CN116554368B - Preparation method and application of beta-cyclodextrin derivative - Google Patents
Preparation method and application of beta-cyclodextrin derivative Download PDFInfo
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- CN116554368B CN116554368B CN202310840775.9A CN202310840775A CN116554368B CN 116554368 B CN116554368 B CN 116554368B CN 202310840775 A CN202310840775 A CN 202310840775A CN 116554368 B CN116554368 B CN 116554368B
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- manganese dioxide
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- mesoporous manganese
- cyclodextrin
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- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical class OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 title claims abstract description 60
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims abstract description 132
- 238000003756 stirring Methods 0.000 claims abstract description 61
- 239000002245 particle Substances 0.000 claims abstract description 40
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 36
- 239000001116 FEMA 4028 Substances 0.000 claims abstract description 36
- 229960004853 betadex Drugs 0.000 claims abstract description 36
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims abstract description 31
- 238000001914 filtration Methods 0.000 claims abstract description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 27
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- 238000001291 vacuum drying Methods 0.000 claims abstract description 25
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000003513 alkali Substances 0.000 claims abstract description 20
- 239000000706 filtrate Substances 0.000 claims abstract description 20
- 238000010438 heat treatment Methods 0.000 claims abstract description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 11
- 238000005406 washing Methods 0.000 claims abstract description 9
- 239000005457 ice water Substances 0.000 claims abstract description 7
- 238000009835 boiling Methods 0.000 claims abstract description 6
- 238000002156 mixing Methods 0.000 claims abstract description 5
- 230000001376 precipitating effect Effects 0.000 claims abstract description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 36
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 36
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- SJECZPVISLOESU-UHFFFAOYSA-N 3-trimethoxysilylpropan-1-amine Chemical compound CO[Si](OC)(OC)CCCN SJECZPVISLOESU-UHFFFAOYSA-N 0.000 claims description 8
- 239000012065 filter cake Substances 0.000 claims description 7
- 238000001728 nano-filtration Methods 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 6
- 238000011010 flushing procedure Methods 0.000 claims description 6
- 238000007789 sealing Methods 0.000 claims description 6
- 238000000227 grinding Methods 0.000 claims description 5
- 239000002244 precipitate Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims 2
- 239000000047 product Substances 0.000 abstract description 8
- 231100000956 nontoxicity Toxicity 0.000 abstract description 3
- 230000001105 regulatory effect Effects 0.000 abstract description 3
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical class O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 8
- MWDZOUNAPSSOEL-UHFFFAOYSA-N kaempferol Natural products OC1=C(C(=O)c2cc(O)cc(O)c2O1)c3ccc(O)cc3 MWDZOUNAPSSOEL-UHFFFAOYSA-N 0.000 description 8
- IQPNAANSBPBGFQ-UHFFFAOYSA-N luteolin Chemical compound C=1C(O)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(O)C(O)=C1 IQPNAANSBPBGFQ-UHFFFAOYSA-N 0.000 description 8
- LRDGATPGVJTWLJ-UHFFFAOYSA-N luteolin Natural products OC1=CC(O)=CC(C=2OC3=CC(O)=CC(O)=C3C(=O)C=2)=C1 LRDGATPGVJTWLJ-UHFFFAOYSA-N 0.000 description 8
- 235000009498 luteolin Nutrition 0.000 description 8
- 239000006227 byproduct Substances 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 230000001276 controlling effect Effects 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 238000010612 desalination reaction Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- 238000005063 solubilization Methods 0.000 description 4
- 230000007928 solubilization Effects 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- PDVFSPNIEOYOQL-UHFFFAOYSA-N (4-methylphenyl)sulfonyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OS(=O)(=O)C1=CC=C(C)C=C1 PDVFSPNIEOYOQL-UHFFFAOYSA-N 0.000 description 3
- 238000011049 filling Methods 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- 238000013270 controlled release Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000007873 sieving Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical compound NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229960003151 mercaptamine Drugs 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000009210 therapy by ultrasound Methods 0.000 description 1
- -1 thiol derivatives Chemical class 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
- B01J23/16—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of arsenic, antimony, bismuth, vanadium, niobium, tantalum, polonium, chromium, molybdenum, tungsten, manganese, technetium or rhenium
