WO2015103895A1 - 一种制备磺丁基醚-β-环糊精的方法 - Google Patents

一种制备磺丁基醚-β-环糊精的方法 Download PDF

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WO2015103895A1
WO2015103895A1 PCT/CN2014/088579 CN2014088579W WO2015103895A1 WO 2015103895 A1 WO2015103895 A1 WO 2015103895A1 CN 2014088579 W CN2014088579 W CN 2014088579W WO 2015103895 A1 WO2015103895 A1 WO 2015103895A1
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cyclodextrin
activated carbon
sulfobutylether
sodium hydroxide
product
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PCT/CN2014/088579
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English (en)
French (fr)
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洪浩
李常峰
申理滔
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凯莱英医药集团（天津）股份有限公司
凯莱英生命科学技术(天津)有限公司
天津凯莱英制药有限公司
凯莱英医药化学（阜新）技术有限公司
吉林凯莱英医药化学有限公司
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Priority to US15/108,495 priority Critical patent/US10246524B2/en
Publication of WO2015103895A1 publication Critical patent/WO2015103895A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
    • C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/16—Cyclodextrin; Derivatives thereof

Definitions

  • the present invention relates to the field of organic synthetic pharmaceutical excipients, and more particularly to a process for preparing sulfobutylether- ⁇ -cyclodextrin.
  • SBE- ⁇ -CD chemical name: sulfobutyl ether- ⁇ -cyclodextrin
  • SBE- ⁇ -CD chemical name: sulfobutyl ether- ⁇ -cyclodextrin
  • sulfobutyl ether- ⁇ -cyclodextrin is a new pharmaceutical preparation auxiliary, belonging to a sulfonic acid derivative of anionic high water-soluble cyclodextrin. It can well form a non-covalent complex with drug molecules, improve the stability, water solubility, safety of the drug and effectively improve the biological activity of the drug molecule; it has low nephrotoxicity and can alleviate drug hemolysis. Sex, control the rate of drug release. At present, it has been commercialized and applied to injectable drugs, oral drugs, nasal medicines, eye medications, etc., and has special affinity and inclusion for nitrogen-containing drugs.
  • the existing synthesis method of sulfobutylether- ⁇ -cyclodextrin mainly utilizes the substitution reaction of the hydroxyl group at the 2, 3, and 6 carbons of the ⁇ -cyclodextrin glucose unit with the sulfolactone in an alkaline aqueous solution or
  • the ⁇ -cyclodextrin is obtained by substituting sodium sulfonate with sodium sulfonate in an organic solvent to obtain a hydroxyl proton:
  • US Patent No. 5,134,127 first uses ⁇ -cyclodextrin and 1,4-sulfolactone to react in aqueous sodium hydroxide solution, deionization, ultrafiltration, and freeze-drying to obtain a sulfobutyl group having a degree of substitution of 7.0 to 7.1. Ether- ⁇ -cyclodextrin pure product. Later, U.S. Patent No. 6,153,746 refers to this method.
  • Chinese patent CN1858071A uses ⁇ -cyclodextrin to take a hydroxyl proton from sodium in 1,4-dioxane and then undergoes a substitution reaction with 1,4-sulfobutyrol. After the reaction is completed, the product is filtered, and further methanol is used. After washing, the crude product was dissolved in water, purified by desalting using a glucose gel column (G-25), and the solution was concentrated and lyophilized to obtain a sulfobutylether- ⁇ -cyclodextrin product.
  • the disadvantage of this method is that the use of the more dangerous metal sodium as a reagent, purification using an expensive glucose gel column, the yield of the obtained sulfobutyl ether- ⁇ -cyclodextrin product is 49 to 51%.
  • the method overcomes the deficiencies of the prior art, and increases the amount of ⁇ -cyclodextrin (Compound 1) and 1,4-sulfolactone (Compound 2) by introducing an appropriate amount of organic solvent into an alkaline aqueous solution.
  • the solubility of 1,4-sulfolactone increases the synthesis yield of sulfobutylether- ⁇ -cyclodextrin; the obtained product solution is subjected to ultrasonic dialysis, activated carbon decolorization, freeze-drying, etc.
  • the method has stable process, mild reaction condition, good selectivity, simple post-treatment operation, high purity and yield of the obtained product, and provides a new idea for large-scale production of sulfobutylether- ⁇ -cyclodextrin. And methods.
  • step (2) Purification process: temperature control 20-30 ° C, the reaction mixture obtained in step (1) is added to the dialysis bag, ultrasonic dialysis to detect chloride ion content ⁇ 10ppm; the obtained dialysate is treated with activated carbon, and the product is detected to ultraviolet Absorbing ⁇ 0.5 AU, washing the activated carbon twice with a volume ratio of 1 to 2 Vol/g of the raw material ⁇ -cyclodextrin, washing the filtrate and then carrying out the next operation; combining the filtrate with 0.65-0.22 um precision filtration After concentration, the concentration was determined to be 30 to 35% by weight of the total weight of the solution of sulfobutylether- ⁇ -cyclodextrin, and lyophilized to obtain sulfobutylether- ⁇ -cyclodextrin, and the sulfonate was detected by capillary electrophoresis. The average degree of substitution of the ether- ⁇ -cyclodextrin was 6.7.
  • the ⁇ -cyclodextrin is a product obtained by crystallizing the commercial ⁇ -cyclodextrin 2 to 3 times in hot water of 90 to 100 degrees.
  • the organic solvent is at least one of tetrahydrofuran, 1,4-dioxane or 2-methyltetrahydrofuran.
  • the ratio of the organic solvent to the ⁇ -cyclodextrin is 0.02 to 0.20 ml/g, and the ratio of the sodium hydroxide to the ⁇ -cyclodextrin in the aqueous sodium hydroxide solution is 7.0 molar equivalent.
  • the ratio of 1,4-sulfolactone to ⁇ -cyclodextrin is 8.0 molar equivalent, and the ratio of sodium hydroxide to ⁇ -cyclodextrin in the aqueous sodium hydroxide solution used to adjust the pH of the system is 3.5 moles. equivalent.
  • the molecular weight cut off of the dialysis bag is 1000; the ratio of the activated carbon to the ⁇ -cyclodextrin is 0.05-0.2 g/g; the ratio of the deionized water and the ⁇ -cyclodextrin used for washing the activated carbon It is 1 to 2 ml/g.
  • step (2) if the ultraviolet absorption value of the activated carbon treated product is still greater than or equal to 0.5 AU, the product is again subjected to activated carbon treatment.
  • a process for producing a sulfobutylether- ⁇ -cyclodextrin comprising: mixing an ether solvent and an aqueous sodium hydroxide solution to form a first mixed liquid; After the liquid is heated to 60-70 ° C, it is mixed with ⁇ -cyclodextrin to form a second mixed liquid; the second mixed liquid is heated to 70-75 ° C and mixed with 1,4-sulfolactone to form a reaction system; The reaction system is stirred at 70-75 ° C and the pH of the reaction system is controlled to be greater than 9.
  • the reaction system is cooled to 20-25. °C, and adjust the pH of the reaction system to between 7.0 and 7.5 to obtain a product system containing sulfobutylether- ⁇ -cyclodextrin; the product system is purified to obtain sulfobutylether- ⁇ -cyclodextrin .
  • the concentration of the aqueous sodium hydroxide solution is 3.7 N; the above method uses a sodium hydroxide aqueous solution having a concentration of 3.7 N to control the pH of the reaction system to be greater than 9; the above method uses concentrated hydrochloric acid to adjust the pH of the reaction system to 7.0 Between 7.5.
  • the ratio of the above ether solvent to ⁇ -cyclodextrin is 0.02 to 0.20 ml/g; and the molar equivalent ratio of sodium hydroxide to ⁇ -cyclodextrin in the aqueous solution of sodium hydroxide in the first mixture is 6.0 to 8.0, preferably 7.0; the molar equivalent ratio of 1,4-sulfolactone to ⁇ -cyclodextrin is 7.0 to 9.0, preferably 8.0; the above-mentioned sodium hydroxide aqueous solution used to control the pH of the reaction system
  • the molar equivalent ratio of sodium hydroxide to ⁇ -cyclodextrin is from 3.0 to 4.0, preferably 3.5.
  • ⁇ -cyclodextrin is a product obtained by crystallizing commercial ⁇ -cyclodextrin in hot water at 90 to 100 ° C for 1 to 3 times.
  • the ether solvent is one or more selected from the group consisting of tetrahydrofuran, 1,4-dioxane or 2-methyltetrahydrofuran.
  • the above purification process of the product system comprises: dialysis the product system to a product system with a chloride ion content of ⁇ 10 ppm at 20-30 ° C to obtain a first purification system; and the first purification system is treated with activated carbon.
  • the system was lyophilized to give sulfobutylether- ⁇ -cyclodextrin.
  • the above process for treating the first purification system by using activated carbon comprises: mixing activated carbon and the first purification system, filtering to obtain adsorbed activated carbon and a filtrate; washing the adsorbed activated carbon to obtain a washing liquid; mixing the washing liquid and the filtrate to obtain a first Two purification systems.
  • the ratio of activated carbon to ⁇ -cyclodextrin is 0.05-0.2 g/g; the activated carbon is washed with deionized water, and the ratio of deionized water to ⁇ -cyclodextrin is 1-2 ml. /g.
  • the above process of treating the first purification system with activated carbon can be repeated until the UV absorption of the product recovered from the filtrate is ⁇ 0.5 AU.
  • the second purification system is subjected to filtration concentration using a precision filter having a filter element accuracy of 0.65 to 0.22 ⁇ m.
  • the advantages of the invention 1, ⁇ -cyclodextrin and 1,4-sulfolactone as raw materials, by adding an appropriate amount of organic solvent into the alkaline aqueous solution, increasing the solubility of 1,4-sulfobutyrol, greatly
  • the synthetic yield of sulfobutylether- ⁇ -cyclodextrin is improved.
  • the method has stable process, mild reaction condition, simple post-treatment and easy operation, and the yield of the obtained product is high, and the yield is 75%-80%, which is suitable for industrial production.
  • Figure 1 is a graph showing the chemical reaction process of a process for producing sulfobutylether- ⁇ -cyclodextrin (SBE- ⁇ -CD) according to the present invention.
  • a process for preparing a sulfobutylether- ⁇ -cyclodextrin comprising: mixing an ether solvent and an aqueous sodium hydroxide solution to form a first mixed solution; The first mixed liquid is heated to 60-70 ° C and mixed with ⁇ -cyclodextrin to form a second mixed liquid; the second mixed liquid is heated to 70-75 ° C and mixed with 1,4-sulfolactone to form a reaction system.
  • the reaction system is stirred at 70-75 ° C and the pH of the reaction system is controlled to be greater than 9, and when the remaining amount of ⁇ -cyclodextrin is less than 0.5% by weight of the ⁇ cyclodextrin input, the reaction system is cooled to 20 ⁇ 25 ° C, and the pH of the reaction system is adjusted to between 7.0 and 7.5 to obtain a product system containing sulfobutyl ether- ⁇ -cyclodextrin; the product system is purified to obtain a sulfobutyl ether- ⁇ -ring dextrin.
