A method for splitting tetramisole hydrochloride

Abstract

The present invention relates to a method for splitting tetramisole hydrochloride. A chiral metal-organic framework material is added as a nucleating agent to a saturated solution of tetramisole hydrochloride racemization to induce preferential crystallization of levamisole hydrochloride, thereby splitting the tetramisole hydrochloride. The chiral metal-organic framework material is MIL-101-L-Mand, which is MIL-101 modified with L-mandelic acid at the metal site. A method for splitting tetramisole hydrochloride of the present invention synthesizes a novel chiral metal-organic framework material of L-mandelic acid grafted MIL-101 through a simple preparation process. The obtained chiral metal-organic framework material is a novel nucleating agent for crystallization splitting, has the effect of selectively recognizing tetramisole hydrochloride, and has a splitting ee value of up to 97.26%.

Description

Technical Field

[0001] The invention belongs to the technical field of chiral material separation and relates to a method for separating tetramisole hydrochloride. Background Art

[0002] Chiral drug molecules consist of two mirror-image enantiomers, each with distinct biological activities. The inactive enantiomer may have adverse side effects or even be toxic. Levamisole hydrochloride, an anthelmintic, is the active L-isomer of tetramisole hydrochloride, while dexvamisole hydrochloride is biologically inactive. Therefore, efficient methods for separating enantiomers to obtain pure chiral compounds are crucial for drug development.

[0003] Current chiral separation methods can be categorized into crystallization, kinetic resolution, liquid-liquid extraction, membrane separation, and chromatography. Crystallization is a powerful separation technique for large-scale production of purified products, and can be used to separate and purify chiral racemates. Its ease of use, cost-effectiveness, and widespread applicability make it highly practical. Using chiral metal-organic frameworks as nucleating agents in combination with crystallization can selectively induce the nucleation of a specific single enantiomer from a racemic solution, thereby obtaining a single enantiomer.

[0004] Reference 1 (Synthesis and Application of Optically Active Substituted Acetylene Helical Polymer Microparticles [D]. Beijing University of Chemical Technology, 2013) prepared helical polymer microspheres PSA with high optical activity, which were used to chirally induce the selective crystallization of alanine. The maximum ee value at the end of crystallization was 85%.

[0005] Reference 2 (Preparation and Application Research of Optically Active PA11DT / SiO2 Core-Shell Particles [D]. Zhengzhou University, 2019) prepared PA11DT / SiO2 core-shell particles as nucleating agents to induce the preferential crystallization of D-alanine, and the ee value of D-alanine can reach up to 68.0%.

[0006] Patent CN113929590A discloses a method for resolving chiral aspartic acid by heterogeneous nucleation crystallization. A surfactant is added as a nucleating agent to a saturated solution of racemic aspartic acid to induce preferential crystallization of D-aspartic acid, thereby achieving a chiral resolution of aspartic acid with an ee value of up to 76.9%.

[0007] Reference 3 (Design and construction of functional micro-nanochannels and research on their chiral transport and separation of drugs [D]. Central China Normal University, 2023) prepared a chiral nanochannel membrane that can efficiently separate naproxen with an ee value of up to 90.2%.

[0008] It can be seen that the existing technology has studied the separation effect of different enantiomers by preparing polymer particles, core-shell particles, surfactants, and functional micro-nanochannel membranes. The preparation steps are cumbersome, the separation ee value is not high, and the effect is not good.

[0009] Reference 4 (Using a novel molecular surface imprinting technology to construct chiral cavities to achieve molecular recognition and efficient resolution of chiral drug enantiomers [J]. Acta Chimica Sinica, 2011, 69(24): 3019-3027) prepared a molecular surface imprinted material and applied it to the resolution of tetramisole hydrochloride. It showed high recognition selectivity for levamisole hydrochloride with a selectivity coefficient of 4.03. However, it only studied the adsorption effect of the chiral material on tetramisole hydrochloride, and did not report the ee value of the direct application to the resolution of the racemate.

[0010] Patent CN114307991A discloses a chiral separation column for the preparation of tetramisole hydrochloride. Levamisole hydrochloride with a specific rotation of -85° is obtained using the chiral separation column (calculated based on the reported specific rotation of pure levamisole hydrochloride of -128°, resulting in an ee value of approximately 66.4%). However, this method involves numerous steps, uses environmentally unfriendly and durable resin materials, and exhibits low resolution efficiency. Currently, there are no reports of direct crystallization resolution of tetramisole hydrochloride.

