Preparation method of methyl-beta-cyclodextrin

Abstract

The invention provides a preparation method of methyl-beta-cyclodextrin, which comprises the following steps: methylating beta-cyclodextrin (BCD) in a barium hydroxide alkaline aqueous solution at 60 DEG C by using dimethyl sulfate (DMS) as a methylation reagent, monitoring the reaction degree by using a thin layer chromatography (TLC) technology, baking a plate for 30 seconds in an electric furnace at 200-400 DEG C for color development by using methanol and dichloromethane as developing solvents and sulfuric acid and ethanol as color developing agents, and finally obtaining the methyl-beta-cyclodextrin. The methylation degree can be simply and conveniently detected. And after the reaction is completed, removing impurities, concentrating and drying to obtain methyl-beta-cyclodextrin (MBCD). The preparation method is simple, conditions are mild, organic reagents which have toxic pollution and are expensive are almost avoided, the product is easy to transfer out, the yield is high, and the average substitution degree is stable. According to the MBCD prepared by the method, the average methylation substitution degree is about 10 (+ / -2), and the blank of MBCD products with the average methylation substitution degree of about 10 (+ / -2) is filled.

Description

Technical Field

[0001] The invention belongs to the field of biomedicine and relates to a method for preparing methyl-β-cyclodextrin, and specifically relates to a method for preparing methyl-β-cyclodextrin with an average methylation substitution degree of 8 to 12. Background Art

[0002] Cyclodextrin (abbreviated as CD) is a general term for cyclic oligosaccharides generated by amylose under the action of cyclodextrin glucosyltransferase produced by Bacillus. Among them, the molecules containing 6, 7, and 8 D-pyranose units are the most studied and of great significance, which are called α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin respectively.

[0003] β-cyclodextrin (BCD for short) is a macrocyclic compound composed of D-pyranose glucose units connected head to tail through α-1,4 glycosidic bonds, with 7 glucose units. Figure 1 As shown in the figure, the slightly conical ring has a hydrophobic inner cavity and a hydrophilic outer side. The structure is rigid, and the secondary hydroxyl groups form a complete annular hydrogen bond, so the water solubility is very low. At room temperature, the solubility in 100 mL of water is only 1.85 g. In addition, the hydroxyl groups of BCD have a certain enzyme-like catalytic effect, which will affect the stability of the inclusion complex. This characteristic seriously restricts its application in the fields of medicine, food, analytical chemistry, daily chemical industry, environmental protection, agriculture, etc. Therefore, the research on the modification of BCD has become the focus of many scholars.

[0004] In order to solve this technical problem, the prior art generally uses methylation to improve β-cyclodextrin. Methyl-β-cyclodextrin (MBCD for short) is a derivative of β-cyclodextrin modified (substituted) by methyl. It is highly soluble in water and has high surface activity and strong hemolytic effect. The structure of MBCD is as follows: Figure 2 As shown, it has excellent solubilizing and inclusion effects, and its characteristics are related to the substitution position, degree of substitution and number of substitutions at the same substitution position of the methyl group in β-cyclodextrin. BCD has seven glucose hydroxyl groups, and the C2, C3 and C6 positions on each glucose hydroxyl group can be substituted by methyl groups. Due to its different substitution degrees, its crystal form, water solubility, fat solubility, recognition ability for guest substances and inclusion ability are all different.

[0005] After BCD is methylated, its solubility in water is increased. After BCD is methylated, it still has the inclusion property. The solubility of the inclusion compound in water is also significantly increased. MBCD also has the characteristics of low hygroscopicity and high surface activity. It can be widely used in food, cosmetics, pesticides, daily chemical products, textile dyeing and finishing, printing, ink, coating thickener, etc.