- B01J23/32—Manganese, technetium or rhenium
- B01J23/34—Manganese
-
- 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
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- Chemical & Material Sciences (AREA)
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- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
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- Engineering & Computer Science (AREA)
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- Animal Behavior & Ethology (AREA)
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- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Materials Engineering (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Polymers & Plastics (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
Abstract
The invention discloses a preparation method and application of a beta-cyclodextrin derivative, belonging to the technical field of cyclodextrin derivative synthesis, wherein the preparation method comprises the following steps: preparing amino modified mesoporous manganese dioxide, preparing mesoporous manganese dioxide particles subjected to alkali treatment, and mixing for reaction; pouring the beta-cyclodextrin solution into a reaction vessel, adding p-toluenesulfonyl chloride, stirring at room temperature, adding alkaline-treated mesoporous manganese dioxide particles under the condition of ice water bath, stirring, and filtering out the alkaline-treated mesoporous manganese dioxide particles; heating the cooled filtrate in a boiling water bath, introducing mesoporous manganese dioxide particles subjected to alkali treatment, filtering, nano-filtering the filtrate, regulating pH, refrigerating, standing, completely precipitating, filtering, washing, recrystallizing, and vacuum drying; the invention can obtain the beta-cyclodextrin derivative product with high yield and high stability, and has the advantages of industrial controllability, simple operation and no toxicity.
Description
Technical Field
The invention relates to the technical field of cyclodextrin derivative synthesis, in particular to a preparation method and application of a beta-cyclodextrin derivative.
Background
Mono- [ 6-p-toluenesulfonyl-6-deoxidisation]Beta-cyclodextrin is one of beta-cyclodextrin derivatives and has the molecular formula of C 49 H 76 O 36 S is an important medical intermediate, can be used as a raw material to react with other substances to further generate derivatives of beta-cyclodextrin, such as thiol derivatives, and has a molecular recognition function; the beta-cyclodextrin modified electrode can also be prepared by directly reacting with cysteamine assembled on a gold electrode, and can be also used for identifying specific molecules and preparing the beta-cyclodextrin modified electrodeHas a profound application prospect in measurement.
The current methods for preparing mono- [ 6-p-toluenesulfonyl-6-deoxy ] -beta-cyclodextrin mainly comprise the following steps: the pyridine method has the advantages that the yield is higher, but the pyridine medium is a toxic and harmful substance, the using amount is large, and anhydrous treatment is needed before the pyridine method is used, so that the early anhydrous treatment also makes the experimental steps complicated; acetonitrile, which is relatively less toxic than the medium used, but which is less productive and too much; the method for preparing the p-toluenesulfonic acid anhydride does not need toxic solvents, the yield is improved compared with the method, but the existing finished product of the p-toluenesulfonic acid anhydride serving as the raw material is available abroad, but the cost is high, and if the p-toluenesulfonic acid anhydride is prepared by self, the conditions are difficult to control, so that the experiment difficulty is increased.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention provides a preparation method and application of the beta-cyclodextrin derivative, which can obtain the beta-cyclodextrin derivative product with high yield and high stability, and has the advantages of industrial controllability, simple operation and no toxicity.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
a method for preparing a beta-cyclodextrin derivative, which comprises the following steps: preparing amino modified mesoporous manganese dioxide, preparing mesoporous manganese dioxide particles subjected to alkali treatment, and mixing for reaction;
adding mesoporous manganese dioxide and anhydrous toluene into a reaction container, stirring, replacing air in the reaction container with nitrogen, sealing the reaction container, heating to 110 ℃, then dropwise adding 3-aminopropyl trimethoxy silane, continuously stirring for 12 hours after the dropwise adding is finished, filtering after the reaction is finished, flushing a filter cake, drying and grinding to obtain the amino-modified mesoporous manganese dioxide;