[0011] Therefore, it is of great significance to study a method for splitting tetramisole hydrochloride to solve the problem of poor splitting effect of tetramisole hydrochloride in the prior art. Summary of the Invention

[0012] The purpose of the present invention is to solve the problems existing in the prior art and provide a method for splitting tetramisole hydrochloride.

[0013] In order to achieve the above object, the technical solution adopted by the present invention is as follows:

[0014] A method for resolving tetramisole hydrochloride, comprising adding a chiral metal organic framework material as a nucleating agent to a saturated racemic solution of tetramisole hydrochloride to induce preferential crystallization of levamisole hydrochloride, thereby achieving the resolution of tetramisole hydrochloride;

[0015] The chiral metal-organic framework material is MIL-101-L-Mand (Mand is the abbreviation of mandelic acid in English), which is MIL-101 modified with L-mandelic acid at the metal site.

[0016] As the preferred technical solution:

[0017] In the above method for resolving tetramisole hydrochloride, the ee value of the resolution of tetramisole hydrochloride is 90.25-97.26%.

[0018] In the above-mentioned method for splitting tetramisole hydrochloride, the average particle size of MIL-101-L-Mand is 200-300 nm, and the BET specific surface area is 700-1000 m 2 g -1 , the average pore diameter is 2 to 3 nm.

[0019] In the aforementioned method for resolving tetramisole hydrochloride, the preparation method of MIL-101-L-Mand comprises: opening the metal sites of MIL-101 and grafting L-mandelic acid onto MIL-101 at a temperature of 150-180°C and a pressure of 0.06-0.1 MPa to produce MIL-101-L-Mand. Heating to 150-180°C is used to open the metal sites on MIL-101. Lower temperatures prevent activation, while higher temperatures cause the MIL-101 structure to collapse and decompose.

[0020] The specific preparation process of MIL-101-L-Mand is as follows: MIL-101 is first heated at 150-180°C for 24 hours, L-mandelic acid and the heated MIL-101 are dissolved in chloroform (or DMF), and then, under nitrogen protection, the reaction is refluxed at 65°C (or 100°C) for 24 hours (or 10 hours) with a stirring rate of 250-350 rpm to obtain MIL-101-L-Mand. The mass ratio of L-mandelic acid, MIL-101, and chloroform is 1:0.67:130.59 (or the mass ratio of L-mandelic acid, MIL-101, and DMF is 1:0.55:47.25). The above parameters are set to better complete the coordination functionalization modification and obtain a stable chiral metal-organic framework material for subsequent chiral separation operations.

[0021] The preparation process of MIL-101 is as follows: first, chromium nitrate nonahydrate, terephthalic acid, tetramethylammonium hydroxide and water are mixed, ultrasonicated at room temperature for 30 minutes to uniformly disperse them, the solution is reacted at 200-220°C for 8-12 hours, and finally cooled to room temperature. After centrifugation at 8000 rpm for 8 minutes, it is washed with N,N-dimethylformamide and methanol (or ethanol), centrifuged, and finally vacuum dried at 60°C. The solid is collected to obtain MIL-101 nanocrystals; wherein the mass ratio of chromium nitrate nonahydrate, terephthalic acid, tetramethylammonium hydroxide and water is 1:0.415:0.2-0.032:24-25.

[0022] In the above-mentioned method for resolving tetramisole hydrochloride, the grafting rate of L-mandelic acid on MIL-101-L-Mand is 20-30%.

[0023] The above-mentioned method for splitting tetramisole hydrochloride comprises the following specific steps:

[0024] (1) Adding methanol and excess tetramisole hydrochloride to a constant temperature crystallizer at 25°C, stirring for 12 to 24 hours and then maintaining the temperature for 12 to 24 hours to completely clarify the solution, thereby obtaining a racemic saturated solution of tetramisole hydrochloride;

[0025] (2) The racemic saturated solution of tetramisole hydrochloride was transferred to a constant temperature crystallizer at 30°C, and the temperature was maintained at this temperature for 1 to 2 hours, then the temperature was lowered to 26°C at a rate of 0.1 to 0.2°C / min and maintained for 30 to 60 minutes; the temperature was raised to 30°C to ensure that the tetramisole hydrochloride in the solution was completely dissolved, and the temperature was lowered to 26°C and maintained for a period of time to allow the solution to reach a steady state and prevent nucleation;

[0026] (3) adding a chiral metal organic framework material as a nucleating agent to the solution obtained in step (2) and inducing recognition for 30 minutes;

[0027] (4) The solution obtained in step (3) is cooled at a cooling rate of 0.1 to 0.2° C. / min for 70 to 140 min, filtered and separated, and vacuum dried to obtain a mixture of levamisole hydrochloride, tetramisole hydrochloride in excess, and the chiral metal organic framework material, which is then dissolved and filtered to obtain a mixture of tetramisole hydrochloride in excess.

