WO2020113725A1 - 一种手性化合物的检测方法 - Google Patents

一种手性化合物的检测方法 Download PDF

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WO2020113725A1
WO2020113725A1 PCT/CN2018/124284 CN2018124284W WO2020113725A1 WO 2020113725 A1 WO2020113725 A1 WO 2020113725A1 CN 2018124284 W CN2018124284 W CN 2018124284W WO 2020113725 A1 WO2020113725 A1 WO 2020113725A1
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chiral
detecting
chiral compound
spectrometer
sample
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车顺爱
刘泽栖
段瑛滢
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Tongji University
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/65—Raman scattering
    • G01N21/658—Raman scattering enhancement Raman, e.g. surface plasmons
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/65—Raman scattering

Definitions

  • the invention relates to a method for detecting chiral compounds.
  • Chiral compounds refer to a class of compounds that have the same molecular structure but mirror each other in configuration.
  • a mirror image of a chiral compound usually has different characteristics.
  • thalidomide has two mirror image enantiomer configurations, S and R, of which R type has central sedation. Function, S type has a strong teratogenic effect. Therefore, in the R&D and production process involving chiral compounds, the distinction between enantiomers and content detection are crucial steps.
  • the analysis and detection methods of chiral compounds mainly include two types, that is, spectrum types and chromatography types.
  • the detection of chiral compounds must be distinguished by matching chiral structures to chiral structures.
  • Spectroscopy uses chiral compounds to identify chiral circular polarized light
  • chromatographic techniques uses chiral fixed relative chiral compounds.
  • Spectroscopic methods mostly use the optical rotation and circular dichroism of chiral compounds (that is, the characteristics of deflecting polarized light and the interaction characteristics different from the left and right circular polarized light), which cannot detect racemization
  • the latter is susceptible to the interference of linearly polarized light generated during the process of switching between left and right circularly polarized light, and cannot detect molecules without chromophoric groups.
  • Chromatographic methods mainly rely on the adsorption capacity of chromatographic column packing for different configurations of chiral compounds for separation and content detection.
  • chromatographic methods can be applied in a limited range, and commonly used chiral chromatographic columns can only be applied to some Chiral compounds with adsorption characteristics cannot detect compounds with too large molecular weight, too small molecular weight, or non-polarity.
  • the inventors of the present invention conducted research on the characteristics of chiral recognition, and found that chiral recognition and detection of the following characteristics: when materials with chiral characteristics interact with chiral compounds, due to the electromagnetic field Sexual characteristics, unichiral materials have different strengths for the interaction of different enantiomers of chiral compounds. Not only that, the inventors also found that this difference in interaction strength can be characterized by the optical properties of materials and compounds. Moreover, its interaction strength is linearly related to the content ratio (ee value) of enantiomers in the chiral compound system to be tested. Therefore, based on the performance of the optical properties of the interaction between the chiral material and the chiral compound, the content ratio can be deduced, thereby realizing the detection of the chiral compound.
  • ee value content ratio
  • the present invention provides a method for detecting chiral compounds, which is characterized in that a material with chiral characteristics is used as a base material to cooperate with a spectrometer to detect chiral compounds.
  • the method includes the following steps: Step S1: The test sample is placed on the substrate material; Step S2, the spectrometer is used to detect the sample to be tested to obtain the characteristic spectrum of the sample to be tested, wherein both the light source and the detection light of the spectrometer are unpolarized light.
  • the method for detecting chiral compounds provided by the present invention may also have such technical characteristics, wherein the material with chiral characteristics in step S1 is a micro-nano powder or micro-nano film material with a chiral structure.
  • the method for detecting chiral compounds provided by the present invention may also have such technical characteristics, wherein the material with chiral characteristics is composed of an inorganic material, an organic material or an organic-inorganic composite material.
  • the method for detecting chiral compounds provided by the present invention may also have such technical characteristics, wherein the inorganic material is a plasmon resonance material and the spectrometer is a Raman spectrometer.
  • the method for detecting chiral compounds provided by the present invention may also have such technical characteristics, wherein the plasmon resonance material is a metal, a metal oxide, or a mixture of both.
  • the method for detecting chiral compounds provided by the present invention may also have such technical characteristics, wherein the metal is one or a combination of gold, silver, copper and platinum, and the metal oxide is copper oxide or titanium oxide , Zinc oxide, tin oxide, iron oxide, cobalt oxide one or a combination of several.
  • the method for detecting chiral compounds provided by the present invention may also have such technical characteristics, wherein the chiral structure is any one of a spiral fiber structure, a flower-shaped structure, a fan-shaped structure, and a propeller-shaped structure.
  • step S3 the characteristic spectrum obtained in step S2 is analyzed to obtain the enantiomeric content in the chiral compound.
  • step S3 includes the following steps: step S3-1, preparing multiple standards of chiral compounds, each of which contains Enantiomers of different amounts of chiral compounds; Step S3-2, the standards are placed on the base material, and the standards are detected by spectrometers to obtain the characteristic spectra of the standards; Step S3-3, The characteristic spectra of the standard product and the test sample are compared and analyzed to obtain the enantiomeric content of the chiral compound in the test sample.
  • the detection method of the chiral compound provided by the present invention may also have such technical characteristics, wherein the comparative analysis is to draw a standard curve according to the characteristic peak intensity and enantiomeric content relationship in the standard product, according to the standard curve and the sample to be tested The characteristic peak intensity of gives the enantiomeric content of the chiral compound.
  • the detection method of the present invention since materials with chiral qualities are used as the base materials for the spectrometer detection, they can produce different strength interactions of different enantiomers of the chiral compound. The detection of this effect can obtain the content ratio of the enantiomers to achieve the detection of chiral compounds. Compared with the chiral compound detection method in the prior art, the detection method of the present invention has the advantages of simple operation and accurate results.
