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-6-
nitroquinazolin-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-7-
chloroquinazolin-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.