[0028] In the above-mentioned method for resolving tetramisole hydrochloride, the concentration of the racemic saturated solution of tetramisole hydrochloride in step (1) is 126 mg / ml.

[0029] In the above-mentioned method for resolving tetramisole hydrochloride, the content of the chiral metal organic framework material in the solution obtained in step (3) is 0.25-0.5 wt%.

[0030] In the above-mentioned method for resolving tetramisole hydrochloride, the vacuum drying temperature in step (4) is 40-60°C.

[0031] Principle of the invention:

[0032] The nucleating agent (MIL-101-L-Mand) synthesized by the present invention is a chiral metal organic framework material formed by coordinating L-mandelic acid on the blank metal site of the metal organic framework material (MOF);

[0033] Among them, L-mandelic acid has a benzene ring, hydroxyl groups, and carboxyl groups, and can produce different interactions with chiral molecules. According to the chiral ligand exchange mechanism of the "three-point interaction" theory, the interaction between L-mandelic acid and levamisole hydrochloride includes the π-π interaction of the benzene ring and hydrogen bonding. Due to the stereoisomerism of levamisole hydrochloride and dextroimisole hydrochloride, the interaction force between MIL-101-L-Mand and levamisole hydrochloride is greater than the interaction between L-mandelic acid and dextroimisole hydrochloride, so the material preferentially adsorbs levamisole hydrochloride.

[0034] MOF materials have a large specific surface area, high porosity, a porous structure with adjustable pore size, and good adsorption performance. They have unsaturated metal sites that can react with chiral ligands, have good chemical and thermal stability, and remain stable in various solvents (methanol, ethanol, water, etc.), laying the foundation for the application of MIL-101-L-Mand as a nucleating agent in crystallization splitting.

[0035] The chiral metal-organic framework material MIL-101-L-Mand obtained by MOF grafting L-mandelic acid is a crystalline material with uniform size, good dispersibility, and is not easy to agglomerate in solution. In addition, the material has good stability, high porosity, high permeability in various solvents (water, methanol, ethanol, etc.), and molecules can be transported quickly.

[0036] The MIL-101-L-Mand material has a large specific surface area and a high grafting rate of L-mandelic acid, meaning it is densely modified with L-mandelic acid. The pores are densely packed with L-mandelic acid recognition receptors, providing numerous sites for interaction with tetramisole hydrochloride molecules, thereby enhancing the material's enantioselectivity. The levamisole hydrochloride molecule measures approximately 1 × 0.7 × 0.6 nm, while the pore size of MIL-101-L-Mand is approximately 2 nm. L-mandelic acid, a chiral recognition receptor, is grafted onto the metal sites, creating a chiral microporous environment. This interaction, both spatially and at the site of interaction, strongly interacts with the levamisole hydrochloride molecule, resulting in preferential binding. Due to the small pore size of MIL-101-L-Mand, the levamisole hydrochloride near the L-mandelic acid within the pores readily interacts with the L-mandelic acid, resulting in highly enantioselective chiral resolution.

[0037] The polymer microparticles, core-shell particles, and surfactants (the surfactants here are the nucleating agents in patent CN113929590A) in the prior art have large molecular weights, are easy to agglomerate, and are not as good as MIL-101-L-Mand in dispersibility. In addition, these substances lack a crystalline framework structure and a pore structure, and their interactions with enantiomers only occur on the surface, not within the material, resulting in low resolution ee values.

[0038] The MOF grafted with L-mandelic acid has the following advantages, thus showing excellent separation effect:

[0039] (1) The pore structure of MIL-101-L-Mand enhances the accessibility of L-mandelic acid to the racemic form (i.e., the pore structure allows for better contact between the chiral ligand and racemic tetramisole hydrochloride). The pore size is approximately 2 nm, and grafted L-mandelic acid forms a chiral microenvironment, which enhances chiral recognition selectivity in terms of spatial structure.