in the preparation of the amino modified mesoporous manganese dioxide, the mass volume ratio of the mesoporous manganese dioxide to the anhydrous toluene to the 3-aminopropyl trimethoxysilane is 60g:160 mL:12mL;
the dropping speed of the 3-aminopropyl trimethoxysilane is 0.30g/min;
the stirring speed during stirring is 40rpm;
the filter cake is washed by toluene, acetone and absolute ethyl alcohol respectively;
the mass volume ratio of the mesoporous manganese dioxide in the preparation of the amino modified mesoporous manganese dioxide to the toluene, the acetone and the absolute ethyl alcohol in the flushing filter cake is 60g:800mL:400mL:500mL;
the temperature during drying is 60 ℃;
the grinding mesh number is 200 mesh;
adding amino modified mesoporous manganese dioxide into a reaction vessel, stirring, adding sodium hydroxide solution, stirring for 2 hours, filtering, and vacuum drying the precipitate to obtain mesoporous manganese dioxide particles after alkali treatment;
in the mesoporous manganese dioxide particles subjected to alkali treatment, the mass volume ratio of the amino modified mesoporous manganese dioxide to the sodium hydroxide solution is 50-60g:100mL;
the concentration of the sodium hydroxide solution is 5-6mol/L;
the stirring speed during stirring is 35rpm;
the temperature during vacuum drying is 60 ℃;
adding dry beta-cyclodextrin into water, fully stirring to obtain beta-cyclodextrin solution, pouring the beta-cyclodextrin solution into a reaction container, adding p-toluenesulfonyl chloride, stirring for the first time at room temperature, adding alkaline-treated mesoporous manganese dioxide particles under the condition of ice water bath, stirring for the second time, and filtering out the alkaline-treated mesoporous manganese dioxide particles; performing first vacuum drying on the filtered mesoporous manganese dioxide particles subjected to alkali treatment to obtain mesoporous manganese dioxide particles subjected to vacuum drying treatment; heating the cooled filtrate through a boiling water bath, introducing mesoporous manganese dioxide particles subjected to vacuum drying treatment for filtering, then nanofiltration the filtrate, dropwise adding hydrochloric acid to adjust the pH of the filtrate to 5.5-6.5, refrigerating and standing, completely precipitating, filtering, washing, recrystallizing, and performing secondary vacuum drying to obtain the beta-cyclodextrin derivative;
in the mixing reaction, the mass volume ratio of the dry beta-cyclodextrin to water in the beta-cyclodextrin solution is 36-48g:400mL;
the mass ratio of the dried beta-cyclodextrin to the p-toluenesulfonyl chloride to the alkali-treated mesoporous manganese dioxide particles is 36-48:6-12:20-50;
the rotation speed of the first stirring is 250rpm, and the time is 2 hours;
the rotation speed of the second stirring is 100rpm, and the time is 2 hours;
the temperature of the first vacuum drying is 60 ℃;
the nanofiltration membrane used in the nanofiltration has the model of NF90-400, the precision of 0.001nm and the desalination rate of more than 97%;
the concentration of the hydrochloric acid is 2mol/L;
the temperature of the cold storage and standing is 4 ℃ and the time is 12 hours;
the number of times of recrystallization is two;
the temperature of the second vacuum drying is 60 ℃ and the time is 12 hours.
Use of a beta-cyclodextrin derivative prepared by the aforementioned preparation method.
Compared with the prior art, the invention has the beneficial effects that:
(1) The preparation method of the beta-cyclodextrin derivative, specifically the synthesis method of the mono- [ 6-p-toluenesulfonyl-6-deoxidization ] -beta-cyclodextrin, introduces mesoporous manganese dioxide particles after alkali treatment simultaneously by adopting a water phase synthesis method, and releases-OH in a solution by an alkaline substance in a charge gradient way, thereby avoiding the generation of a large amount of byproducts under the condition of overbase, improving the yield and purity of the product, and the manganese dioxide particles can be used as an adsorption and filtration material while being used as a catalyst, and the obtained recovered particles can be reused, and simplify the steps, and the method has the advantages of high yield, good product stability, simplicity in operation, no toxicity and the like;
(2) The purity of the beta-cyclodextrin derivative prepared by the preparation method can reach 95.6-96.4%, and the yield is 48.5-50.4%;
(3) The preparation method of the beta-cyclodextrin derivative has high inclusion rate, and the inclusion rate of the prepared beta-cyclodextrin derivative can reach 93.87-94.61%;
(4) The beta-cyclodextrin derivative prepared by the preparation method of the beta-cyclodextrin derivative has high solubilization rate, less drug release, certain controlled release and stability, and higher safety of the prepared inclusion compound drug, the solubilization rate can reach 502.8-532.6, and the release amount of 24 hours can be reduced to 0.005-0.008 percent when the beta-cyclodextrin derivative prepared by the preparation method is used for inclusion of luteolin.