  • Example 1 is a flowchart of a method for detecting chiral compounds according to Example 1 of the present invention
  • Example 2 is a characteristic spectrum chart obtained by detecting the mixture of R-limonene and S-limonene by using the detection method in Example 1 of the present invention
  • Example 3 is a linear fitting diagram of the characteristic peak intensity and the percentage of chiral molecular content obtained by detecting the mixture of R-limonene and S-limonene using the detection method in Example 1 of the present invention
  • Example 4 is a characteristic spectrum diagram obtained by detecting the mixture of L-cyclohexylglycine and D-cyclohexylglycine by using the detection method in Example 1 of the present invention
  • Example 5 is a linear fitting diagram of the characteristic peak intensity and the percentage of chiral enantiomeric content obtained by performing characteristic spectrum detection on a mixture of L-cyclohexylglycine and D-cyclohexylglycine using the detection method in Example 1 of the present invention;
  • Example 6 is a characteristic spectrum diagram obtained by detecting the mixture of L-phenylglycine and D-phenylglycine by using the detection method in Example 1 of the present invention
  • Example 7 is a linear fitting diagram of the characteristic peak intensity and the percentage of chiral enantiomer content obtained by detecting the mixture of L-phenylglycine and D-phenylglycine using the detection method of Example 1 of the present invention
  • Example 8 is a characteristic spectrum chart obtained by respectively detecting N-acetyl-L-cysteine and N-acetyl-D-cysteine at the same concentration by using the detection method in Example 4 of the present invention;
  • FIG. 10 is a Raman spectrogram of a conventional example of the present invention for detecting limonene using a common Raman spectrometer;
  • FIG. 11 is a Raman spectrum diagram of a comparative example of the present invention for detecting limonene using a common Raman spectrometer and a substrate material without chirality.
  • the gold nanospiral fiber array is used as a base material, which is combined with a Raman spectrometer to detect chiral compounds.
  • the above-mentioned base material has the following characteristics: 1) Gold is a metal-based plasmon resonance material, which can enhance the Raman signal of the sample when used as the base material in the Raman spectroscopy detection process; 2) Gold nanospiral fibers
  • the array is a film material formed on a silicon substrate by a growth method, and is composed of a plurality of single-stranded gold spiral fibers arranged neatly.
  • the spiral fiber structure is a single chiral structure.
  • this gold nanospiral fiber Arrays are materials with chiral qualities.
  • the Raman spectrometer used in this embodiment is a general Raman spectrometer, that is, both the light source and the detection light of the Raman spectrometer are unpolarized light.
  • the light emitted by the light source is unpolarized light
  • the photodetection unit that detects the detection light is also Ordinary detection unit for unpolarized light.
  • FIG. 1 is a flowchart of a chiral compound detection method according to Embodiment 1 of the present invention.
  • the first embodiment of the present invention uses the above-mentioned gold nanospiral fiber array as a base material, combined with a Raman spectrometer to detect chiral compounds, specifically including the following steps:
  • Step S1 placing the test sample of the chiral compound on the base material
  • Step S2 a spectrometer is used to detect the sample to be tested to obtain a characteristic spectrum (ie, Raman spectrum) of the sample to be tested;
  • a characteristic spectrum ie, Raman spectrum
  • step S3 the characteristic spectrum obtained in step S2 is analyzed to obtain the enantiomeric content in the chiral compound.
  • the standard curve analysis method is used to quantify the content of the enantiomer in the sample to be tested.
  • the analysis process in step S3 further includes the following steps:
  • Step S3-1 preparing a plurality of standards of chiral compounds, each of which contains different amounts of enantiomers of the chiral compounds;
  • Step S3-2 placing the standard products on the base material respectively, and respectively detecting the standard products with a characteristic spectrometer to obtain the characteristic spectrum of each standard product;
  • step S3-3 the characteristic spectra of the standard product and the test sample are compared and analyzed to obtain the enantiomeric content of the chiral compound in the test sample.
  • This example uses limonene as the chiral compound to be tested, which has two configurations, namely R-limonene and S-limonene.
  • FIG. 2 is a characteristic spectrum chart obtained by detecting the mixture of R-limonene and S-limonene by using the detection method in Example 1 of the present invention.
  • -100% is a sample containing only R-limonene
  • 100% is a sample containing only S-limonene
  • -50% is a sample with a content ratio of R-limonene to S-limonene of 75:25
  • 0% It is a sample with an R-limonene to S-limonene content ratio of 50:50
  • 50% is a R-limonene to S-limonene content ratio of 25:75.
  • FIG. 3 is a linear fitting diagram of the characteristic peak intensity and the percentage of chiral molecular content obtained by detecting the mixture of R-limonene and S-limonene using the detection method in Example 1 of the present invention.
  • the abscissa is the percentage of chiral molecules (ee value)
  • the ordinate is the characteristic peak intensity (that is, the characteristic peak intensity in the Raman spectrum).
  • the detection method of this embodiment is used to perform characteristic spectrum detection, and then the test result of the sample to be tested is compared with the test result of the standard product (for example, The characteristic peak intensity of the sample to be tested is compared with the fitting curve of the characteristic peak intensity of the standard product), and the content ratio of S-limonene and R-limonene in the sample to be tested can be calculated.
  • cyclohexylglycine has two configurations, namely L-cyclohexylglycine and D-cyclohexylglycine.
  • FIG. 4 is a characteristic spectrum diagram obtained by detecting the mixture of L-cyclohexylglycine and D-cyclohexylglycine by using the detection method in Example 1 of the present invention.
