Binaphthalene functionalized chiral hybrid stationary phase as well as preparation method and application thereof

Abstract

The invention relates to the technical field of chromatographic chiral molecular separation, in particular to a binaphthyl functionalized chiral hybrid stationary phase and a preparation method and application thereof.The binaphthyl functionalized chiral hybrid stationary phase is prepared by taking a non-porous silicon dioxide microsphere as a core layer, binaphthol derived from 3-isocyanate propyl triethoxysilane as a chiral functional monomer and tetraethyl silicate as a precursor; n-lauroyl-L-arginyl histidine sodium and folic acid are taken as dual surfactants, and a chiral binaphthyl hybrid shell layer is constructed on the surface of a non-porous silicon dioxide microsphere through sol-gel, so that the binaphthyl functionalized chiral hybrid microsphere with a core-shell structure is formed. The prepared hybrid microspheres have excellent monodispersity and a unique core-shell structure. The shell layer is rich in chiral binaphthalene derivatives, and the chiral binaphthalene derivatives have chiral selectivity, so that the chiral binaphthalene derivatives can be used as a stationary phase of chiral chromatography for resolution of enantiomers of chiral naphthol compounds.

Description

Technical Field

[0001] The present invention relates to the technical field of chromatographic chiral molecule separation, and particularly relates to a binaphthalene-functionalized chiral hybrid stationary phase, a preparation method thereof, and an application thereof. Background Art

[0002] During the chromatographic detection process, the main challenge is how to quickly separate and analyze complex samples. To achieve efficient and rapid separation and analysis, chromatographic packing materials have evolved from amorphous silica gel to non-porous spherical silica gel, fully porous spherical silica gel, and finally to core-shell silica gel packing materials. This development has greatly promoted the progress in fields such as life medicine, environment, food, and chemistry. The structure of the core-shell chromatographic packing material consists of an ultra-pure solid silica core and a porous shell layer with a certain thickness. Compared with non-porous silica microspheres, the core-shell silica microspheres have a shorter separation time compared with porous silica microspheres; compared with non-porous silica microspheres, they have a lower column pressure and a larger sample loading capacity.

[0003] In chromatographic analysis, chiral separation technology is crucial for improving the purity of drugs and the detection accuracy of biomolecules. Traditional chiral stationary phases (CSPs) often immobilize chiral ligands on the silica surface through physical coating or chemical bonding, but there are problems such as uneven group distribution and pore blockage, which affect the separation effect. With the development of nanotechnology, mesoporous materials have become ideal chromatographic stationary phases due to their high specific surface area and uniform pore size distribution. Silica microspheres with a binaphthalene-containing shell layer show great potential due to their unique chiral structure and chemical stability. However, the binaphthalene-containing shell layer in the prior art has relatively single and unevenly distributed chiral sites, which limits the separation efficiency. Summary of the Invention

[0004] To solve the above problems, the present invention provides a binaphthalene-functionalized chiral hybrid stationary phase, its preparation, and application. By using an alkylated binaphthalene derivative as a chiral functional monomer and tetraethyl orthosilicate as a precursor to obtain a chiral binaphthalene hybrid shell layer, it provides abundant chiral sites and introduces functional groups such as amino groups and carboxyl groups, effectively improving the separation efficiency.

[0005] To achieve the above object, the technical solution of the present invention is as follows.

[0006] The first aspect of the present invention provides a binaphthalene-functionalized chiral hybrid stationary phase, which includes a core layer and a shell layer; the core layer is a silica microsphere, and the shell layer is a chiral binaphthalene hybrid shell layer; The silica microsphere is a non-porous solid silica microsphere with a particle size of 2.2 μm to 2.3 μm; The chiral binaphthalene hybrid shell is obtained by using an alkylated binaphthalene derivative as a chiral functional monomer and tetraethyl orthosilicate as a precursor, and wrapping it on the surface of silica microspheres through a sol-gel method; the alkylated binaphthalene derivative is obtained by an alkylation reaction of 3-isocyanatopropyltriethoxysilane and binaphthol; The particle size of the chiral hybrid stationary phase is 2.4 μm to 2.6 μm.

[0007] In the present invention, through the core-shell structure, with a solid silica microsphere core layer, the pore volume of the filler is reduced, and the mass transfer resistance of molecules is reduced; the chiral binaphthalene hybrid shell structure with a porous structure significantly improves the mass transfer efficiency and separation ability. The chiral binaphthalene hybrid shell provides abundant chiral sites, and functional groups such as amino groups and carboxyl groups can be introduced to enhance the affinity and selectivity. Its mesoporous structure promotes mass transfer and improves the separation efficiency.