Detailed Description
Specific embodiments of the present invention will now be described in order to provide a clearer understanding of the technical features, objects and effects of the present invention.
Example 1
1. 60g of mesoporous manganese dioxide and 1600mL of anhydrous toluene are added into a 2L four-necked flask, a stirring device is built at the straight mouth of the four-necked flask, a reflux condenser pipe is built at one inclined mouth, nitrogen is introduced into the other inclined mouth, and the rest inclined mouth is opened first; filling nitrogen into a 5L nitrogen bag, connecting a nitrogen guide pipe to the position below the liquid level, starting stirring, controlling the stirring speed to 40rpm, connecting a liquid sealing device on a reflux condenser pipe, extruding the nitrogen bag to exhaust for 3min so as to exhaust air in the four-neck flask, filling the nitrogen into the four-neck flask, sealing the four-neck flask, putting the flask into an oil bath pot for heating, adding 12mL of 3-aminopropyl trimethoxysilane at a speed of 0.30g/min after the temperature is stabilized at 110 ℃, and continuously stirring for 12h at a rotating speed of 40rpm; after the reaction is finished, carrying out suction filtration, respectively flushing the obtained filter cake with 800mL of toluene, 400mL of acetone and 500mL of absolute ethyl alcohol, drying at 60 ℃ to constant weight, grinding to powder, and sieving by a 200-mesh sieve to obtain amino-modified mesoporous manganese dioxide;
2. adding 50g of amino modified mesoporous manganese dioxide into a reaction bottle, magnetically stirring at a speed of 35rpm, simultaneously adding 100mL of sodium hydroxide (NaOH) solution with a concentration of 5mol/L, stirring for 2 hours, filtering, and vacuum drying the precipitate at 60 ℃ to obtain mesoporous manganese dioxide particles after alkali treatment;
3. placing 36g of fully dried beta-cyclodextrin into 400mL of water, fully stirring to be milky, pouring into a 1L four-neck flask, adding 6g of p-toluenesulfonyl chloride, stirring at a stirring speed of 250rpm for 2 hours at room temperature, adding 20g of alkali-treated mesoporous manganese dioxide particles under the condition of ice water bath, controlling the stirring speed to be 100rpm, stirring for 2 hours, stopping stirring, and filtering out the alkali-treated mesoporous manganese dioxide particles; vacuum drying the filtered alkali-treated mesoporous manganese dioxide particles at 60 ℃ to obtain vacuum-dried mesoporous manganese dioxide particles; filtering cooled filtrate by passing through a boiling water bath, heating, introducing mesoporous manganese dioxide particles subjected to vacuum drying treatment, removing part of byproducts such as polyphthalation byproducts and C-2 sulfophthalation products by adsorption, separating and removing small molecular impurities from filtrate by a nanofiltration membrane NF90-400 with the precision of 0.001nm and the desalination rate of more than 97%, adding hydrochloric acid with the concentration of 2mol/L dropwise, regulating the filtrate to pH value of 5.5, refrigerating and standing at 4 ℃ for 12 hours, completely precipitating, filtering to obtain white solid, washing with purified water, recrystallizing twice, and vacuum drying at 60 ℃ for 12 hours to obtain 20.45g of white powder (namely beta-cyclodextrin derivative), wherein the purity is 95.6%, and the yield is 48.5%.
Example 2
1. 60g of mesoporous manganese dioxide and 1600mL of anhydrous toluene are added into a 2L four-necked flask, a stirring device is built at the straight mouth of the four-necked flask, a reflux condenser pipe is built at one inclined mouth, nitrogen is introduced into the other inclined mouth, and the rest inclined mouth is opened first; filling nitrogen into a 5L nitrogen bag, connecting a nitrogen guide pipe to the lower part of the liquid surface, starting stirring, controlling the stirring speed to 40rpm, connecting a liquid sealing device on a reflux condenser pipe, extruding the nitrogen bag to exhaust for 3min, sealing a four-neck flask, heating the flask in an oil bath pot, adding 12mL of 3-aminopropyl trimethoxysilane at the speed of 0.30g/min after the temperature is stabilized at 110 ℃, and continuously stirring at the rotating speed of 40rpm for reaction for 12h; after the reaction is finished, carrying out suction filtration, respectively flushing the obtained filter cake with 800mL of toluene, 400mL of acetone and 500mL of absolute ethyl alcohol, drying to constant weight at 60 ℃, grinding to powder, and sieving by a 200-mesh sieve to obtain the amino-modified mesoporous manganese dioxide.
