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Date Published: 25/01/2025
Abstract Views: 346
Views PDF: 110
DOI: 10.58490/ctump.2025i83.3294
Issue
No. 83 (2025)
Section
Article
How to Cite
Nguyen, T. N., Luong, T. T., Vu, T. N. T., Nguyen, H. A. V., Nguyen, H. B., Nguyen, V. G., Nguyen, V. H., Dao, N. S. H., Bui, T. T. C., & Truong, T. H. H. (2025). IMPROVE THE SYNTHESIS PROCESS OF 7-CHLORO-6- NITROQUINAZOLIN-4(3H)-ONE AS A RAW MATERIAL INTERMEDIATES IN THE PREPARATION OF SECOND-GENERATION EGFR TYROSINE KINASE INHIBITORS. Cantho Journal of Medicine and Pharmacy, 83, 23-30. https://doi.org/10.58490/ctump.2025i83.3294

IMPROVE THE SYNTHESIS PROCESS OF 7-CHLORO-6- NITROQUINAZOLIN-4(3H)-ONE AS A RAW MATERIAL INTERMEDIATES IN THE PREPARATION OF SECOND-GENERATION EGFR TYROSINE KINASE INHIBITORS

Thi Ngoc Nguyen1, , Thi Thanh Luong2,3, Thi Ngoc Trang Vu3, Hoang Anh Vuong Nguyen2, Hoa Binh Nguyen3, Van Giang Nguyen3, Van Hai Nguyen3, Nguyet Suong Huyen Dao3, Thi Thanh Cham Bui1,3, Thi Hong Hanh Truong1
1 Thai Nguyen University of Medicine and Pharmacy
2 Ha Noi University of Industry
3 Ha Noi University of Pharmacy

Main Article Content

Abstract

Background: 7-Chloro-6-nitro-quinazolin-4(3H)-one plays a significant role in the synthesis of targeted anticancer agents such as afatinib, dacomitinib, and poziotinib. In Vietnam, some studies have been conducted on the reactions involved in the synthesis of this intermediate, but they were limited in scale (ranging from a few mg to under 30 g), achieving reaction efficiencies of only 70-85%. Therefore, further research is needed to improve reaction conditions and equipment to enhance the synthesis efficiency of 7-chloro-6-nitroquinazolin-4(3H)-one, laying the groundwork for subsequent steps in the synthesis of drugs in this class. Objectives: To improve the equipment, reagents, molar ratios of reactants, and product purification methods in the synthesis of 7-chloro-6nitroquinazolin-4(3H)-one from 2-amino-4-chlorobenzoic acid, achieving high efficiency and purity above 99%. After that, the reaction process can be advanced to a 20 g/batch scale. Materials and methods: From 2-amino-4-chlorobenzoic acid, condensation reactions were carried out to form quinazolin-4(3H)-one and nitration. The conditions for equipment, reagents, molar ratios of the substances, and purification solvents were examined to obtain the highest efficiency. The product structure was determined using spectroscopic methods: IR, MS, 1H-NMR, 13C-NMR, HPLC. Results: 7-chloro-6-nitroquinazolin-4(3H)-one was synthesized and its structures confirmed. A hydrothermal autoclave reactor was used to enhance the quinazolin ring closure step, reducing the molar ratio of 2-amino-4-chlorobenzoic acid : formamide to 1:8. This produced a product yield of over 90% and a purity of 99.9% without the need for additional purification. In the nitration reaction, NaNO3 was used instead of fuming HNO3, and the product was crystallized using acetone, achieving a yield of 80.8% and purity exceeding 99.7%. This enabled the scale-up of the synthesis of 6-nitro-7chloroquinazolin-4(3H)-one to 20 g/batch, with an overall process yield of 75.7%. Conclusion: An enhanced method has been used to synthesis and purify 7-chloro-6-nitroquinazolin-4(3H)-one, producing a product with good efficiency and high purity. The equipment, a hydrothermal autoclave reactor, is straightforward and easy to use, and the reagents are safer and more widely available.

Keywords

7-chloro-6-nitroquinazolin-4(3H)-one, 7-chloroquinazolin-4-(3H)-on, 2-amino-4- clorobenzoic acid, sodium nitrate / H2SO4

Article Details

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