[0040] (2) The mass of MIL-101-L-Mand relative to methanol only needs to be less than 1wt% to induce heterogeneous nucleation and crystallization to separate high-purity products, greatly reducing costs;

[0041] (3) MIL-101-L-Mand has a crystalline structure with good stability and dispersibility. The steps for using it in crystallization are simple. It is insoluble in solvents, and the steps for separating the crystallized product are simpler. The material is easy to recycle and can be reused.

[0042] Beneficial effects:

[0043] (1) The present invention provides a method for splitting tetramisole hydrochloride. A novel chiral metal-organic framework material of L-mandelic acid grafted with MIL-101 is synthesized through a simple preparation process. The prepared chiral metal-organic framework material is a novel nucleating agent for direct crystallization splitting, exhibiting a specific splitting effect.

[0044] (2) The MIL-101-L-Mand prepared by the present invention has the effect of selectively recognizing tetramisole hydrochloride, and the ee value of tetramisole hydrochloride resolution can reach up to 97.26%;

[0045] (3) In the method for splitting tetramisole hydrochloride of the present invention, the chiral metal organic framework material has the characteristics of simple preparation, high grafting rate, good dispersibility, multiple pores, good chemical stability and thermal stability, large specific surface area, and moderate pore size.

[0046] (4) The present invention provides a method for resolving tetramisole hydrochloride, which combines the chiral recognition performance of a chiral metal organic framework material with a crystallization process, and adds the chiral metal organic framework material to a racemic saturated solution of tetramisole hydrochloride in the form of a nucleating agent. Since the chiral metal organic framework material has chiral selectivity and has a stronger interaction with levamisole hydrochloride of the same configuration, the preferential crystallization of levamisole hydrochloride can be achieved, thereby realizing the chiral resolution of the racemic tetramisole. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 This is the synthesis route of the chiral metal organic framework material MIL-101-L-Mand in Example 1;

[0048] Figure 2 IR spectra of MIL-101-L-Mand, wherein (a) is MIL-101, (b) is MIL-101-L-Mand, and (c) is L-Mandelic acid (i.e., L-mandelic acid);

[0049] Figure 3Thermogravimetric analysis of MIL-101-L-Mand, where (a) is MIL-101, (b) is MIL-101-L-Mand, and (c) is L-mandelic acid;

[0050] Figure 4 This is the H NMR spectrum of MIL-101-L-Mand;

[0051] Figure 5 Scanning electron micrographs of MIL-101 and MIL-101-L-Mand, where (a) is MIL-101 and (b) is MIL-101-L-mandelic acid;

[0052] Figure 6 This is the nitrogen adsorption curve of MIL-101-L-Mand;

[0053] Figure 7 is the average pore size distribution curve of MIL-101-L-Mand, where the ordinate is the logarithm of the pore area obtained according to the BJH method;

[0054] Figure 8 X-ray powder diffraction patterns of MIL-101 and MIL-101-L-Mand, where (a) is MIL-101 and (b) is MIL-101-L-Mand;

[0055] Figure 9 The curve of enantiomeric excess percentage changing with cooling time at different induction recognition times and cooling rates is shown; 0.1°C / min and 0.2°C / min represent different cooling rates, and 0.25wt% and 0.5wt% represent different nucleating agent contents;

[0056] Figure 10 This is a liquid chromatogram of the levamisole hydrochloride in excess of tetramisole hydrochloride in Example 5;

[0057] Figure 11 This is a liquid chromatogram of the levamisole hydrochloride in excess of tetramisole hydrochloride in Example 10;

[0058] Figure 12 This is the liquid chromatogram of tetramisole hydrochloride, the raw material of Examples 5 to 11. DETAILED DESCRIPTION

[0059] Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiments are only used to illustrate the present invention and are not used in limiting the scope of the present invention.In addition, should be understood that after reading the content taught by the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms fall equally within the scope limited by the appended claims of the application.

[0060] The test / calculation methods involved in the embodiment are as follows:

[0061] Resolution ee value: HPLC with an AD-H chiral column, mobile phase consisting of n-hexane:isopropanol:diethylamine (80:20:0.1%, v / v / v), elution rate of 1 ml / min, elution time of 20 min, column oven temperature of 25°C; resolution ee value = (levamisole hydrochloride content - dexamisole hydrochloride content) / (levamisole hydrochloride content + dexamisole hydrochloride content) × 100%;

[0062] Grafting rate: the ratio of the weight of grafted ligand to the weight before grafting;

[0063] BET specific surface area: The nitrogen adsorption experiment adopts the static capacity method. The chiral metal organic framework material is pre-dried in vacuum at 120°C for 12 hours. The test parameters are: temperature is 77K, and the gas is nitrogen.

