CN112661874B - 6-hydroxypropyl substituted beta-cyclodextrin functional medicine adjuvant and preparation method thereof - Google Patents
6-hydroxypropyl substituted beta-cyclodextrin functional medicine adjuvant and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a 6-hydroxypropyl substituted beta-cyclodextrin functional pharmaceutical adjuvant and a preparation method thereof, belonging to the field of synthesis of supermolecular chemistry, pharmaceutical adjuvant and functional polymer intermediates; beta-cyclodextrin and ethylene oxide are used as raw materials, and 5-4 parts of beta-cyclodextrin and 4-part of ethylene oxide are adoptedoC, preparing a series of specific 6-position hydroxypropyl substituted beta-cyclodextrin by matching a specific reaction medium, namely a saturated sodium carbonate solution, a saturated potassium carbonate solution or a sodium hydroxide aqueous solution with the pH value of 10, and obtaining a series of 6-position mono/poly-hydroxypropyl substituted-beta-cyclodextrin functional pharmaceutical adjuvant by water dialysis, freeze drying, separation and purification; the series of auxiliary agents have different inclusion capacities and biological activities, are novel guest molecule selective inclusion reagents, and have potential application values in the fields of functional polymer/supermolecule chemistry, pharmaceutical adjuvant and the like.
Description
Technical Field
The invention relates to the technical field of synthesis of supermolecule chemistry, pharmaceutical adjuvant and functional polymer intermediates, in particular to a 6-hydroxypropyl substituted beta-cyclodextrin functional pharmaceutical adjuvant and a preparation method thereof.
Background
Cyclodextrin (CD) is a generic name for a series of cyclic oligosaccharides produced by amylose under the action of Cyclodextrin glucosyltransferase produced by Bacillus. Cyclodextrins containing seven glucose units are known as beta-cyclodextrins, and each glucose unit is joined by a 1, 4-glycosidic bond to form a slightly tapered circular ring. At present, beta-cyclodextrin (beta-CD) and derivatives thereof are common and efficient supramolecular inclusion materials, are widely applied to separation and synthesis of organic compounds, and are also used as pharmaceutical excipients, food additives and the like. In medical treatment, people carry out inclusion on cyclodextrin or cyclodextrin derivatives and some drug molecules without biocompatibility, so that the biocompatibility of the drug is increased, and a slow release effect is achieved. The hydroxypropyl beta-cyclodextrin can break the intramolecular cyclic hydrogen bond of the beta-cyclodextrin due to the introduction of hydroxypropyl, effectively overcomes the defect of poor water solubility of the beta-cyclodextrin while maintaining the internal cavity of the cyclodextrin, is an ideal solubilizer and pharmaceutical excipient of an injection, can further improve the water solubility of insoluble drugs, increase the stability of the drugs, improve the bioavailability of the drugs, increase the curative effect or reduce the dosage of the drugs, adjust or control the release rate of the drugs and reduce the toxic and side effects of the drugs.
In the prior art, Chinese patent with application number 201010600228.6 discloses a preparation method of hydroxypropyl-beta-cyclodextrin, which adopts sodium hydroxide, beta-cyclodextrin and 1, 2-propylene oxide as raw materials, and sequentially carries out the procedures of etherification, neutralization, decoloration, nanofiltration, resin purification and spray drying to prepare the hydroxypropyl-beta-cyclodextrin with narrow substitution degree range and low magazine content, wherein the yield reaches 80 percent, and the substitution degree is 4.8-5.0.
However, the hydroxypropyl- β -cyclodextrin obtained by the above method has problems of low yield and high degree of substitution of the product, and the hemolytic property of hydroxypropyl- β -cyclodextrin is related to the degree of substitution, and the lower the degree of substitution, the greater the hemolytic property. Therefore, based on the problem, the Chinese patent application with the application number of 201410419763.X discloses a preparation method of hydroxypropyl-beta-cyclodextrin, which takes self-made beta-cyclodextrin, 1, 2-epoxypropane and sodium hydroxide as raw materials, firstly dissolves the beta-cyclodextrin in a sodium hydroxide aqueous solution with the mass concentration of 20% -25% at the temperature of 50-55 ℃, then dropwise adds the 1, 2-epoxypropane into the beta-cyclodextrin at the temperature of 22-24 ℃, controls the molar ratio of the sodium hydroxide, the beta-cyclodextrin and the 1, 2-epoxypropane to be 4:2-3:1-2, and finally prepares the white amorphous powder hydroxypropyl-beta-cyclodextrin through the procedures of hydrochloric acid neutralization, reduced pressure distillation and spray drying.