[0006] Common public reports in the prior art all synthesize products with an average degree of substitution of less than 7 or greater than 14 (a mixture of dimethyl-β-cyclodextrin and trimethyl-β-cyclodextrin), such as:

[0007] WO2001 / 036490 reports that the target product obtained by methylation with calcium hydroxide and dimethyl sulfate in water has a low degree of methylation, with an average degree of substitution of only 7; CN104892797 reports that the target product obtained by alkylation with 1,4-butanesulfone in an aqueous solution of sodium hydroxide has an average degree of substitution of 3 to 6.

[0008] Gao Dengzheng et al. reported that using dimethyl sulfate (DMS) as a methylating agent and reacting it with sodium hydroxide in water can produce MBCD with an average degree of substitution higher than 14. However, the MBCD was subsequently purified using ion exchange resin, and this type of resin is expensive.

[0009] Yuan.LM et al. reported that by dissolving BCD in dimethylformamide (DMF), using methyl halide as the methylation reagent, and adding the more dangerous active substance NaH to participate in the reaction, MBCD with an average degree of substitution of 7 can be obtained.

[0010] Gan Yongjiang et al. reported that the target product MBCD with an average degree of substitution of 14 was obtained using dimethyl carbonate (DMC) as a methylation reagent under the catalysis of potassium carbonate in DMF.

[0011] The above method is difficult to prepare methyl-β-cyclodextrin with an average methylation substitution degree of about 10 (±2), and the MBCD product with a methyl substitution degree between 8 and 12 is in a blank state; at the same time, the above method has difficulties such as low methylation degree and high post-reaction treatment cost in the reaction of the water system; and there is a disadvantage of a large amount of organic waste liquid in the DMF system. Summary of the invention

[0012] The present invention is conducted to solve the above problems. The reaction characteristics of barium hydroxide and dimethyl sulfate are used to partially optimize the methylation reaction, and a method for preparing methyl-β-cyclodextrin is provided to obtain MBCD with a methyl substitution degree between 8 and 12.

[0013] The main scheme of the preparation method of methyl-β-cyclodextrin provided by the present invention is as follows: dimethyl sulfate (DMS) is used as a methylating agent, β-cyclodextrin (BCD) is methylated in an alkaline aqueous solution of barium hydroxide at 60° C., the reaction degree is monitored by thin layer chromatography (TLC), methanol and dichloromethane are used as developing agents, sulfuric acid and ethanol are used as color developing agents, and an electric furnace is used to bake a plate at 200-400° C. for 30 seconds to develop color, so that the methylation degree can be simply and conveniently detected ( Figure 3 After the reaction is completed, impurities are removed, concentrated and dried to obtain methyl-β-cyclodextrin (MBCD).

[0014] The principle of the present invention is as follows: dimethyl sulfate is mainly used as a methylating agent. Dimethyl sulfate is decomposed into sulfuric acid and active methyl groups by heating in an alkaline solution. The methyl groups can be exchanged with acidic H atoms of hydroxyl, sulfhydryl, amine or imino groups under alkaline conditions. In this reaction, sulfuric acid, a byproduct produced by excessive dimethyl sulfate, can react with barium hydroxide to generate water-insoluble barium sulfate precipitation. After all raw material BCD is methylated, the system is filtered without quenching the reaction to remove the waste solid barium sulfate produced, and then concentrated by an evaporator. After concentration, an appropriate amount of ethanol solvent is added for crystallization, and the acidic filtrate is removed to obtain a white solid powder insoluble in ethanol. After drying, a small amount of water is added for filtration to obtain clear MBCD soluble in water, which is determined to be the target product and does not contain barium sulfate by TLC.

[0015] The specific technical solutions of the present invention are as follows:

[0016] The first aspect of the present invention provides a method for preparing methyl-β-cyclodextrin, comprising the following steps:

[0017] (1) BCD addition

[0018] BCD is added into a container containing an aqueous solution of barium hydroxide to obtain a mixed solution, and the obtained mixed solution is cooled to 5-30°C.

