关键词: 气相色谱法, 手性拆分, 4-氯甲基-2,2-二甲基-1,3-二氧戊环, 对映异构体

Abstract:

Chiral compounds play an important role in the pharmaceutical industry owing to their unique biological activities. The enantiomers must be separated because they can exhibit different pharmacological activities. Thus, the development of chiral separation methods is essential to determine the purity of enantiomers. 4-Chloromethyl-2,2-dimethyl-1,3-dioxolane is an important chiral pharmaceutical intermediate. In this context, a method based on chiral capillary gas chromatography was established for the separation and determination of the enantiomers of 4-chloromethyl-2,2-dimethyl-1,3-dioxolane. The separation of (R)- and (S)-4-chloromethyl-2,2-dimethyl-1,3-dioxolane was initially investigated using two conventional stationary-phase capillary columns: SH-I-5Sil MS and SH-WAX. The stationary phase of SH-I-5Sil MS consisted of 5% phenyl and 95% polymethylsiloxane, whereas the stationary phase of SH-WAX consisted of 100% crosslinked polyethylene glycol. Neither of the columns exhibited chiral selectivity, so they both were unable to separate the enantiomers of 4-chloromethyl-2,2-dimethyl-1,3-dioxolane. Subsequently, the separation of (R)- and (S)-4-chloromethyl-2,2-dimethyl-1,3-dioxolane was investigated using four chiral columns: Rt-bDEXm, Rt-bDEXsm, Rt-bDEXse, and InertCap CHIRAMIX. Among the chiral columns, Rt-bDEXse, which used a stationary phase composed of 2,3-di-O-ethyl-6-O-tert-butyl dimethylsilyl β-cyclodextrin added to 14% cyanopropyl phenyl and 86% dimethyl polysiloxane, achieved the best separation of (R)- and (S)-4-chloromethyl-2,2-dimethyl-1,3-dioxolane. Thus, this column was selected as the analytical column for further method optimization. Detection was performed using a hydrogen flame ionization detector. The effects of various gas chromatographic parameters, such as linear velocity, initial column temperature, column heating rate, and solvent type, on the separation of (R)- and (S)-4-chloromethyl-2,2-dimethyl-1,3-dioxolane were investigated. The optimal chromatographic conditions included a linear velocity of 70 cm/s, an initial column temperature of 70 ℃, and a column heating rate of 2.0 ℃/min. The final column oven temperature was 150 ℃. Methanol, ethanol, ethyl acetate, n-hexane, dichloromethane, and dimethyl sulfoxide were selected as solvents. The results showed that dimethyl sulfoxide interfered with the peaks of the target compounds, whereas the other solvents had no significant effect on the peak shape and separation of (R)- and (S)-4-chloromethyl-2,2-dimethyl-1,3-dioxolane. Methanol was finally selected as the solvent in this study. Further experiments revealed that (R)- and (S)-4-chloromethyl-2,2-dimethyl-1,3-dioxolane could be rapidly separated within 10 min, with a resolution greater than 1.5. A good linear relationship was observed in the range of 0.5-50.0 mg/L, with a linear correlation coefficient greater than 0.998. The limits of detection for (R)- and (S)-4-chloromethyl-2,2-dimethyl-1,3-dioxolane were 0.07 and 0.08 mg/L, respectively, and the corresponding limits of quantification were 0.22 and 0.25 mg/L, respectively. Spiked recovery tests were performed at three spiked levels of 0.5, 2.0, and 10.0 mg/L using methanol as the blank to determine the accuracy of the proposed method. The recoveries for (R)- and (S)-4-chloromethyl-2,2-dimethyl-1,3-dioxolane were 94.0%-99.1% and 96.0%-98.8%, respectively, with relative standard deviations (RSDs) of 1.26%-4.87% and 1.51%-4.46%, respectively. The established method is efficient and reliable; thus, it can serve as a reference for the separation of the enantiomers of 4-chloromethyl-2,2-dimethyl-1,3-dioxolane. It can also potentially be applied to evaluate the enantiomeric purity of other chiral compounds in the pharmaceutical industry and produce chiral drugs and other related compounds.

Key words: gas chromatography (GC), chiral separation, 4-chloromethyl-2,2-dimethyl-1,3-dioxolane, enantiomers