  • the above method uses ⁇ -cyclodextrin and 1,4-sulfobutyrolactone as raw materials, and increases the solubility of 1,4-sulfobutyrol by adding an appropriate amount of ether solvent to the aqueous sodium hydroxide solution, increasing by 1,
  • the contact chance of 4-sulfobutyrolactone with ⁇ -cyclodextrin greatly improves the synthesis yield of sulfobutylether- ⁇ -cyclodextrin and can control the degree of substitution of the product within the desired range;
  • the solvent-like solvent replaces part of the aqueous sodium hydroxide solution, thereby reducing the content of strong alkaline substances in the aqueous solution of sodium hydroxide in the reaction system, which greatly reduces the amount of by-product formation and improves the sulfobutylether- ⁇ -
  • the yield of the cyclodextrin at the same time, the above method is stable in process, mild in reaction conditions, simple in post-treatment, easy
  • the concentration of the aqueous sodium hydroxide solution is 3.7N; the above method uses a sodium hydroxide aqueous solution having a concentration of 3.7N to control the pH of the reaction system to be greater than 9, preferably the pH is 9-9. 10; further, the above method uses concentrated hydrochloric acid to adjust the pH of the reaction system to between 7.0 and 7.5, concentrated salt The acid is easily separated from the organic matter in the product system in the subsequent purification treatment, thereby contributing to the improvement of the yield of sulfobutylether- ⁇ -cyclodextrin.
  • the ratio of the ether solvent to the ⁇ -cyclodextrin is preferably 0.02 to 0.20 ml/g; sodium hydroxide and ⁇ in the aqueous sodium hydroxide solution in the first mixture - the molar equivalent ratio of the cyclodextrin is 6.0 to 8.0, preferably 7.0; the molar equivalent ratio of 1,4-sulfolactone to ⁇ -cyclodextrin is 7.0 to 9.0, preferably 8.0; controlling the pH of the reaction system
  • the molar equivalent ratio of sodium hydroxide to ⁇ -cyclodextrin in the aqueous sodium hydroxide solution used is 3.0 to 4.0, preferably 3.5.
  • the ⁇ -cyclodextrin is preferably a commercial ⁇ -cyclodextrin in a hot water of 90-100° C.
  • the product obtained after crystallization 1 to 3 times further increases the purity of ⁇ -cyclodextrin by the above crystallization method.
  • the above ether solvent is used to increase the solubility of 1,4-sulfolactone, and therefore an ether solvent having a strong solubility for 1,4-sulfobutyrol can be considered for use in the present application.
  • the ether solvent is one of the group consisting of tetrahydrofuran, 1,4-dioxane or 2-methyltetrahydrofuran. Or a variety.
  • the purification of sulfobutylether- ⁇ -cyclodextrin in the product system can be referred to the existing purification method, and the present invention further ensures the product.
  • the sulfobutylether- ⁇ -cyclodextrin in the system is proposed as much as possible.
  • the above purification process of the product system comprises: dialysis of the product system at 20-30 ° C until the chloride ion content of the product system is ⁇ 10 ppm, the first purification system is obtained; the first purification system is treated with activated carbon to remove possible unknown impurities derived from ⁇ -cyclodextrin or the product sulfobutylether- ⁇ -cyclodextrin to obtain a second purification system; The second purification system is concentrated by filtration, and the sulfobutylether- ⁇ -cyclodextrin content is 30-35 wt% of the total weight of the second purification system to obtain a third purification system; the third purification system is freeze-dried to obtain sulfonate.
  • Butyl ether- ⁇ -cyclodextrin After the above product system is purified as described above, it is possible to separate sufficiently sulfobutylether- ⁇ -cyclodextrin such as by-products and impurities to increase the yield of sulfobutylether- ⁇ -cyclodextrin.
  • the above purification process utilizes a dialysis bag having a molecular weight cutoff of 1000 for dialysis to separate macromolecular species from the product system.
  • the process of treating the first purification system with activated carbon comprises: mixing activated carbon and the first purification system and filtering to obtain adsorbed activated carbon and filtrate; washing the activated carbon to obtain a washing liquid; mixing the washing liquid and the filtrate to obtain Second purification system.
  • the above activated carbon and the first purification system are mixed to adsorb unreacted raw materials and impurities in the first purification system by using activated carbon, and the process can be repeated until the ultraviolet absorption of the product recovered from the filtrate is ⁇ 0.5 AU to improve the purity of the final product. .
  • the ratio of the above activated carbon to ⁇ -cyclodextrin is 0.05 to 0.2 g/g; and in order to separate as much as possible the sulfobutylether- ⁇ remaining in the activated carbon.
  • - cyclodextrin preferably washed with deionized water, the ratio of deionized water to ⁇ -cyclodextrin is 1 to 2 ml / g.
  • the second purification system is preferably subjected to filtration and concentration using a precision filter having a filter element accuracy of 0.65 to 0.22 ⁇ m.
  • a precision filter having a filter element accuracy of 0.65 to 0.22 ⁇ m.
  • Example 1 A method for preparing sulfobutylether- ⁇ -cyclodextrin (SBE- ⁇ -CD), characterized in that the specific preparation steps are as follows:
  • Example 2 A method for preparing sulfobutylether- ⁇ -cyclodextrin (SBE- ⁇ -CD), characterized in that the specific preparation steps are as follows:
  • the pH of the system was controlled by using aqueous sodium hydroxide solution (3.7 N, total 30.9 mmol); the HPLC traced to the remaining ⁇ 0.5% wt of ⁇ -cyclodextrin, dropped to 20-25 ° C, and then used.
  • the concentrated hydrochloric acid was adjusted to pH 7.0-7.5, and the obtained reaction mixture was directly used for the next purification operation.
  • Example 3 A method for preparing sulfobutylether- ⁇ -cyclodextrin (SBE- ⁇ -CD), characterized in that the specific preparation steps are as follows:
  • the pH of the system was controlled by using aqueous sodium hydroxide solution (3.7 N, total 30.9 mmol); the HPLC traced to the remaining ⁇ 0.5% wt of ⁇ -cyclodextrin, and dropped to 20-25 ° C.
  • the system was then adjusted to pH 7.0-7.5 using concentrated hydrochloric acid and the resulting reaction mixture was used directly in the next purification.
  • the ⁇ -cyclodextrin was treated by crystallizing the ⁇ -cyclodextrin having a content of 99.8% in hot water at 90 to 100 ° C to obtain ⁇ -cyclodextrin used in the present example.
  • Synthesis reaction temperature control 20-30 ° C, 2-methyltetrahydrofuran (2 ml) and aqueous sodium hydroxide solution (3.7 N, 61.7 mmol) were added to the reaction flask, and the temperature was raised to 60-70 ° C to obtain ⁇ -cyclodextrin ( 10 g, 8.8 mmol) was added to the reaction flask; 1,4-sulfolactone (19.2 g, 71 mmol) was added dropwise to the above system at 70-75 ° C, and the system was stirred at 70-75 ° C for 1 hour after the dropwise addition. The pH of the internal system decreased more obviously.
  • the pH of the system was controlled by using aqueous sodium hydroxide solution (3.7N, total 30.9mmol); the HPLC traced to the remaining ⁇ 0.5%wt of ⁇ -cyclodextrin, dropped to 20-25 °C, and then the concentration was used.
  • the pH of the concentrated hydrochloric acid system of 8.8 N was between 7.0 and 7.5 to obtain a product system.
  • UV absorption ⁇ 0.5AU (if the UV absorption is not in this range, repeat the operation once), wash the activated carbon twice with 20ml of deionized water, wash the filtrate and then carry out the next operation; after the filtrate is passed through the 0.65-0.22 ⁇ m precision filter
  • the mixture was concentrated to a sulfobutylether- ⁇ -cyclodextrin content of 30 to 35% by weight, and lyophilized to obtain 13.7 g of sulfobutylether- ⁇ -cyclodextrin in a yield of 72%.
  • the average degree of substitution of sulfobutylether- ⁇ -cyclodextrin was 6.7 by capillary electrophoresis.
  • ⁇ -cyclodextrin having a content of 98% was crystallized three times in hot water at 90 to 100 ° C to obtain ⁇ -cyclodextrin used in the present example.
  • Synthesis reaction temperature control 20 ⁇ 30 ° C, the reaction flask was added tetrahydrofuran (1ml) and aqueous sodium hydroxide (concentration of 3.7N, wherein the total number of moles of sodium hydroxide used is 61.7mmol) to form a first mixture; After the first mixed solution was heated to 60 to 70 ° C, ⁇ -cyclodextrin (10 g, 8.8 mmol) was added to the reaction flask to form a second mixed solution; after the second mixture was heated to 70 to 75 ° C, To the above system, 1,4-sulfolactone (9.6 g, 71 mmol) was added dropwise to form a reaction system, and the reaction was carried out at 70 to 75 ° C with stirring, and an aqueous sodium hydroxide solution (concentration: 3.7 N) was used.
  • control reaction system 9 ⁇ pH ⁇ 10; using HPLC to trace the remaining ⁇ -cyclodextrin in the reaction system to ⁇ 20 wt%, the temperature is lowered to 20 to 25 ° C, and then The pH of the system was adjusted to a pH between 7.0 and 7.5 using concentrated hydrochloric acid at a concentration of 8.0 N to obtain a product system.
  • Purification process temperature control 20 ⁇ 30 ° C, the above product system solution was added to a dialysis bag with a molecular weight cut off of 1000, and ultrasonic dialysis in deionized water to detect chloride ion content ⁇ 10ppm, the first purification system was obtained;
  • the first purification system is filtered through activated carbon (1g) to obtain filtrate and adsorbed activated carbon, and a part of the filtrate is freeze-dried to obtain a solid product.
  • the ultraviolet absorption of the solid product is detected to be ⁇ 0.5 AU, and then the activated carbon is washed twice with deionized water to obtain twice the adsorbed activated carbon.
  • the washing liquid and the washing liquid are combined to obtain a second purification system; the second purification system is obtained by using a precision filter with a filter core precision of 0.65-0.22 ⁇ m to obtain a third purification system, and the third purification system is concentrated to detect sulfobutyl ether- ⁇ .
  • the cyclodextrin content was 30 to 35 wt%, and lyophilized to obtain 14.9 g of sulfobutylether- ⁇ -cyclodextrin in a yield of 78%.
  • the average degree of substitution of sulfobutylether- ⁇ -cyclodextrin was 6.7 by capillary electrophoresis.
  • ⁇ -cyclodextrin having a content of 98% was crystallized three times in hot water at 90 to 100 ° C to obtain ⁇ -cyclodextrin used in the present example.
  • Synthesis reaction temperature control 20 ⁇ 30 ° C, the reaction flask was added tetrahydrofuran (1ml) and aqueous sodium hydroxide (concentration of 3.8N, the total number of moles of sodium hydroxide used is 67.3mmol) to form a first mixture; After the first mixed solution was heated to 60 to 70 ° C, ⁇ -cyclodextrin (10 g, 8.8 mmol) was added to the reaction flask to form a second mixed solution; after the second mixture was heated to 70 to 75 ° C, To the above system, 1,4-sulfolactone (20.2 g, 74.8 mmol) was added dropwise to form a reaction system, and the reaction was carried out at 70 to 75 ° C with stirring, and an aqueous sodium hydroxide solution (concentration of 3.8) was used.
  • a concentrated hydrochloric acid concentration system having a concentration of 8.5 N has a pH between 7.0 and 7.5 to obtain a product system.
  • Purification process temperature control 20 ⁇ 30 ° C, the above product system solution was added to a dialysis bag with a molecular weight cut off of 1000, and ultrasonic dialysis in deionized water to detect chloride ion content ⁇ 10ppm, the first purification system was obtained;
  • the first purification system is filtered through activated carbon (1g) to obtain filtrate and adsorbed activated carbon, and a part of the filtrate is freeze-dried to obtain a solid product.
  • the ultraviolet absorption of the solid product is detected to be ⁇ 0.5 AU, and then the activated carbon is washed twice with deionized water to obtain twice the adsorbed activated carbon.
