苯丙胺类、氯胺酮、卡西酮类毒品手性分离的研究进展

doi:10.3724/SP.J.1123.2020.05020

摘要/Abstract

摘要：

对映异构体在自然界中普遍存在,在药物化学领域尤为突出。虽然手性药物的对映异构体之间具有相同的化学结构,但它们在药理、毒理、药代动力学、代谢等生物活性方面存在明显差异。苯丙胺类、氯胺酮、卡西酮类毒品也是如此,这3类毒品的手性分离研究在常见毒品中具有代表性。目前常用的手性分离色谱方法有气相色谱法(GC)、高效液相色谱法(HPLC)和毛细管电泳法(CE)。苯丙胺类、氯胺酮、卡西酮类毒品使用以上3种方法进行的手性分离研究具有一定共性:GC较多使用N-三氟乙酰-L-脯胺酰氯和(+)R-α-甲氧基α-三氟甲基苯乙酸两种典型的手性衍生化试剂,HPLC主要应用蛋白质类、多聚糖类和大环抗生素类3种手性固定相,CE中环糊精及其衍生物是最常用的手性选择剂。然而这3种手性分离方法存在各自的不足,GC存在手性衍生化引入杂质、反应温度高影响手性分离等问题,HPLC的应用范围比较有限,成本较高,CE没有明确的方法判断哪种物质是合适的手性选择剂。近年来,这3类毒品的手性分离研究在法医毒物学领域的应用有各自的特点,苯丙胺类毒品的手性分离研究多用于推断市场上毒品的原型及合成路线,氯胺酮的手性分离研究涉及多种生物检材,卡西酮类毒品侧重于手性分离方法的广泛适用性。该文主要遴选近10年国内外核心期刊的文献,对苯丙胺类、氯胺酮、卡西酮类毒品的手性异构体特点及色谱法的手性识别机理进行简单介绍,重点对已有研究的共性以及手性分离在法医毒物学中的应用等内容进行综述。基于以上研究,该文提出未来可以从以下3个方面进行深入研究:一是利用计算机技术建立分子模型深入探究手性识别机理;二是研发新型技术,对超临界流体法进行商用研究;三是将手性分离应用于司法实践、医药研发等实际工作领域。

关键词: 手性分离, 对映异构体, 毒品, 苯丙胺类, 氯胺酮, 卡西酮类, 法医毒物学

Abstract:

Enantiomers are ubiquitous in nature, and they are especially important in the field of pharmaceutical chemistry. Although the enantiomers of chiral drugs have identical chemical structures, they differ notably in their pharmacological, toxicological, pharmacokinetic, metabolic, and other biological activities. The same is true for amphetamines, ketamine, and cathinones, as the chiral separation of these three drugs is representative of drugs. Gas chromatography (GC), high performance liquid chromatography (HPLC), and capillary electrophoresis (CE) are widely used for the chiral separation of these three kinds of drugs. There are some similarities among the three methods for the chiral separation of amphetamines, ketamine, and cathinones: n-trifluoroacetyl-L-prolinyl chloride and (+)R-α-methoxy-α-trifluoromethylphenylacetic acid are the two typical chiral derivatization reagents used in GC. In HPLC, three kinds of chiral stationary phases are used: proteins, polysaccharides, and macrocyclic antibiotics. Cyclodextrin and its derivatives are most commonly used in CE. However, these three methods have inherent shortcomings. In the case of GC, impurities produced during chiral derivatization may interfere with the analysis, and high reaction temperatures affect the efficiency of chiral separation. HPLC has limited application scope and is expensive. In CE, there has no established process to determine the appropriate chiral selector. In recent years, research into application of the chiral separation of the above-mentioned three kinds of drugs has its own characteristics in forensic toxicology. The chiral separation of amphetamine drugs is mostly used to infer the prototype and synthesis route of drugs on the market. The chiral separation of ketamine involves a variety of biological samples. For cathinones, chiral separation methods emphasize their wide applicability. In this review, 66 reports published in professional local and overseas magazines during the past decade are collated. The characteristics of the enantiomers of amphetamines, ketamine, and cathinones as well as the mechanism of chiral recognition are briefly introduced. The commonness of the research and the application of chiral separation in forensic toxicology are reviewed. This paper proposes that the chiral separation of drugs can be further investigated from the following three aspects: 1) the use of computer technology to establish a molecular model for exploring the mechanism of chiral recognition; 2) developing new technologies for chiral separation and carrying out commercial research on the supercritical fluid method; 3) applying chiral separation to judicial practice, pharmaceutical research and development, and other practical fields.

