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【结 构 式】

【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
Extended Information