[0008] The second aspect of the present invention provides a preparation method of the chiral hybrid stationary phase, which is characterized by including the following steps: After mixing the 3-isocyanatopropyltriethoxysilane dispersion liquid and the binaphthol dispersion liquid, carry out an alkylation reaction at 80 °C to 90 °C for 10 h to 12 h, and then dry to obtain the alkylated binaphthalene derivative; wherein, the mass-volume ratio of binaphthol to 3-isocyanatopropyltriethoxysilane is 0.5 kg to 1 kg: 1 L to 2 L; Mix non-porous solid silica microspheres, a surfactant, a catalyst and water according to a ratio of 4 kg to 4.5 kg: 7 kg to 8 kg: 2.5 kg to 3.5 kg: 120 L to 140 L by mass-volume ratio to obtain a mixed solution; Mix an oil phase solvent, an alkylated binaphthalene derivative and tetraethyl orthosilicate according to a ratio of 4.5 kg to 5.5 kg: 58.5 L to 69.5 L: 1.5 L to 2.5 L by mass-volume ratio, then add it to the mixed solution, carry out a sol-gel reaction at 60 °C to 80 °C for 20 h to 24 h, centrifuge to obtain a precipitate, and dry to obtain a binaphthalene-functionalized chiral hybrid stationary phase; The mass ratio of the non-porous solid silica microspheres to the alkylated binaphthalene derivative is 4 to 4.5: 4.5 to 5.5.

[0009] In another preferred embodiment, the 3-isocyanatopropyltriethoxysilane dispersion liquid is obtained by dispersing 3-isocyanatopropyltriethoxysilane in dichloromethane according to a volume ratio of 1 to 2: 3 to 6.

[0010] In another preferred embodiment, the specific process for obtaining the binaphthol dispersion liquid is as follows: Disperse binaphthol in a mixed solution of anhydrous dichloromethane and triethylamine to obtain it; The mass-volume ratio of binaphthol, anhydrous dichloromethane, and triethylamine is 0.5 kg to 0.8 kg: 60 L to 80 L: 0.4 L to 0.6 L.

[0011] In another preferred embodiment, the surfactant is obtained by mixing sodium N-lauroyl-L-arginylhistidinate and folic acid in a mass ratio of 4 to 4.5: 3 to 3.5.

[0012] In another preferred embodiment, the catalyst is urea.

[0013] In another preferred embodiment, the oil-phase solvent is obtained by mixing toluene and isopropanol in a volume ratio of 55 to 65: 3.5 to 4.5.

[0014] The third aspect of the present invention provides the application of the binaphthol-functionalized chiral hybrid stationary phase in the separation of enantiomers of chiral binaphthol derivatives.

[0015] In another preferred embodiment, the chiral binaphthol derivative enantiomer is any one of R / S-1,1'-bi-2,2'-naphthol, 2,2'-dibromo-1,1'-binaphthol, 2,2'-dimethoxy-1,1'-binaphthol, and 2,2'-diethoxy-1,1'-binaphthol.

[0016] Compared with the prior art, the present invention has the following beneficial effects.

[0017] The chiral hybrid stationary phase in the present invention has an obvious core-shell structure. Due to the presence of the solid core, the pore volume of the packing is reduced, the diffusion path of the molecules is shortened, the longitudinal diffusion of the molecules is reduced, and the mass transfer resistance of the molecules is reduced, thereby improving the separation efficiency of chromatography while shortening the analysis time; the chiral binaphthol hybrid shell is a porous hybrid shell, which contains rich chiral binaphthol derivatives, introduces functional groups such as amino and carboxyl groups, enhances the affinity and selectivity, and its mesoporous structure promotes mass transfer and improves the separation efficiency. The conventional monolayer chiral agent only forms a thin modification layer on the surface of the matrix, resulting in uneven distribution and lack of porous structure, leading to low mass transfer efficiency and poor separation effect.

[0018] The present invention uses the sol-gel method to wrap alkylated binaphthol derivatives on the surface of non-porous silica microspheres, forming a porous shell outside the core layer. The porous shell has a uniform thickness and contains a rich pore structure. The chiral sites are evenly distributed, the specific surface area is high, and the pore size distribution is uniform, significantly improving the chiral separation ability. The obtained chiral hybrid stationary phase has good monodispersity, effectively reducing the eddy diffusion phenomenon that causes chromatographic peak broadening and improving the column efficiency of the chromatographic column.

[0019] The preparation process of the method in the present invention is simple, the raw materials are easy to obtain, and the reaction conditions are mild, which is suitable for large-scale industrial preparation. Description of the Drawings

[0020] Figure 1 It is a schematic diagram of the preparation process of the chiral hybrid stationary phase. The part circled in red in the figure is the molecular formula of the chiral binaphthyl hybrid shell, and SiO2@SiO2-binol represents the chiral hybrid stationary phase.

[0021] Figure 2 It is the structural characterization diagram of SiO2@SiO2-binol-1 in Example 1; among them, a is the scanning electron microscope image, b is the scanning electron microscope image of SiO2@SiO2-binol-1, and c is the transmission electron microscope image.