2. Adding 60g of amino modified mesoporous manganese dioxide into a reaction bottle, magnetically stirring at a speed of 35rpm, simultaneously adding 100mL of NaOH solution with a concentration of 6mol/L, stirring for 2 hours, filtering, and vacuum drying a precipitate at a temperature of 60 ℃ to obtain mesoporous manganese dioxide particles after alkali treatment;
3. placing 48g of fully dried beta-cyclodextrin into 400mL of water, fully stirring to be milky, pouring into a 1L four-neck flask, adding 12g of p-toluenesulfonyl chloride, stirring at the stirring speed of 250rpm for 2 hours at room temperature, adding 50g of alkali-treated mesoporous manganese dioxide particles under the ice water bath condition, controlling the stirring speed to be 100rpm, stirring for 2 hours, stopping stirring, and filtering out the alkali-treated mesoporous manganese dioxide particles; vacuum drying the filtered mesoporous manganese dioxide particles at 60 ℃ to obtain mesoporous manganese dioxide particles after vacuum drying treatment; filtering cooled filtrate through vacuum drying treated mesoporous manganese dioxide particles after boiling water bath heating to adsorb and remove part of byproducts such as polyphthalation byproducts and C-2 sulfophthalation products, separating and removing small molecular impurities from filtrate through a nanofiltration membrane NF90-400 with the precision of 0.001nm and the desalination rate of more than 97%, adding hydrochloric acid with the concentration of 2mol/L dropwise to adjust the filtrate to pH value of 6.5, refrigerating and standing for 12h at 4 ℃, standing for complete precipitation, filtering to obtain white solid, washing with purified water, performing vacuum drying for 12h at 60 ℃ on the obtained white solid for two times to obtain 28.13g of white powder (namely beta-cyclodextrin derivative), wherein the purity is 96.4%, and the yield is 50.4%.
Example 3
Placing 36g of fully dried beta-cyclodextrin into 400mL of water, fully stirring to be milky, pouring into a 1L four-neck flask, adding 6g of p-toluenesulfonyl chloride, stirring at a stirring speed of 250rpm for 2 hours at room temperature, adding 20g of untreated mesoporous manganese dioxide particles under the condition of ice water bath, controlling the stirring speed to be 100rpm, stirring for 2 hours, stopping stirring, and filtering the untreated mesoporous manganese dioxide particles; vacuum drying the filtered untreated mesoporous manganese dioxide particles at 60 ℃ to obtain vacuum-dried mesoporous manganese dioxide; filtering cooled filtrate through vacuum-dried mesoporous manganese dioxide after boiling water bath heating to adsorb and remove partial byproducts such as polyphthalation byproducts and C-2 sulfophthalation products, separating and removing micromolecular impurities from filtrate through a nanofiltration membrane NF90-400 with the precision of 0.001nm and the desalination rate of more than 97%, adding hydrochloric acid with the concentration of 2mol/L dropwise to adjust the filtrate to pH=6.5, refrigerating and standing for 12h at 4 ℃, standing for complete precipitation, filtering to obtain white solid, washing with purified water, recrystallizing twice, and vacuum-drying at 60 ℃ for 12h to obtain 17.26g of white powder (namely beta-cyclodextrin derivative), wherein the purity is 90.1%, and the yield is 38.5%.