[0019] Preferably, the barium hydroxide aqueous solution is prepared by adding barium hydroxide in batches to prevent excessive heat release; during the preparation process, the stirring speed is optional, and when the barium hydroxide aqueous solution is cooled to 20-30° C., BCD is added;

[0020] The molar ratio of BCD to barium hydroxide is preferably 1:5-15 (preferably 1:6), and the mass ratio of BCD to water is 1:5-50 (preferably 1:10); when the solution is prepared, the stirring speed is 300-800 rpm (preferably 400-600 rpm, more preferably 500 rpm), and the stirring time is 5-30 min (preferably 10 min).

[0021] In the present invention, part of the barium hydroxide is used to activate BCD, and part of the barium hydroxide is used to neutralize the sulfuric acid generated by the partial decomposition of DMS, so as to act as an acid-binding agent to make the reaction proceed in the forward direction. Although other metal hydroxides can also provide an alkaline environment, some (such as calcium hydroxide) have poor solubility in water and cannot fully provide an alkaline environment, resulting in the inability to stably carry out the methylation reaction of dimethyl sulfate; some metal elements cannot produce insoluble salts with sulfuric acid, which introduces new impurities that are difficult to remove into the reaction system.

[0022] In addition, although some metal cations (such as Ag, Pb, etc.) or non-metal cations will produce precipitation with sulfuric acid, in the present invention, the methylation reaction of dimethyl sulfate must be carried out in an alkaline environment. If other non-metal elements are used, an alkaline environment cannot be provided and the reaction cannot proceed.

[0023] (2) Methylation reaction

[0024] According to the molar ratio of BCD to methylating agent DMS of 1:5-18 (preferably 1:12), the methylating agent is slowly added to the container in batches while stirring. After the methylating agent is added, stir for 0.5-2h (preferably 1h), then heat the reaction system to 60°C and stir for 8-24h (preferably 18h) to react.

[0025] The present invention selects DMS as the methylation reagent based on the reaction effect and price: it can use water as a solvent for the methylation reaction, dimethyl carbonate cannot reach a substitution degree of 10, and methyl iodide is obviously too expensive. DMS is the cheapest methylation reagent.

[0026] When the methylating agent is added in batches, it is preferred to add the methylating agent slowly, for example, by adding in drops, or the speed of adding the methylating agent is 0.1 to 0.5 ml / min, preferably 0.2 ml / min. During industrial scale-up production, the adding speed can be adjusted according to actual conditions. The dropping method is implemented by using a dropping device or equipment in the prior art, for example, in industrial production, a dropping tank can be used.

[0027] Excess or insufficient amount of the methylating agent DMS will affect the average degree of substitution (MS) of the final product (MBCD). Therefore, the molar ratio of DMS to BCD within the above range can obtain a product with an average degree of substitution of 10 (±2).

[0028] (3) Reaction monitoring

[0029] The sulfuric acid produced by the reaction reacts with barium hydroxide to form a water-insoluble barium sulfate precipitate. The originally water-insoluble BCD is converted into water-soluble 10MBCD after the methylation reaction.

[0030] During the reaction, the pH of the reaction system is adjusted to 2-5 (preferably pH 3), and the progress of the reaction is monitored. The methylation reagent DMS is in excess, and sulfuric acid byproducts generated by thermal decomposition must exist in the system; after the reaction is completed, the generated barium sulfate precipitate is filtered out and the filtrate is taken.

[0031] Among them, the method for monitoring the progress of the reaction is as follows: use thin layer chromatography (TLC) technology to monitor the degree of reaction, use methanol and dichloromethane as developing agents, and a mixture of sulfuric acid and ethanol in a volume ratio of 1:2 as a color developer, and bake the plate at 200-400°C in an electric furnace for 30 seconds to develop color.

[0032] (4) Filtrate Concentration

[0033] The filtrate is evaporated to remove the solvent, and the filtrate is concentrated to a nearly saturated state. The filtrate is concentrated to a volume weight ratio of BCD of 1 volume part: 2 to 5 weight parts, preferably, the filtrate is concentrated to a volume weight ratio of BCD of 1 volume part: 3 weight parts.