  • -100% is a sample containing only L-cyclohexylglycine
  • 100% is a sample containing only D-cyclohexylglycine
  • -50% is the content ratio of L-cyclohexylglycine to D-cyclohexylglycine is
  • 75:25 samples 0% is a sample with a 50:50 ratio of L-cyclohexylglycine and D-cyclohexylglycine
  • 50% is a 25:25 ratio with L-cyclohexylglycine and D-cyclohexylglycine: 75 samples.
  • FIG. 5 is a linear fitting diagram of the characteristic peak intensity and the percentage of chiral enantiomer content obtained by performing characteristic spectrum detection on a mixture of L-cyclohexylglycine and D-cyclohexylglycine by using the detection method in Example 1 of the present invention.
  • the abscissa is the percentage of chiral molecule content (ee value)
  • the ordinate is the characteristic peak intensity.
  • the detection method of the chiral compound cyclohexylglycine when the detection method of the chiral compound cyclohexylglycine is detected by the detection method of the gold nanohelical fiber array combined with the Raman spectrometer, the signal intensity is positively proportional to the chiral enantiomer in the sample Than relationship.
  • the detection method of this embodiment when it is necessary to detect two samples of cyclohexylglycine with unknown enantiomer content, the detection method of this embodiment is used to perform characteristic spectrum detection, and then the test result of the sample to be tested is compared with the test result of the standard product, namely The content ratio of D-cyclohexylglycine and L-cyclohexylglycine in the sample to be tested can be calculated.
  • Example 1 the inventors also used the detection method of Example 1 to detect a variety of other chiral compounds, and found that this detection method can achieve the enantiomeric content ratio detection of different chiral compounds.
  • FIG. 6 is a characteristic spectrum chart obtained by detecting the mixture of L-phenylglycine and D-phenylglycine using the detection method of Embodiment 1 of the present invention
  • FIG. 7 is a detection method of L using the detection method of Embodiment 1 of the present invention.
  • the characteristic peak intensity is proportional to the ratio of chiral enantiomers in the sample.
  • the chiral compounds that can be detected by the detection method of the present invention in the ratio of enantiomeric content are close to one hundred pairs, and these chiral compounds have different characteristics.
  • Table 1 For example, according to the number of chiral centers, single-chiral center compounds and multi-chiral center compounds are included in Table 1; by polar classification, polar compounds and non-polar compounds are included in Table 1; in addition, in Table 1 It also contains many different kinds of chiral compounds such as chromophore molecules, non-chromophore molecules, macromolecules, small molecules and biological molecules. It can be seen that as long as the compound has Raman scattering properties, the enantiomeric content ratio can be detected by the detection method of the gold nanohelical fiber array of Example 1 combined with the Raman spectrometer.
  • gold-silver nanohelical wire array is used as the base material, and chiral compound detection is carried out in combination with Raman spectrometer.
  • the gold-silver nanospiral fiber array is formed by attaching silver again on the basis of the gold nanospiral fiber array of the first embodiment.
  • the gold-silver nanospiral fiber array is composed of a plurality of neatly arranged single-strand gold-silver composite spiral fibers, and its characteristics are similar to those of the gold nanospiral fiber array of the first embodiment, and also belong to the plasmon resonance material, and also With chiral characteristics.
  • the above-mentioned gold-silver nanospiral array can also exhibit the same characteristics as the gold nanospiral fiber array of Example 1.
  • the gold-silver nanospiral array can also be used as a base material in conjunction with a Raman spectrometer to achieve the detection of the content ratio of chiral compounds with different configurations in the sample to be tested.
  • flower-shaped nano titanium oxide powder was used as the base material, and chiral compound detection was carried out in combination with a Raman spectrometer.
  • Titanium oxide is a metal oxide plasma resonance material, which can enhance the Raman signal of the sample when used as the base material in the Raman spectrum detection process
  • Flower shape Nano titanium oxide powder is a material composed of nano titanium oxide particles, wherein the titanium oxide particles have a flower-shaped structure. Similar to the gold nanospiral fiber array and the gold-silver nanospiral array, this flower-shaped nanometer titanium oxide powder has a single-chiral structure and is also a material with chiral characteristics.
  • this example uses N-acetylcysteine as the chiral compound to be tested, which has two configurations, namely N-acetyl-L-cysteine and N-acetyl-D-cysteine .
  • Example 8 is a characteristic spectrum diagram obtained by respectively detecting N-acetyl-L-cysteine and N-acetyl-D-cysteine at the same concentration by using the detection method in Example 4 of the present invention.
  • fan-shaped nano silver powder is used as the base material, and chiral compound detection is carried out in combination with a Raman spectrometer.
  • the fan-shaped nano silver powder is also a material with chiral characteristics.
  • silver is also a metal-based plasma resonance material.
  • Example 9 is a characteristic spectrum diagram obtained by detecting the same concentration of N-acetyl-L-cysteine and N-acetyl-D-cysteine respectively by using the detection method in Example 5 of the present invention.
  • the detection method using fan-shaped nano silver powder as the base material can also make the two The samples exhibit different signal intensities.
  • the fingerprint characteristics in this Raman spectrum are not obvious enough, the peak height of the highest peak is analyzed (for example, comparing the peak height of the highest peak in the sample spectrum with the peak height of a standard that combines different proportions of enantiomeric content. ), the enantiomeric content ratio in the sample can also be calculated.
  • the inventors also used ordinary plasmon resonance materials and ordinary Raman spectrometers to detect the two limonenes in the first embodiment.
  • Fig. 10 is a Raman spectrum diagram of a conventional example of the present invention for detecting limonene using a common Raman spectrometer.
  • FIG. 11 is a Raman spectrum diagram of a comparative example of the present invention for detecting limonene using a common Raman spectrometer and a substrate material without chirality.
