Pyrrolotriazine-5-carboxylate ester inhibitors of EGFR and HER2 protein tyrosine kinases and a novel one-pot synthesis of C-4 subsitituted pyrrole-2,3-dicarboxylate diesters
Pyrrolotriazine-5-carboxylate ester inhibitors of EGFR and HER2 protein tyrosine kinases and a novel one-pot synthesis of C-4 subsitituted pyrrole-2,3-dicarboxylate diesters
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DOI：
10.1139/v06-037
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发表时间：
2006-04-01
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影响因子：
--
通讯作者：
Vyas, Dolatrai M.
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文献类型：
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作者：
Mastalerz, Harold;Gavai, Ashvinikumar V.;Vyas, Dolatrai M.
在C-5处有酯基团的吡咯三嗪被制备和评估为EGFR和HER2受体酪氨酸激酶的抑制剂，证实了癌症治疗的靶点。C-5酯（15）至少与其C-6酯类似物（17）一样有效，这是已知的吡罗三嗪类EGRF/HER2激酶抑制剂系列的一个例子，显示出良好的生化和细胞活性。以吡咯2,3-二酯为原料，采用一锅法合成了C-5酯。这涉及到易于获得的α -氨基酸酯或酮的n -甲酰衍生物与三苯基膦和二乙基乙酰二羧酸酯通过分子内维提格烯化反应生成3-吡咯啉。3-吡咯中间体不分离，直接用碱处理，消除甲苯磺酸，产率高，得到吡咯2,3-二酯。
Pyrrolotriazines with an ester group at C-5 were prepared and evaluated as inhibitors of the EGFR and HER2 receptor tyrosine kinases, validated targets for cancer therapy. The C-5 ester (15) was at least as potent as its C-6 ester analogue (17), an example of a known series of pyrrolotriazine EGRF/HER2 kinase inhibitors that show good biochemical and cellular activity. The C-5 esters were synthesized from pyrrole 2,3-diesters that were made by a new, one-pot procedure. This involved reaction of readily available N-tosyl derivatives of alpha-amino acid esters or ketones with triphenylphosphine and diethyl acetylenedicarboxylate to form 3-pyrrolines via an intramolecular Wittig olefination. The 3-pyrroline intermediates were not isolated but treated directly with base to eliminate toluenesulfinic acid and generate the pyrrole 2,3-diesters in good yield.