[0022] Figure 3 It is the N2 adsorption / desorption curve and pore size distribution diagram of SiO2@SiO2-binol-1 in Example 1; among them, a is the N2 adsorption / desorption curve diagram, and b is the pore size distribution diagram.

[0023] Figure 4 It is the infrared spectrum diagram of SiO2@SiO2-binol-1 in Example 1.

[0024] Figure 5 It is the chromatogram of the separation of four chiral compounds by SiO2@SiO2-binol-1 in Example 1. In the figure, a is R / S-1,1'-bi-2,2'-naphthol, b is 2,2'-dibromo-1,1'-binaphthol, c is 2,2'-dimethoxy-1,1'-binaphthol, and d is 2,2'-diethoxy-1,1'-binaphthol.

[0025] Figure 6 It is the structural characterization diagram of SiO2@SiO2-binol-2 in Example 2; among them, (a) is the scanning electron microscope image, (b) is the scanning electron microscope image of SiO2@SiO2-binol-2, and (c) is the transmission electron microscope image.

[0026] Figure 7 The N2 adsorption / desorption curve and pore size distribution diagram of SiO2@SiO2-binol-2 in Example 2; among them, (a) is the N2 adsorption / desorption curve diagram, and (b) is the pore size distribution diagram.

[0027] Figure 8 It is the chromatogram of the separation of four chiral compounds by SiO2@SiO2-binol-2 in Example 2: a is R / S-1,1'-bi-2,2'-naphthol, b is 2,2'-dibromo-1,1'-binaphthol, c is 2,2'-dimethoxy-1,1'-binaphthol, and d is 2,2'-diethoxy-1,1'-binaphthol.

[0028] Figure 9Structural characterization diagrams of SiO2@SiO2-binol-3 in Example 3; among them, (a) is a scanning electron microscope image, (b) is a scanning electron microscope image of SiO2@SiO2-binol-3, and (c) is a transmission electron microscope image.

[0029] Figure 10 N2 adsorption / desorption isotherm and pore size distribution diagrams of SiO2@SiO2-binol-3 in Example 3; among them, (a) is the N2 adsorption / desorption isotherm diagram, and (b) is the pore size distribution diagram.

[0030] Figure 11 Chromatograms of the separation of four chiral compounds by SiO2@SiO2-binol-3 in Example 3: a is R / S-1,1'-bi-2,2'-naphthol, b is 2,2'-dibromo-1,1'-binaphthol, c is 2,2'-dimethoxy-1,1'-binaphthol, and d is 2,2'-diethoxy-1,1'-binaphthol.

[0031] Figure 12 Structural characterization diagrams of SiO2@SiO2-binol-4 in Comparative Example 1; among them, (a) is a scanning electron microscope image, (b) is a scanning electron microscope image of SiO2@SiO2-binol-4, and (c) is a transmission electron microscope image.

[0032] Figure 13 N2 adsorption / desorption isotherm and pore size distribution diagrams of SiO2@SiO2-binol-4 in Comparative Example 1; among them, (a) is the N2 adsorption / desorption isotherm diagram, and (b) is the pore size distribution diagram.

[0033] Figure 14 Chromatograms of the separation of four chiral compounds by SiO2@SiO2-binol-4 in Comparative Example 1: a is R / S-1,1'-bi-2,2'-naphthol, b is 2,2'-dibromo-1,1'-binaphthol, c is 2,2'-dimethoxy-1,1'-binaphthol, and d is 2,2'-diethoxy-1,1'-binaphthol.

[0034] Figure 15 Structural characterization diagrams of SiO2@SiO2-binol-5 in Comparative Example 2; among them, (a) is a scanning electron microscope image, (b) is a scanning electron microscope image of a single SiO2@SiO2-binol-5, and (c) is a transmission electron microscope image.

[0035] Figure 16 N2 adsorption / desorption isotherm and pore size distribution diagrams of SiO2@SiO2-binol-5 in Comparative Example 2; among them, (a) is the N2 adsorption / desorption isotherm diagram, and (b) is the pore size distribution diagram.

[0036] Figure 17Chromatogram of the separation of four chiral compounds by SiO2@SiO2-binol-5 in Comparative Example 2: a is R / S-1,1'-bi-2,2'-naphthol, b is 2,2'-dibromo-1,1'-binaphthol, c is 2,2'-dimethoxy-1,1'-binaphthol, and d is 2,2'-diethoxy-1,1'-binaphthol.

[0037] Figure 18 Structure characterization diagram of SiO2@SiO2-binol-ICPTMS in Comparative Example 3; among them, (a) is a scanning electron micrograph, (b) is a scanning electron micrograph of SiO2@SiO2-binol-ICPTMS, and (c) is a transmission electron micrograph.

[0038] Figure 19 N2 adsorption / desorption curve and pore size distribution diagram of SiO2@SiO2-ICPTMS in Comparative Example 3; among them, (a) is the N2 adsorption / desorption curve diagram, and (b) is the pore size distribution diagram.