  • an ordinary Raman spectrometer and a plasmon resonance material without chirality are used (this comparative example uses gold nanoparticles, which are plasmon resonance materials, but the structure is a conventional structure and therefore does not have Chiral characteristics)
  • this comparative example uses gold nanoparticles, which are plasmon resonance materials, but the structure is a conventional structure and therefore does not have Chiral characteristics
  • the characteristic peak intensity of each limonene sample is stronger overall, but the five kinds of Raman spectra are also completely the same, indicating the combination of ordinary Raman spectrometers Materials without chiral qualities can achieve good qualitative and quantitative results, but they cannot distinguish between enantiomers and cannot detect content ratios of different configurations.
  • Example 1 Comparative Example 1
  • the chiral trait material of the present invention when used as a base material and a Raman spectrometer for detection, limonene samples with different ee values show different characteristic peak intensities, while ordinary The base material does not have this characteristic.
  • the inventor speculates that the reason for this phenomenon may be that the electromagnetic field generated by the material with chiral characteristics under the detection light irradiation also has chiral characteristics, which can specifically enhance the Raman signal of a certain chiral conformation (For example, it has a stronger enhancement effect on the S-limonene molecule) and has little enhancement effect on another chiral conformation.
  • Example 2 to Example 5 1.
  • the chiral qualities of the present invention and the detection method of the Raman spectrometer can detect hundreds of chiral compounds; 2. Even if other For the kind of materials with chiral characteristics, the detection method of the present invention can also realize the detection of chiral compounds.
  • the substrate material is a material with chiral characteristics (especially a plasmon resonance material with a chiral structure), it can more or less Raman signal of the chiral compound With specific enhancement, it can also be combined with Raman spectrometer to detect the ratio of enantiomeric content of chiral compounds.
  • the detection method of the present invention has low cost and simple operation , Low interference, accurate results, simple operation and wide application.
  • the material with chiral characteristics is a nano metal film material having a single chiral structure, a nano metal powder material, a nano metal oxide powder material and the like.