[0034] In the present invention, MBCD has a strong inclusion property and is easy to include reaction impurities and unreacted BCD, and is not easy to dry, so the filtered mother liquor needs to be rotary evaporated to a nearly saturated state.

[0035] (5) Product extraction

[0036] A crystallizing agent is added to the concentrate of step (4) to obtain a white suspension, and the acidic waste liquid is filtered to obtain a filter cake; the filter cake is dissolved in water and filtered to remove impurities, and after the solvent in the filtrate is evaporated, the concentrate is dried to obtain the target product methyl-β-cyclodextrin.

[0037] Preferably, the crystallizing agent is selected from ethanol, which can remove the concentrate. The volume weight ratio of ethanol solvent to concentrate is 5 parts by volume: 1 part by weight;

[0038] Only part of the by-products sulfuric acid and barium sulfate are removed from the crude product, and pure MBCD cannot be obtained. Due to the good water solubility of MBCD, it can be further removed by re-dissolving and filtering. The volume weight ratio of the aqueous solution to the white filter cake solid is (2 to 20) parts by volume: 1 part by weight;

[0039] The conditions for drying the concentrate are as follows: the drying temperature is 40 to 80° C. (preferably 55° C.) and the drying time is 10 to 14 h (preferably 12 h).

[0040] In a second aspect, the present invention provides a methyl-β-cyclodextrin, which is prepared by the method described above. After testing, the methylation degree of the methyl-β-cyclodextrin is 8 to 12, and the melting range is 181 to 185°C.

[0041] The methyl-β-cyclodextrin prepared by the present invention, β-cyclodextrin and methyl-β-cyclodextrin with an average methylation degree of substitution of 14 were subjected to TLC analysis at the same time. The results showed that the displacement value of β-cyclodextrin was 0-0.2; the displacement value of methyl-β-cyclodextrin with an average methylation degree of substitution of 10 (±2) was about 0.7-0.9; the displacement value of methyl-β-cyclodextrin with an average methylation degree of substitution of 14 was 0.9-1.0 ( Figure 3 ). Perform all three simultaneously 1 HNMR spectrum detection shows that the characteristic peaks of the three are obviously different.

[0042] Functions and Effects of the Invention

[0043] In terms of products, the methyl-β-cyclodextrin provided by the present invention has an average methylation substitution degree of about 10 (±2), that is, between 8 and 12, filling the gap of MBCD products with an average methylation substitution degree of about 10 (±2);

[0044] In terms of preparation technology, the preparation method is simple and the conditions are mild, and toxic and expensive organic reagents are almost avoided. The product is easy to transfer out, the yield is high, and the average degree of substitution is stable. At the same time, the present invention uses TLC technology to monitor the degree of reaction, methanol is used as a developing agent, sulfuric acid and ethanol are used as a color developer in a volume ratio of 1:2, and an electric furnace is used to bake a plate at 200°C for 30 seconds for color development, which replaces instrument detection means and simply and quickly detects the degree of methylation. The average methylation degree of substitution is 10 (±2) and its preparation and detection method are provided. The preparation method is simple, the conditions are mild, the raw material cost is low, and the application range of methyl-β-cyclodextrin is broadened.

[0045] In terms of yield, the preparation method uses DMS as a methylation agent and ethanol as a crystallization solvent to crystallize the product, making it easy to transfer the product out. The yield of the obtained product can reach 60%, and the average methylation degree of substitution of the obtained methyl-β-cyclodextrin is stable. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] Figure 1 The chemical structure and spatial configuration of β-cyclodextrin are shown, a is the chemical structural formula of β-cyclodextrin, and b is the spatial configuration of β-cyclodextrin;

[0047] Figure 2 The chemical structure of methyl-β-cyclodextrin is shown, the value of R and the average degree of substitution MS;