  • the washing liquid and the washing liquid are combined to obtain a second purification system; the second purification system is obtained by using a precision filter with a filter core precision of 0.65-0.22 ⁇ m to obtain a third purification system, and the third purification system is concentrated to detect sulfobutyl ether- ⁇ .
  • the cyclodextrin content was 30 to 35 wt%, and lyophilized to obtain 15.3 g of sulfobutylether- ⁇ -cyclodextrin in a yield of 80%.
  • the average degree of substitution of sulfobutylether- ⁇ -cyclodextrin was 6.9 by capillary electrophoresis.
  • ⁇ -cyclodextrin having a content of 98% was crystallized three times in hot water at 90 to 100 ° C to obtain ⁇ -cyclodextrin used in the present example.
  • Synthesis reaction temperature control 20 ⁇ 30 ° C, the reaction flask was added tetrahydrofuran (1ml) and aqueous sodium hydroxide (concentration of 3.6N, the total number of moles of sodium hydroxide used is 57.4mmol) to form a first mixture; After the first mixed solution was heated to 60 to 70 ° C, ⁇ -cyclodextrin (10 g, 8.8 mmol) was added to the reaction flask to form a second mixed solution; after the second mixture was heated to 70 to 75 ° C, To the above system, 1,4-sulfolactone (17.9 g, 66 mmol) was added dropwise to form a reaction system, and the reaction was carried out at 70 to 75 ° C with stirring, and an aqueous sodium hydroxide solution (concentration: 4.2 N) was used.
  • aqueous sodium hydroxide solution concentration: 4.2 N
  • Purification process temperature control 20 ⁇ 30 ° C, the above product system solution was added to a dialysis bag with a molecular weight cut off of 1000, and ultrasonic dialysis in deionized water to detect chloride ion content ⁇ 10ppm, the first purification system was obtained; The first purification system is filtered through activated carbon (1g) to obtain a filtrate and adsorbed activated carbon, and a part of the filtrate is taken.
  • Freeze-drying to obtain a solid product detecting the ultraviolet absorption of the solid product ⁇ 0.5 AU, then washing the activated carbon twice with 15 ml of deionized water to obtain a washing liquid, and washing the filtrate to obtain a second purification system;
  • a precision filter of 0.65-0.22 ⁇ m is used to obtain a third purification system, and the third purification system is concentrated to detect a sulfobutylether- ⁇ -cyclodextrin content of 30 to 35 wt%, and freeze-dried to obtain a sulfobutylether- ⁇ -ring.
  • Dextrin 14.7 g, yield 77%.
  • the average degree of substitution of sulfobutylether- ⁇ -cyclodextrin was determined by capillary electrophoresis to be 6.5.
  • ⁇ -cyclodextrin having a content of 98% was crystallized three times in hot water at 90 to 100 ° C to obtain ⁇ -cyclodextrin used in the present example.
  • Synthesis reaction temperature control 20 ⁇ 30 ° C, the reaction flask was added tetrahydrofuran (1ml) and sodium hydroxide aqueous solution (concentration of 4.0N, the total number of moles of sodium hydroxide used is 53.5mmol) to form a first mixture; After the first mixed solution was heated to 60 to 70 ° C, ⁇ -cyclodextrin (10 g, 8.8 mmol) was added to the reaction flask to form a second mixed solution; after the second mixture was heated to 70 to 75 ° C, To the above system, 1,4-sulfolactone (16.7 g, 61.6 mmol) was added dropwise to form a reaction system, and the reaction was carried out at 70 to 75 ° C with stirring, and an aqueous sodium hydroxide solution (concentration of 3.7) was used.
  • Purification process temperature control 20 ⁇ 30 ° C, the above product system solution was added to a dialysis bag with a molecular weight cut off of 1000, and ultrasonic dialysis in deionized water to detect chloride ion content ⁇ 10ppm, the first purification system was obtained;
  • the first purification system is filtered through activated carbon (1g) to obtain filtrate and adsorbed activated carbon, and a part of the filtrate is freeze-dried to obtain a solid product.
  • the ultraviolet absorption of the solid product is detected to be ⁇ 0.5 AU, and then the activated carbon is washed twice with deionized water to obtain twice the adsorbed activated carbon.
  • the washing liquid and the washing liquid are combined to obtain a second purification system; the second purification system is obtained by using a precision filter with a filter core precision of 0.65-0.22 ⁇ m to obtain a third purification system, and the third purification system is concentrated to detect sulfobutyl ether- ⁇ .
  • the cyclodextrin content was 30 to 35 wt%, and lyophilized to obtain 14.9 g of sulfobutylether- ⁇ -cyclodextrin in a yield of 78%.
  • the average degree of substitution of sulfobutylether- ⁇ -cyclodextrin was determined by capillary electrophoresis to be 6.3.
  • ⁇ -cyclodextrin having a content of 98% was crystallized three times in hot water at 90 to 100 ° C to obtain ⁇ -cyclodextrin used in the present example.
  • Synthesis reaction temperature control 20 ⁇ 30 ° C, the reaction flask was added tetrahydrofuran (0.2 ml) and aqueous sodium hydroxide (concentration of 3.7N, the total number of moles of sodium hydroxide used was 61.7mmol) to form the first mixture ; After the first mixed solution was heated to 60 to 70 ° C, ⁇ -cyclodextrin (10 g, 8.8 mmol) was added to the reaction flask to form a second mixed solution; after the second mixture was heated to 70 to 75 ° C, To the above system, 1,4-sulfolactone (9.6 g, 71 mmol) was added dropwise to form a reaction system, and the reaction was carried out at 70 to 75 ° C with stirring, and an aqueous sodium hydroxide solution (concentration: 3.7 N) was used.
  • control reaction system 9 ⁇ pH ⁇ 10; using HPLC to trace the remaining ⁇ -cyclodextrin in the reaction system to ⁇ 20 wt%, the temperature is lowered to 20 to 25 ° C, and then The pH of the system was adjusted to a pH between 7.0 and 7.5 using concentrated hydrochloric acid at a concentration of 8.0 N to obtain a product system.
  • Purification process temperature control 20 ⁇ 30 ° C, the above product system solution was added to a dialysis bag with a molecular weight cut off of 1000, and ultrasonic dialysis in deionized water to detect chloride ion content ⁇ 10ppm, the first purification system was obtained;
  • the first purification system is filtered through activated carbon (1g) to obtain filtrate and adsorbed activated carbon, and a part of the filtrate is freeze-dried to obtain a solid product.
  • the ultraviolet absorption of the solid product is detected to be ⁇ 0.5 AU, and then the activated carbon is washed twice with deionized water to obtain twice the adsorbed activated carbon.
  • the washing liquid and the washing liquid are combined to obtain a second purification system; the second purification system is obtained by using a precision filter with a filter core precision of 0.65-0.22 ⁇ m to obtain a third purification system, and the third purification system is concentrated to detect sulfobutyl ether- ⁇ .
  • the cyclodextrin content was 30 to 35 wt%, and lyophilized to obtain 14.5 g of sulfobutylether- ⁇ -cyclodextrin in a yield of 76%.
  • the average degree of substitution of sulfobutylether- ⁇ -cyclodextrin was 6.7 by capillary electrophoresis.
  • ⁇ -cyclodextrin having a content of 98% was crystallized three times in hot water at 90 to 100 ° C to obtain ⁇ -cyclodextrin used in the present example.
  • Synthesis reaction temperature control 20 ⁇ 30 ° C, the reaction flask was added tetrahydrofuran (2ml) and aqueous sodium hydroxide (concentration of 3.7N, the total number of moles of sodium hydroxide used is 61.7mmol) to form a first mixture; After the first mixed solution was heated to 60 to 70 ° C, ⁇ -cyclodextrin (10 g, 8.8 mmol) was added to the reaction flask to form a second mixed solution; after the second mixture was heated to 70 to 75 ° C, To the above system, 1,4-sulfolactone (9.6 g, 71 mmol) was added dropwise to form a reaction system, and the reaction was carried out at 70 to 75 ° C with stirring, and an aqueous sodium hydroxide solution (concentration: 3.7 N) was used.
  • control reaction system 9 ⁇ pH ⁇ 10; using HPLC to trace the remaining ⁇ -cyclodextrin in the reaction system to ⁇ 20 wt%, the temperature is lowered to 20 to 25 ° C, and then The pH of the system was adjusted to a pH between 7.0 and 7.5 using concentrated hydrochloric acid at a concentration of 8.0 N to obtain a product system.
  • Purification process temperature control 20 ⁇ 30 ° C, the above product system solution was added to a dialysis bag with a molecular weight cut off of 1000, and ultrasonic dialysis in deionized water to detect chloride ion content ⁇ 10ppm, the first purification system was obtained;
  • the first purification system is filtered through activated carbon (1g) to obtain a filtrate and adsorbed activated carbon, and a part of the filtrate is freeze-dried to obtain a solid product, and the solid product is detected to have an ultraviolet absorption of ⁇ 0.5 AU, and then 15 ml of deionized water.
  • the adsorption activated carbon is washed twice to obtain a washing liquid, and the washing liquid is combined to obtain a second purification system; the second purification system is obtained by using a precision filter with a precision of 0.65-0.22 ⁇ m in the second purification system, and the third purification system is concentrated to detect
  • the sulfobutylether- ⁇ -cyclodextrin content was 30 to 35 wt%, and lyophilized to obtain 15.5 g of sulfobutylether- ⁇ -cyclodextrin in a yield of 81%.
  • the average degree of substitution of sulfobutylether- ⁇ -cyclodextrin was 6.7 by capillary electrophoresis.
  • ⁇ -cyclodextrin having a content of 98% was crystallized three times in hot water at 90 to 100 ° C to obtain ⁇ -cyclodextrin used in the present example.
  • Synthesis reaction temperature control 20 ⁇ 30 ° C, the reaction flask was added tetrahydrofuran (1ml) and aqueous sodium hydroxide (concentration of 3.7N, wherein the total number of moles of sodium hydroxide used is 61.7mmol) to form a first mixture; After the first mixed solution was heated to 60 to 70 ° C, ⁇ -cyclodextrin (10 g, 8.8 mmol) was added to the reaction flask to form a second mixed solution; after the second mixture was heated to 70 to 75 ° C, To the above system, 1,4-sulfolactone (9.6 g, 71 mmol) was added dropwise to form a reaction system, and the reaction was carried out at 70 to 75 ° C with stirring, and an aqueous sodium hydroxide solution (concentration: 3.7 N) was used.
  • control reaction system 9 ⁇ pH ⁇ 10; using HPLC to trace the remaining ⁇ -cyclodextrin in the reaction system to ⁇ 20 wt%, the temperature is lowered to 20 to 25 ° C, and then The pH of the system was adjusted to a pH between 7.0 and 7.5 using concentrated hydrochloric acid at a concentration of 8.0 N to obtain a product system.
  • the washing liquid is obtained, and the filtrate is combined to obtain a second purification system; the second purification system is obtained by using a precision filter with a precision of 0.65-0.22 ⁇ m in the second purification system, and the third purification system is concentrated to detect sulfobutyl ether-
  • the ⁇ -cyclodextrin content was 30 to 35 wt%, and lyophilized to obtain 14.1 g of sulfobutylether- ⁇ -cyclodextrin in a yield of 74%.
  • the average degree of substitution of sulfobutylether- ⁇ -cyclodextrin was 6.7 by capillary electrophoresis.
  • ⁇ -cyclodextrin having a content of 98% was crystallized three times in hot water at 90 to 100 ° C to obtain ⁇ -cyclodextrin used in the present example.
