Microwave Reaction Improved Heterocyclization of Quinazolinone Ring in Synthesis of Erlotinib Analogues

Background Tinibs were a kind of important epidermal growth factor receptor (EGFR) inhibitors used as potential therapeutic agents in treating non-small cell lung cancer (NSCLC) in clinic. The drug resistance of clinical used tinibs made the development of more active tinib analogues an attractive field in research. Quinazoline ring was regarded as the key fragment in tinibs and quinazolinone was indispensible intermediate in the synthesis of quinazoline. Thus, synthesis of quinazolinone intermediates was a key step which would further limit the overall yield of final product of tinib analogues. However, the commonly used synthetic scheme was somewhat complicated and time consuming with relatively low yield in heterocylization of quinazolinone and its derivatives. Aim In this work, we intended to explore an effective way to improve synthesis of heterocyclization of 6,7-bis(2-methoxyethoxy)quinazolin-4(3H)-one (compound 5), the key fragment of erlotinib analogues, in both reaction procedure and yield, thus to provide reference to synthesis of other quinazolinone derivatives. Methods A simple microwave-assisted one-pot reaction was employed to improve the synthesis of heterocyclization of quinazolinone ring. The reaction conditions, including microwave power, temperature and time of reaction, were screened to achieve high yield under simple operation. Results 6,7-bis(2-methoxyethoxy)quinazolin-4(3H)-one (compound 5) was successfully synthesized from starting material of 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile by microwave reaction, which was finished in 1 hour just by one step. The yield of heterocyclization was increased from 29.8% of commonly used three-step scheme to 50% herein. Conclusion Microwave reaction efficiently improved synthesis of heterocyclization of 6,7-bis(2-methoxyethoxy)quinazolin-4(3H)-one into "quinazolinone in both synthetic procedure and yield. The results may provide valuable reference to synthesis of other quinazolinone derivatives.