  • the material with chiral characteristics can also be other types of materials, including micro-nano material powders or micro-materials with chiral structure composed of other types of organic substances, inorganic substances, or organic substance-inorganic substance mixtures. Nano film material.
  • the inorganic substance may include a metal and a metal oxide
  • the metal may be one or a combination of gold, silver, copper, platinum
  • the metal oxide may be copper oxide, titanium oxide, zinc oxide, tin oxide, One or a combination of iron oxide and cobalt oxide
  • the chiral structure may also be a variety of chiral structures such as a propeller-shaped structure.
  • the spectrometer used in the examples is a Raman spectrometer.
  • it can also be another kind of spectrometer as long as it can detect the interaction between the base material and the compound to be tested.

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Abstract

提供了一种手性化合物的检测方法，其特征在于，采用具有手性特质的材料作为基底材料与光谱仪配合从而对手性化合物进行检测，包括如下步骤：步骤S1，将手性化合物的待测样品载置在基底材料上；步骤S2，采用光谱仪对待测样品进行检测从而得到待测样品的特征光谱，其中，光谱仪的光源和检测光都为非偏振光。与现有技术中的手性化合物检测方法相比，该检测方法具有操作简单、结果准确等优点。

Description

一种手性化合物的检测方法 技术领域
本发明涉及一种手性化合物的检测方法。
背景技术
手性化合物是指分子结构相同，但构型上互为镜像的一类化合物。在医药化工领域中，互为镜像的一对手性化合物之间通常具有不同的特性，例如，沙利度胺具有S和R两种互为镜像的对映体构型，其中R型具有中枢镇静作用，S型却具有强烈的致畸作用。因此，在涉及手性化合物的研发生产过程中，对映体之间的区分及含量检测是至关重要的步骤。
现有技术中，手性化合物的分析检测方法主要包括两类，即光谱类和色谱类。手性化合物的检测必须通过手性结构对手性结构的匹配来进行识别性区别。光谱法采用的是手性化合物对手性圆偏振光的识别，色谱发采用的是手性固定相对手性化合物的识别。光谱类的方法多利用手性化合物的旋光性和圆二色性(即，分别为让偏振光发生偏转的特性和与左右圆偏振光发生不同的相互作用特性)实现，其无法检测外消旋体，且后者容易受到左右圆偏振光切换过程中所产生的线偏振光的干扰，无法检测无发色基团的分子。色谱类方法主要依赖于色谱柱填料对不同构型手性化合物吸附能力的不同而进行分离及含量检测，然而，色谱类方法能够应用的范围有限，常用的手性色谱柱仅能应用于一部分符合其吸附特性的手性化合物，对分子量过大、分子量过小或没有极性的化合物都无法进行检测。
发明内容
为解决上述问题，本发明的发明人针对手性识别的特性进行了研究，发现手性识别和检测如下特性：具有手性特质的材料与手性化合物发生相互作用时，由于其电磁场具有的手性特质，单手性材料对不同对映异构体的手性化合物产生的相互作用具有不同的强度。不仅如此，发明人还发现，这种相互作用强度的不同可以通过材料和化合物的光学性质进行表征。并且，其相互作用强度与被测手性化合物体系中对映异构体的含量比例(ee值)线性相关。因此，根据手性材料与手性化合物的相互作用在光学性质上的表现即可推算出其含量比例，从而实现手性化合物的检测。
基于上述发现，发明人提出了一种手性化合物的检测方法，具体采用了如下技术方案：
本发明提供了一种手性化合物的检测方法，其特征在于，采用具有手性特质的材料作为基底材料与光谱仪配合从而对手性化合物进行检测，包括如下步骤：步骤S1，将手性化合物的待测样品载置在基底材料上；步骤S2，采用光谱仪对待测样品进行检测从而得到待测样品的特征光谱，其中，光谱仪的光源和检测光都为非偏振光。
本发明提供的手性化合物的检测方法，还可以具有这样的技术特征，其中，步骤S1中的具有手性特质的材料为具有手性结构的微纳米粉末或微纳米膜材料。
本发明提供的手性化合物的检测方法，还可以具有这样的技术特征，其中，具有手性特质的材料由无机材料、有机材料或有机-无机复合材料构成。
本发明提供的手性化合物的检测方法，还可以具有这样的技术特征，其中，无机材料为等离子体共振材料，光谱仪为拉曼光谱仪。
本发明提供的手性化合物的检测方法，还可以具有这样的技术特征，其中，等离子体共振材料为金属、金属氧化物或二者的混合物。
本发明提供的手性化合物的检测方法，还可以具有这样的技术特征，其中，金属为金、银、铜、铂中的一种或几种的组合物，金属氧化物为氧化铜、氧化钛、氧化锌、氧化锡、氧化铁、氧化钴中的一种或几种的组合物。
本发明提供的手性化合物的检测方法，还可以具有这样的技术特征，其中，手性结构为螺旋纤维结构、花形结构、扇形结构、螺旋桨形结构中的任意一种。
本发明提供的手性化合物的检测方法，还可以具有这样的技术特征，步骤S3，对步骤S2得到的特征光谱进行分析，从而得到手性化合物中的对映体含量。