  • Synthesis reaction temperature control 20 ⁇ 30 ° C, the reaction flask was added tetrahydrofuran (2.5 ml) and aqueous sodium hydroxide (concentration of 3.7N, the total number of moles of sodium hydroxide used was 61.7mmol) to form the first mixture
  • ⁇ -cyclodextrin 10 g, 8.8 mmol
  • the second mixed liquid was formed; after the second mixture was heated to 70 to 75 ° C, 1,4-sulfolactone (9.6 g, 71 mmol) was added dropwise to the above system to form a reaction system, and the reaction system was at 70 °.
  • the reaction was carried out under stirring at 75 ° C, and the reaction system 9 was controlled to pH ⁇ 10 using an aqueous solution of sodium hydroxide (concentration: 3.7 N, wherein the number of moles of sodium hydroxide used was 30.9 mmol); When the remaining ⁇ -cyclodextrin was ⁇ 0.5 wt%, the temperature was lowered to 20 to 25 ° C, and then the pH of the system was adjusted to be between 7.0 and 7.5 using concentrated hydrochloric acid having a concentration of 8.0 N to obtain a product system.
  • Purification process temperature control 20 ⁇ 30 ° C, the above product system solution was added to a dialysis bag with a molecular weight cut off of 1000, and ultrasonic dialysis in deionized water to detect chloride ion content ⁇ 10ppm, the first purification system was obtained;
  • the first purification system is filtered through activated carbon (1g) to obtain filtrate and adsorbed activated carbon, and a part of the filtrate is freeze-dried to obtain a solid product.
  • the ultraviolet absorption of the solid product is detected to be ⁇ 0.5 AU, and then the activated carbon is washed twice with deionized water to obtain twice the adsorbed activated carbon.
  • the washing liquid and the washing liquid are combined to obtain a second purification system; the second purification system is obtained by using a precision filter with a filter core precision of 0.65-0.22 ⁇ m to obtain a third purification system, and the third purification system is concentrated to detect sulfobutyl ether- ⁇ .
  • the cyclodextrin content was 30 to 35 wt%, and lyophilized to obtain 14.5 g of sulfobutylether- ⁇ -cyclodextrin in a yield of 76%.
  • the average degree of substitution of sulfobutylether- ⁇ -cyclodextrin was 6.7 by capillary electrophoresis.
  • ⁇ -cyclodextrin having a content of 98% was crystallized three times in hot water at 90 to 100 ° C to obtain ⁇ -cyclodextrin used in the present example.
  • Synthesis reaction temperature control 20 ⁇ 30 ° C, the reaction flask was added tetrahydrofuran (1ml) and aqueous sodium hydroxide (concentration of 3.7N, wherein the total number of moles of sodium hydroxide used is 61.7mmol) to form a first mixture; After the first mixed solution was heated to 60 to 70 ° C, ⁇ -cyclodextrin (10 g, 8.8 mmol) was added to the reaction flask to form a second mixed solution; after the second mixture was heated to 70 to 75 ° C, To the above system, 1,4-sulfolactone (7.7 g, 57 mmol) was added dropwise to form a reaction system, and the reaction was carried out at 70 to 75 ° C with stirring, and an aqueous sodium hydroxide solution (concentration: 3.7 N) was used.
  • control reaction system 9 ⁇ pH ⁇ 10; followed by HPLC to reduce the temperature of the ⁇ -cyclodextrin remaining ⁇ 0.5 wt% to 20-25 ° C, and then The pH of the system was adjusted to a pH between 7.0 and 7.5 using concentrated hydrochloric acid at a concentration of 8.0 N to obtain a product system.
  • Purification process temperature control 20 ⁇ 30 ° C, the above product system solution was added to a dialysis bag with a molecular weight cut off of 1000, and ultrasonic dialysis in deionized water to detect chloride ion content ⁇ 10ppm, the first purification system was obtained;
  • the first purification system is filtered through activated carbon (1g) to obtain filtrate and adsorbed activated carbon, and a part of the filtrate is freeze-dried to obtain a solid product.
  • the ultraviolet absorption of the solid product is detected to be ⁇ 0.5 AU, and then the activated carbon is washed twice with deionized water to obtain twice the adsorbed activated carbon.
  • the washing liquid, the washing liquid and the filtrate are combined to obtain a second purification system; the second purification system is passed A precision filter with a filter accuracy of 0.65-0.22 ⁇ m obtains a third purification system, and the third purification system is concentrated to detect a sulfobutylether- ⁇ -cyclodextrin content of 30 to 35 wt%, and freeze-dried to obtain a sulfobutylether- ⁇ .
  • the average degree of substitution of sulfobutylether- ⁇ -cyclodextrin was 6.7 by capillary electrophoresis.
  • the average degree of substitution of the sulfobutylether- ⁇ -cyclodextrin obtained in each of the above examples can meet the requirements of the pharmacopoeia, and the sulfobutylether- ⁇ -cyclodextrin can be adjusted by adjusting the amount of the organic solvent and sodium hydroxide.
  • the yield of the above method is mild, easy to handle, and suitable for industrial large-scale use.
  • a method for synthesizing sulfobutylether- ⁇ -cyclodextrin disclosed in the present invention is carried out by introducing ⁇ -cyclodextrin and 1,4-sulfobutyrolactone into an alkaline aqueous solution.