[0039] Figure 20 Chromatogram of the separation of four chiral compounds by SiO2@SiO2-ICPTMS in Comparative Example 3: a is R / S-1,1'-bi-2,2'-naphthol, b is 2,2'-dibromo-1,1'-binaphthol, c is 2,2'-dimethoxy-1,1'-binaphthol, and d is 2,2'-diethoxy-1,1'-binaphthol. Detailed implementation manners

[0040] In order to more clearly understand the above objects, features and advantages of the present invention, the present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments. It should be noted that, without conflict, the embodiments of the present application and the features in the embodiments can be combined with each other.

[0041] Many specific details are set forth in the following description in order to fully understand the present invention. However, the present invention can also be implemented in other ways different from those described herein. Therefore, the protection scope of the present invention is not limited by the specific embodiments disclosed below.

[0042] 3-Isocyanatopropyltriethoxysilane was purchased from Aladdin; binaphthol was purchased from Aladdin; sodium N-lauroyl-L-arginylhistidinate was purchased from Aladdin; folic acid was purchased from Aladdin; urea was purchased from Aladdin; tetraethyl orthosilicate was purchased from Aladdin.

[0043] The preparation method of the non-porous silica microspheres in the following examples is as follows: Measure 150 mL of tetraethyl orthosilicate and 400 mL of n-propanol, and ultrasonically mix them to obtain solution A; Weigh 0.15 g of potassium chloride into a flask containing 800 mL of n-propanol and 120 mL of ammonia water, and mix well by ultrasonic to obtain solution B; Solution B is placed in an oil bath at 30 °C and mechanically stirred at 500 rpm. While solution A is slowly added dropwise to solution B, the reaction is carried out for 3 h to obtain microspheres. The obtained microspheres are washed with water until neutral and then placed in a vacuum drying oven at 60 °C for drying for 12 h to obtain non-porous silica microspheres.

[0044] The room temperature in the following examples is 25 °C.

[0045] In the present invention, an alkylated binaphthyl derivative is obtained by alkylation reaction of binaphthol with 3-isocyanatopropyltriethoxysilane. Then, through the sol-gel method, the alkylated binaphthyl derivative, non-porous silica microspheres and the precursor tetraethyl orthosilicate are mixed and reacted to form a chiral binaphthyl hybrid shell layer with a porous structure on the surface of the non-porous silica microspheres, and a chiral hybrid stationary phase is obtained. The specific process is as Figure 1 shown. The chiral hybrid stationary phase in the present invention uses solid non-porous silica microspheres as the core layer, which reduces the pore volume of the packing, shortens the diffusion path of molecules, and reduces the mass transfer resistance of molecules, thereby improving the separation efficiency of chromatography while shortening the analysis time; the chiral binaphthyl hybrid shell layer is a porous hybrid shell layer, which contains abundant chiral binaphthyl derivatives. This derivative can be used as a chiral selector for separating chiral compounds. Thus, the problems of low mass transfer efficiency and poor separation effect existing in the existing chiral stationary phases are solved. The preparation and application of a binaphthyl-functionalized chiral hybrid stationary phase are specifically described below.

[0046] Example 1 A preparation method of a binaphthyl-functionalized chiral hybrid stationary phase includes the following steps: S1. Weigh 0.5 g of binaphthol into a flask, and successively add 60 mL of anhydrous dichloromethane and 0.4 mL of triethylamine, and mix well by ultrasonic to obtain a binaphthol dispersion. Then, disperse 1 mL of 3-isocyanatopropyltriethoxysilane in 3 mL of dichloromethane to obtain a 3-isocyanatopropyltriethoxysilane dispersion. The 3-isocyanatopropyltriethoxysilane dispersion is added dropwise to the binaphthol dispersion. After adjusting the stirring speed to 200 rpm, the temperature is raised to 80 °C. After reacting for 12 h, it is placed in a vacuum drying oven at 80 °C for drying for 12 h to obtain an alkylated binaphthyl derivative.

[0047] S2. Weigh 4 g of non-porous silica microspheres, 4 g of N-lauroyl-L-arginylhistidine sodium, 3 g of folic acid, and 2.5 g of urea, disperse them in 120 mL of deionized water, and ultrasonically disperse and mix well. Stir at 200 rpm under room temperature conditions for 30 min to obtain a mixed solution. Measure 60 mL of toluene, 3.5 mL of isopropanol, 2.5 mL of tetraethyl orthosilicate, and 4.5 g of the dried binaphthyl derivative. After adjusting the stirring speed to 80 rpm, add it to the mixed solution, raise the temperature to 70 °C, react for 24 h, then centrifuge and wash. Take the precipitate and dry it in a vacuum drying oven at 80 °C for 24 h to obtain binaphthyl-functionalized core-shell chiral hybrid microspheres, which are binaphthyl-functionalized chiral hybrid stationary phases, named SiO2@SiO2-binol-1.

