A method for preparing vacuum gas phase derived chiral separation material
By performing the derivatization reaction of chiral separation of materials under vacuum, the problems of large consumption of organic solvents, complex operation and low reaction efficiency in liquid phase reactions are solved, and efficient and environmentally friendly derivatization reactions are achieved, and the product is highly purified.
Patent Information
- Application Number
- CN202411149233.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2024-08-21
- Publication Date
- 2025-02-07
- Estimated Expiration
- 2044-08-21
AI Technical Summary
The derivatization reaction of the chiral stationary phase of the existing polysaccharides is carried out under liquid phase conditions, and there are problems such as high consumption of organic solvents, complex operation, and low reaction efficiency.
The derivatization reaction of chiral separation materials is carried out by using the vacuum air phase. The derivatization reaction is carried out by heating in the reactor, vacuuming and dehydrating, and after cooling, the derivatization raw materials are added, and heated under vacuum to react.
The consumption of organic solvents is reduced, the efficiency of derivatization reactions is improved, the operation is simplified, and the purity of the product is improved.
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Figure CN118649665B_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of chiral separation materials, and in particular to a method for preparing a vacuum vapor-phase derived chiral separation material. Background Art
[0002] Chiral separation materials are of great significance for drug analysis and preparation. Polysaccharide chiral stationary phases are currently the most widely used and important type of chiral separation materials. They are mainly composed of natural or modified polysaccharide molecules (such as cellulose, starch, cyclodextrin, etc.) and their derivatives. These polysaccharide molecules are chemically modified (such as hydroxypropylation, etherification, esterification, etc.) to enhance their chiral selectivity. Common polysaccharide chiral stationary phases include cellulose tris(3,5-dimethylbenzoate), starch tris(3,5-dimethylbenzoate), etc. This type of material has high selectivity and separation ability, high stability and reproducibility, and rich diversity.
[0003] In order to improve the chiral separation selectivity of polysaccharide chiral stationary phases, it is necessary to perform various chemical derivatizations on the hydroxyl groups on the polysaccharides. In the prior art, the derivatization reaction of polysaccharide chiral stationary phases is mainly carried out under liquid phase conditions. This type of preparation method has the following problems:
[0004] (1) Large consumption of organic solvents: A large amount of organic solvents is required to dissolve and clean samples, causing great pollution and waste.
[0005] (2) Dehydration is required: All reagents, equipment, and atmosphere must be strictly dehydrated because water will compete with the hydroxyl groups on the sugars and reduce the reaction efficiency.
[0006] (3) Low reaction efficiency: Since sugar molecules contain a large number of densely packed hydroxyl groups and organic solvents produce significant steric hindrance, the efficiency of the derivatization reaction in the liquid phase is low, and it is difficult to obtain products with high derivatization conversion rates. Summary of the invention
[0007] In view of the shortcomings of the prior art, the purpose of the present invention is to develop a method for preparing a derivative chiral separation material to solve the problems of the prior art such as complex operation, large consumption of organic solvents and low reaction efficiency.
[0008] To achieve the above object, the present invention provides a method for preparing a vacuum vapor-phase derived chiral separation material, comprising the following steps:
[0009] S1. Adding a separation material raw material into a reactor, wherein the separation material raw material includes a separation material carrier and a polysaccharide chiral stationary phase modified on the separation material carrier;
[0010] S2, heating up the reactor, evacuating the reactor, removing water and oxygen;
[0011] S3, adding the derivative raw material into the reactor after cooling;
[0012] S4, evacuating the reactor and heating it to allow the separation material and the derivative raw material to react;
[0013] S5. After the reaction is completed, the product is collected and washed to obtain a derivative chiral separation material.
[0014] The present invention adopts a vacuum gas phase method to carry out a chiral separation material derivatization reaction. Compared with the liquid phase reaction in the prior art, the preparation method has the advantages of less solvent consumption, high derivatization reaction efficiency, simple operation, high product purity, etc.
[0015] In a preferred or optional embodiment, the separation material carrier has a structure of non-porous microspheres, porous microspheres or fibers.