  • Appropriate amount of organic solvent increases the solubility of 1,4-sulfolactone and increases the synthesis yield of sulfobutylether- ⁇ -cyclodextrin; the obtained product solution undergoes ultrasonic dialysis, decolorization of activated carbon, freeze-drying, etc.
  • Butyl ether- ⁇ -cyclodextrin powder product The invention has stable process, mild reaction condition, easy operation and high yield of the obtained product, and provides a new idea and method for large-scale production of sulfobutylether- ⁇ -cyclodextrin (SBE- ⁇ -CD).

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Abstract

本发明公开了一种制备磺丁基醚-β-环糊精的方法。该方法克服了现有技术存在的不足，以β-环糊精和1,4-磺丁内酯为原料，通过向碱性水溶液中引入适量有机溶剂，增加了1,4-磺丁内酯的溶解度，提高了磺丁基醚-β-环糊精的合成收率；所得产品溶液经过超声透析，活性炭脱色，冷冻干燥等操作得到磺丁基醚-β-环糊精粉末产品。该方法工艺稳定，反应条件温和，选择性好，且后处理操作简单，所得产品纯度及收率都很高，为规模化生产磺丁基醚-β-环糊精提供了一种新的思路和方法。

Description

一种制备磺丁基醚-β-环糊精的方法 技术领域
本发明涉及有机合成药物辅料领域，特别是一种制备磺丁基醚-β-环糊精的方法。
背景技术
Figure PCTCN2014088579-appb-000001
SBE-β-CD，化学名为：磺丁基醚-β-环糊精，是一种新型药物制剂辅料，属于阴离子型高水溶性环糊精的一种磺酸基衍生物。它能很好地与药物分子包合形成非共价复合物，提高了药物的稳定性、水溶性、安全性并且有效的提高了药物分子的生物活性；它的肾毒性小，能缓和药物溶血性，控制药物释放速率。目前它已经商业化，应用于注射药、口服药、鼻部用药、眼部用药等，对于含氮类药物具有特殊的亲和力和包合性。
由于合成方法单一，如何提高其收率并且找到一条适合规模化生产的方法是合成磺丁基醚-β-环糊精的关键。
现有的磺丁基醚-β-环糊精的合成方法主要利用β-环糊精葡萄糖单元的2,3,6位碳上的羟基与磺丁内酯在碱性水溶液中发生取代反应或者β-环糊精在有机溶剂中用钠夺取羟基质子后和磺丁内酯发生取代反应得到的：
美国专利US5134127首次使用β-环糊精和1,4-磺丁内酯在氢氧化钠水溶液中反应，经过去离子化，超滤，以及冷冻干燥，得到取代度为7.0～7.1的磺丁基醚-β-环糊精纯品。后来，美国专利US6153746参考这一方法，改进后，合成分离得到一系列不同取代度的磺丁基醚-β-环糊精；在对磺丁基醚-β-环糊精放大合成后，经过透析，超滤，以及活性炭脱色，精密过滤后，产品水溶液冷冻干燥得到取代度为6.5的磺丁基醚-β-环糊精。美国专利US7635773使用相同试剂，对磺丁基醚-β-环糊精进行了工业化生产，经过透析，活性炭脱色，精密过滤后，产品水溶液通过喷雾干燥得到了取代度为6.6的磺丁基醚-β-环糊精。但是这一系列报道合成，磺丁基醚-β-环糊精的分离收率在60～70％之间。
中国专利CN1858071A使用β-环糊精在1,4-二氧六环中用钠夺取羟基质子后和1,4-磺丁内酯发生取代反应，反应结束后，过滤得到产品，经过进一步使用甲醇洗涤后，再将粗品溶于水，使用葡萄糖凝胶柱(G-25)除盐纯化，浓缩溶液，冷冻干燥得到磺丁基醚-β-环糊精产品。该方法的缺点是使用危险性较高的金属钠为试剂，纯化使用昂贵的葡萄糖凝胶柱，所得磺丁基醚-β-环糊精产品的收率中等49～51％。
因此，为解决现有技术中存在的难题，急待找到一条工艺简单，成本低廉，收率较高，易于操作且适合规模化生产的切实可行的合成路线。
发明内容
本发明的目的在于提供一种制备磺丁基醚-β-环糊精的方法(见图1)。该方法克服了现有技术存在的不足，以β-环糊精(化合物1)和1,4-磺丁内酯(化合物2)为原料，通过向碱性水溶液中引入适量有机溶剂，增加了1,4-磺丁内酯的溶解度，提高了磺丁基醚-β-环糊精的合成收率；所得产品溶液经过超声透析，活性炭脱色，冷冻干燥等操作得到磺丁基醚-β-环糊精粉末产品。该方法工艺稳定，反应条件温和，选择性好，且后处理操作简单，所得产品纯度及收率都很高，为规模化生产磺丁基醚-β-环糊精提供了一种新的思路和方法。
本发明的技术方案：一种制备磺丁基醚-β-环糊精的方法，其特征在于具体制备步骤如下：
(1)合成反应：控温20-30℃，向反应瓶中加入有机溶剂和浓度为3.7N的氢氧化钠水溶液，升温至60～70℃，将β-环糊精(化合物1)加入到反应瓶中；于70～75℃向体系中滴加1,4-磺丁内酯(化合物2)，滴加完毕后体系于70～75℃下搅拌，使用浓度为3.7N的氢氧化钠水溶液控制体系pH>9；HPLC跟踪至β-环糊精剩余量占β-环 糊精投入总量的百分比小于0.5％wt，降至20～25℃，然后使用浓盐酸调节体系pH＝7.0～7.5，所得反应混合液直接用于下一步纯化操作；
(2)纯化过程：控温20-30℃，将步骤(1)所得反应混合液加入到透析袋中，超声透析至氯离子含量检测<10ppm；将所得透析液用活性炭处理，检测产品至紫外吸收<0.5AU，使用相对于原料β-环糊精的体积比1～2Vol/g的去离子水洗涤活性炭两次，洗液合并滤液后进行下一步操作；合并滤液过0.65-0.22um精密过滤器后，浓缩至检测磺丁基醚-β-环糊精含量占溶液总重的百分比为30～35％wt，冷冻干燥得到磺丁基醚-β-环糊精，通过毛细管电泳检测磺丁基醚-β-环糊精的平均取代度为6.7。
上述所述步骤(1)中，β-环糊精为商业品β-环糊精在90～100度的热水中结晶2～3次后制得的产物。
上述所述步骤(1)中，有机溶剂为四氢呋喃、1，4-二氧六环或2-甲基四氢呋喃中的至少一种。
上述所述步骤(1)中，有机溶剂与β-环糊精的用量比为0.02～0.20ml/g，氢氧化钠水溶液中的氢氧化钠与β-环糊精的用量比为7.0摩尔当量，1,4-磺丁内酯与β-环糊精的用量比为8.0摩尔当量，调节体系pH值使用的氢氧化钠水溶液中的氢氧化钠与β-环糊精的用量比为3.5摩尔当量。
上述所述步骤(2)中，透析袋的截留分子量为1000；活性炭与β-环糊精的用量比为0.05～0.2g/g；洗活性炭的去离子水与β-环糊精的用量比例为1～2ml/g。
上述所述步骤(2)中，若活性炭处理后的产品的紫外吸收值仍大于等于0.5AU，则将产品再一次进行活性炭处理。
根据本发明的另一方面，提供了一种制备磺丁基醚-β-环糊精的方法，该方法包括：将醚类溶剂和氢氧化钠水溶液混合形成第一混合液；将第一混合液升温至60～70℃后与β-环糊精混合形成第二混合液；将第二混合液升温至70～75℃后与1,4-磺丁内酯混合，形成反应体系；以及在70～75℃下搅拌反应体系并控制反应体系的pH值大于9，当β-环糊精的剩余量占β环糊精投入量的百分比小于0.5wt％时，将反应体系降温至20～25℃，并将反应体系的pH值调节至7.0～7.5之间，得到含有磺丁基醚-β-环糊精的产物体系；对产物体系进行纯化，得到磺丁基醚-β-环糊精。
进一步地，上述氢氧化钠水溶液的浓度为3.7N；上述方法采用浓度为3.7N的氢氧化钠水溶液控制反应体系的pH值大于9；上述方法采用浓盐酸将反应体系的pH值调节至7.0～7.5之间。
进一步地，上述醚类溶剂与β-环糊精的用量比为0.02～0.20ml/g；上述第一混合液中氢氧化钠水溶液中的氢氧化钠与β-环糊精的摩尔当量比为6.0～8.0，优选为7.0；1,4-磺丁内酯与β-环糊精的摩尔当量比为7.0～9.0，优选为8.0；上述控制反应体系的pH值所使用的氢氧化钠水溶液中的氢氧化钠与β-环糊精的摩尔当量比为3.0～4.0，优选为3.5。
进一步地，上述β-环糊精为商业品β-环糊精在90～100℃的热水中结晶1～3次后制得的产物。
进一步地，上述醚类溶剂为四氢呋喃、1，4-二氧六环或2-甲基四氢呋喃组成的组中的一种或多种。
进一步地，上述对产物体系进行纯化的过程包括:在20～30℃下，将产物体系进行透析至产物体系中氯离子含量<10ppm，得到第一纯化体系；将第一纯化体系采用活性炭处理，得到第二纯化体系；对第二纯化体系进行过滤浓缩，至磺丁基醚-β-环糊精含量占第二纯化体系总重的30～35wt％，得到第三纯化体系；将第三纯化体系进行冷冻干燥，得到磺丁基醚-β-环糊精。
进一步地，上述纯化过程采用截留分子量为1000的透析袋进行透析。
进一步地，上述采用活性炭处理第一纯化体系的过程包括：将活性炭和第一纯化体系混合后过滤，得到吸附活性炭和滤液；对吸附活性炭进行洗涤，得到洗液；将洗液和滤液混合得到第二纯化体系。
进一步地，上述纯化过程中活性炭与β-环糊精的用量比为0.05～0.2g/g；采用去离子水对吸附活性炭进行洗涤，去离子水与β-环糊精的比例为1～2ml/g。
进一步地，上述采用活性炭处理第一纯化体系的过程可重复进行至从滤液中回收到的产品的紫外吸收<0.5AU。
进一步地，上述纯化过程采用滤芯精度为0.65-0.22μm的精密过滤器对第二纯化体系进行过滤浓缩。
本发明的优越性：1、β-环糊精和1,4-磺丁内酯为原料，通过向碱性水溶液中引入适量有机溶剂，增加了1,4-磺丁内酯的溶解度，大大提高了磺丁基醚-β-环糊精的合成收率。2、本方法工艺稳定，反应条件温和，后处理简单，易于操作，所得产品收率较高，收率为75％-80％，适合工业化生产的需要。
附图说明
构成本申请的一部分的说明书附图用来提供对本发明的进一步理解，本发明的示意性实施例及其说明用于解释本发明，并不构成对本发明的不当限定。在附图中：
图1示出了本发明所涉一种制备磺丁基醚-β-环糊精(SBE-β-CD)的方法的化学反应过程图。
具体实施方式
需要说明的是，在不冲突的情况下，本申请中的实施例及实施例中的特征可以相互组合。下面将参考附图并结合实施例来详细说明本发明。
在本发明一种典型的实施方式中，提供了一种制备磺丁基醚-β-环糊精的方法，该方法包括：将醚类溶剂和氢氧化钠水溶液混合形成第一混合液；将第一混合液升温至60～70℃后与β-环糊精混合形成第二混合液；将第二混合液升温至70～75℃后与1,4-磺丁内酯混合，形成反应体系；在70～75℃下搅拌反应体系并控制反应体系的pH值大于9，当β-环糊精的剩余量占β环糊精投入量的百分比小于0.5wt％时，将反应体系降温至20～25℃，并将反应体系的pH值调节至7.0～7.5之间，得到含有磺丁基醚-β-环糊精的产物体系；对产物体系进行纯化，得到磺丁基醚-β-环糊精。
上述方法采用β-环糊精和1,4-磺丁内酯为原料，通过向氢氧化钠水溶液中引入适量醚类溶剂，增加了1,4-磺丁内酯的溶解度，增加了1,4-磺丁内酯与β-环糊精的接触机会，大大提高了磺丁基醚-β-环糊精的合成收率以及能够将产物的取代度控制在理想的范围内；而且采用醚类溶剂替代了部分氢氧化钠水溶液，进而降低了反应体系中氢氧化钠水溶液中强碱性物质的含量，在很大程度上减少了副产物的生成量，提高了磺丁基醚-β-环糊精的产率；同时，上述方法工艺稳定，反应条件温和，后处理简单，易于操作，产品收率较高，适合工业化生产的需要。
在本发明一种优选的实施例中，上述氢氧化钠水溶液的浓度为3.7N；上述方法采用浓度为3.7N的氢氧化钠水溶液控制反应体系的pH值大于9，优选该pH值在9～10之间；进一步地，上述方法采用浓盐酸将反应体系的pH值调节至7.0～7.5之间，浓盐 酸在后续的纯化处理中易与产物体系中的有机质分离，从而有利于提高磺丁基醚-β-环糊精的收率。
为了控制产品的取代度在6.2～6.9之间，优选醚类溶剂与β-环糊精的用量比为0.02～0.20ml/g；第一混合液中氢氧化钠水溶液中的氢氧化钠与β-环糊精的摩尔当量比为6.0～8.0，优选为7.0；1,4-磺丁内酯与β-环糊精的摩尔当量比为7.0～9.0，优选为8.0；控制反应体系的pH值所使用的氢氧化钠水溶液中的氢氧化钠与β-环糊精的摩尔当量比为3.0～4.0，优选为3.5。
本发明为了尽可能避免原料中杂质较多影响磺丁基醚-β-环糊精的收率，优选上述β-环糊精为商业品β-环糊精在90～100℃的热水中结晶1～3次后制得的产物，采用上述结晶方法进一步提高β-环糊精的纯度。