[0048] Characterize SiO2@SiO2-binol-1, and the results are as follows: The scanning electron microscopy results are as Figure 2 shown. From Figure 2 a and b in it, it can be seen that the SiO2@SiO2-binol-1 microspheres are monodispersed, with a uniform particle size distribution in the range of 2.3 μm to 2.4 μm, the average particle size is 2.3 μm, and there are fine pores on the surface. Figure 2 c in it is the transmission electron microscopy image of SiO2@SiO2-binol-1. From the figure, it can be observed that the microspheres have a complete core-shell structure, the shell layer is uniform, with a thickness of 100 nm to 110 nm, and the average thickness is 106 nm.

[0049] Figure 3 a in it is the isothermal adsorption curve obtained from the nitrogen adsorption / desorption experiment of SiO2@SiO2-binol-1. An obvious hysteresis loop appears in the figure, indicating the presence of a large number of pores in the material. And the source of the large number of pores is only the shell layer, further proving the success of the shell layer preparation. From Figure 3 b in it, it can be seen that the pore size of SiO2@SiO2-binol-1 is mainly distributed in the range of 3.5 nm to 7.5 nm, and the specific surface area measured is 83.3 m 2 / g.

[0050] Figure 4 is the infrared spectrum of SiO2@SiO2-binol-1. Strong absorption peaks at 1025 cm -1 and 854 cm -1 respectively belong to the asymmetric stretching vibration and symmetric stretching vibration of the Si-O-Si bond in the silica microsphere matrix; the stronger characteristic absorption at 3174 cm -1 belongs to the C-H stretching vibration absorption peak on the binaphthyl aromatic ring; 1452 cm -1The strong characteristic absorption peak at 40° is attributed to the C=C skeleton vibration absorption peak of the aromatic ring. These results indicate that the binaphthyl functional group is hybridized in the shell.

[0051] In order to further illustrate the separation effect of SiO2@SiO2-binol-1 on the enantiomers of chiral binaphthyl derivatives, the following experiments were performed.

[0052] SiO2@SiO2-binol-1 was used as the liquid chromatography stationary phase to separate four chiral compounds: R / S-1,1'-bi-2,2'-naphthol, 2,2'-dibromo-1,1'-binaphthol, 2,2'-dimethoxy-1,1'-binaphthol and 2,2'-diethoxy-1,1'-binaphthol. The enantiomers of the chiral binaphthol derivatives were purchased from Aladdin.

[0053] Detection instrument: APUS model ultra-high performance liquid chromatograph of Chengdu Ke Rui Technology Co., Ltd.; chromatographic column specifications: 4.6×50 mm; mobile phase: dichloromethane / hexane, (50 / 50, v / v); flow rate: 1.0 mL / min; column pressure: 10.2 MPa; UV detector wavelength 254 nm.

[0054] The results are as follows Figure 5 As shown in Table 1, from Figure 5 It can be seen that the chiral separation of the four chiral compounds can be completed within 4 minutes, which takes a short time and has a good separation effect. All of them can achieve baseline separation, that is, the separation degree R s A value greater than 1.5 can be considered as baseline separation. In particular, the resolution of 2,2'-diethoxy-1,1'-binaphthol enantiomers is the best, with a resolution of 2.34. This indicates that SiO2@SiO2-binol-1 has a high chiral resolution capability.

[0055] Table 1 Separation results of four chiral compounds Example 2 A chiral hybrid stationary phase functionalized with binaphthyl is prepared in the same manner as in Example 1 except that the amount of tetraethyl silicate used is 2 mL and the amount of the binaphthyl derivative used is 5 g. The obtained chiral hybrid stationary phase functionalized with binaphthyl is named SiO2@SiO2-binol-2.

[0056] SiO2@SiO2-binol-2 was characterized and the results are as follows: Scanning electron microscopy results showed that Figure 6 As shown in a and b, SiO2@SiO2-binol-2 microspheres are monodisperse with uniform particle size distribution in the range of 2.5μm~2.7μm, with an average particle size of 2.6μm, and there are evenly distributed pores on the surface of the microspheres.Figure 6 In [description], c is the transmission electron microscope image of SiO2@SiO2-binol-2. From the figure, a clear core-shell structure of the microspheres can be observed. The shell layer contains outwardly divergent channels along the axis. The thickness of the shell layer is 180 nm to 200 nm, with an average thickness of 190 nm, which is thicker than the shell layer prepared in Example 1. It can be speculated that increasing the amount of alkylated binaphthalene derivative in the raw materials can increase the thickness of the shell layer.

[0057] Figure 7 In [description], a is the nitrogen adsorption / desorption experimental result of SiO2@SiO2-binol-2. The adsorption and desorption curves show an obvious hysteresis loop, indicating its shell layer structure. Figure 7 In [description], b shows that the specific surface area of SiO2@SiO2-binol-2 is 123.5 m 2 / g, and the pore size is mainly distributed around 12 nm. Compared with Example 1, due to the increase in the thickness of the shell layer with pore channel structure, the specific surface area of SiO2@SiO2-binol-2 is significantly higher than that of SiO2@SiO2-binol-1.

