CẢI TIẾN QUY TRÌNH TỔNG HỢP 2-NITROMESITYLEN ĐẠT ĐỘ TINH KHIẾT CAO LÀM NGUYÊN LIỆU ĐIỀU CHẾ THUỐC RILPIVIRIN ĐIỀU TRỊ HIV

Abstract

Background: Rilpivirine, an HIV treatment drug approved for use in the United States since May 2011 under the trade name Edurant, needs to be studied for synthesis using inexpensive and locally available materials to reduce dependence on imports. 2-Nitromesitylene, a key intermediate in many rilpivirine synthesis processes, currently faces challenges in synthesis and purification due to the selectivity of the reaction. Additionally, quality control of the product is a mandatory requirement in the registration of active pharmaceutical ingredients (API) in Vietnam. Objectives: The synthesis and purification of 2-nitromesitylene with high purity can be achieved through the nitration of mesitylene using a new nitrating agent. Materials and Methods: The synthesis of 2-nitromesitylene was carried out by nitration of mesitylene using acylnitrate (acetyl nitrate) as the reagent, with an investigation into factors affecting the reaction selectivity. The product structure was characterized using IR, MS, ¹H-NMR, and ¹³C-NMR spectroscopy, while its purity was evaluated through thin-layer chromatography (TLC), melting point determination, and high-performance liquid chromatography (HPLC). Results: Nitration of mesitylene using a novel reagent, acetyl nitrate (comprising 65% nitric acid in acetic anhydride), at a scale of 2 g per batch achieved a yield of 95.6%. The structure of the product was accurately confirmed by melting point determination, IR, MS, ¹H-NMR, and ¹³C-NMR spectra. Optimization of the molar ratio of acetyl nitrate to mesitylene (1.4:1.0) and reaction temperature (5–15 °C) enabled upscaling of the synthesis and purification to 30 g per batch, with a stable yield of 93.9%. New conditions for the HPLC method were established, confirming the product's purity at 99.37%. Conclusion: 2-Nitromesitylene with a purity of 99.37% (HPLC) was successfully synthesized and purified through the nitration of mesitylene using a novel reagent, 65% nitric acid, at a scale of 30 g per batch, achieving a yield of 93.9%.