[0064] Example 1

[0065] A method for preparing a chiral metal organic framework material MIL-101-L-Mand, such as Figure 1 The specific steps are as follows:

[0066] (1) Preparation of MIL-101: First, chromium nitrate nonahydrate, terephthalic acid, tetramethylammonium hydroxide, and water were mixed in a mass ratio of 1:0.415:0.032:24, and ultrasonicated at room temperature for 30 min to uniformly disperse them. The solution was reacted at 200°C for 8 h, and finally cooled to room temperature. After centrifugation at 8000 rpm for 8 min, it was washed with N,N-dimethylformamide and methanol, centrifuged, and finally dried in vacuo at 60°C. The solid was collected to obtain MIL-101 nanocrystals.

[0067] (2) Preparation of MIL-101-L-Mand: MIL-101 was first heated at 170°C and 0.06 MPa for 24 h, and L-mandelic acid and the heated MIL-101 were dissolved in chloroform. The mixture was then refluxed at 65°C for 24 h at a stirring rate of 300 rpm under nitrogen protection. The unreacted MIL-101 was removed by centrifugation at 3000 rpm for 15 min, and then washed with chloroform and methanol and centrifuged to obtain MIL-101-L-Mand. The mass ratio of L-mandelic acid, MIL-101, and chloroform was 1:0.67:130.59.

[0068] like Figure 5As shown in the figure, the crystal structure of the prepared MIL-101-L-Mand has not changed compared with that of MIL-101, and both are octahedral crystal structures. MIL-101-L-Mand is an octahedral material with an average particle size of 241.5 nm and a BET specific surface area of ​​762.9 m 2 g -1 ; MIL-101-L-Mand was obtained by BJH method as follows Figure 7 As shown in the pore size distribution curve, the material pore size is most distributed at 2.36 nm, that is, the average pore size of MIL-101-L-Mand is 2.36 nm; the grafting rate of L-mandelic acid on MIL-101-L-Mand is 26% (calculated from NMR).

[0069] like Figure 2 As shown, (c) is L-mandelic acid, with a wave number of 3300 cm -1 ~2500cm -1 The stretching vibration peak of OH on the carboxyl group is 1723 cm -1 The stretching vibration peak of C=O on the carboxyl group; (a) is MIL-101, and its characteristic peak is consistent with that in the literature, indicating the successful synthesis of MIL-101; (b) is MIL-101-L-Mand, with a wave number of 3300 cm -1 ~2500cm -1 The hydroxyl stretching vibration peak of L-mandelic acid disappears at 1723 cm -1 The C=O stretching vibration peak at 370 nm red-shifted, indicating that the metal site on MIL-101 underwent a coordination reaction with L-mandelic acid, and it was preliminarily determined that MIL-101-L-Mand was synthesized.

[0070] like Figure 3 As shown, MIL-101 loses 10% of its weight at 30-125°C due to the loss of framework water molecules, there is no obvious weight loss at 125-250°C, and after 250°C the framework collapses and begins to decompose; L-mandelic acid has no obvious weight loss at 30-125°C, begins to lose weight at 125-250°C, and gradually decomposes; the prepared MIL-101-L-Mand also has obvious weight loss at 125-250°C, which shows that the prepared MIL-101-L-Mand is successfully coordinated with L-mandelic acid.

[0071] like Figure 8 As shown, by comparing the powder diffraction pattern of MIL-101 (a) and the powder diffraction pattern of MIL-101-L-Mand (b), it can be found that the characteristic peaks have not changed, indicating that the grafting of L-mandelic acid has not changed the crystal structure of the MOF material, and the crystal structure of MIL-101-L-Mand remains consistent with that of MIL-101.

[0072] like Figure 4 As shown, 1H NMR (400 MHz, Deuterium Oxide) shows obvious peaks of MIL-101 and L-Mand; the peak near 8.05 ppm is the hydrogen signal of MIL-101, 7.40-7.34 ppm is the benzene ring hydrogen signal of L-mandelic acid, and 5.01 ppm is the hydroxyl hydrogen signal of L-mandelic acid, which further proves that MIL-101-L-Mand is synthesized.

