Lopinavir preparation and purification process

Abstract

The invention relates to a lopinavir preparation and purification process, and belongs to the field of drug synthesis. The purification process comprises: dissolving a lopinavir crude product in methanol, cooling to a temperature of 0-5 DEG C, adding water firstly, continuously cooling to a temperature of 5-15 DEG C, carrying out first thermal insulation stirring, standing, separating to obtain a supernatant, adding water secondly to the supernatant in a dropwise manner, stirring until the solid is precipitated, adding water thirdly, carrying out second thermal insulation stirring at a temperature of 10-15 DEG C after completing the water adding, and separating to obtain the lopinavir, wherein the concrete step of the third water adding is that the water is added in a dropwise manner in a plurality of batches within an interval time. According to the present invention, in the purification process, a small amount of the methanol and a large amount of the water are adopted as the purification solvent, such that the toxicity is low, and the cost is low; and with the purification process, the lopinavir crude product with the HPLC purity (peak area%) of less than 99.5%, preferably less than 99.1% and containing more than two single impurities with the content of more than 0.1% can be purified into the lopinavir with the single impurity content of less than 0.1% and the HPLC purity of more than 99.5%, wherein the loss during the purification process is less than 10%.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a preparation and purification process of lopinavir. Background technique [0002] Lopinavir, the chemical name is (2S)-N-[(2R,4S,5S)-5-[[2-(2,6-Dimethylphenoxy)acetyl]amino]-4-hydroxy- 1,6-Diphenyl-hex-2-yl]-3-methyl-2-(2-oxo-1,3-diazacyclohex-1-yl)butyramide is a proprietary A new generation of HIV protease inhibitors designed and improved by Tonavir, structurally as shown in formula (I) [0003] [0004] Lopinavir contains 4 chiral carbons of S-configuration, and the intermediates involved in the synthesis process all have diastereoisomers (about 10% in total) leading to an increase in the number of impurities, which further leads to the quality of industrial production. Control becomes more difficult. The quality control of raw materials conforms to the national standard. The USP standard of lopinavir requires that the content of individual impurities should not exceed 0.1...

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Problems solved by technology

[0005] The crude product of lopinavir is prepared by using the existing synthesis process. After analyzing according to the USP35 standard, the impurity content of retention time (RT) 33 minutes or RRT0.74 exceeds 0.3%. Traditional purification methods cannot remove and reduce this impurity, making lopinavir It is difficult for Weiwei to meet the requirements of USP standards

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