[0058] To further illustrate the separation effect of SiO2@SiO2-binol-2 on chiral binaphthalene derivative enantiomers, the following experiments were conducted.

[0059] Using SiO2@SiO2-binol-2 as the liquid chromatography stationary phase to resolve chiral compound enantiomers, the chromatographic conditions are the same as in Example 1.

[0060] The results are as Figure 8 shown in [figure] and Table 2. Figure 8 They are the chiral resolution results of four chiral compounds on SiO2@SiO2-binol-2. All four chiral compounds can complete the enantiomer resolution within 6 minutes, and the resolution effect is good, all reaching baseline separation, and the resolution degrees are all higher than 2.31. Especially for the resolution of 2,2'-dibromo-1,1'-binaphthol, the enantiomer resolution degree is 2.74. Compared with Example 1, SiO2@SiO2-binol-2 has a better resolution effect. This should be attributed to the fact that SiO2@SiO2-binol-2 has a thicker hybrid shell layer and more chiral sites, so it also has better separation ability.

[0061] Table 2 Chiral resolution results of 4 chiral compounds Example 3 A binaphthalene-functionalized chiral hybrid stationary phase, with the amount of tetraethyl orthosilicate being 1.5 mL and the amount of binaphthalene derivative being 5.5 g, and the remaining preparation steps being the same as those in Example 1. The obtained binaphthalene-functionalized chiral hybrid stationary phase was named SiO2@SiO2-binol-3.

[0062] SiO2@SiO2-binol-3 was characterized, and the results are as follows: The scanning electron microscope results showed that, as shown in a and b of Figure 9 , the SiO2@SiO2-binol-3 microspheres were monodisperse, with a uniform particle size distribution in the range of 2.3 μm to 2.4 μm, an average particle size of 2.4 μm, and the surface of the microspheres was rough, having a fine pore structure. Figure 9 c in

[0063] Figure 10 was the transmission electron microscope image of SiO2@SiO2-binol-3. It could be clearly observed in the figure that the microspheres had an obvious core-shell structure, the shell thickness was 120 nm to 130 nm, the average thickness was 127 nm, and the shell contained outward divergent pores along the axis. Figure 10 It can be seen from b in

[0064] that the pore diameter of SiO2@SiO2-binol-3 was mainly distributed around 15 nm. Compared with Example 2, due to the reduction of the shell thickness containing the pore structure, the specific surface area of SiO2@SiO2-binol-3 was lower than that of SiO2@SiO2-binol-2.

[0065] Taking SiO2@SiO2-binol-3 as the liquid chromatography stationary phase to resolve the chiral compound enantiomers, and the chromatographic conditions were the same as those in Example 1.

[0066] Figure 11The chiral separation results of four chiral compounds on SiO2@SiO2-binol-3 are shown. All four chiral compounds can complete the enantiomeric separation within 3 minutes with good separation effects. The resolution is greater than 1.6 for all, achieving baseline separation. In particular, the separation effect of 2,2'-dibromo-1,1'-binaphthol enantiomers is the best, with a resolution reaching 2.41. Compared with the SiO2@SiO2-binol-3 prepared in Example 2, the shell of the SiO2@SiO2-binol-3 prepared in this example becomes thinner, the chiral sites in the shell decrease, and the resolution drops.

[0067] Table 3 Separation results of 4 chiral compounds Comparative Example 1 A binaphthyl-functionalized chiral hybrid stationary phase, with the amount of tetraethyl orthosilicate being 3 mL and the amount of binaphthyl derivative being 4 g. The remaining steps are the same as in Example 1. The obtained chiral hybrid microspheres are named SiO2@SiO2-binol-4.

[0068] SiO2@SiO2-binol-4 was characterized, and the results are as follows: The scanning electron microscopy results show that, as shown in a and b of Figure 12 , a large number of nanoparticles are interspersed in the SiO2@SiO2-binol-4 microspheres. The particle size distribution is in the range of 2.2 μm to 2.4 μm, with an average particle size of 2.3 μm, and the pore structure on the surface of the microspheres is not obvious. Figure 12 c in

[0069] Figure 13 is the transmission electron microscopy image of SiO2@SiO2-binol-4. It can be observed from the figure that the microspheres have an obvious core-shell structure. The shell thickness is 80 nm to 100 nm, with an average thickness of 90 nm, but there is no obvious radioactive pore structure in the shell. Compared with Example 1, its shell thickness decreases, and the particle size distribution range and the shell thickness distribution range are also larger than those in Example 1. This shows that when the ratio of tetraethyl orthosilicate to alkylated binaphthyl derivative exceeds a certain range, it will not only affect the distribution of particle size and shell thickness, reducing the uniformity, but also affect the shell thickness, thereby affecting the separation effect. In addition, when the ratio of tetraethyl orthosilicate to alkylated binaphthyl derivative exceeds a certain range, it will also result in a shell structure without pore structure, which seriously affects the separation effect of chiral compounds. Figure 13It can be seen from b in that the pore size is mainly distributed in the range of 5 nm to 9 nm. Compared with Examples 1 to 3, when the ratio of tetraethyl silicate to alkylated binaphthyl derivative exceeds a certain range, the morphology and monodispersity of the prepared product will change significantly.