[0048] Figure 3 The TLC detection diagram of the present invention is shown, point 1 is β-cyclodextrin, and the displacement value is 0-0.2; point 2 is methyl-β-cyclodextrin with an average methylation substitution degree of 10 (±2) prepared by the present invention, and the displacement value is about 0.7-0.9; point 3 is methyl-β-cyclodextrin with an average methylation substitution degree of 14, and the displacement value is 0.9-1.0;

[0049] Figure 4 The 1HNMR spectra of the methyl-β-cyclodextrin obtained in the present invention are shown, wherein Figure A is a standard β-cyclodextrin, Figure B is a methyl-β-cyclodextrin with an average degree of substitution of about 10, and Figure C is a standard dimethyl-β-cyclodextrin with an average degree of methylation substitution of 14;

[0050] Figure 5 The process flow chart of the present invention is shown. DETAILED DESCRIPTION

[0051] The present invention is described in detail below in conjunction with the embodiments and the accompanying drawings. However, the following embodiments should not be considered as limiting the scope of the present invention.

[0052] The experimental methods in the following examples without specifying specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturers.

[0053] 1. Preparation process of methyl-β-cyclodextrin

[0054] See the preparation process Figure 5 , the specific process is as follows:

[0055] Step 1: Add BCD into a container containing a barium hydroxide aqueous solution to obtain a mixed solution.

[0056] The barium hydroxide aqueous solution is obtained by mixing barium hydroxide with water. When barium hydroxide and water are mixed, heat is obviously released, so the barium hydroxide can be added in batches.

[0057] Step 1 includes:

[0058] Step 1.1, adding water and barium hydroxide into a container, preferably adding barium hydroxide in batches, optionally stirring, to obtain a barium hydroxide aqueous solution;

[0059] Step 1.2: After the barium hydroxide aqueous solution is cooled to 20-30° C., BCD is added and stirred to obtain a mixed solution.

[0060] Preferably, in step 1.1, barium hydroxide is added in batches under stirring to prevent excessive heat release;

[0061] The molar ratio of BCD to barium hydroxide is 1:(5-15), preferably 1:6; the mass ratio of BCD to water is 1:(5-50), preferably 1:10;

[0062] A portion of the alkali metal hydroxide is used to activate BCD, and a portion is used to neutralize the sulfuric acid produced by the partial decomposition of DMS, acting as an acid-binding agent to allow the reaction to proceed in the forward direction.

[0063] Preferably, in step 1.2, when the temperature of the barium hydroxide aqueous solution is 20 to 30°C, preferably room temperature 25°C, BCD is added and stirred until dissolved. Preferably, the stirring speed is 200 to 800 rpm, preferably 400 to 600 rpm, more preferably 500 rpm, and the stirring time is 5 to 30 min, preferably 10 minutes.

[0064] Step 2: Add methylating agent to the container and heat the reaction

[0065] In the present invention, DMS is used as a methylating agent to methylate BCD in an alkaline aqueous solution of barium hydroxide at 25° C. Selecting DMS as a methylating agent allows the methylation reaction to be carried out using water as a solvent. Dimethyl carbonate cannot achieve a degree of substitution of 10, and methyl iodide is obviously too expensive. DMS is the cheapest methylating agent. In summary, selecting DMS as a methylating agent to obtain MBCD with a degree of substitution of about 10 is of great significance to the industrialization of 10MBCD.

[0066] According to the present invention, step 2 comprises:

[0067] Step 2.1, adding a methylating agent in batches, stirring for 5 to 30 minutes, preferably stirring for 10 minutes; the methylating agent is DMS, and the molar ratio of BCD to the methylating agent is 1: (5 to 18), preferably 1: 12;

[0068] Step 2.2, heat to 60°C and continue stirring.

[0069] Preferably, in step 2.1, the methylating agent is added in batches, preferably slowly, for example, by dropwise addition, or the methylating agent is added at a speed of 0.1 to 0.5 ml / min, preferably 0.2 ml / min. During industrial scale-up production, the addition speed can be adjusted according to actual conditions;

[0070] The dripping method is implemented by using a dripping device or equipment in the prior art. For example, in industrial production, a dripping tank can be used.

