羟氯喹(HCQ),2-([4-([7-氯-4-喹啉基]氨基)戊基]乙基氨基)乙醇,表现出显著的生物活性,虽然它的副作用不容忽视。研究了RP-HPLC对映体分离以经济有效且方便的HCQ光学纯度分析。Rac-HCQ的热力学解析,由焓和熵驱动,在C18色谱柱上使用羧甲基-β-环糊精(CM-β-CD)作为手性流动相试剂(CMPA)。CCM-β-CD的作用,pH值,和三乙胺(TEA)V%对对映体分离过程的影响进行了探讨。在24°C的最佳条件下,两种对映异构体的保留时间为tR1=29.39min$${t}_{R1}=29.39\\\\min$$和tR2=32.42min$${t}_{R2}=32.42\\\min$$$,结果Rs=1.87$${R}_s=1.87$$。开发了通过形成Rac-HCQ的非对映体盐的拆分以获得单一对映体S-HCQ的活性药物成分。二-对-苯异酰基-L-酒石酸(L-DATA)被证明是有效的Rac-HCQ的拆分剂。令人惊讶的是,发现回流时间是影响分辨效率的关键事实,这意味着在决议过程中动能占主导地位。四个因素-溶剂体积,回流时间,过滤温度,采用单因素法和响应面法进行优化。建立了两个立方模型,可靠性随后得到验证。在最优条件下,获得2L-DATA:S-HCQ的较不溶性盐,产率为96.9%,光学纯度为63.0%。在三轮重结晶后,这种溶解性较低的盐的光学纯度增加到99.0%,产率为74.2%。
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-β-cyclodextrin (CM-β-CD) as the chiral mobile phase agent (CMPA). The effects of CCM-β-CD, pH, and triethylamine (TEA) V% on the enantio-separation process were explored. Under the optimum conditions at 24°C, the retention times for the two enantiomers were t R 1 = 29.39 min $$ {t}_{R1}=29.39\\ \\min $$ and t R 2 = 32.42 min $$ {t}_{R2}=32.42\\ \\min $$ , resulting in R s = 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.