文献类型：期刊文献

英文题名：New methods for resolution of hydroxychloroquine by forming diastereomeric salt and adding chiral mobile phase agent on RP-HPLC

作者：Chen, Chen[1];Peng, Yangfeng[1];Wei, Yongming[1];Liu, Mengyuan[1];Wang, Yu[1];Xiong, Siqi[1];Li, Huiyi[1];He, Quan[2]

机构：[1]East China Univ Sci & Technol, Sch Chem Engn, 130 Meilong Rd, Shanghai 200237, Peoples R China;[2]Dalhousie Univ, Fac Agr, Dept Engn, Truro, NS, Canada

年份：2024

卷号：36

期号：5

外文期刊名：CHIRALITY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001210984100001)】；

基金：The authors are thankful for the financial support provided by the National Natural Science Foundation of China (21978082).

语种：英文

外文关键词：carboxymethyl-beta-cyclodextrin; diastereomeric salts; Di-p-anisoyl-L-tartaric acid; enantio-separation; hydroxychloroquine; RP-HPLC

摘要：Hydroxychloroquine (HCQ), 2-([4-([7-Chloro-4-quinolyl]amino)pentyl]ethylamino)ethanol, exhibited significant biological activity, while its side effects cannot be overlooked. The RP-HPLC enantio-separation was investigated for cost-effective and convenient optical purity analysis of HCQ. The thermodynamic resolution of Rac-HCQ, driven by enthalpy and entropy, was achieved on the C18 column using Carboxymethyl-beta-cyclodextrin (CM-beta-CD) as the chiral mobile phase agent (CMPA). The effects of CCM-beta-CD, pH, and triethylamine (TEA) V% on the enantio-separation process were explored. Under the optimum conditions at 24 degrees C, the retention times for the two enantiomers were tR1=29.39min$$ {t}_{R1}=29.39\ \min $$ and tR2=32.42min$$ {t}_{R2}=32.42\ \min $$, resulting in Rs=1.87$$ {R}_s=1.87 $$. The resolution via diastereomeric salt formation of Rac-HCQ was developed to obtain the active pharmaceutical ingredient of single enantiomer S-HCQ. Di-p-Anisoyl-L-Tartaric Acid (L-DATA) was proved effective as the resolution agent for Rac-HCQ. Surprisingly, it was found that refluxing time was a key fact affecting the resolution efficiency, which meant the kinetic dominate during the process of the resolution. Four factors-solvent volume, refluxing time, filtration temperature, and molar ratio-were optimized using the single-factor method and the response surface method. Two cubic models were established, and the reliability was subsequently verified. Under the optimal conditions, the less soluble salt of 2L-DATA:S-HCQ was obtained with a yield of 96.9% and optical purity of 63.0%. The optical purity of this less soluble salt increases to 99.0% with a yield of 74.2% after three rounds recrystallization. Hydroxychloroquine enantiomers was selectivity separated by di-p-anisoyl-L-tartaric acid through forming diastereomeric salt. Using carboxymethyl-beta-cyclodextrin as the chiral mobile phase agent, the optical purity of hydroxychloroquine enantiomers in the less salt of S-Hydroxychloroquine2di-p-anisoyl-L-tartaric acid was determined conveniently and successfully on the RP-HPLC of OSD-C18 column. image