[0070] In order to further illustrate the separation effect of SiO2@SiO2-binol-4 on the enantiomers of chiral binaphthyl derivatives, the following experiments were performed.

[0071] SiO2@SiO2-binol-4 was used as a liquid chromatography stationary phase to separate the enantiomers of the chiral compound. The chromatographic conditions were the same as those in Example 1.

[0072] Figure 14 The results of liquid chromatography analysis of four chiral compounds on SiO2@SiO2-binol-4 are shown in Figure 2. The four chiral compounds were detected within 5 minutes, but none of the enantiomers achieved baseline separation. The highest degree of separation of the enantiomers was only 0.85, indicating that the selected stationary phase may not be suitable for the separation of these compounds. This result should be attributed to the large number of nanoparticles contained in the microspheres, which led to severe eddy diffusion during separation, decreased column efficiency, and decreased separation ability.

[0073] Table 4 Separation results of four chiral compounds Comparative Example 2 A chiral hybrid stationary phase functionalized with binaphthyl, the amount of tetraethyl silicate used is 1 mL, the amount of alkylated binaphthyl derivative used is 6 g, and the remaining steps are the same as those in Example 1. The obtained chiral hybrid microspheres are named SiO2@SiO2-binol-5.

[0074] SiO2@SiO2-binol-5 was characterized and the results are as follows: Scanning electron microscopy results showed that Figure 15 As shown in a and b, SiO2@SiO2-binol-5 microspheres are adhered, with a particle size distribution in the range of 2.3μm~2.5μm, an average particle size of 2.4μm, and a pore structure visible to the naked eye on the surface of the microspheres. Figure 15 C in the figure is a transmission electron microscope image of SiO2@SiO2-binol-5, from which it can be observed that the microspheres have a core-shell structure, and the shell thickness is uneven, ranging from 110nm to 130nm, with an average thickness of 115nm. Compared with Example 1, the particle size and shell thickness distribution are both larger, that is, the amount of tetraethyl silicate is reduced, and the amount of alkylated binaphthyl derivatives is increased, which will affect the distribution of particle size and shell thickness, thereby reducing the distribution uniformity and having a certain impact on the subsequent separation effect.

[0075] Figure 16In a, the nitrogen adsorption / desorption experimental results of SiO2@SiO2-binol-5 are shown. The adsorption and desorption curves show a weak hysteresis loop, and the specific surface area is only 77.3 m 2 / g, Figure 13 In b, it can be seen that the pore sizes are mainly distributed in the range of 7 nm to 11 nm.

[0076] To further illustrate the separation effect of SiO2@SiO2-binol-5 on chiral binaphthyl derivatives enantiomers, the following experiments were conducted.

[0077] Using SiO2@SiO2-binol-5 as the liquid chromatography stationary phase to resolve chiral compound enantiomers, the chromatographic conditions are the same as in Example 1.

[0078] Figure 17 The following are the liquid chromatography analysis results of four chiral compounds on SiO2@SiO2-binol-5. The four chiral compounds were detected within 6 minutes, but the chiral resolution effect was very weak. Especially for 2,2'-dibromo-1,1'-binaphthol, there was almost no separation of its enantiomers. This should also be attributed to the fact that the adhered microspheres are not suitable as the stationary phase for chromatography.

[0079] Table 5 Resolution results of 4 chiral compounds Comparative Example 3 In the preparation process of Example 1, no alkylated binaphthyl derivative was added, and the remaining steps were kept the same as in Example 1. The obtained product was named SiO2@SiO2-ICPTMS.

[0080] Characterization of SiO2@SiO2-ICPTMS was carried out, and the results are as follows: The scanning electron microscopy results show that, as Figure 18 shown in a and b, the SiO2@SiO2-ICPTMS microspheres are monodispersed, the surface of the microspheres is smooth, and almost no obvious pore structure can be observed. The particle size is 2.2 μm to 2.3 μm, which is similar to the particle size of non-porous silica microspheres, indicating that the shell layer is very thin. Figure 18 In c is the transmission electron microscopy image of SiO2@SiO2-ICPTMS. The shell layer structure of the microspheres cannot be clearly observed from the figure.

[0081] Figure 19 The following are the nitrogen adsorption / desorption experimental results of SiO2@SiO2-ICPTMS. The adsorption and desorption curves show a very weak hysteresis loop, and the specific surface area is only 7.1 m² / g, indicating that it basically has no shell layer structure.

