER2 Inhibitor, Oncolytic |
合成路线1
Acylation of 6-amino-4-(3-chloro-4-fluorophenylamino)-7-[tetrahydrofuran-3(S)-yloxy]quinazoline (I) with the acid chloride generated from bromocrotonic acid (II) and oxalyl chloride leads to the bromocrotonamide (III), which is finally submitted to bromide displacement with dimethylamine (1). Scheme1.
In an alternative method, aminoquinazoline (I) is acylated with diethylphosphonoacetic acid (IV) by means of carbonyldiimidazole in THF to give the phosphonoacetamide (V), which is finally condensed with (dimethylamino)acetaldehyde diethyl acetal (VI) under basic conditions (2). Scheme 1.
| 【1】 Himmelsbach, F., Langkopf, E., Solca, F., Jung, B., Baum, A., Blech, S. (Boehringer Ingelheim Pharma GmbH & Co., KG). Quinazoline derivatives, medicaments containing said compounds, their utilization and method for the production thereof. DE 10063435, EP 1345910, JP 2004516283, US 2002173509, US 2006100223, US 7019012, WO 0250043. |
| 【2】 Soyka, R., Rall, W., Kulinna, C., Sieger, P., Schnaubelt, J. (Boehringer Ingelheim Pharma GmbH & Co., KG). Process for preparing amino crotonyl compounds. DE 10349113, EP 1678165, JP 2007510624, US 2005085495, WO 2005037824. |
| 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) | 65710 | N4-(3-Chloro-4-fluorophenyl)-7-[[(3S)-tetrahydro-3-furanyl]oxy]-4,6-quinazolinediamine | 314771-76-1 | C18H16ClFN4O2 | 详情 | 详情 |
| (II) | 50563 | (E)-4-bromo-2-butenoic acid | 13991-36-1 | C4H5BrO2 | 详情 | 详情 |
| (III) | 65711 | C22H19BrClFN4O3 | 详情 | 详情 | ||
| (IV) | 36512 | 2-(diethoxyphosphoryl)acetic acid | 3095-95-2 | C6H13O5P | 详情 | 详情 |
| (V) | 65712 | C24H27ClFN4O6 | 详情 | 详情 | ||
| (VI) | 65713 | 2,2-Diethoxy-N,N-dimethylethylamine; (Dimethylamino)acetaldehyde diethyl acetal | 3616-56-6 | C8H19NO2 | 详情 | 详情 |
合成路线2
The aminoquinazoline precursor (I) is prepared by condensation of 4-(3-chloro-4-fluorophenylamino)-7-fluoro-6-nitroquinazoline (VII) with 3(R)-hydroxytetrahydrofuran (VIII) by means of potassium tert-butoxide in DMF to yield the tetrahydrofuranyloxyquinazoline (IX), which is then reduced at the nitro group by catalytic hydrogenation over PtO2 (1). Scheme 2.
| 【1】 Himmelsbach, F., Langkopf, E., Solca, F., Jung, B., Baum, A., Blech, S. (Boehringer Ingelheim Pharma GmbH & Co., KG). Quinazoline derivatives, medicaments containing said compounds, their utilization and method for the production thereof. DE 10063435, EP 1345910, JP 2004516283, US 2002173509, US 2006100223, US 7019012, WO 0250043. |
| 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) | 65710 | N4-(3-Chloro-4-fluorophenyl)-7-[[(3S)-tetrahydro-3-furanyl]oxy]-4,6-quinazolinediamine | 314771-76-1 | C18H16ClFN4O2 | 详情 | 详情 |
| (VII) | 54956 | N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazolinamine; N-(3-chloro-4-fluorophenyl)-N-(7-fluoro-6-nitro-4-quinazolinyl)amine | 162012-67-1 | C14H7ClF2N4O2 | 详情 | 详情 |
| (VIII) | 44420 | (3S)-tetrahydro-3-furanol; (S)-3-Hydroxytetrahydrofuran | 86087-23-2 | C4H8O2 | 详情 | 详情 |
| (IX) | 65714 | N-(3-Chloro-4-fluorophenyl)-6-nitro-7-[[(3S)-tetrahydro-3-furanyl]oxy]-4-quinazolinamine | 314771-88-5 | C18H14ClFN4O4 | 详情 | 详情 |