[0016] In a preferred or optional embodiment, the component of the separation material carrier is selected from one of silicon dioxide, zirconium dioxide, aluminum oxide, inorganic oxides, cellulose, starch, polyimide, polyetheretherketone, and polybenzimidazole.
[0017] In a preferred or optional embodiment, the polysaccharide chiral stationary phase is selected from one or more of cyclodextrin and its derivatives, cellulose and its derivatives, starch and its derivatives.
[0018] In a preferred or optional embodiment, the polysaccharide chiral stationary phase is modified by covalent bonding or physical encapsulation.
[0019] In a preferred or optional embodiment, the derivative raw material is selected from one or more of isocyanate compounds, organic acids, and epoxy compounds.
[0020] In a preferred or optional embodiment, in step S2, the heating temperature is 30-200° C. The heating temperature is not higher than the thermal decomposition temperature and thermal denaturation temperature of the polysaccharide chiral stationary phase and the separation material carrier.
[0021] In a preferred or optional embodiment, in step S3, evacuating the vacuum to a vacuum pressure less than or equal to 10 KPa.
[0022] In a preferred or optional embodiment, in step S4, the reaction temperature is 50-250° C. The reaction temperature is not higher than the thermal decomposition and thermal denaturation temperature of the polysaccharide chiral stationary phase, the separation material carrier, and the derivative raw material.
[0023] In a preferred or optional embodiment, in step S4, the reaction time is 0.5 to 120 hours.
[0024] In a preferred or optional embodiment, the derivatized chiral separation material obtained in step S5 is used as the separation material starting material of step S1, and steps S1 to S5 are repeated once or multiple times, thereby further improving the purity of the product.
[0025] Compared with the prior art, the present invention has the following beneficial effects:
[0026] (1) High reaction efficiency: The derivatization reaction is carried out under vacuum, the molecular diffusion free path is long, the steric hindrance is small, and there is no competing side reaction with water vapor, so the reaction efficiency is high.
[0027] (2) High product purity: Vacuum reaction improves the utilization efficiency of derivative raw materials, the side reactions of derivative raw materials are less, and the product purity is high.
[0028] (3) Environmentally friendly: The derivatization reaction requires almost no organic solvents, which greatly reduces the consumption of organic solvents. At the same time, since there is no solvent in the reaction, the consumption of subsequent cleaning solvents is also greatly reduced.
[0029] (4) Simple operation: By placing the raw materials and reactor under vacuum, the air is completely isolated and water vapor is efficiently removed, simplifying the operation. BRIEF DESCRIPTION OF THE DRAWINGS
[0030] Figure 1 This is a diagram showing the separation results of the chiral enantiomers of 6-methoxyflavanone by β-cyclodextrin derived from 3,5-dimethylphenylisocyanate in Example 5.
[0031] Figure 2 This is a diagram showing the separation results of the chiral enantiomers of biphenyltriazole by β-cyclodextrin derived from 3,5-dichlorophenylisocyanate in Example 6.
[0032] Figure 3 This is a diagram showing the separation results of β-cyclodextrin derived from 3,5-dichloromethyl isocyanate for 1-(4-chlorophenyl)ethanol enantiomers in Example 7. DETAILED DESCRIPTION
[0033] In order to make the above-mentioned purposes, features and advantages of the present invention more obvious and easy to understand, the specific embodiments of the present invention are described in detail below in conjunction with the accompanying drawings. It should be noted that the following embodiments are only used to illustrate the implementation method and typical parameters of the present invention, and are not used to limit the parameter range described in the present invention. Reasonable changes derived therefrom are still within the scope of protection of the claims of the present invention.
[0034] It should be noted that the endpoints and any values of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values should be understood to include values close to these ranges or values. For numerical ranges, the endpoint values of each range, the endpoint values of each range and the individual point values, and the individual point values can be combined with each other to obtain one or more new numerical ranges, and these numerical ranges should be regarded as specifically disclosed in this article.