本发明提供的手性化合物的检测方法，还可以具有这样的技术特征，其中，步骤S3的分析包括如下步骤：步骤S3-1，配制多个手性化合物的标准品，每个标准品中含有不同量的手性化合物的对映体；步骤S3-2，分别将标准品载置在基底材料上，并分别采用光谱仪对标准品进行检测从而得到各个标准品的特征光谱；步骤S3-3，将标准品和待测样品的特征光谱进行对比分析，得到待测样品中的手性化合物的对映体含量。
本发明提供的手性化合物的检测方法，还可以具有这样的技术特征，其中，对比分析为根据标准品中的特征峰强度及对映体含量关系绘制标准曲线，根据该标准曲线以及待测样品的特征峰强度得出手性化合物的对映体含量。
发明作用与效果
根据本发明提供的手性化合物的检测方法，由于采用具有手性特质的材料作为光谱仪检测时的基底材料，其能够对手性化合物的不同对映体产生不同强度的相互作用，因此，通过光谱仪对这种作用效果进行检测即可得出对映体的含量比例从而实现手性化合物的检测。与现有技术中的手性化合物检测方法相比，本发明的检测方法具有操作简单、结果准确等优点。
附图说明
图1是本发明实施例一的手性化合物检测方法的流程图；
图2是采用本发明实施例一的检测方法对R-柠檬烯和S-柠檬烯的混合物进行检测得到的特征光谱图；
图3是采用本发明实施例一的检测方法对R-柠檬烯和S-柠檬烯的混合物进行检测得到的特征峰强度与手性分子含量百分比的线性拟合图；
图4是采用本发明实施例一的检测方法对L-环己基甘氨酸和D-环己基甘氨酸的混合物进行检测得到的特征光谱图；
图5是采用本发明实施例一的检测方法对L-环己基甘氨酸和D-环己基甘氨酸的混合物进行特征光谱检测得到的特征峰强度与手性对映体含量百分比的线性拟合图；
图6是采用本发明实施例一的检测方法对L-苯基甘氨酸和D-苯基甘氨酸的混合物进行检测得到的特征光谱图；
图7是采用本发明实施例一的检测方法对L-苯基甘氨酸和D-苯基甘氨酸的混合物进行检测得到的特征峰强度与手性对映体含量百分比的线性拟合图；
图8是采用本发明实施例四的检测方法对相同浓度的N-乙酰-L-半胱氨酸和N-乙酰-D-半胱氨酸分别进行检测得到的特征光谱图；
图9是采用本发明实施例五的检测方法对相同浓度的N-乙酰-L-半胱氨酸和N-乙酰-D-半胱氨酸分别进行检测得到的特征光谱图；
图10是本发明比较例的采用普通拉曼光谱仪对柠檬烯进行检测的拉曼光谱图；
图11是本发明比较例的采用普通拉曼光谱仪以及不具有手性的基底材料对柠檬烯进行检测的拉曼光谱图。
具体实施方式
以下结合附图来说明本发明的具体实施方式。
<实施例一>
本实施例将金纳米螺旋纤维阵列作为基底材料，与拉曼光谱仪相结合来进行手性化合物的检测。
上述基底材料具有这样的特点：1)金是一种金属类的等离子体共振材料，其在拉曼光谱检测过程中作为基底材料时能够对样品的拉曼信号进行增强；2)金纳米螺旋纤维阵列是一种经由生长方法形成在硅基板上的膜材料，由多根整齐排列的单股金螺旋纤维构成，该螺旋纤维结构是一种单手性结构，相应地，这种金纳米螺旋纤维阵列是具有手性特质的材料。
另外，本实施例采用的拉曼光谱仪为通常的拉曼光谱仪，即，该拉曼光谱仪的光源和检测光都为非偏振光。也就是说，该拉曼光谱仪中，光源所发出的光是非偏振光，并且对检测光(经光源所发出的光激发后，检测对象所产生的拉曼散射光)进行检测的光电探测单元也是针对非偏振光的普通探测单元。
图1是本发明实施例一的手性化合物检测方法的流程图。
如图1所示，本发明的实施例一采用上述金纳米螺旋纤维阵列作为基底材料，结合拉曼光谱仪对手性化合物进行检测，具体包括如下步骤：
步骤S1，将手性化合物的待测样品载置在基底材料上；
步骤S2，采用光谱仪对待测样品进行检测从而得到待测样品的特征光谱(即拉曼光谱)；
步骤S3，对步骤S2得到的特征光谱进行分析，从而得到手性化合物中的对映体含量。
本实施例中采用标准曲线分析的方法对待测样品中的对映体含量进行定量。具体地，步骤S3中的分析过程进一步包括如下步骤：
步骤S3-1，配制多个手性化合物的标准品，每个标准品中含有不同量的手性化合物的对映体；
步骤S3-2，分别将标准品载置在基底材料上，并分别采用特征光谱仪对标准品进行检测从而得到各个标准品的特征光谱；
步骤S3-3，将标准品和待测样品的特征光谱进行对比分析，得到待测样品中的手性化合物的对映体含量。
本实施例采用柠檬烯作为待测的手性化合物，其具有两种构型，即R-柠檬烯和S-柠檬烯。
图2是采用本发明实施例一的检测方法对R-柠檬烯和S-柠檬烯的混合物进行检测得到的特征光谱图。图2中，-100％是仅含有R-柠檬烯的样品，100％是仅含有S-柠檬烯的样品，-50％是R-柠檬烯与S-柠檬烯的含量比为75:25的样品，0％是R-柠檬烯与S-柠檬烯的含量比为50:50的样品，50％是R-柠檬烯与S-柠檬烯的含量比为25:75的样品。
图3是采用本发明实施例一的检测方法对R-柠檬烯和S-柠檬烯的混合物进行检测得到的特征峰强度与手性分子含量百分比的线性拟合图。图3中，横坐标为手性分子含量百分比(ee值)，纵坐标为特征峰强度(即拉曼光谱中的特征峰强度)。
如图2和图3所示，当采用金纳米螺旋纤维阵列结合拉曼光谱仪的检测方法对柠檬烯这种手性化合物进行检测时，其信号强度(即拉曼信号强度)与样品中的手性对映体比例呈正比关系。也就是说，当需要对两种对映体含量未知的柠檬烯样品进行检测时，采用本实施例的检测方法进行特征光谱检测，然后将待测样品检测结果与标准品检测结果进行对比(例如将待测样品的特征峰强度与标准品特征峰强度的拟合曲线进行对比)，即可计算得到待测样品中S-柠檬烯和R-柠檬烯的含量比例。
<实施例二>
本实施例采用与实施例一相同的检测方法对环己基甘氨酸这种手性化合物进行检测。其 中，环己基甘氨酸具有两种构型，即L-环己基甘氨酸和D-环己基甘氨酸。
图4是采用本发明实施例一的检测方法对L-环己基甘氨酸和D-环己基甘氨酸的混合物进行检测得到的特征光谱图。
图4中，-100％是仅含有L-环己基甘氨酸的样品，100％是仅含有D-环己基甘氨酸的样品，-50％是L-环己基甘氨酸与D-环己基甘氨酸的含量比为75:25的样品，0％是L-环己基甘氨酸与D-环己基甘氨酸的含量比为50:50的样品，50％是L-环己基甘氨酸与D-环己基甘氨酸的含量比为25:75的样品。