Comparative example 1
Placing 36g of fully dried beta-cyclodextrin into 400mL of water, fully stirring to be milky, pouring into a 1L four-neck flask, adding 6g of p-toluenesulfonyl chloride, stirring at 250rpm for 2h at room temperature, adding 40mL of NaOH solution with the concentration of 4.0mol/L under the condition of ice water bath, controlling the stirring speed to be 100rpm, stirring for 2h, stopping stirring, filtering to remove insoluble matters, collecting filtrate, dripping hydrochloric acid with the concentration of 2.0mol/L, regulating the filtrate to pH=6, refrigerating at 4 ℃ for 12h, standing for complete precipitation, filtering to obtain white solid, washing with purified water, recrystallizing twice, drying in vacuum at 60 ℃ for 12h to obtain 14.48g of white powder (namely beta-cyclodextrin derivative), wherein the purity is 85.8%, and the yield is 30.8%.
Comparative example 2
36g of fully dried beta-cyclodextrin is weighed and suspended in 300mL of water, and fully stirred into emulsion to obtain beta-cyclodextrin solution; 6.4g of NaOH is dissolved in 10mL of water to obtain NaOH solution; stirring the beta-cyclodextrin solution at room temperature at a stirring speed of 200rpm, then pouring the NaOH solution into the beta-cyclodextrin solution, and clarifying the solution to obtain a mixed solution of the beta-cyclodextrin; 6g of p-toluenesulfonyl chloride is dissolved in 1mL of acetonitrile, a mixed solution of beta-cyclodextrin is added dropwise at the speed of 0.30g/min at the temperature of 0 ℃, after the dropwise addition is finished, the mixture is stirred for 2 hours at the stirring speed of 250rm at room temperature, hydrochloric acid with the concentration of 2mol/L is used for neutralizing the mixture to the pH value of 6.0, then the white solid is obtained by vacuum filtration, 100mL of ethanol is used for washing, the mixture is recrystallized twice, and after the mixture is dried in vacuum at the temperature of 60 ℃ for 12 hours, 12.60g of white powder (namely beta-cyclodextrin derivative) with the purity of 84.3 percent and the yield of 26.3 percent is obtained.
Wherein, the comparative example 1 is a water phase synthesis method, and the reaction principle is that the beta-cyclodextrin derivative is prepared by an inclusion mechanism; comparative example 2 is an acetonitrile/water solvent process with a reaction mechanism that produces a beta-cyclodextrin derivative via a non-inclusion mechanism.
Test example 1 detection of drug inclusion by mono- [ 6-p-toluenesulfonyl-6-deoxy ] -beta-cyclodextrin
Weighing 858.7mg of luteolin, adding into 50mL of 40% methanol by mass fraction, and dissolving in hot water bath at 60 ℃ to obtain luteolin methanol solution; 3.864g of the mono- [ 6-p-toluenesulfonyl-6-deoxy ] -beta-cyclodextrin prepared in examples 1-3 and comparative examples 1-2 are weighed according to the same amount of substances, 60mL of water is added, the mixture is heated to 60 ℃ to be dissolved and become saturated solution, the luteolin methanol solution is dropwise added into the cyclodextrin derivative solution at the speed of 3mL/min under the condition of constant temperature of 60 ℃, reflux stirring is carried out for 3 hours, a reflux device is removed, heating is carried out for 0.5 hours at the temperature of 60 ℃ again, methanol is removed, natural cooling is carried out, standing overnight, filtering precipitation is carried out, each washing is carried out for 3 times by using methanol and distilled water, the filtrate is frozen and dried to obtain a solid inclusion compound, three times are parallel, and the inclusion rate is averaged.
Test example 2 detection of solubilization of drug by mono- [ 6-p-toluenesulfonyl-6-deoxy ] -beta-cyclodextrin
Weighing 0.3g of the solid inclusion compound prepared in the test example 1 and 0.3g of luteolin, respectively placing the solid inclusion compound and the 0.3g of luteolin into a 100mL volumetric flask, adding water into the volumetric flask to fix the volume to 100mL, preparing supersaturated solution, oscillating for 1h at 40 ℃, taking supernatant, centrifuging for 10min, respectively precisely measuring 2mL of supernatant in the 10mL volumetric flask, using 40% methanol to fix the volume, carrying out ultrasonic treatment for 20min, measuring under chromatographic conditions, recording peak area, substituting a regression equation to calculate the solubility of the inclusion compound and the luteolin, wherein the solubility of the inclusion compound is = (the solubility of the inclusion compound)/(the solubility of the luteolin is multiplied by 10). The release of the drug was monitored by uv-vis spectrophotometry for 24 hours and the release was recorded for 24 hours.