上述醚类溶剂的使用是为了增加1,4-磺丁内酯的溶解度，因此对1,4-磺丁内酯具有较强溶解性的醚类溶剂都可以考虑用于本申请，本申请发明人经过对多种醚类溶剂在本发明技术方案中的应用效果进行比较后，优选上述醚类溶剂为四氢呋喃、1，4-二氧六环或2-甲基四氢呋喃组成的组中的一种或多种。
采用上述方法得到含有磺丁基醚-β-环糊精的产物体系后，对产物体系中磺丁基醚-β-环糊精的提纯可以参考现有的提纯方法，本发明为了进一步保证产物体系中的磺丁基醚-β-环糊精被尽可能地提出，优选上述对产物体系进行纯化的过程包括:在20～30℃下，将产物体系进行透析至产物体系中氯离子含量<10ppm，得到第一纯化体系；将第一纯化体系采用活性炭处理用以除去来源于β-环糊精或者产物磺丁基醚-β-环糊精的可能未知杂质，得到第二纯化体系；对第二纯化体系进行过滤浓缩，至磺丁基醚-β-环糊精含量占第二纯化体系总重的30～35wt％，得到第三纯化体系；将第三纯化体系进行冷冻干燥，得到磺丁基醚-β-环糊精。将上述产物体系进行上述纯化后，能够将副产物、杂质等充分地磺丁基醚-β-环糊精进行分离，提高磺丁基醚-β-环糊精的收率。
在又一种优选的实施例中，上述纯化过程采用截留分子量为1000的透析袋进行透析，从而将大分子物质从产物体系中分离出去。
上述纯化过程中，采用活性炭处理第一纯化体系的过程包括：将活性炭和第一纯化体系混合后过滤，得到吸附活性炭和滤液；对吸附活性炭进行洗涤，得到洗液；将洗液和滤液混合得到第二纯化体系。上述将活性炭和第一纯化体系混合以利用活性炭吸附第一纯化体系中未反应原料及杂质，且该过程可以重复至从滤液中回收到的产品的紫外吸收<0.5AU，以提高最终产品的纯度。
在上述纯化过程中，为了使提高活性炭的吸附效果，优选上述活性炭与β-环糊精的用量比为0.05～0.2g/g；且为了尽可能分离残留在活性炭中的磺丁基醚-β-环糊精，优选采用去离子水对吸附活性炭进行洗涤，去离子水与β-环糊精的比例为1～2ml/g。
本申请为了从颗粒大小上控制杂质含量，优选采用滤芯精度为0.65-0.22μm的精密过滤器对第二纯化体系进行过滤浓缩。为了充分说明本发明专利的实质、制备思路及构思，在下述实施例中验证本发明所述的制备方法，这些实施例仅供举例说明和特例代表，不应被解释或理解为对本发明保护的限制。
实施例1：一种制备磺丁基醚-β-环糊精(SBE-β-CD)的方法，其特征在于具体制备步骤如下：
(1)合成反应：控温20-30℃，向反应瓶中加入1,4-二氧六环(0.4ml)以及氢氧化钠水溶液(3.7N,123.3mmol)，升温至60～70℃，将β-环糊精(20g,17.6mmol)加入到反应瓶中；70～75℃向上述体系滴加1,4-磺丁内酯(19.2g,141.0mmol)，滴加完毕后体系于70～75℃下搅拌，1小时内体系pH下降较为明显，使用氢氧化钠水溶液(3.7N，共计61.7mmol)控制体系pH>9；HPLC跟踪至β-环糊精剩余<0.5％wt，降至20～25℃，然后使用浓盐酸调节体系pH7.0～7.5，所得反应混合液直接用于下一步纯化操作。
(2)纯化过程：控温20-30℃，将所得反应处理液加入到透析袋中，超声透析，至氯离子含量检测<10ppm；将所得透析液用活性炭(1g)处理，检测产品至紫外吸收<0.5AU(如果紫外吸收不在此范围，则重复操作一次)，用去离子水20ml洗活性炭两次，洗液合并滤液后进行下一步操作；合并滤液过0.65-0.22μm精密过滤器后，浓缩至检测磺丁基醚-β-环糊精含量30～35％wt，冷冻干燥得到磺丁基醚-β-环糊精30.5g,收率80％。通过毛细管电泳检测磺丁基醚-β-环糊精的平均取代度为6.7。
实施例2：一种制备磺丁基醚-β-环糊精(SBE-β-CD)的方法，其特征在于具体制备步骤如下：
(1)合成反应：控温20-30℃，向反应瓶中加入四氢呋喃(1.0ml)以及氢氧化钠水溶液(3.7N,61.7mmol)，升温至60～70℃，将β-环糊精(10g,8.8mmol)加入到反应瓶中；70～75℃向上述体系滴加1,4-磺丁内酯(9.6g,70.5mmol)，滴加完毕后体系于70～75℃下搅拌，1小时内体系pH下降较为明显，使用氢氧化钠水溶液(3.7N，共计30.9mmol)控制体系pH>9；HPLC跟踪至β-环糊精剩余<0.5％wt，降至20～25℃，然后使用浓盐酸调节体系pH7.0～7.5，所得反应混合液直接用于下一步纯化操作。
(2)纯化过程：控温20-30℃，将所得反应处理液加入到透析袋中，超声透析，至氯离子含量检测<10ppm；将所得透析液用活性炭(1g)处理，检测产品至紫外吸收<0.5AU(如果紫外吸收不在此范围，则重复操作一次)，用去离子水15ml.洗活性炭两次，洗液合并滤液后进行下一步操作；合并滤液过0.65-0.22μm精密过滤器后，浓缩至检测磺丁基醚-β-环糊精含量30～35％wt，冷冻干燥得到磺丁基醚-β-环糊精14.9g,收率78％。通过毛细管电泳检测磺丁基醚-β-环糊精的平均取代度为6.7。
实施例3：一种制备磺丁基醚-β-环糊精(SBE-β-CD)的方法，其特征在于具体制备步骤如下：
(1)合成反应：控温20-30℃，向反应瓶中加入2-甲基四氢呋喃(2ml)以及氢氧化钠水溶液(3.7N,61.7mmol)，升温至60～70℃，将β-环糊精(10g,8.8mmol)加入到反应瓶中；70～75℃向上述体系滴加1,4-磺丁内酯(19.2g,71mmol)，滴加完毕后体系于70～75℃下搅拌，1小时内体系pH下降较为明显，使用氢氧化钠水溶液(3.7N，共计30.9mmol)控制体系pH>9；HPLC跟踪至β-环糊精剩余<0.5％wt，降至20～25℃，然后使用浓盐酸调节体系pH7.0～7.5，所得反应混合液直接用于下一步纯化操作。
(2)纯化过程：控温20-30℃，将所得反应处理液加入到透析袋中，超声透析，至氯离子含量检测<10ppm；将所得透析液用活性炭(2g)处理，检测产品至紫外吸收<0.5AU(如果紫外吸收不在此范围，则重复操作一次)，用去离子水20ml洗活性炭两次，洗液合并滤液后进行下一步操作；合并滤液过0.65-0.22μm精密过滤器后，浓缩至检测磺丁基醚-β-环糊精含量30～35％wt，冷冻干燥得到磺丁基醚-β-环糊精14.3g,收率75％。通过毛细管电泳检测磺丁基醚-β-环糊精的平均取代度为6.7。
实施例4
β-环糊精的处理，将含量为99.8％的β-环糊精在90～100℃的热水中结晶一次得到本实施例所采用的β-环糊精。
合成反应：控温20-30℃，向反应瓶中加入2-甲基四氢呋喃(2ml)以及氢氧化钠水溶液(3.7N,61.7mmol)，升温至60～70℃，将β-环糊精(10g,8.8mmol)加入到反应瓶中；70～75℃向上述体系滴加1,4-磺丁内酯(19.2g,71mmol)，滴加完毕后体系于70～75℃下搅拌，1小时内体系pH下降较为明显，使用氢氧化钠水溶液(3.7N，共计30.9mmol)控制体系pH>9；HPLC跟踪至β-环糊精剩余<0.5％wt，降至20～25℃，然后使用浓度为8.8N的浓盐酸调节体系pH值在7.0～7.5之间，得到产物体系。
纯化过程：控温20-30℃，将所得反应处理液加入到透析袋中，在去离子水中搅拌透析，至氯离子含量检测<10ppm；将所得透析液用活性炭(2g)处理，检测产品至紫外吸收<0.5AU(如果紫外吸收不在此范围，则重复操作一次)，用去离子水20ml洗活性炭两次，洗液合并滤液后进行下一步操作；合并滤液过0.65-0.22μm精密过滤器后，浓缩至检测磺丁基醚-β-环糊精含量30～35％wt，冷冻干燥得到磺丁基醚-β-环糊精13.7g,收率72％。通过毛细管电泳检测磺丁基醚-β-环糊精的平均取代度为6.7。
实施例5
β-环糊精的处理，将含量为98％的β-环糊精在90～100℃的热水中结晶三次得到本实施例所采用的β-环糊精。
合成反应：控温20～30℃，向反应瓶中加入四氢呋喃(1ml)以及氢氧化钠水溶液(浓度为3.7N,其中所使用的氢氧化钠的摩尔数共计61.7mmol)形成第一混合液；将第一混合液升温至60～70℃后，将β-环糊精(10g,8.8mmol)加入到上述反应瓶中形成第二混合液；在将第二混合升温至70～75℃后，向上述体系滴加1,4-磺丁内酯(9.6g,71mmol)，形成反应体系，将该反应体系于70～75℃在搅拌下进行反应，并使用氢氧化钠水溶液(浓度为3.7N，其中所使用的氢氧化钠的摩尔数共计30.9mmol)控制反应体系9＜pH＜10；采用HPLC跟踪至反应体系中β-环糊精剩余<0.5wt％时降温至20～25℃，然后使用浓度为8.0N的浓盐酸调节体系pH值在7.0～7.5之间，得到产物体系。
纯化过程：控温20～30℃，将上述产物体系液加入到截留分子量为1000的透析袋中，并在去离子水中进行超声透析至氯离子含量检测<10ppm，得到第一纯化体系；将所得第一纯化体系过活性炭(1g)过滤处理得到滤液和吸附活性炭，取部分滤液进行冷冻干燥，得到固体产品，检测该固体产品紫外吸收<0.5AU，然后用去离子水15ml冲洗吸附活性炭两次得到洗液，洗液合并滤液得到第二纯化体系；将第二纯化体系过滤芯精度为0.65-0.22μm的精密过滤器后得到第三纯化体系，浓缩第三纯化体系至检测磺丁基醚-β-环糊精含量30～35wt％，冷冻干燥得到磺丁基醚-β-环糊精14.9g,收率78％。通过毛细管电泳检测磺丁基醚-β-环糊精的平均取代度为6.7。
实施例6
β-环糊精的处理，将含量为98％的β-环糊精在90～100℃的热水中结晶三次得到本实施例所采用的β-环糊精。
合成反应：控温20～30℃，向反应瓶中加入四氢呋喃(1ml)以及氢氧化钠水溶液(浓度为3.8N,其中所使用的氢氧化钠的摩尔数共计67.3mmol)形成第一混合液；将第一混合液升温至60～70℃后，将β-环糊精(10g,8.8mmol)加入到上述反应瓶中形成第二混合液；在将第二混合升温至70～75℃后，向上述体系滴加1,4-磺丁内酯(20.2g,74.8mmol)，形成反应体系，将该反应体系于70～75℃在搅拌下进行反应，并使用氢氧化钠水溶液(浓度为3.8N，其中所使用的氢氧化钠的摩尔数共计33.0mmol)控制反应体系pH>9；采用HPLC跟踪至反应体系中β-环糊精剩余<0.5wt％时降温至20～25℃，然后使用浓度为8.5N的浓盐酸调节体系pH值在7.0～7.5之间，得到产物体系。
纯化过程：控温20～30℃，将上述产物体系液加入到截留分子量为1000的透析袋中，并在去离子水中进行超声透析至氯离子含量检测<10ppm，得到第一纯化体系；将所得第一纯化体系过活性炭(1g)过滤处理得到滤液和吸附活性炭，取部分滤液进行冷冻干燥，得到固体产品，检测该固体产品紫外吸收<0.5AU，然后用去离子水15ml冲洗吸附活性炭两次得到洗液，洗液合并滤液得到第二纯化体系；将第二纯化体系过滤芯精度为0.65-0.22μm的精密过滤器后得到第三纯化体系，浓缩第三纯化体系至检测磺丁基醚-β-环糊精含量30～35wt％，冷冻干燥得到磺丁基醚-β-环糊精15.3g,收率80％。通过毛细管电泳检测磺丁基醚-β-环糊精的平均取代度为6.9。
实施例7
β-环糊精的处理，将含量为98％的β-环糊精在90～100℃的热水中结晶三次得到本实施例所采用的β-环糊精。
合成反应：控温20～30℃，向反应瓶中加入四氢呋喃(1ml)以及氢氧化钠水溶液(浓度为3.6N,其中所使用的氢氧化钠的摩尔数共计57.4mmol)形成第一混合液；将第一混合液升温至60～70℃后，将β-环糊精(10g,8.8mmol)加入到上述反应瓶中形成第二混合液；在将第二混合升温至70～75℃后，向上述体系滴加1,4-磺丁内酯(17.9g,66mmol)，形成反应体系，将该反应体系于70～75℃在搅拌下进行反应，并使用氢氧化钠水溶液(浓度为4.2N，其中所使用的氢氧化钠的摩尔数共计31mmol)控制反应体系pH>9；采用HPLC跟踪至反应体系中β-环糊精剩余<0.5wt％时降温至20～25℃，然后使用浓度为8.8N的浓盐酸调节体系pH值在7.0～7.5之间，得到产物体系。
纯化过程：控温20～30℃，将上述产物体系液加入到截留分子量为1000的透析袋中，并在去离子水中进行超声透析至氯离子含量检测<10ppm，得到第一纯化体系；将所得第一纯化体系过活性炭(1g)过滤处理得到滤液和吸附活性炭，取部分滤液进行 冷冻干燥，得到固体产品，检测该固体产品紫外吸收<0.5AU，然后用去离子水15ml冲洗吸附活性炭两次得到洗液，洗液合并滤液得到第二纯化体系；将第二纯化体系过滤芯精度为0.65-0.22μm的精密过滤器后得到第三纯化体系，浓缩第三纯化体系至检测磺丁基醚-β-环糊精含量30～35wt％，冷冻干燥得到磺丁基醚-β-环糊精14.7g,收率77％。通过毛细管电泳检测磺丁基醚-β-环糊精的平均取代度为6.5。