The hydroxypropyl-beta-cyclodextrin prepared by the preparation method of the prior art such as the above also has the following problems: as described in the application document with the application number of 201010600228.6, a beta-cyclodextrin molecule contains a plurality of hydroxyl groups with the same reaction activity, so that hydroxypropyl-beta-cyclodextrin is a mixture generated by randomly substituting hydroxyl groups on a beta-cyclodextrin ring by hydroxypropyl groups, so that the hydroxypropyl groups are obtained by randomly substituting primary and secondary hydroxyl groups on the beta-cyclodextrin by hydroxypropyl groups, the product structure is complex, the selective guest inclusion capacity is low, and the inclusion performance is single and has no controllability. However, no research has been made in the prior art on which method can be used to achieve a specific substitution site on hydroxypropyl-substituted beta-cyclodextrin, particularly a substitution at a specific 6-position to obtain 6-hydroxypropyl-substituted beta-cyclodextrin.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a 6-hydroxypropyl substituted beta-cyclodextrin functional pharmaceutical adjuvant and a preparation method thereof aiming at the defects of the prior art, the method is simple and convenient to operate, no new organic reagent is introduced in the synthesis process, no toxicity or pollution is caused, and the process conditions are convenient and controllable.
The technical scheme for solving the technical problems is as follows: the preparation method of the 6-hydroxypropyl substituted beta-cyclodextrin functional medicine adjuvant is characterized by comprising the following steps:
taking beta-cyclodextrin as a raw material, adding a reaction medium into the beta-cyclodextrin, wherein the reaction medium adopts saturated sodium carbonate solution and saturated carbonic acidPotassium solution or sodium hydroxide aqueous solution with pH of 10, after completely dissolving, adjusting the temperature of the system to keep it at-5 to 4oC is between; then slowly and dropwise adding the epoxy propane into the reaction system; after the dropwise addition, the mixture is added at-5 to 4oC, reacting at constant temperature; after the reaction is finished, removing inorganic salt in the mixture by a deionized water dialysis method; obtaining a 6-hydroxypropyl substituted beta-cyclodextrin functional monomer crude product by a freeze drying method; then separating and purifying to obtain 6-hydroxypropyl substituted-beta-cyclodextrin.
Further, after the beta-cyclodextrin is completely dissolved in the reaction medium, the beta-cyclodextrin is placed in an ice salt bath to keep the beta-cyclodextrin at-5 to 4 DEGoAnd C.
Furthermore, the dropping mode of the propylene oxide adopts a constant-pressure dropping funnel to slowly and dropwise add the propylene oxide into the reaction system.
Furthermore, the main product of 6-position single hydroxypropyl substituted-beta-cyclodextrin or 6-position polyhydroxy propyl substituted-beta-cyclodextrin is prepared by controlling the dosage ratio of the dropwise added epoxypropane to the beta-cyclodextrin.
Furthermore, the mol ratio of the added propylene oxide to the beta-cyclodextrin is controlled not to exceed 10.5:1, and the main product is 6-site single hydroxypropyl substituted-beta-cyclodextrin or 6-site poly hydroxypropyl substituted-beta-cyclodextrin.
Further, controlling the mol ratio of the dropwise added propylene oxide to the beta-cyclodextrin not to exceed 1.5:1 to prepare a main product of 6-site mono-hydroxypropyl substituted-beta-cyclodextrin; or controlling the molar ratio of the added propylene oxide to the beta-cyclodextrin to be more than 1.5N: 1 and not more than 1.5 (N + 1): 1, preparing a main product 6-site N hydroxypropyl substituted-beta-cyclodextrin, wherein N is a positive integer not more than 6, namely 6-site di-, tri-, tetra-, penta-, hexa-or heptahydroxypropyl substituted-beta-cyclodextrin.
Further, after the dropwise adding is finished, the solution is added at-5 to 4 DEG CoAnd C, reacting for 12-24 h at constant temperature.