[0071] Excess or insufficient amount of the methylating agent DMS will affect the average degree of substitution (MS) of the final product (MBCD). Therefore, the molar ratio of DMS to BCD within the above range can obtain a product with an average degree of substitution of 10 (±2).

[0072] Preferably, in step 2.2, after the methylating agent is added, the mixture is stirred for 0.5 to 2 h, preferably for 1 h, and then the reaction system is heated to 60° C. and stirred overnight, preferably for 8 to 24 h, more preferably for 18 h.

[0073] Step 3: Monitor the reaction progress, filter, and take the filtrate

[0074] In the present invention, the sulfuric acid produced by the reaction and the barium hydroxide generate a water-insoluble barium sulfate precipitate, and the originally water-insoluble BCD is converted into water-soluble 10MBCD after the methylation reaction.

[0075] Step 3 includes:

[0076] Step 3.1, measuring the pH value to 2-5, preferably the pH value is 3;

[0077] Step 3.2, filter to obtain an aqueous solution.

[0078] Preferably, in step 3.1, the methylating agent DMS is in excess, and sulfuric acid byproduct produced by thermal decomposition is bound to exist in the system.

[0079] Step 4: Evaporate the filtrate from step 3 to remove solvent

[0080] In the present invention, MBCD has a strong inclusion property and is easy to include reaction impurities and unreacted BCD, and is not easy to dry, so the filtered mother liquor needs to be rotary evaporated to a nearly saturated state.

[0081] Step 4 includes:

[0082] Preferably, the volume-to-weight ratio of evaporating and concentrating the aqueous solution to BCD is 1 part by volume: (2-5) parts by weight, more preferably 1 part by volume: 3 parts by weight, wherein 1 part by volume is 1 ml and 1 part by weight is 1 g.

[0083] Step 5: Add ethanol to the concentrate of step 4 to obtain a white suspension, filter the acidic waste liquid, and take the filter cake.

[0084] In the present invention, ethanol is added to the concentrate in step 4 to desolventize the concentrate and precipitate a white solid mixture, which makes it easier to transfer the material from a container such as a reactor, thereby improving the yield.

[0085] Preferably, step 5 comprises:

[0086] Add ethanol solvent for crystallization and filter to obtain a white solid powder mixture. Preferably, the volume weight ratio of ethanol solvent to concentrated solution is 5 parts by volume: 1 part by weight, wherein 1 part by volume is 1 ml and 1 part by weight is 1 g.

[0087] Step 6: Add water to the filter cake of step 5 to dissolve it to obtain a white suspension, filter the waste residue and take the filtrate.

[0088] In the present invention, only part of the by-products sulfuric acid and barium sulfate are removed from the crude product obtained in step 5, and pure MBCD cannot be obtained. Due to the good water solubility of MBCD, it can be further removed by re-dissolving and filtering.

[0089] Preferably, step 6 comprises: taking an appropriate amount of the white solid mixture obtained in step 5, adding water to dissolve; preferably, the volume weight ratio of the aqueous solution to the white solid is (2 to 20) parts by volume: 1 part by weight, more preferably 10 parts by volume: 1 part by weight, wherein 1 part by volume is 1 ml and 1 part by weight is 1 g.

[0090] Step 7: evaporate the filtrate from step 6 to remove the solvent to obtain a concentrate.

[0091] In the present invention, the concentrate obtained in step 6 is pure enough and can be directly further dried and crystallized to obtain the product.

[0092] Preferably, step 7 comprises: concentrating and evaporating the aqueous solution obtained in step 6 to remove water, preferably evaporating it to a solid state as much as possible.

[0093] Step 8: Dry the concentrate of step 7 to obtain the target product methyl-β-cyclodextrin.

[0094] Step 8 obtains the final product, namely methyl-β-cyclodextrin, which is a white powdery solid.