实施例8
β-环糊精的处理，将含量为98％的β-环糊精在90～100℃的热水中结晶三次得到本实施例所采用的β-环糊精。
合成反应：控温20～30℃，向反应瓶中加入四氢呋喃(1ml)以及氢氧化钠水溶液(浓度为4.0N,其中所使用的氢氧化钠的摩尔数共计53.5mmol)形成第一混合液；将第一混合液升温至60～70℃后，将β-环糊精(10g,8.8mmol)加入到上述反应瓶中形成第二混合液；在将第二混合升温至70～75℃后，向上述体系滴加1,4-磺丁内酯(16.7g,61.6mmol)，形成反应体系，将该反应体系于70～75℃在搅拌下进行反应，并使用氢氧化钠水溶液(浓度为3.7N，其中所使用的氢氧化钠的摩尔数共计30mmol)控制反应体系pH>9；采用HPLC跟踪至反应体系中β-环糊精剩余<0.5wt％时降温至20～25℃，然后使用浓度为8.8N的浓盐酸调节体系pH值在7.0～7.5之间，得到产物体系。
纯化过程：控温20～30℃，将上述产物体系液加入到截留分子量为1000的透析袋中，并在去离子水中进行超声透析至氯离子含量检测<10ppm，得到第一纯化体系；将所得第一纯化体系过活性炭(1g)过滤处理得到滤液和吸附活性炭，取部分滤液进行冷冻干燥，得到固体产品，检测该固体产品紫外吸收<0.5AU，然后用去离子水15ml冲洗吸附活性炭两次得到洗液，洗液合并滤液得到第二纯化体系；将第二纯化体系过滤芯精度为0.65-0.22μm的精密过滤器后得到第三纯化体系，浓缩第三纯化体系至检测磺丁基醚-β-环糊精含量30～35wt％，冷冻干燥得到磺丁基醚-β-环糊精14.9g,收率78％。通过毛细管电泳检测磺丁基醚-β-环糊精的平均取代度为6.3。
实施例9
β-环糊精的处理，将含量为98％的β-环糊精在90～100℃的热水中结晶三次得到本实施例所采用的β-环糊精。
合成反应：控温20～30℃，向反应瓶中加入四氢呋喃(0.2ml)以及氢氧化钠水溶液(浓度为3.7N,其中所使用的氢氧化钠的摩尔数共计61.7mmol)形成第一混合液； 将第一混合液升温至60～70℃后，将β-环糊精(10g,8.8mmol)加入到上述反应瓶中形成第二混合液；在将第二混合升温至70～75℃后，向上述体系滴加1,4-磺丁内酯(9.6g,71mmol)，形成反应体系，将该反应体系于70～75℃在搅拌下进行反应，并使用氢氧化钠水溶液(浓度为3.7N，其中所使用的氢氧化钠的摩尔数共计30.9mmol)控制反应体系9＜pH＜10；采用HPLC跟踪至反应体系中β-环糊精剩余<0.5wt％时降温至20～25℃，然后使用浓度为8.0N的浓盐酸调节体系pH值在7.0～7.5之间，得到产物体系。
纯化过程：控温20～30℃，将上述产物体系液加入到截留分子量为1000的透析袋中，并在去离子水中进行超声透析至氯离子含量检测<10ppm，得到第一纯化体系；将所得第一纯化体系过活性炭(1g)过滤处理得到滤液和吸附活性炭，取部分滤液进行冷冻干燥，得到固体产品，检测该固体产品紫外吸收<0.5AU，然后用去离子水15ml冲洗吸附活性炭两次得到洗液，洗液合并滤液得到第二纯化体系；将第二纯化体系过滤芯精度为0.65-0.22μm的精密过滤器后得到第三纯化体系，浓缩第三纯化体系至检测磺丁基醚-β-环糊精含量30～35wt％，冷冻干燥得到磺丁基醚-β-环糊精14.5g,收率76％。通过毛细管电泳检测磺丁基醚-β-环糊精的平均取代度为6.7。
实施例10
β-环糊精的处理，将含量为98％的β-环糊精在90～100℃的热水中结晶三次得到本实施例所采用的β-环糊精。
合成反应：控温20～30℃，向反应瓶中加入四氢呋喃(2ml)以及氢氧化钠水溶液(浓度为3.7N,其中所使用的氢氧化钠的摩尔数共计61.7mmol)形成第一混合液；将第一混合液升温至60～70℃后，将β-环糊精(10g,8.8mmol)加入到上述反应瓶中形成第二混合液；在将第二混合升温至70～75℃后，向上述体系滴加1,4-磺丁内酯(9.6g,71mmol)，形成反应体系，将该反应体系于70～75℃在搅拌下进行反应，并使用氢氧化钠水溶液(浓度为3.7N，其中所使用的氢氧化钠的摩尔数共计30.9mmol)控制反应体系9＜pH＜10；采用HPLC跟踪至反应体系中β-环糊精剩余<0.5wt％时降温至20～25℃，然后使用浓度为8.0N的浓盐酸调节体系pH值在7.0～7.5之间，得到产物体系。
纯化过程：控温20～30℃，将上述产物体系液加入到截留分子量为1000的透析袋中，并在去离子水中进行超声透析至氯离子含量检测<10ppm，得到第一纯化体系；将所得第一纯化体系过活性炭(1g)过滤处理得到滤液和吸附活性炭，取部分滤液进行冷冻干燥，得到固体产品，检测该固体产品紫外吸收<0.5AU，然后用去离子水15ml 冲洗吸附活性炭两次得到洗液，洗液合并滤液得到第二纯化体系；将第二纯化体系过滤芯精度为0.65-0.22μm的精密过滤器后得到第三纯化体系，浓缩第三纯化体系至检测磺丁基醚-β-环糊精含量30～35wt％，冷冻干燥得到磺丁基醚-β-环糊精15.5g,收率81％。通过毛细管电泳检测磺丁基醚-β-环糊精的平均取代度为6.7。
实施例11
β-环糊精的处理，将含量为98％的β-环糊精在90～100℃的热水中结晶三次得到本实施例所采用的β-环糊精。
合成反应：控温20～30℃，向反应瓶中加入四氢呋喃(1ml)以及氢氧化钠水溶液(浓度为3.7N,其中所使用的氢氧化钠的摩尔数共计61.7mmol)形成第一混合液；将第一混合液升温至60～70℃后，将β-环糊精(10g,8.8mmol)加入到上述反应瓶中形成第二混合液；在将第二混合升温至70～75℃后，向上述体系滴加1,4-磺丁内酯(9.6g,71mmol)，形成反应体系，将该反应体系于70～75℃在搅拌下进行反应，并使用氢氧化钠水溶液(浓度为3.7N，其中所使用的氢氧化钠的摩尔数共计30.9mmol)控制反应体系9＜pH＜10；采用HPLC跟踪至反应体系中β-环糊精剩余<0.5wt％时降温至20～25℃，然后使用浓度为8.0N的浓盐酸调节体系pH值在7.0～7.5之间，得到产物体系。
纯化过程：控温20～30℃，将上述产物体系液加入到截留分子量为1000的透析袋中，并在去离子水中进行超声透析至氯离子含量检测<10ppm，得到第一纯化体系；将所得第一纯化体系过活性炭(2.5g)过滤处理得到滤液和吸附活性炭，取部分滤液进行冷冻干燥，得到固体产品，检测该固体产品紫外吸收<0.5AU，然后用去离子水20ml冲洗吸附活性炭两次得到洗液，洗液合并滤液得到第二纯化体系；将第二纯化体系过滤芯精度为0.65-0.22μm的精密过滤器后得到第三纯化体系，浓缩第三纯化体系至检测磺丁基醚-β-环糊精含量30～35wt％，冷冻干燥得到磺丁基醚-β-环糊精14.1g,收率74％。通过毛细管电泳检测磺丁基醚-β-环糊精的平均取代度为6.7。
实施例12
β-环糊精的处理，将含量为98％的β-环糊精在90～100℃的热水中结晶三次得到本实施例所采用的β-环糊精。
合成反应：控温20～30℃，向反应瓶中加入四氢呋喃(2.5ml)以及氢氧化钠水溶液(浓度为3.7N,其中所使用的氢氧化钠的摩尔数共计61.7mmol)形成第一混合液；将第一混合液升温至60～70℃后，将β-环糊精(10g,8.8mmol)加入到上述反应瓶中 形成第二混合液；在将第二混合升温至70～75℃后，向上述体系滴加1,4-磺丁内酯(9.6g,71mmol)，形成反应体系，将该反应体系于70～75℃在搅拌下进行反应，并使用氢氧化钠水溶液(浓度为3.7N，其中所使用的氢氧化钠的摩尔数共计30.9mmol)控制反应体系9＜pH＜10；采用HPLC跟踪至反应体系中β-环糊精剩余<0.5wt％时降温至20～25℃，然后使用浓度为8.0N的浓盐酸调节体系pH值在7.0～7.5之间，得到产物体系。
纯化过程：控温20～30℃，将上述产物体系液加入到截留分子量为1000的透析袋中，并在去离子水中进行超声透析至氯离子含量检测<10ppm，得到第一纯化体系；将所得第一纯化体系过活性炭(1g)过滤处理得到滤液和吸附活性炭，取部分滤液进行冷冻干燥，得到固体产品，检测该固体产品紫外吸收<0.5AU，然后用去离子水15ml冲洗吸附活性炭两次得到洗液，洗液合并滤液得到第二纯化体系；将第二纯化体系过滤芯精度为0.65-0.22μm的精密过滤器后得到第三纯化体系，浓缩第三纯化体系至检测磺丁基醚-β-环糊精含量30～35wt％，冷冻干燥得到磺丁基醚-β-环糊精14.5g,收率76％。通过毛细管电泳检测磺丁基醚-β-环糊精的平均取代度为6.7。
实施例13
β-环糊精的处理，将含量为98％的β-环糊精在90～100℃的热水中结晶三次得到本实施例所采用的β-环糊精。
合成反应：控温20～30℃，向反应瓶中加入四氢呋喃(1ml)以及氢氧化钠水溶液(浓度为3.7N,其中所使用的氢氧化钠的摩尔数共计61.7mmol)形成第一混合液；将第一混合液升温至60～70℃后，将β-环糊精(10g,8.8mmol)加入到上述反应瓶中形成第二混合液；在将第二混合升温至70～75℃后，向上述体系滴加1,4-磺丁内酯(7.7g,57mmol)，形成反应体系，将该反应体系于70～75℃在搅拌下进行反应，并使用氢氧化钠水溶液(浓度为3.7N，其中所使用的氢氧化钠的摩尔数共计26.4mmol)控制反应体系9＜pH＜10；采用HPLC跟踪至反应体系中β-环糊精剩余<0.5wt％时降温至20～25℃，然后使用浓度为8.0N的浓盐酸调节体系pH值在7.0～7.5之间，得到产物体系。
纯化过程：控温20～30℃，将上述产物体系液加入到截留分子量为1000的透析袋中，并在去离子水中进行超声透析至氯离子含量检测<10ppm，得到第一纯化体系；将所得第一纯化体系过活性炭(1g)过滤处理得到滤液和吸附活性炭，取部分滤液进行冷冻干燥，得到固体产品，检测该固体产品紫外吸收<0.5AU，然后用去离子水15ml冲洗吸附活性炭两次得到洗液，洗液合并滤液得到第二纯化体系；将第二纯化体系过 滤芯精度为0.65-0.22μm的精密过滤器后得到第三纯化体系，浓缩第三纯化体系至检测磺丁基醚-β-环糊精含量30～35wt％，冷冻干燥得到磺丁基醚-β-环糊精14.9g,收率78％。通过毛细管电泳检测磺丁基醚-β-环糊精的平均取代度为6.7。
上述各实施例得到的磺丁基醚-β-环糊精的平均取代度均能够满足药典要求，且可以通过调整有机溶剂与氢氧化钠的用量调整磺丁基醚-β-环糊精的收率；同时上述方法反应条件温和，易于操作，适用于工业化大规模使用。
由此可见，本发明中公开的一种合成磺丁基醚-β-环糊精的方法，以β-环糊精和1,4-磺丁内酯为原料，通过向碱性水溶液中引入适量有机溶剂，增加了1,4-磺丁内酯的溶解度，提高了磺丁基醚-β-环糊精的合成收率；所得产品溶液经过超声透析，活性炭脱色，冷冻干燥等操作得到磺丁基醚-β-环糊精粉末产品。本发明工艺稳定，反应条件温和，易于操作，所得产品收率较高，为规模化生产磺丁基醚-β-环糊精(SBE-β-CD)提供了一种新的思路和方法。
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (17)

  1. 一种制备磺丁基醚-β-环糊精的方法，其特征在于具体制备步骤如下：
    (1)合成反应：控温20-30℃，向反应瓶中加入醚类溶剂和浓度为3.7N的氢氧化钠水溶液，升温至60～70℃，将β-环糊精加入到反应瓶中；于70～75℃向体系中滴加1,4-磺丁内酯，滴加完毕后体系于70～75℃下搅拌，使用浓度为3.7N的氢氧化钠水溶液控制体系pH>9；HPLC跟踪至β-环糊精剩余量占β-环糊精投入总量的百分比小于0.5％wt，降至20～25℃，然后使用浓盐酸调节体系pH＝7.0～7.5，所得反应混合液直接用于下一步纯化操作；
    (2)纯化：控温20-30℃，将步骤(1)所得反应混合液加入到透析袋中，超声透析至氯离子含量检测<10ppm；将所得透析液用活性炭处理，检测产品至紫外吸收<0.5AU，使用相对于原料β-环糊精的体积比1～2Vol/g的去离子水洗涤活性炭两次，洗液合并滤液后进行下一步操作；合并滤液过0.65-0.22um精密过滤器后，浓缩至检测磺丁基醚-β-环糊精含量占溶液总重的百分比为30～35％wt，冷冻干燥得到磺丁基醚-β-环糊精，通过毛细管电泳检测磺丁基醚-β-环糊精的平均取代度为6.7。