Further, the purification of the 6-hydroxypropyl substituted-beta-cyclodextrin adopts sephadex G-25 as a carrier and deionized water as an eluent, and the 6-hydroxypropyl substituted-beta-cyclodextrin functional monomer crude product is separated and purified to obtain the 6-hydroxypropyl substituted-beta-cyclodextrin
The 6-hydroxypropyl substituted beta-cyclodextrin functional medicine adjuvant prepared by the preparation method is characterized by having the following structural formula:
wherein: r =
Or H, and at least one R is
。
The invention has the beneficial effects that:
1. in order to effectively regulate the intramolecular cyclic hydrogen bond of beta-cyclodextrin and the entrance and exit of guest molecules into and out of the internal cavity of cyclodextrin, the inclusion performance of cyclodextrin on different guests is regulated, taking beta-cyclodextrin (beta-CD) as an example, the steric effect of primary hydroxyl at 6-position and secondary hydroxyl at other positions and the nucleophilic activity difference of oxygen are utilized, the beta-cyclodextrin and ethylene oxide are taken as raw materials, and 5-4 parts of beta-cyclodextrin and ethylene oxide are adoptedoC, under the temperature condition, slowly dripping ethylene oxide, matching with a specific reaction medium, namely a saturated sodium carbonate solution, a saturated potassium carbonate solution or a sodium hydroxide aqueous solution with the pH value of 10, selectively carrying out hydroxypropylation on 6-position primary hydroxyl to prepare a series of specific 6-position hydroxypropyl substituted beta-cyclodextrins, and selectively changing the possibility that different drug molecules enter a cyclodextrin cavity by effectively controlling the size of an inlet aperture of the cyclodextrin, so that the inclusion capacity and selectivity of different drug objects are improved, and the yield is 21.8-40.3%;
2. the method is simple and convenient to operate, does not introduce a new organic reagent in the synthesis process, is non-toxic and pollution-free, and is a potential functional medicine adjuvant;
in addition, by implementing the preparation method, the control of the main product to be mono-substituted or multi-substituted can be realized only by simply adjusting the dosage ratio of the ethylene oxide to the beta-cyclodextrin, the process conditions are more convenient and controllable, the series of auxiliary products have different inclusion capacities and biological activities, are novel guest molecule selective inclusion reagents, and have potential application values in the fields of functional polymer/supramolecular chemistry, pharmaceutical auxiliaries and the like.
Drawings
FIG. 1 shows a process for preparing beta-cyclodextrin as a starting material of the present invention1H NMR spectrum;
FIG. 2 shows the preparation of the desired product 6-position mono-hydroxypropyl substituted-beta-cyclodextrin functional drug adjuvant according to example 1 of the present invention1H NMR spectrum;
FIG. 3 shows the preparation of the desired product 6-heptahydroxypropyl-substituted-beta-cyclodextrin as an adjuvant1H NMR spectrum.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Further, it should be understood that various changes or modifications of the present invention may be made by those skilled in the art after reading the teaching of the present invention, and such equivalents may fall within the scope of the present invention as defined in the appended claims.
Example 1
Weighing 4.54 g (0.4 mmol) of beta-cyclodextrin which is dried overnight in vacuum and placed in a 100 mL round-bottom flask, adding 50.0 mL of saturated sodium carbonate solution, completely dissolving the beta-cyclodextrin under ultrasonic condition, placing the beta-cyclodextrin in a cold salt bath, and allowing the temperature of the system to be stabilized at-5-4 DEG CoBetween C, 0.0348 g (0.6 mmol) of propylene oxide was slowly and dropwise added to the reaction system through a constant pressure dropping funnel; after the dropwise addition, the mixture is added at-5 to 4oC, after the mixture is subjected to constant-temperature reaction for 12 hours, inorganic salt in the mixture is removed by a simple dialysis method of deionized water, a crude product of the 6-hydroxypropyl monosubstituted-beta-cyclodextrin functional monomer is obtained by a freeze drying method, and then the pure 6-hydroxypropyl monosubstituted-beta-cyclodextrin functional pharmaceutical adjuvant is obtained by separation and purification by taking glucan gel G-25 as a carrier and deionized water as an eluent, wherein the yield is 37.6%.
Example 2
Weighing4.54 g (0.4 mmol) of beta-cyclodextrin which is dried overnight in vacuum is placed in a 100 mL round-bottom flask, 50.0 mL of saturated potassium carbonate solution is added, the beta-cyclodextrin is completely dissolved under the ultrasonic condition, the beta-cyclodextrin is placed in a salt bath with ice, and when the temperature of the system is stabilized at-5-4 DEG CoBetween C, 0.0696 g (1.2 mmol) of propylene oxide is added into the reaction system dropwise through a constant pressure dropping funnel; after the dropwise addition, the mixture is added at-5 to 4oC, after reacting for 16 hours at constant temperature, removing inorganic salts in the mixture by a simple dialysis method of deionized water, obtaining a 6-position hydroxypropyl polysubstituted-beta-cyclodextrin functional monomer crude product by a freeze drying method, separating and purifying by using dextran gel G-25 as a carrier and deionized water as an eluent to obtain a main product 6-position dihydroxypropyl substituted-beta-cyclodextrin functional medicine auxiliary agent, wherein the yield is 32.3%.
