Sains Malaysiana 54(4)(2025): 1053-1062

http://doi.org/10.17576/jsm-2025-5404-07

 

A Novel Synthesis of Anti-Cancer Drug Gefitinib from 6,7-Dimethoxy-3H-Quinazolin-4-One

(Suatu Sintesis Baharu Ubat Anti-Kanser Gefitinib daripada 6,7-Dimetoksi-3H-Kuinazolin-4-One)

 

PRIO SANTOSO^1,2, ADE DANOVA¹, ELVIRA HERMAWATI¹, DESSY NATALIA¹ & ANITA ALNI^1,*

 

¹Chemistry Department, Faculty of Mathematics and Natural Sciences, Institut Teknologi Bandung, Jl. Ganesa 10, Bandung, Indonesia

²Chemistry Department, Faculty of Sciences, Institut Teknologi Sumatera, Jl. Terusan Ryacudu, South Lampung, Indonesia

 

Diserahkan: 25 Julai 2024/ Diterima: 17 Disember 2024

 

Abstract

A novel synthesis of the anticancer drug gefitinib (Iressa) through novel alternative pathway has been successfully carried out. The synthesis was performed using 6,7-dimethoxy-3H-quinazolin-4-one as the starting material through four reaction stages: Chlorination, nucleophilic aromatic substitution, demethylation, and Williamson etherification to produce gefitinib. The chlorination of 6,7-dimethoxy-3H-quinazolin-4-one as the first key step in this synthesis followed by aromatic substitution were effective to produce the target product with high yield (98% for two steps). In addition, synthesis of gefitinib from this precursor omits the necessity for functional group protection and deprotection. Purification was carried out using crystallization and radial chromatography. The structural analysis of the resulting compound was performed using FTIR, ¹H-NMR, ¹³C-NMR, and mass spectrometry. The purity of the resulting compounds was measured using HPLC and melting point measurements (195-197 °C). The overall yield obtained through this pathway was 21%.

Keywords: Anticancer; gefitinib; Iressa; synthesis; 4-chloroquinazoline

Abstrak

Suatu sintesis baharu ubat antikanser gefitinib (Iressa) melalui laluan alternatif baharu telah berjaya dijalankan. Sintesis dilakukan menggunakan 6,7-dimetoksi-3H-kuinazolin-4-one sebagai bahan permulaan melalui empat peringkat tindak balas: pengklorinan, penggantian aromatik nukleofilik, demetilasi dan eterifikasi Williamson untuk menghasilkan gefitinib. Pengklorinan 6,7-dimetoksi-3H-kuinazolin-4-one sebagai langkah utama pertama dalam sintesis ini diikuti dengan penggantian aromatik adalah berkesan untuk menghasilkan produk sasaran dengan hasil yang tinggi (98% untuk dua langkah). Di samping itu, sintesis gefitinib daripada prekursor ini menghilangkan keperluan untuk perlindungan dan penyahlindungan kumpulan berfungsi. Pemurnian dijalankan menggunakan penghabluran dan kromatografi jejari. Analisis struktur sebatian yang terhasil dilakukan menggunakan FTIR, 1H-NMR, 13C-NMR dan spektrometri jisim. Ketulenan sebatian yang terhasil diukur menggunakan HPLC dan ukuran takat lebur (195-197 °C). Hasil keseluruhan yang diperoleh melalui laluan ini ialah 21%.

Kata kunci: Antikanser; gefitinib; Iressa; sintesis; 4-klorokuinazolin

 

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*Pengarang untuk surat-menyurat; email: alni@itb.ac.id