[0073] like Figure 6 As shown in Figure 2, the nitrogen adsorption-desorption curve of MIL-101-L-Mand is a type IV isotherm model, revealing the presence of mesopores (pores of 2-50 nm) in this material. Its single-point BET (P / P0 = 0.2) specific surface area is 638.5 m 2 / g, and the multi-point BET specific surface area was calculated to be 762.9 m 2 / g, the large specific surface area and mesoporous structure endow MIL-101-L-Mand with abundant active sites, which are beneficial to the adsorption and interaction of tetramisole hydrochloride.

[0074] Comparative Example 1

[0075] A method for preparing a chiral metal-organic framework material is basically the same as Example 1, except that the L-mandelic acid in step (2) is replaced with an equimolar mass of L-glutamic acid, the solvent is N,N-dimethylformamide, and the reaction is refluxed at 100°C for 10 hours.

[0076] The chiral metal organic framework material prepared is an octahedral material with an average particle size of 235.6 nm and a BET specific surface area of ​​676.5 m 2 g -1 , with an average pore diameter of 2.51 nm; the grafting rate of L-glutamic acid on the metal-organic framework material is 31%.

[0077] By comparing Comparative Example 1 with Example 1, it can be found that the particle sizes of MIL-101-L-Glu and MIL-101-L-Mand are basically the same, but MIL-101-L-Glu has a higher grafting rate, a larger pore size, and a smaller specific surface area than MIL-101-L-Mand. This is because the L-glutamic acid molecule does not have a benzene ring compared to L-mandelic acid, and the reaction is relatively less sterically hindered, so the grafting rate is high, the pore size is large, and the specific surface area is small.

[0078] Example 2

[0079] A method for preparing a chiral metal-organic framework material MIL-101-L-Mand, comprising the following steps:

[0080] (1) Preparation of MIL-101: First, chromium nitrate nonahydrate, terephthalic acid, tetramethylammonium hydroxide, and water were mixed in a mass ratio of 1:0.415:0.2:25, and ultrasonicated at room temperature for 30 min to uniformly disperse them. The solution was reacted at 220°C for 8 h, and finally cooled to room temperature. After centrifugation at 8000 rpm for 8 min, it was washed with N,N-dimethylformamide and ethanol, centrifuged, and finally dried in vacuo at 80°C. The solid was collected to obtain MIL-101 nanocrystals.

[0081] (2) Preparation of MIL-101-L-Mand: MIL-101 was first heated at 170°C and 0.06 MPa for 24 h, and L-mandelic acid and the heated MIL-101 were dissolved in chloroform. The mixture was then refluxed at 65°C for 24 h at a stirring rate of 300 rpm under nitrogen protection. The unreacted MIL-101 was removed by centrifugation at 3000 rpm for 15 min, and then washed with chloroform and methanol and centrifuged to obtain MIL-101-L-Mand. The mass ratio of L-mandelic acid, MIL-101, and chloroform was 1:0.67:130.59.

[0082] The average particle size of the prepared MIL-101-L-Mand is 200.1 nm and the BET specific surface area is 805.2 m 2 g -1 The average pore size is 2.32 nm; the grafting rate of L-mandelic acid on MIL-101-L-Mand is 27%.

[0083] Example 3

[0084] A method for preparing a chiral metal-organic framework material MIL-101-L-Mand is basically the same as Example 1, except that in step (2), MIL-101 is heated at a temperature of 150° C. and a pressure of 0.1 MPa for 24 hours.

[0085] The average particle size of the prepared MIL-101-L-Mand was 245.2 nm and the BET specific surface area was 722.8 m 2 g -1 The average pore size is 2.43 nm; the grafting rate of L-mandelic acid on MIL-101-L-Mand is 24%.

[0086] Example 4

[0087] A method for preparing a chiral metal-organic framework material MIL-101-L-Mand, comprising the following steps:

[0088] (1) Preparation of MIL-101: First, chromium nitrate nonahydrate, terephthalic acid, tetramethylammonium hydroxide, and water were mixed in a mass ratio of 1:0.415:0.032:24, and ultrasonicated at room temperature for 30 min to uniformly disperse them. The solution was reacted at 200°C for 8 h, and finally cooled to room temperature. After centrifugation at 8000 rpm for 8 min, it was washed with N,N-dimethylformamide and methanol, centrifuged, and finally dried in vacuo at 60°C. The solid was collected to obtain MIL-101 nanocrystals.