  2. 根据权利要求1所述一种制备磺丁基醚-β-环糊精的方法，其特征在于所述步骤(1)中，β-环糊精为商业品β-环糊精在90～100℃的热水中结晶2～3次后制得的产物。
  3. 根据权利要求1所述一种制备磺丁基醚-β-环糊精的方法，其特征在于所述步骤(1)中，醚类溶剂为四氢呋喃、1，4-二氧六环或2-甲基四氢呋喃中的至少一种。
  4. 根据权利要求1所述一种制备磺丁基醚-β-环糊精的方法，其特征在于所述步骤(1)中，醚类溶剂与β-环糊精的用量比为0.02～0.20ml/g，氢氧化钠水溶液中的氢氧化钠与β-环糊精的用量比为7.0摩尔当量，1,4-磺丁内酯与β-环糊精的用量比为8.0摩尔当量，调节体系pH值使用的氢氧化钠水溶液中的氢氧化钠与β-环糊精的用量比为3.5摩尔当量。
  5. 根据权利要求1所述一种制备磺丁基醚-β-环糊精的方法，其特征在于所述步骤(2)中，透析袋的截留分子量为1000；活性炭与β-环糊精的用量比为0.05～0.2g/g；洗活性炭的去离子水与β-环糊精的用量比例为1～2ml/g。
  6. 根据权利要求1所述一种制备磺丁基醚-β-环糊精的方法，其特征在于所述步骤(2)中，若活性炭处理后的产品的紫外吸收值仍大于等于0.5AU，则将产品再一次进行活性炭处理。
  7. 一种制备磺丁基醚-β-环糊精的方法，其特征在于，所述方法包括：
    将醚类溶剂和氢氧化钠水溶液混合形成第一混合液；
    将所述第一混合液升温至60～70℃后与β-环糊精混合形成第二混合液；
    将所述第二混合液升温至70～75℃后与1,4-磺丁内酯混合，形成反应体系；
    在70～75℃下搅拌所述反应体系并控制所述反应体系的pH值大于9，当所述β-环糊精的剩余量占所述β环糊精投入量的百分比小于0.5wt％时，将所述反应体系降温至20～25℃，并将所述反应体系的pH值调节至7.0～7.5之间，得到含有所述磺丁基醚-β-环糊精的产物体系；以及
    对所述产物体系进行纯化，得到所述磺丁基醚-β-环糊精。
  8. 根据权利要求7所述的方法，其特征在于，所述氢氧化钠水溶液的浓度为3.7N；所述方法采用浓度为3.7N的氢氧化钠水溶液控制所述反应体系的pH值大于9；所述方法采用浓盐酸将所述反应体系的pH值调节至7.0～7.5之间。
  9. 根据权利要求8所述的方法，其特征在于，所述醚类溶剂与所述β-环糊精的用量比为0.02～0.20ml/g；所述第一混合液中所述氢氧化钠水溶液中的氢氧化钠与所述β-环糊精的摩尔当量比为6.0～8.0，优选为7.0；所述1,4-磺丁内酯与所述β-环糊精的摩尔当量比为7.0～9.0，优选为8.0；所述控制反应体系的pH值所使用的氢氧化钠水溶液中的氢氧化钠与所述β-环糊精的摩尔当量比为3.0～4.0，优选为3.5。
  10. 根据权利要求7所述的方法，其特征在于，所述β-环糊精为商业品β-环糊精在90～100℃的热水中结晶1～3次后制得的产物。
  11. 根据权利要求7所述的方法，其特征在于，所述醚类溶剂为四氢呋喃、1，4-二氧六环或2-甲基四氢呋喃组成的组中的一种或多种。
  12. 根据权利要求7所述的方法，其特征在于，所述对产物体系进行纯化的过程包括:
    在20～30℃下，将所述产物体系进行透析至所述产物体系中氯离子含量<10ppm，得到第一纯化体系；
    将所述第一纯化体系采用活性炭处理，得到第二纯化体系；
    对所述第二纯化体系进行过滤浓缩，至磺丁基醚-β-环糊精含量占第二纯化体系总重的30～35wt％，得到第三纯化体系；
    将所述第三纯化体系进行冷冻干燥，得到所述磺丁基醚-β-环糊精。
  13. 根据权利要求12所述的方法，其特征在于，所述纯化过程采用截留分子量为1000的透析袋进行所述透析。
  14. 根据权利要求12所述的方法，其特征在于，所述采用活性炭处理所述第一纯化体系的过程包括：
    将所述活性炭和所述第一纯化体系混合后过滤，得到吸附活性炭和滤液；
    对所述吸附活性炭进行洗涤，得到洗液；
    将所述洗液和所述滤液混合得到所述第二纯化体系。
  15. 根据权利要求14所述的方法，其特征在于，所述纯化过程中所述活性炭与所述β-环糊精的用量比为0.05～0.2g/g；采用去离子水对所述吸附活性炭进行洗涤，所述去离子水与所述β-环糊精的比例为1～2ml/g。
  16. 根据权利要求14所述的方法，其特征在于，所述采用活性炭处理所述第一纯化体系的过程可重复进行至从所述滤液中回收到的产品的紫外吸收<0.5AU。
  17. 根据权利要求12所述的方法，其特征在于，所述纯化过程采用滤芯精度为0.65-0.22μm的精密过滤器对所述第二纯化体系进行过滤浓缩。
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Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103694376B (zh) * 2014-01-10 2016-04-13 凯莱英医药集团（天津）股份有限公司 一种制备磺丁基醚-β-环糊精的方法
CN104151438A (zh) * 2014-06-04 2014-11-19 江苏大学 一种超声波辅助透析纯化辛烯基琥珀酸菊粉酯的方法
CN104892797B (zh) * 2015-05-28 2017-03-22 天津大学 特定平均取代度磺丁基醚‑β‑环糊精的合成方法
CN104974275A (zh) * 2015-07-30 2015-10-14 淄博千汇生物科技有限公司 磺烷基醚环糊精衍生物的合成方法
CN105924545B (zh) * 2016-05-20 2018-05-22 山东滨州智源生物科技有限公司 一种高安全性磺丁基醚-β-环糊精钠盐的生产工艺
EP3487508B1 (en) * 2016-07-22 2023-09-13 Ecole Polytechnique Fédérale de Lausanne (EPFL) Virucidal compounds and uses thereof
CN107129546B (zh) * 2017-06-27 2019-05-21 淄博千汇生物科技有限公司 磺烷基倍他环糊精的绿色合成方法
CN108484799A (zh) * 2018-03-15 2018-09-04 山东滨州智源生物科技有限公司 微波去除磺丁基醚倍他环糊精钠盐粗品液中1,4-丁烷磺内酯的方法
CN110575826A (zh) * 2019-09-16 2019-12-17 天津科技大学 一种磺酸基环糊精衍生物及其修饰的纳米二氧化钛的制备方法
CN110590973B (zh) * 2019-10-28 2021-11-05 淮北云端文化传媒有限公司 环糊精衍生物及其制备方法
JP2023502399A (ja) * 2019-11-18 2023-01-24 サイデックス・ファーマシューティカルズ・インコーポレイテッド アルキル化シクロデキストリン組成物並びにこれを製造及び使用する方法
CN113943383A (zh) * 2021-11-19 2022-01-18 秦大伟 绿色无毒磺丁基醚-β-环糊精钠盐的生产工艺

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5134127A (en) * 1990-01-23 1992-07-28 University Of Kansas Derivatives of cyclodextrins exhibiting enhanced aqueous solubility and the use thereof
US6153746A (en) * 1997-07-01 2000-11-28 Pfizer Inc. Process for making a cyclodextrin
CN1858071A (zh) * 2006-05-25 2006-11-08 重庆通量精细化工有限公司 水溶性磺烷基醚－β－环糊精的合成工艺
CN101959508A (zh) * 2008-04-28 2011-01-26 锡德克斯药物公司 磺烷基醚环糊精组合物
WO2013123254A1 (en) * 2012-02-15 2013-08-22 Cydex Pharmaceuticals, Inc. Manufacturing process for cyclodextrin derivatives
WO2013130666A1 (en) * 2012-02-28 2013-09-06 Cydex Pharmaceuticals, Inc. Alkylated cyclodextrin compositions and processes for preparing and using the same
CN103694376A (zh) * 2014-01-10 2014-04-02 凯莱英医药集团（天津）股份有限公司 一种制备磺丁基醚-β-环糊精的方法

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2623507B2 (ja) * 1989-08-30 1997-06-25 キッコーマン株式会社 マルトオリゴ糖の製造法
US7834612B2 (en) * 2007-07-26 2010-11-16 Altronix Corporation Method and apparatus for regulating voltage in a remote device
CN101314045B (zh) * 2008-05-09 2013-01-23 沈阳药科大学 桂利嗪的磺丁基醚-β-环糊精包合物及其制剂和制备方法
CN101519460A (zh) * 2009-03-20 2009-09-02 南京威尔化工有限公司 羟丙基-β-环糊精的合成方法
CN102382210B (zh) * 2011-09-01 2012-11-28 浙江理工大学 一种双活性反应型环糊精及制备方法
CN102921018A (zh) * 2012-11-27 2013-02-13 重庆市畜牧科学院 恩诺沙星/磺丁基醚-β-环糊精包合物、制备方法和其药物制剂
US20160000980A1 (en) * 2014-03-20 2016-01-07 Naya Health, Inc. Pump apparatus and methods for expression of human breast milk

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5134127A (en) * 1990-01-23 1992-07-28 University Of Kansas Derivatives of cyclodextrins exhibiting enhanced aqueous solubility and the use thereof
US6153746A (en) * 1997-07-01 2000-11-28 Pfizer Inc. Process for making a cyclodextrin
CN1858071A (zh) * 2006-05-25 2006-11-08 重庆通量精细化工有限公司 水溶性磺烷基醚－β－环糊精的合成工艺
CN101959508A (zh) * 2008-04-28 2011-01-26 锡德克斯药物公司 磺烷基醚环糊精组合物
WO2013123254A1 (en) * 2012-02-15 2013-08-22 Cydex Pharmaceuticals, Inc. Manufacturing process for cyclodextrin derivatives
WO2013130666A1 (en) * 2012-02-28 2013-09-06 Cydex Pharmaceuticals, Inc. Alkylated cyclodextrin compositions and processes for preparing and using the same
CN103694376A (zh) * 2014-01-10 2014-04-02 凯莱英医药集团（天津）股份有限公司 一种制备磺丁基醚-β-环糊精的方法

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