A Concise Five-Step Synthesis of Erlotinib via Direct Schmidt Nitrilation and Microwave-Assisted Cyclization

Erlotinib is an important tyrosine kinase inhibitor in receptors overexpressed in malignant tumors, such as lung cancer, acting directly on the epidermal growth factor receptor. Existing synthetic routes to prepare this drug typically require multiple steps, harsh conditions, or expensive reagents, which limits their scalability and sustainability. Herein, it is described an efficient and cost‑effective synthesis of erlotinib, comprising only five steps from 3,4-dihydroxybenzaldehyde. The approach is highlighted by a direct Schmidt nitrilation of 3,4-bis(2-methoxyethoxy) benzaldehyde under mild, transition-metal-free conditions, achieving high conversion without the need for oxime intermediates or dehydrating agents. The final cyclization, promoted via a microwave-assisted cyclization, affords erlotinib in high yield. Overall, this route combines synthetic efficiency with methodological improvements, achieving an average yield of 87% per step