[0095] The concentrate obtained in step 7 is dried to obtain methyl-β-cyclodextrin as a white solid powder.

[0096] Preferably, the drying process is carried out under vacuum, preferably in a vacuum drying oven, such as a double cone rotary vacuum drying oven. Preferably, the drying process temperature is 40 to 80° C., preferably 55° C., and the drying process time is 10 to 14 hours, preferably 12 hours.

[0097] 2. Embodiment

[0098] Add 300 ml of water to a 1L three-necked flask equipped with a mechanical stirrer, a thermometer, and a constant pressure dropping funnel. Add 24.5 g of barium hydroxide in batches while stirring. Exotherm is evident. Cool to room temperature.

[0099] Add 30 g of BCD and stir thoroughly until it is completely dissolved. Cool the temperature of the obtained clear solution to 25°C and slowly add 18.5 g of DMS dropwise over 10 min. After the addition is complete, continue stirring at 25°C for 1 h. Raise the temperature of the reaction system to 60°C and stir overnight. After monitoring the disappearance of the reaction raw materials, filter the obtained solution with a Buchner funnel to obtain a filtrate.

[0100] The filtrate was swirled to a nearly saturated state, and 70 ml of ethanol was added. A white suspension was obtained under stirring and beating. 24.9 g of a white powdery solid was obtained by filtration. The mixture was redissolved and filtered, and the evaporation and concentration steps were repeated. Finally, the mixture was dried at 55°C for 12 h to obtain 21.2 g of the product. The yield was 60.2%, and the degree of methylation was about 10 (±2).

[0101] The methyl-β-cyclodextrin prepared in the example was subjected to TLC analysis simultaneously with β-cyclodextrin and methyl-β-cyclodextrin with an average methylation substitution degree of 14. The results are as follows: Figure 3 As shown: the displacement value of β-cyclodextrin (point 1) is 0 to 0.2, the displacement value of methyl-β-cyclodextrin (point 2) with an average methylation substitution degree of 10 (±2) is about 0.7 to 0.9, and the displacement value of methyl-β-cyclodextrin with an average methylation substitution degree of 14 (point 3) is 0.9 to 1.0.

[0102] The three were tested by 1HNMR spectrum at the same time, and the results were as follows Figure 4 As shown, there are obvious differences in the characteristic peaks of the three.

[0103] 3. Comparative Examples

[0104] Add 800 ml of water to a 2L three-necked flask equipped with a mechanical stirrer, a thermometer, and a constant pressure dropping funnel, and add 141 g of sodium hydroxide in batches while stirring. Exotherm is obvious, and the mixture is cooled to room temperature.

[0105] Add 200 g of BCD and stir thoroughly until it is completely dissolved. Cool the obtained clear solution to 0°C and slowly add 333.38 g of DMS dropwise in 24 batches over 24 hours. After the addition is complete, continue stirring at 0°C for 1 hour. Warm the reaction system to room temperature and stir overnight. Add 25% ammonia water to quench the reaction and continue stirring for 2 hours.

[0106] The resulting solution was adjusted to pH 3.5 with 2M sulfuric acid solution and transferred to a separatory funnel. It was extracted with 300ml*2 chloroform, dried with anhydrous sodium sulfate, and filtered;

[0107] The mother liquor was vortexed to a nearly saturated state, 300 ml of n-hexane was added under stirring, and 130 g of a white powdery solid was obtained by suction filtration. The solid was then transferred to a vacuum drying oven and dried at 85° C. for 12 h to obtain 106.2 g of the product with a yield of 46.2%.

[0108] The above shows and describes the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The above embodiments and descriptions are only for explaining the principles of the present invention. The present invention may be subject to various changes and improvements without departing from the spirit and scope of the present invention. These changes and improvements fall within the scope of the present invention. The scope of protection of the present invention is defined by the attached claims and their equivalents.