[0035] A specific embodiment of the present invention provides a method for preparing a vacuum vapor-derived chiral separation material, comprising the following steps:
[0036] S1. Adding separation material raw materials into a reaction kettle. The separation material raw materials include a separation material carrier, and the separation material carrier is modified with a polysaccharide chiral stationary phase, specifically by covalent bonding or physical encapsulation.
[0037] In a specific embodiment, the structure of the separation material carrier is non-porous microspheres, porous microspheres or fibers; the components are inorganic oxides, such as silicon dioxide, zirconium dioxide, aluminum oxide, etc., or polymers, such as cellulose, starch, polyimide, polyetheretherketone, polybenzimidazole, etc. The polysaccharide chiral stationary phase can be selected from cyclodextrin and its derivatives, cellulose and its derivatives, starch and its derivatives, etc.
[0038] S2. The reactor is heated and evacuated to remove water and oxygen in a high-temperature vacuum environment.
[0039] In a specific embodiment, the above steps can be achieved by placing an open reactor in a vacuum oven, with a vacuum pressure of no more than 10 KPa and a heating temperature no higher than the thermal decomposition temperature and thermal denaturation temperature of the polysaccharide chiral stationary phase and the separation material carrier, preferably 30-200°C.
[0040] S3. Add the derivative raw material into the reactor after cooling.
[0041] In a specific embodiment, the derivative raw material is selected from one of an isocyanate compound, an organic acid, and an epoxy compound. Different addition methods can be selected according to the properties of the derivative raw material. For a high-boiling point derivative raw material whose saturated vapor pressure at 25°C is not greater than 10 Kpa, it can be directly added to the reactor, and then the reactor is sealed and vacuumed; for other liquid derivatives or derivative solutions, the reactor is first sealed, vacuumed, and then the derivative raw material is injected through the injection port of the reactor.
[0042] S4. Evacuate the reactor and heat it to allow the separation material and the derivative raw material to react.
[0043] In a specific embodiment, after adding the derivative raw material, the reactor is evacuated to a vacuum pressure of less than or equal to 10 KPa; the reaction temperature is not higher than the thermal decomposition and thermal denaturation temperature of the polysaccharide chiral stationary phase, the separation material carrier, and the derivative raw material, preferably 50~250°C; the required reaction time is 0.5~120 hours, preferably 5~48 hours; during the reaction, the reaction reagents are mixed evenly by shaking or stirring.
[0044] S5. After the reaction is completed, the product is collected and washed to obtain a derivative chiral separation material.
[0045] In some embodiments, the derivatized chiral separation material obtained in step S5 can be used as the separation material raw material of step S1, and steps S1 to S5 can be cycled once or multiple times, thereby further improving the purity of the product.
[0046] The above preparation method is mainly aimed at the requirements of green, low carbon and environmental protection. The derivatization method of polysaccharide chiral stationary phase is improved and a vacuum gas phase reaction is adopted. Compared with the existing liquid phase reaction, it has very significant advantages: (1) the consumption of organic solvents is greatly reduced, and basically no solvent is required in the entire derivatization reaction process; (2) the operation is greatly simplified, and there is no need to strictly remove water from the reactor, reagents and reaction atmosphere; (3) the efficiency of the derivatization reaction is greatly improved. Under vacuum, the side reaction of water vapor is eliminated, and the steric effect of the solvent is avoided, which is very beneficial to improve the reaction efficiency; (4) the utilization efficiency of the derivatization raw materials is improved, the side reaction of the derivatization raw materials is less, and the product purity is high, so the amount of derivatization raw materials required can be greatly reduced.
[0047] The technical solutions and effects of the present invention are described below through specific embodiments.
[0048] Example 1
[0049] (1) Weigh 5 g of porous silica spheres, activate with 6M hydrochloric acid, wash, and vacuum dry them, then add them into the reactor liner, add 50 ml of toluene, add 5 mL of isocyanatepropyltriethoxysilane, and react at 50°C for 6 hours. Wash them three times with ethanol and vacuum dry them.