图5是采用本发明实施例一的检测方法对L-环己基甘氨酸和D-环己基甘氨酸的混合物进行特征光谱检测得到的特征峰强度与手性对映体含量百分比的线性拟合图。图5中，横坐标为手性分子含量百分比(ee值)，纵坐标为特征峰强度。
如图4和图5所示，当采用金纳米螺旋纤维阵列结合拉曼光谱仪的检测方法对环己基甘氨酸这种手性化合物进行检测时，其信号强度与样品中的手性对映体比例呈正比关系。相应地，当需要对两种对映体含量未知的环己基甘氨酸样品进行检测时，采用本实施例的检测方法进行特征光谱检测，然后将待测样品检测结果与标准品检测结果进行对比，即可计算得到待测样品中D-环己基甘氨酸和L-环己基甘氨酸的含量比例。
另外，发明人还采用实施例一的检测方法对其他多种手性化合物进行了检测，发现这种检测方法能够实现不同手性化合物的对映体含量比例检测。
例如，图6是采用本发明实施例一的检测方法对L-苯基甘氨酸和D-苯基甘氨酸的混合物进行检测得到的特征光谱图，图7是采用本发明实施例一的检测方法对L-苯基甘氨酸和D-苯基甘氨酸的混合物进行检测得到的特征峰强度与手性对映体含量百分比的线性拟合图。
如图6及图7所示，当采用金纳米螺旋纤维阵列结合拉曼光谱仪的检测方法对苯基甘氨酸进行检测时，其特征峰强度与样品中的手性对映体比例呈正比关系。
经验证，其他多种常见手性化合物均能够通过实施例一的检测方法进行手性对映体比例检测，并且其ee值和特征峰强度均呈现正比关系。发明人验证过的手性化合物如下表1所示：
表1经验证能够通过本发明实施例一的检测方法进行手性对映体比例检测的手性化合物
Figure PCTCN2018124284-appb-000001
Figure PCTCN2018124284-appb-000002
Figure PCTCN2018124284-appb-000003
Figure PCTCN2018124284-appb-000004
根据表1可知，能够通过本发明的检测方法进行对映体含量比例检测的手性化合物接近百对，并且这些手性化合物特性各异。例如，以手性中心数量分类，表1中包含了单手性中心化合物和多手性中心化合物；以极性分类，表1中包含了极性化合物和非极性化合物；另外，表1中还包含了有发色基团分子、无发色基团分子、大分子、小分子和生物分子等多种不同种类的手性化合物。可见，只要是具有拉曼散射特性的化合物，均可通过实施例一的金纳米螺旋纤维阵列结合拉曼光谱仪的检测方法来进行对映体含量比例检测。
<实施例三>
为验证其他具有手性结构的等离子体共振材料是否也能用于手性化合物检测，本实施例采用金-银纳米螺旋线阵列作为基底材料，结合拉曼光谱仪进行了手性化合物检测。
本实施例中，金-银纳米螺旋纤维阵列是在实施例一的金纳米螺旋纤维阵列的基础上再次进行银附着而形成的。由此，该金-银纳米螺旋纤维阵列由多根整齐排列的单股金-银复合螺旋纤维构成，其特性与实施例一的金纳米螺旋纤维阵列类似，也属于等离子体共振材料，并且也具有手性特质。
经拉曼光谱检测试验，上述金-银纳米螺旋阵列也能够表现出与实施例一的金纳米螺旋 纤维阵列相同的特性。也就是说，金-银纳米螺旋阵列也可以作为基底材料与拉曼光谱仪配合使用，从而实现待测样品中不同构型手性化合物的含量比例检测。
<实施例四>
为验证其他具有手性结构的等离子体共振材料是否也能用于手性化合物检测，本实施例采用花形纳米氧化钛粉末作为基底材料，结合拉曼光谱仪进行了手性化合物检测。
上述基底材料具有这样的特点：1)氧化钛是一种金属氧化物类的等离子体共振材料，其在拉曼光谱检测过程中作为基底材料时能够对样品的拉曼信号进行增强；2)花形纳米氧化钛粉末是一种由纳米氧化钛颗粒构成的材料，其中氧化钛颗粒具有花形结构。与金纳米螺旋纤维阵列和金-银纳米螺旋线阵列类似，这种花形纳米氧化钛粉末具有单手性结构，也是具有手性特质的材料。
另外，本实施例采用N-乙酰半胱氨酸作为待测的手性化合物，其具有两种构型，即N-乙酰-L-半胱氨酸和N-乙酰-D-半胱氨酸。
图8是采用本发明实施例四的检测方法对相同浓度的N-乙酰-L-半胱氨酸和N-乙酰-D-半胱氨酸分别进行检测得到的特征光谱图。
如图8所示，当N-乙酰-L-半胱氨酸和N-乙酰-D-半胱氨酸的浓度相同时，采用花形纳米氧化钛粉末结合拉曼光谱仪的检测方法能够让该两种样品呈现出不同的信号强度。显然，与前述各实施例类似，这样的信号强度差异证明本实施例的检测方法也能够检测出N-乙酰半胱氨酸样品中的对映体含量比例。
<实施例五>
为验证其他具有手性结构的等离子体共振材料是否也能用于手性化合物检测，本实施例采用扇形纳米银粉末作为基底材料，结合拉曼光谱仪进行了手性化合物检测。
与前述的金纳米螺旋纤维阵列、金-银纳米螺旋纤维阵列以及花形纳米氧化钛粉末类似，扇形纳米银粉末也是具有手性特质的材料。并且，银也是一种金属类的等离子共振材料。
图9是采用本发明实施例五的检测方法对相同浓度的N-乙酰-L-半胱氨酸和N-乙酰-D-半胱氨酸分别进行检测得到的特征光谱图。
如图9所示，当N-乙酰-L-半胱氨酸和N-乙酰-D-半胱氨酸的浓度相同时，采用扇形纳米银粉末作为基底材料的检测方法也能够让该两种样品呈现出不同的信号强度。虽然该拉曼光谱中的指纹特征不够明显，但通过最高峰的峰高结果分析(例如，将样品图谱中最高峰的峰高与结合不同对映体含量比例的标准品的峰高相比对)，也能够推算出样品中的对映体含量比例。
<比较例>
为说明本发明的检测方法的作用效果，发明人还采用普通等离子体共振材料及普通拉曼光谱仪对实施例一中的两种柠檬烯进行了检测。
图10是本发明比较例的采用普通拉曼光谱仪对柠檬烯进行检测的拉曼光谱图。
如图10所示，采用普通拉曼光谱仪(不使用基底材料)对总含量相同但ee值不同的五个柠檬烯样品进行检测时，各个柠檬烯样品特征峰强度完全相同，说明普通拉曼光谱仪能够对柠檬烯样品进行定性(通过特征峰位移)和定量(通过特征峰强度)，但无法区分对映体，也就无法实现不同构型的含量比例检测。另外，从图10可以看出，不使用基底材料时，拉曼光谱中的特征峰强度较低，因此还存在信号弱、定性和定量较为困难的问题。
图11是本发明比较例的采用普通拉曼光谱仪以及不具有手性的基底材料对柠檬烯进行检测的拉曼光谱图。