[0082] In order to further illustrate the separation effect of SiO2@SiO2-ICPTMS on enantiomers of chiral binaphthyl derivatives, the following experiments were conducted.

[0083] Using SiO2@SiO2-ICPTMS as the liquid chromatography stationary phase to resolve chiral compound enantiomers, the chromatographic conditions were the same as those in Example 1.

[0084] Figure 20 Figure 7 shows the liquid chromatography analysis results of four chiral compounds on SiO2@SiO2-ICPTMS. There was almost no chiral separation effect of the four chiral compounds on SiO2@SiO2-ICPTMS. This indicates that the chiral resolution ability of the stationary phase is mainly provided by the binaphthyl functional group.

[0085] Table 6 Resolution results of 4 chiral compounds The above examples illustrate that the ratio of tetraethyl orthosilicate to alkylated binaphthyl in the preparation system is the main factor affecting the thickness of the hybrid shell and the chiral separation ability of the hybrid microspheres.

[0086] Although the preferred embodiments of the present invention have been described, those skilled in the art can make additional changes and modifications once they know the basic creative concepts. Therefore, the appended claims are intended to be construed to include the preferred embodiments and all changes and modifications falling within the scope of the present invention.

[0087] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalent technologies, the present invention also intends to include these modifications and variations.

Claims

1. A chiral hybrid stationary phase functionalized with binaphthyl, characterized in that: It comprises a core layer and a shell layer; the core layer is a silicon dioxide microsphere, and the shell layer is a chiral binaphthalene hybrid shell layer; The silica microspheres are non-porous solid silica microspheres with a particle size of 2.2 μm to 2.3 μm; The chiral binaphthyl hybrid shell layer is obtained by using an alkylated binaphthyl derivative as a chiral functional monomer and tetraethyl silicate as a precursor, and by using a sol-gel method to encapsulate the alkylated binaphthyl derivative on the surface of a silica microsphere; The alkylated binaphthyl derivative is obtained by alkylating 3-isocyanate propyltriethoxysilane with binaphthol; The particle size of the chiral hybrid stationary phase is 2.4 μm to 2.6 μm.

2. A method for preparing the chiral hybrid stationary phase according to claim 1, characterized in that: The following steps are involved: After mixing the 3-isocyanate propyl triethoxysilane dispersion with the binaphthol dispersion, the mixture is subjected to an alkylation reaction at 80°C to 90°C for 10h to 12h, and then dried to obtain an alkylated binaphthol derivative; wherein the mass volume ratio of the binaphthol to the 3-isocyanate propyl triethoxysilane is 0.5kg to 1kg: 1L to 2L; The non-porous solid silica microspheres, a surfactant, a catalyst and water are mixed in a mass volume ratio of 4kg-4.5kg:7kg-8kg:2.5kg-3.5kg:120L-140L to obtain a mixed solution; The oil phase solvent, alkylated binaphthyl derivative and tetraethyl silicate are mixed in a mass volume ratio of 4.5kg-5.5kg:58.5L-69.5L:1.5L-2.5L, and then added to the mixed solution. Sol-gel reaction is performed at 60°C-80°C for 20h-24h, and the precipitate is centrifuged and dried to obtain a binaphthyl functionalized chiral hybrid stationary phase. The mass ratio of nonporous solid silica microspheres to alkylated binaphthyl derivatives is 4-4.5:4.5-5.

5.

3. The preparation method according to claim 2, characterized in that: The 3-isocyanate propyl triethoxy silane dispersion is obtained by dispersing 3-isocyanate propyl triethoxy silane in dichloromethane in a volume ratio of 1-2:3-6.

4. The preparation method according to claim 2, characterized in that: The specific process of obtaining the binaphthol dispersion is as follows: Dispersing binaphthol in a mixed solution of anhydrous dichloromethane and triethylamine; The mass volume ratio of binaphthol, anhydrous dichloromethane and triethylamine is 0.5kg~0.8kg:60L~80L:0.4L~0.6L.

5. The preparation method according to claim 2, characterized in that: The surfactant is obtained by mixing sodium N-lauroyl-L-arginyl histidine and folic acid in a mass ratio of 4-4.5:3-3.

5.

6. The preparation method according to claim 2, characterized in that: The catalyst is urea.

7. The preparation method according to claim 2, characterized in that: The oil phase solvent is obtained by mixing toluene and isopropanol in a volume ratio of 55-65:3.5-4.

5.

8. Use of the chiral hybrid stationary phase functionalized with binaphthyl according to claim 1 in the separation of enantiomers of chiral binaphthyl derivatives.

9. The use according to claim 8, characterized in that: The chiral binaphthol derivative enantiomer is any one of R / S-1,1'-binaphthol-2,2'-naphthol, 2,2'-dibromo-1,1'-binaphthol, 2,2'-dimethoxy-1,1'-binaphthol and 2,2'-diethoxy-1,1'-binaphthol.

Images