[0050] (2) The material obtained in step (1) was added into the inner tank of the reactor, and 3 mL of dimethylformamide and 5 g of β-cyclodextrin were added. The solution was mixed and rotary evaporated at 80°C. The mixture was placed in a vacuum oven and reacted at 140°C for 4 hours to generate a white powder. The powder was washed with dimethylformamide and ethanol and dried to obtain a chiral separation material with a covalently bonded β-cyclodextrin stationary phase.
[0051] Example 2
[0052] (1) Weigh 0.5 g of the chiral separation material with a covalently bonded β-cyclodextrin stationary phase obtained in Example 1, place it in a vacuum autoclave, heat it to 80° C., evacuate it to an absolute pressure below 10 KPa, and maintain it for 2 hours.
[0053] (2) The reactor was cooled to room temperature, opened, and 0.5 g of 3,5-dimethylphenylisocyanate powder was added. The reactor was sealed, evacuated to below 10 kPa, and placed in a homogeneous reaction oven. The reaction was heated to 95°C and 100 rpm, and the reaction was carried out under vacuum heating for 24 hours.
[0054] (3) After the reactor is cooled to room temperature, the reactor is opened, and the product is washed with dimethylformamide and ethanol, and dried to obtain a β-cyclodextrin stationary phase chiral separation material derived from 3,5-dimethylphenylisocyanate.
[0055] Example 3
[0056] (1) Weigh 0.5 g of the chiral separation material with a covalently bonded β-cyclodextrin stationary phase obtained in Example 1, put it into a vacuum autoclave, heat it to 80° C., evacuate it to an absolute pressure below 1 KPa, and maintain it for 2 hours.
[0057] (2) The reactor was cooled to room temperature, opened, and 0.5 g of 3,5-dichlorophenyl isocyanate powder was added. The reactor was sealed, evacuated to below 1 kPa, and placed in a homogeneous reaction oven. The reaction was heated to 80°C and 100 rpm, and the reaction was carried out under vacuum heating for 48 hours.
[0058] (3) After the reactor is cooled to room temperature, the reactor is opened, and the product is washed with dimethylformamide and ethanol, and dried to obtain a β-cyclodextrin stationary phase chiral separation material derived from 3,5-dichlorophenylisocyanate.
[0059] Example 4
[0060] (1) Weigh 0.5 g of the chiral separation material with a covalently bonded β-cyclodextrin stationary phase obtained in Example 1, place it in a vacuum autoclave, heat it to 70° C., evacuate it to an absolute pressure below 1 KPa, and maintain it for 1 hour.
[0061] (2) The reactor was cooled to room temperature, opened, and 0.5 g of 3,5-dichloromethyl isocyanate powder was added. The reactor was sealed, evacuated to below 1 kPa, and placed in a homogeneous reaction oven. The reaction was heated to 100°C and 100 rpm, and the reaction was carried out under vacuum heating for 12 hours.
[0062] (3) After the reactor is cooled to room temperature, the reactor is opened, and the product is washed with dimethylformamide and ethanol, and dried to obtain a β-cyclodextrin stationary phase chiral separation material derived from 3,5-dichloromethyl isocyanate.
[0063] Example 5
[0064] (1) The 3,5-dimethylphenylisocyanate-derived β-cyclodextrin stationary phase chiral separation material prepared in Example 2 was dispersed in ethanol and loaded into a stainless steel chromatographic column tube (100 mm × 2.1 mm) at 50 MPa using a high-pressure homogenization method.
[0065] (2) The chiral chromatographic column obtained in step (1) was used to separate the chiral enantiomers of flavanone compounds, with a mobile phase flow rate of 0.3 ml / min, a column temperature of 25°C, and a UV detector at a wavelength of 250 nm. Using MeOH / H2O (v / v = 50 / 50) as the mobile phase, the separation degree for flavanones was 4.3; using MeOH / H2O (v / v = 40 / 60) as the mobile phase, the separation degree for 2-hydroxyflavanones was 2.2; using MeOH / H2O (v / v = 40 / 60) as the mobile phase, the separation degree for naringin was 2.9; using MeOH / H2O (v / v = 60 / 40) as the mobile phase, the separation degree for 6-methoxyflavanone was 8.3. The separation results are as follows: Figure 1 shown.