Claims

1. A method for preparing methyl-β-cyclodextrin, characterized in that: The steps include: (1) adding BCD to a container containing an aqueous solution of barium hydroxide to obtain a mixed solution, and cooling the obtained mixed solution to 5 to 30° C., wherein the molar ratio of BCD to barium hydroxide is 1:5 to 15; (2) slowly adding the methylating agent to the container in batches according to a molar ratio of BCD to the methylating agent of 1:5 to 18, stirring while adding, and then heating to 60° C. and reacting under stirring; (3) adjusting the pH of the reaction system to 2-5 and monitoring the progress of the reaction. After the reaction is completed, filtering and collecting the filtrate; (4) evaporating the filtrate to remove the solvent and concentrating the filtrate to a nearly saturated state; (5) adding a crystallizing agent to the concentrate of step (4) to obtain a white suspension, filtering the acidic waste liquid, and taking a filter cake; the filter cake is dissolved in water and then filtered to remove impurities, and after the solvent in the filtrate is evaporated, the concentrate is dried to obtain the target product methyl-β-cyclodextrin.

2. The method for preparing methyl-β-cyclodextrin according to claim 1, characterized in that: in, In step (1), the barium hydroxide aqueous solution is prepared by adding barium hydroxide in batches, and BCD is added after the barium hydroxide aqueous solution is cooled to 20-30° C.; The molar ratio of BCD to barium hydroxide is 1:6, and the mass ratio of BCD to water is 1:5-50; when the solution is prepared, the stirring speed is 300-800 rpm, and the stirring time is 5-30 minutes.

3. The method for preparing methyl-β-cyclodextrin according to claim 1, characterized in that: in, In step (2), the methylating agent is selected from DMS, the molar ratio of BCD to the methylating agent is 1:12, and the addition rate of the methylating agent is 0.1-0.5 ml / min; During the addition of the methylating agent, stir for 5 to 30 minutes after each addition; after the addition of the methylating agent is completed, stir for 0.5 to 2 hours, then heat the reaction system to 60° C. and stir for 8 to 24 hours to react.

4. The method for preparing methyl-β-cyclodextrin according to claim 1, characterized in that: in, In step (3), DMS is added to adjust the pH of the reaction system to 3, and the progress of the reaction is monitored. After the reaction is completed, the generated barium sulfate precipitate is filtered out and the filtrate is collected.

5. The method for preparing methyl-β-cyclodextrin according to claim 1, characterized in that: in, In step (3), the method for monitoring the progress of the reaction is as follows: using thin layer chromatography (TLC) to monitor the degree of reaction, using methanol and dichloromethane as developing agents, a mixture of sulfuric acid and ethanol in a volume ratio of 1:2 as a color developer, and baking the plate in an electric furnace at 200-400° C. for 30 seconds to develop color.

6. The method for preparing methyl-β-cyclodextrin according to claim 1, characterized in that: in, In step (4), the filtrate is concentrated to a volume weight ratio of BCD of 1 part by volume: 2 to 5 parts by weight.

7. The method for preparing methyl-β-cyclodextrin according to claim 1, characterized in that: in, In step (4), the filtrate is concentrated to a volume weight ratio of BCD of 1 part by volume: 3 parts by weight.

8. The method for preparing methyl-β-cyclodextrin according to claim 1, characterized in that: in, In step (5), the crystallizing agent is selected from ethanol, and the volume weight ratio of the ethanol solvent to the concentrated solution is 5 parts by volume: 1 part by weight; the volume weight ratio of the aqueous solution to the white filter cake solid is (2-20) parts by volume: 1 part by weight; The conditions for drying the concentrate are as follows: the drying temperature is 40 to 80° C., and the drying time is 10 to 14 hours.

9. A methyl-β-cyclodextrin, characterized in that The method is used to prepare the product according to any one of claims 1 to 8.

10. The methyl-β-cyclodextrin according to claim 9, characterized in that The methyl-β-cyclodextrin has a methylation substitution degree of 8-12.

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