如图11所示，采用普通拉曼光谱仪以及不具有手性的等离子体共振材料(本比较例采用了金纳米颗粒，该金纳米颗粒为等离子体共振材料，但其结构为常规结构因而不具有手性特质)对总含量相同但ee值不同的五个柠檬烯样品进行检测时，各个柠檬烯样品特征峰强度整体较强，但这五种的拉曼图谱也是完全相同的，说明普通拉曼光谱仪结合不具有手性特质的材料能够很好地实现定性和定量，但无法区分对映体，无法实现不同构型的含量比例检测。
实施例作用与效果
从上述实施例中可以看出，当采用具有手性特质的材料作为基底材料对手性化合物进行拉曼光谱检测时，其对手性化合物不同对映体的表面增强作用有明显区别，这样的区别反映到光谱图上就使得不同对映体的特征峰强度有明显差异。因此，通过特征峰强度即可推算得出对映体含量比例。
将实施例一与比较例一对比可以看出，采用本发明的具有手性特质的材料作为基底材料配合拉曼光谱仪进行检测时，不同ee值的柠檬烯样品表现出不同的特征峰强度，而普通基底材料则不具有这种特性。发明人推测，这种现象发生的原因可能是具有手性特征的材料在检测光照射下产生的电磁场也具有类似于手性的特性，可以特异性地增强某一种手性构象的拉曼信号(例如，对S-柠檬烯分子增强作用更强)而对另一种手性构象则几乎不具增强作用。
另外，从实施例二-实施例五可以得出如下结果：1、本发明的具有手性特质的材料配合拉曼光谱仪的检测方法能够对上百种手性化合物实现检测；2、即使更换其他种类的具有手性特质的材料，本发明的检测方法也能够实现手性化合物的检测。
结合上述检测原理方面的推断可以得知，只要基底材料是具有手性特质的材料(尤其是 具有手性结构的等离子体共振材料)，其都能够或多或少地对手性化合物的拉曼信号进行特异性增强，因而也能够结合拉曼光谱仪来实现手性化合物的对映体含量比例检测。
进一步，通过上述各实施例的检测过程可以得知，上述具有手性特质的材料与手性化合物发生相互作用时，其对不同对映异构体的手性化合物产生的信号增强作用不同，这种相互作用的不同可以通过材料和化合物的光学性质(在上述实施例中为拉曼检测)进行表征。显然，当这类具有手性特质的材料与手性化合物发生其他相互作用时，其所产生的相互作用强度也将有所不同，并且能够被相应的光学检测手段表征(即，被相应的光谱仪检测时体现出信号强度等方面的差异)。所以，本发明的这种具有手性特质的材料与光谱仪配合使用就可以对手性化合物进行检测，与现有技术中的手性化合物检测手段相比，本发明的检测方法具有成本低、操作简单、干扰小、结果准确、操作简单且应用广泛等优点。
上述实施例仅用于举例说明本发明的具体实施方式，而本发明的手性化合物的检测方法不限于上述实施例所描述的范围。
实施例中，具有手性特质的材料为具有单手性结构的纳米金属膜材料、纳米金属粉末材料、纳米金属氧化物粉末材料等。然而，在本发明中，具有手性特质的材料还可以是其他种类的材料，包括由其他种类的有机物、无机物或有机物-无机物混合物所构成的具有手性结构的微纳米材料粉末或微纳米膜材料。其中，无机物可以包含金属和金属氧化物，金属可以是金、银、铜、铂中的一种或几种的组合物，金属氧化物可以是氧化铜、氧化钛、氧化锌、氧化锡、氧化铁、氧化钴中的一种或几种的组合物；手性结构除了实施例的螺旋纤维结构、花形结构、扇形结构以外，还可以是螺旋桨形结构等多种手性结构。
另外，实施例中所用的光谱仪为拉曼光谱仪，然而在本发明中，其还可以是其他种类的光谱仪，只要能够检测基底材料与待测化合物的相互作用即可。

Claims (10)

  1. 一种手性化合物的检测方法，其特征在于，采用具有手性特质的材料作为基底材料与光谱仪配合从而对所述手性化合物进行检测，包括如下步骤：
    步骤S1，将手性化合物的待测样品载置在所述基底材料上；
    步骤S2，采用光谱仪对所述待测样品进行检测从而得到所述待测样品的特征光谱，
    其中，所述光谱仪的光源和检测光都为非偏振光。
  2. 根据权利要求1所述的手性化合物的检测方法，其特征在于：
    其中，步骤S1中的所述具有手性特质的材料为具有手性结构的微纳米粉末或微纳米膜材料。
  3. 根据权利要求2所述的手性化合物的检测方法，其特征在于：
    其中，所述具有手性特质的材料由无机材料、有机材料或有机-无机复合材料构成。
  4. 根据权利要求3所述的手性化合物的检测方法，其特征在于：
    其中，所述无机材料为等离子体共振材料，
    所述光谱仪为拉曼光谱仪。
  5. 根据权利要求4所述的手性化合物的检测方法，其特征在于：
    其中，所述等离子体共振材料为金属、金属氧化物或二者的混合物。
  6. 根据权利要求5所述的手性化合物的检测方法，其特征在于：
    其中，所述金属为金、银、铜、铂中的一种或几种的组合物，
    所述金属氧化物为氧化铜、氧化钛、氧化锌、氧化锡、氧化铁、氧化钴中的一种或几种的组合物。
  7. 根据权利要求2-6中任一项所述的手性化合物的检测方法，其特征在于：
    其中，所述手性结构为螺旋纤维结构、花形结构、扇形结构、螺旋桨形结构中的任意一种。
  8. 根据权利要求1所述的手性化合物的检测方法，其特征在于，还包括如下步骤：
    步骤S3，对步骤S2得到的所述特征光谱进行分析，从而得到所述手性化合物中的对映体含量。
  9. 根据权利要求8所述的手性化合物的检测方法，其特征在于：
    其中，步骤S3的所述分析包括如下步骤：
    步骤S3-1，配制多个所述手性化合物的标准品，每个所述标准品中含有不同量的所述手性化合物的对映体；
    步骤S3-2，分别将所述标准品载置在所述基底材料上，并分别采用所述光谱仪对所述标准品进行检测从而得到各个所述标准品的特征光谱；
    步骤S3-3，将所述标准品和所述待测样品的特征光谱进行对比分析，得到所述待测样品中的所述手性化合物的对映体含量。
  10. 根据权利要求9所述的手性化合物的检测方法，其特征在于：
    其中，所述对比分析为根据所述标准品中的特征峰强度及对映体含量关系绘制标准曲线，根据该标准曲线以及所述待测样品的特征峰强度得出所述手性化合物的对映体含量。
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