Example 3
Weighing 4.54 g (0.4 mmol) of beta-cyclodextrin which is dried overnight in vacuum and placed in a 100 mL round-bottom flask, adding 50.0 mL of saturated potassium carbonate solution, completely dissolving the beta-cyclodextrin under ultrasonic condition, placing the beta-cyclodextrin in a salt-ice bath, and standing until the temperature of the system is stabilized at-5-4 DEG CoBetween C, 0.1044 g (1.8 mmol) of propylene oxide was added dropwise to the reaction system through a constant pressure dropping funnel; after the dropwise addition, the mixture is added at-5 to 4oAnd C, after reacting for 18 hours at constant temperature, removing inorganic salts in the mixture by a simple deionized water dialysis method, obtaining a 6-position hydroxypropyl polysubstituted-beta-cyclodextrin functional monomer crude product by a freeze drying method, and separating and purifying by using dextran gel G-25 as a carrier and deionized water as an eluent to obtain a main product 6-position trihydroxypropyl substituted-beta-cyclodextrin functional medicine auxiliary agent with the yield of 27.4%.
Example 4
Weighing 4.54 g (0.4 mmol) of beta-cyclodextrin which is dried overnight in vacuum and placed in a 100 mL round-bottom flask, adding 50.0 mL of saturated potassium carbonate solution, completely dissolving the beta-cyclodextrin under ultrasonic condition, placing the beta-cyclodextrin in a salt-ice bath, and standing until the temperature of the system is stabilized at-5-4 DEG CoBetween C, 0.1392 g (2.4 mmol) of propylene oxide was added dropwise to the reaction system through a constant pressure dropping funnel; after the dropwise addition, the mixture is added at-5 to 4oC, after the mixture is subjected to constant temperature reaction for 20 hours, inorganic salt in the mixture is removed by a simple deionized water dialysis method,the 6-bit hydroxypropyl poly-substituted-beta-cyclodextrin functional monomer crude product is obtained by a freeze drying method, and then is separated and purified by taking glucan gel G-25 as a carrier and deionized water as an eluent to obtain the main product 6-bit tetra-hydroxypropyl substituted-beta-cyclodextrin functional medicine auxiliary agent, wherein the yield is 32.6%.
Example 5
Weighing 4.54 g (0.4 mmol) of beta-cyclodextrin which is dried overnight in vacuum and placed in a 100 mL round-bottom flask, adding 50.0 mL of saturated potassium carbonate solution, completely dissolving the beta-cyclodextrin under ultrasonic condition, placing the beta-cyclodextrin in a salt-ice bath, and standing until the temperature of the system is stabilized at-5-4 DEG CoBetween C, 0.174 g (3.0 mmol) of propylene oxide was added dropwise to the reaction system through a constant pressure dropping funnel; after the dropwise addition, the mixture is added at-5 to 4oAnd C, after the mixture is subjected to constant-temperature reaction for 24 hours, inorganic salt in the mixture is removed by a simple deionized water dialysis method, a 6-position hydroxypropyl polysubstituted-beta-cyclodextrin functional monomer crude product is obtained by a freeze drying method, then the crude product is separated and purified by using glucan gel G-25 as a carrier and deionized water as an eluent to obtain a main product 6-position pentahydroxypropyl substituted-beta-cyclodextrin functional medicine auxiliary agent, and the yield is 24.6%.
Example 6
Weighing 4.54 g (0.4 mmol) of beta-cyclodextrin which is dried overnight in vacuum and placed in a 100 mL round-bottom flask, adding 50.0 mL of saturated potassium carbonate solution, completely dissolving the beta-cyclodextrin under ultrasonic condition, placing the beta-cyclodextrin in a salt-ice bath, and standing until the temperature of the system is stabilized at-5-4 DEG CoBetween C, 0.2088 g (3.6 mmol) of propylene oxide was added dropwise to the reaction system through a constant pressure dropping funnel; after the dropwise addition, the mixture is added at-5 to 4oAnd C, after the mixture is subjected to constant-temperature reaction for 24 hours, inorganic salt in the mixture is removed by a simple deionized water dialysis method, a 6-bit hydroxypropyl poly-substituted-beta-cyclodextrin functional monomer crude product is obtained by a freeze drying method, then the crude product is separated and purified by using glucan gel G-25 as a carrier and deionized water as an eluent to obtain a main product 6-bit hexahydroxypropyl substituted-beta-cyclodextrin functional medicine auxiliary agent, and the yield is 21.8%.