The test results of test examples 1 and 2 are shown below:
the results show that the beta-cyclodextrin derivatives prepared in the examples 1-2 have high solubilization rate, less drug release, certain controlled release and stability, and higher safety of inclusion compound drugs.
The percentages used in the present invention are mass percentages unless otherwise indicated.
Finally, it should be noted that: the foregoing description is only a preferred embodiment of the present invention, and the present invention is not limited thereto, but it is to be understood that modifications and equivalents of some of the technical features described in the foregoing embodiments may be made by those skilled in the art, although the present invention has been described in detail with reference to the foregoing embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (6)
1. A method for preparing a beta-cyclodextrin derivative, which is characterized by comprising the following steps: preparing amino modified mesoporous manganese dioxide, preparing mesoporous manganese dioxide particles subjected to alkali treatment, and mixing for reaction;
adding mesoporous manganese dioxide and anhydrous toluene into a reaction container, stirring, replacing air in the reaction container with nitrogen, sealing the reaction container, heating to 110 ℃, then dropwise adding 3-aminopropyl trimethoxy silane, continuously stirring for 12 hours after the dropwise adding is finished, filtering after the reaction is finished, flushing a filter cake, drying and grinding to obtain the amino-modified mesoporous manganese dioxide;
adding amino modified mesoporous manganese dioxide into a reaction vessel, stirring, adding sodium hydroxide solution, stirring for 2 hours, filtering, and vacuum drying the precipitate to obtain mesoporous manganese dioxide particles after alkali treatment;
adding dry beta-cyclodextrin into water, fully stirring to obtain beta-cyclodextrin solution, pouring the beta-cyclodextrin solution into a reaction container, adding p-toluenesulfonyl chloride, stirring for the first time at room temperature, adding alkaline-treated mesoporous manganese dioxide particles under the condition of ice water bath, stirring for the second time, and filtering out the alkaline-treated mesoporous manganese dioxide particles; performing first vacuum drying on the filtered mesoporous manganese dioxide particles subjected to alkali treatment to obtain mesoporous manganese dioxide particles subjected to vacuum drying treatment; and heating the cooled filtrate through a boiling water bath, introducing mesoporous manganese dioxide particles subjected to vacuum drying treatment for filtering, then nanofiltration the filtrate, dropwise adding hydrochloric acid to adjust the pH of the filtrate to 5.5-6.5, refrigerating and standing, completely precipitating, filtering, washing, recrystallizing, and performing secondary vacuum drying to obtain the beta-cyclodextrin derivative.
2. The method for preparing the beta-cyclodextrin derivative according to claim 1, wherein in the preparation of the amino-modified mesoporous manganese dioxide, the mass-volume ratio of the mesoporous manganese dioxide, the anhydrous toluene and the 3-aminopropyl trimethoxysilane is 60g:160 ml:12ml.
3. The method for producing a β -cyclodextrin derivative according to claim 1, wherein the dropping speed of the 3-aminopropyl trimethoxysilane is 0.30g/min.
4. The method for producing a β -cyclodextrin derivative according to claim 1, wherein the flush cake is flushed with toluene, acetone, and absolute ethanol, respectively;
the mass volume ratio of the mesoporous manganese dioxide in the preparation of the amino modified mesoporous manganese dioxide to the toluene, the acetone and the absolute ethyl alcohol in the flushing filter cake is 60g:800mL:400mL:500mL.
5. The method for preparing the beta-cyclodextrin derivative according to claim 1, wherein the mass-volume ratio of the amino-modified mesoporous manganese dioxide to the sodium hydroxide solution in the mesoporous manganese dioxide particles after the alkali treatment is 50-60 g/100 mL.
6. The method for preparing a beta-cyclodextrin derivative according to claim 1, wherein in the mixing reaction, the mass-to-volume ratio of the dried beta-cyclodextrin to water in the beta-cyclodextrin solution is 36-48g:400ml;
the mass ratio of the dried beta-cyclodextrin to the p-toluenesulfonyl chloride to the alkali-treated mesoporous manganese dioxide particles is 36-48:6-12:20-50.
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