Practical and efficient synthesis of gefitinib through selective O-alkylation: A novel concept for a transient protection group

ABSTRACT

A practical process that includes a simple four-step procedure for the preparation of gefitinib (1), a tyrosine kinase inhibitor that targets the epidermal growth factor receptor, is described. Dramatic improvements over previously reported conventional synthetic procedures were achieved. We found effective coupling conditions to minimize the inevitable production of an N-alkylated side product, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-N-(3-morpholinopropyl)-quinazoline-4-amine (3) using a transient trimethylsilyl protecting group. We synthesized gefitinib in an 81.1% overall yield from a commercially available starting material on a multigram scale using a route that did not require work-up of any of the reaction steps.

GRAPHICAL ABSTRACT

KEYWORDS:

• Anilinoquinazoline
• EGFR inhibitor
• gefitinib
• transient protection group

Additional information

Funding

This work was supported by the National Research Foundation of Korea (NRF) grant for the Global Core Research Center (GCRC) funded by the Korea government (MSIP) (No. 2011-0030001) and by the Global Frontier Project grant of National Research Foundation funded by Korea government (MSIP) (NRF-2015M3A6A4065798). We acknowledge the Korea Basic Science Institute, Ochang, Korea, for providing HRMS.