[0066] Example 6
[0067] (1) The 3,5-dichlorophenyl isocyanate-derived β-cyclodextrin stationary phase chiral separation material prepared in Example 3 was dispersed in ethanol and loaded into a stainless steel chromatographic column tube (100 mm×2.1 mm) at 50 MPa using a high-pressure homogenization method.
[0068] (2) Separate the chiral enantiomers of triazole compounds using the chiral chromatographic column obtained in step (1), with a mobile phase flow rate of 0.3 ml / min, a column temperature of 25°C, and a UV detector at a wavelength of 250 nm. Using ACN / H2O (v / v = 35 / 65) as the mobile phase, the separation degree for paclobutrazol is 1.1; using ACN / H2O (v / v = 35 / 65) as the mobile phase, the separation degree for triadimenol is 8.1; using ACN / H2O (v / v = 35 / 65) as the mobile phase, the separation degree for biphenyltriadimenol is 9.2. The separation results are as follows: Figure 2 shown.
[0069] Example 7
[0070] (1) The 3,5-dichloromethyl isocyanate-derived β-cyclodextrin stationary phase chiral separation material prepared in Example 4 was dispersed in ethanol and loaded into a stainless steel chromatographic column tube (100 mm×2.1 mm) at 50 MPa using a high-pressure homogenization method.
[0071] (2) Separate the chiral enantiomers of chiral alcohol compounds using the chiral chromatographic column obtained in step (1), with a mobile phase flow rate of 0.3 ml / min, a column temperature of 25°C, and a UV detector at a wavelength of 250 nm. Using MeOH / H2O (v / v = 25 / 75) as the mobile phase, the separation degree for 1-(2-naphthyl)ethanol is 2.5; using MeOH / H2O (v / v = 12 / 88) as the mobile phase, the separation degree for 1-(4-fluorophenyl)ethanol is 0.9; using MeOH / H2O (v / v = 25 / 75) as the mobile phase, the separation degree for 1-(4-chlorophenyl)ethanol is 4.5. The separation results are as follows: Figure 3 shown.
[0072] Although the present invention is disclosed as above, the present invention is not limited thereto. Any person skilled in the art can make various changes and modifications without departing from the spirit and scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the scope defined by the claims.
Claims
1. A method for preparing a vacuum vapor-derived chiral separation material, characterized in that: The following steps are involved: S1. Adding a separation material raw material into a reactor, the separation material raw material includes a separation material carrier and a polysaccharide chiral stationary phase modified on the separation material carrier, wherein the component of the separation material carrier is selected from one of silicon dioxide, zirconium dioxide, aluminum oxide, inorganic oxide, cellulose, starch, polyimide, polyetheretherketone, and polybenzimidazole, and the polysaccharide chiral stationary phase is selected from one or more of cyclodextrin and its derivatives, cellulose and its derivatives, and starch and its derivatives; S2, heating up the reactor, evacuating the reactor, removing water and oxygen; S3, adding a derivative raw material into the reaction kettle after cooling, wherein the derivative raw material is an isocyanate compound; S4, evacuate the reactor to a vacuum pressure of less than or equal to 10 KPa, heat it up, and react the separation material and the derivative raw material, the reaction temperature is 50-250°C, and the reaction time is 0.5-120 hours; S5. After the reaction is completed, the product is collected and washed to obtain a derivative chiral separation material.
2. The method for preparing a vacuum vapor-derived chiral separation material according to claim 1, characterized in that: The structure of the separation material carrier is non-porous microspheres, porous microspheres or fibers.
3. The method for preparing a vacuum vapor-derived chiral separation material according to claim 1, characterized in that: The modification method of the polysaccharide chiral stationary phase is covalent bond and / or physical encapsulation.
4. The method for preparing a vacuum vapor-derived chiral separation material according to any one of claims 1 to 3, characterized in that: In step S2, the heating temperature is 30-200°C.
5. The method for preparing a vacuum vapor-derived chiral separation material according to claim 1, characterized in that: The step S5 obtains the derived chiral separation material as the separation material starting material of the step S1, and the steps S1 to S5 are repeated once or multiple times.