[0089] (2) Preparation of MIL-101-L-Mand: MIL-101 was first heated at 170°C and 0.06 MPa for 24 h, and L-mandelic acid and the heated MIL-101 were dissolved in DMF. The mixture was then refluxed at 100°C for 10 h at a stirring rate of 300 rpm under nitrogen protection. The unreacted MIL-101 was removed by centrifugation at 1000 rpm for 15 min, and then washed with chloroform and methanol and centrifuged to obtain MIL-101-L-Mand. The mass ratio of L-mandelic acid, MIL-101, and DMF was 1:0.55:47.25.

[0090] The average particle size of the prepared MIL-101-L-Mand was 238.8 nm and the BET specific surface area was 705.3 m 2 g -1 The average pore size is 2.45 nm; the grafting rate of L-mandelic acid on MIL-101-L-Mand is 23%.

[0091] Example 5

[0092] A method for splitting tetramisole hydrochloride, comprising the following steps:

[0093] (1) Methanol and excess tetramisole hydrochloride were added to a thermostatic crystallizer at 25°C, stirred for 12 hours, and then kept at a constant temperature for 12 hours to completely clarify the solution, thereby obtaining a saturated racemic tetramisole hydrochloride solution with a concentration of 126 mg / ml;

[0094] (2) Transfer the racemic saturated solution of tetramisole hydrochloride to a constant temperature crystallizer at 30°C, maintain the constant temperature for 1 hour, then cool it down to 26°C at a rate of 0.1°C / min and maintain it for 30 minutes;

[0095] (3) adding the chiral metal organic framework material of Example 1 as a nucleating agent to the solution obtained in step (2), and inducing recognition for 30 minutes to obtain a solution with a chiral metal organic framework material content of 0.25 wt%;

[0096] (4) The solution obtained in step (3) is cooled at a cooling rate of 0.1° C. / min for 140 min, filtered and separated, and then vacuum dried at a temperature of 50° C. to obtain a mixture of levamisole hydrochloride, tetramisole hydrochloride in excess, and a chiral metal organic framework material, which is then dissolved and filtered to obtain tetramisole hydrochloride in excess.

[0097] like Figure 12 As shown in the liquid chromatogram of the raw material tetramisole hydrochloride, the relative retention time of dextromisole hydrochloride is 9.759 min, and the relative retention time of levamisole hydrochloride is 11.078 min. Figure 10 As shown, the peak area percentage of dextromisole hydrochloride is 1.81%, and the peak area percentage of levamisole hydrochloride is 98.19%. Therefore, the resolution ee value of tetramisole hydrochloride is 96.38%, and levamisole hydrochloride crystallizes preferentially.

[0098] Comparative Example 2

[0099] A method for resolving tetramisole hydrochloride is basically the same as that in Example 5, except that the nucleating agent is the chiral metal organic framework material prepared in Comparative Example 1.

[0100] The final resolution ee value of tetramisole hydrochloride was 31.3%.

[0101] Comparing Comparative Example 2 with Example 5, it can be found that the resolution ee value is not high. This is because L-glutamic acid has no benzene ring and only has hydrogen bonding with tetraimidazole hydrochloride molecules, resulting in weak interaction and poor selectivity.

[0102] Example 6

[0103] A method for splitting tetramisole hydrochloride is basically the same as that in Example 5, except that the nucleating agent in step (3) is the chiral metal organic framework material of Example 2.

[0104] The final resolution ee value of tetramisole hydrochloride was 96.38%.

[0105] Example 7

[0106] A method for splitting tetramisole hydrochloride is basically the same as that in Example 5, except that the nucleating agent in step (3) is the chiral metal organic framework material of Example 3.

[0107] The final resolution ee value of tetramisole hydrochloride was 95.76%.

[0108] Example 8

[0109] A method for splitting tetramisole hydrochloride is basically the same as that in Example 5, except that the nucleating agent in step (3) is the chiral metal organic framework material of Example 4.

[0110] The final resolution ee value of tetramisole hydrochloride was 95.40%.

[0111] Example 9

[0112] A method for resolving tetramisole hydrochloride is basically the same as Example 5, except that in step (4), the temperature is lowered at a cooling rate of 0.2°C / min for 60 minutes.