Key words: chiral separation, enantiomer, drugs, amphetamines, ketamine, cathinones, forensic toxicology

中图分类号:

O658

汤文川, 常靖, 王元凤, 王爱华, 王瑞花. 苯丙胺类、氯胺酮、卡西酮类毒品手性分离的研究进展[J]. 色谱, 2021, 39(3): 271-280.

TANG Wenchuan, CHANG Jing, WANG Yuanfeng, WANG Aihua, WANG Ruihua. Research progress on chiral separation of amphetamines, ketamine, cathinones[J]. Chinese Journal of Chromatography, 2021, 39(3): 271-280.

图/表 3

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Type of chiral column	Name of chiral column	Chiral selector	Separated species	Mobile phase	Ref.
Protein chiral column	Chiralpak CBH	cellobiohydrolase	amphetamine derivatives	1 mmol/L ammonium acetate- methanol (85∶15, v/v)	[35]
	Chiralpak AGP	α_l-acid glycoprotein	ketamine	10 mmol/L ammonium acetate- 2-propanol (94∶6, v/v)	[39]
Polysaccharide derivative-based	Chiralpak AS-3R	amylose tris[S-α-methyl- benzylcarbamate]	ketamine	1 mmol/L ammonium bicarbonate- acetonitrile (54∶46, v/v)	[40]
chiral column	Lux i-cellulose-5	cellulose tris-(3,5-dichloro- phenylcarbamate)	cathinones	n-hexane-isopropanol-diethylamine (95∶5∶0.1, v/v/v)	[43]
	ACQUITY UPC2 Trefoil CEL1	cellulose tris-(3,5-dimethyl- phenylcarbamate)	cathinones	n-hexane-n-butanol-diethylamine (100∶0.3∶0.2, v/v/v) or n-hexane- diethylamine (100∶0.2, v/v)	[44]
Macrocyclic antibiotics chiral	Chirobiotic V	vancomycin	ketamine	methanol-acetic acid-triethylamine (100∶0.02∶0.02, v/v/v)	[42]
column	Chirobiotic V2	vancomycin	amphetamine, methamphetamine	20 mmol/L ammonium acetate (0.1% v/v formic acid)-methanol (1∶99, v/v)	[37]

Type of chiral column	Name of chiral column	Chiral selector	Separated species	Mobile phase	Ref.
Protein chiral column	Chiralpak CBH	cellobiohydrolase	amphetamine derivatives	1 mmol/L ammonium acetate- methanol (85∶15, v/v)	[35]
	Chiralpak AGP	α_l-acid glycoprotein	ketamine	10 mmol/L ammonium acetate- 2-propanol (94∶6, v/v)	[39]
Polysaccharide derivative-based	Chiralpak AS-3R	amylose tris[S-α-methyl- benzylcarbamate]	ketamine	1 mmol/L ammonium bicarbonate- acetonitrile (54∶46, v/v)	[40]
chiral column	Lux i-cellulose-5	cellulose tris-(3,5-dichloro- phenylcarbamate)	cathinones	n-hexane-isopropanol-diethylamine (95∶5∶0.1, v/v/v)	[43]
	ACQUITY UPC2 Trefoil CEL1	cellulose tris-(3,5-dimethyl- phenylcarbamate)	cathinones	n-hexane-n-butanol-diethylamine (100∶0.3∶0.2, v/v/v) or n-hexane- diethylamine (100∶0.2, v/v)	[44]
Macrocyclic antibiotics chiral	Chirobiotic V	vancomycin	ketamine	methanol-acetic acid-triethylamine (100∶0.02∶0.02, v/v/v)	[42]
column	Chirobiotic V2	vancomycin	amphetamine, methamphetamine	20 mmol/L ammonium acetate (0.1% v/v formic acid)-methanol (1∶99, v/v)	[37]