[0113] The final resolution ee value of tetramisole hydrochloride was 90.25%.

[0114] Example 10

[0115] A method for resolving tetramisole hydrochloride is basically the same as that in Example 5, except that the content of the chiral metal organic framework material in step (3) is 0.5 wt%.

[0116] like Figure 11 As shown, the peak area percentage of levamisole hydrochloride is 98.63%, and the peak area percentage of dexvamisole hydrochloride is 1.37%. Therefore, the resolution ee value of tetramisole hydrochloride is 97.26%, and levamisole hydrochloride crystallizes preferentially.

[0117] Example 11

[0118] A method for resolving tetramisole hydrochloride is basically the same as Example 10, except that in step (4), the temperature is lowered at a cooling rate of 0.2°C / min for 60 minutes.

[0119] The final resolution ee value of tetramisole hydrochloride was 91.58%.

[0120] like Figure 9 As shown, when the nucleating agent content is 0.25wt%, the cooling rate is 0.1℃ / min, and the cooling time is 120min, the resolution ee value of tetramisole hydrochloride reaches a maximum of 96.38%; when the nucleating agent content is 0.25wt%, the cooling rate is 0.2℃ / min, and the cooling time is 50min, the resolution ee value of tetramisole hydrochloride reaches a maximum of 90.25%; when the nucleating agent content is 0.5wt%, the cooling rate is 0.1℃ / min, and the cooling time is 120min, the resolution ee value of tetramisole hydrochloride reaches a maximum of 97.26%; when the nucleating agent content is 0.5wt%, the cooling rate is 0.2℃ / min, and the cooling time is 50min, the resolution ee value of tetramisole hydrochloride reaches a maximum of 91.58%.

Claims

1. A method for resolving tetramisole hydrochloride, characterized in that: Chiral metal-organic framework materials are added as nucleating agents to a saturated racemic solution of tetramisole hydrochloride to induce preferential crystallization of levamisole hydrochloride and achieve the resolution of tetramisole hydrochloride. The chiral metal-organic framework material is MIL-101-L-Mand, which is MIL-101 modified with L-mandelic acid at the metal site; The average particle size of MIL-101-L-Mand is 200-300 nm, and the BET specific surface area is 700-1000 m 2 g -1 , the average pore size is 2-3 nm; The preparation method of MIL-101-L-Mand is as follows: L-mandelic acid is grafted onto MIL-101 at a temperature of 150-180° C. and a pressure of 0.06-0.1 MPa to obtain MIL-101-L-Mand; The grafting rate of L-mandelic acid on MIL-101-L-Mand is 20-30%.

2. A method for resolving tetramisole hydrochloride according to claim 1, characterized in that, The resolution ee value of tetramisole hydrochloride is 90.25-97.26%.

3. A method for resolving tetramisole hydrochloride according to claim 1, characterized in that, The specific steps are as follows: (1) adding methanol and excess tetramisole hydrochloride to a constant temperature crystallizer at 25° C., stirring for 12 to 24 hours, and then maintaining the temperature for 12 to 24 hours to obtain a racemic saturated solution of tetramisole hydrochloride; (2) Transfer the saturated racemic tetramisole hydrochloride solution to a constant temperature crystallizer at 30°C, maintain the constant temperature for 1 to 2 hours, then cool the temperature to 26°C at a rate of 0.1 to 0.2°C / min and maintain the temperature for 30 to 60 minutes; (3) adding a chiral metal organic framework material as a nucleating agent to the solution obtained in step (2) and inducing recognition for 30 minutes; (4) The solution obtained in step (3) is cooled at a cooling rate of 0.1 to 0.2° C. / min for 70 to 140 min, filtered and separated, and vacuum dried to obtain a mixture of levamisole hydrochloride, tetramisole hydrochloride in excess, and the chiral metal organic framework material, which is then dissolved and filtered to obtain a mixture of tetramisole hydrochloride in excess.

4. A method for resolving tetramisole hydrochloride according to claim 3, characterized in that, The concentration of the racemic saturated solution of tetramisole hydrochloride in step (1) is 126 mg / ml.

5. A method for resolving tetramisole hydrochloride according to claim 3, characterized in that, In the solution obtained in step (3), the content of the chiral metal organic framework material is 0.25 to 0.5 wt%.

6. A method for resolving tetramisole hydrochloride according to claim 3, characterized in that, The vacuum drying temperature in step (4) is 40-60°C.

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