Example 7
4.54 g (0.4 mmol) of vacuum dried overnight beta-cyclodextrin was weighed into a 100 mL round bottom flask, and 50.0 mL of saturated carbonic acid was addedDissolving the potassium solution completely under the ultrasonic condition, placing the potassium solution in a salt bath with ice until the temperature of the system is stabilized at-5 to 4 DEG CoBetween C, 0.2436 g (4.2 mmol) of propylene oxide was added dropwise to the reaction system through a constant pressure dropping funnel; after the dropwise addition, the mixture is added at-5 to 4oAnd C, after the mixture is subjected to constant-temperature reaction for 24 hours, inorganic salt in the mixture is removed by a simple deionized water dialysis method, a 6-position hydroxypropyl poly-substituted-beta-cyclodextrin functional monomer crude product is obtained by a freeze drying method, then the crude product is separated and purified by using glucan gel G-25 as a carrier and deionized water as an eluent to obtain a main product 6-position heptahydroxypropyl substituted-beta-cyclodextrin functional medicine auxiliary agent, and the yield is 40.3%.
The starting material beta-cyclodextrin used in this example was commercial beta-cyclodextrin.
Referring to the structural formula of the target product 6-hydroxypropyl-substituted-beta-cyclodextrin functional drug adjuvant of the invention, the substitution rate of hydroxypropyl can be determined1The integral area of two peaks at δ =1.27 ppm and δ =5.05 ppm in the HNMR atlas, i.e. the H atomic number ratio, was inferred.
Process for preparing beta-cyclodextrin as raw material of the present invention1The H NMR spectrum is shown in fig. 1, and the raw material β -cyclodextrin has an isolated doublet peak at δ =5.03 ppm, corresponds to a hydrogen atom number of 7, is assigned to H on the tertiary carbon linked to the glycosidic bond in β -cyclodextrin, and has no nuclear magnetic peak below 2 ppm. When the primary hydroxyl group is replaced by the hydroxypropyl group, a double peak appears around delta =1.27 ppm in a nuclear magnetic spectrum of the derivative, the H on the methyl group of the hydroxypropyl substituent is assigned, and the number of the hydroxypropyl substituent is deduced through the ratio of the hydrogen atom number near the delta =1.27 ppm to the hydrogen atom number near the delta =5.05 ppm.
The target product 6-site single hydroxypropyl substituted-beta-cyclodextrin functional drug auxiliary agent of the embodiment 1 of the invention1As shown in fig. 2, the H NMR spectrum demonstrated that the structure was a 6-position monohydroxypropyl-substituted- β -cyclodextrin functional drug adjuvant because the ratio of the number of hydrogen atoms at δ =1.27 ppm to the number of hydrogen atoms at δ =5.03 ppm was 3: 7.
The 1H NMR spectrum of the target product 6-position heptahydroxypropyl-substituted- β -cyclodextrin functional drug auxiliary of example 7 is shown in fig. 3, and the ratio of the number of hydrogen atoms at δ =1.18 ppm to the number of hydrogen atoms at δ =5.03 ppm was 21:7, so that it was confirmed that the structure was the 6-position heptahydroxypropyl-substituted- β -cyclodextrin functional drug auxiliary.
Claims (8)
- The preparation method of the 1.6-hydroxypropyl substituted beta-cyclodextrin functional medicine adjuvant is characterized by comprising the following steps:taking beta-cyclodextrin as a raw material, adding a reaction medium into the beta-cyclodextrin, wherein the reaction medium is a saturated sodium carbonate solution or a saturated potassium carbonate solution, and after the beta-cyclodextrin is completely dissolved, adjusting the temperature of a system to keep the temperature of the system at-5-4 DEG CoC is between; then slowly and dropwise adding the epoxy propane into the reaction system; after the dropwise addition, the mixture is added at-5 to 4oC, reacting at constant temperature; after the reaction is finished, removing inorganic salt in the mixture by a deionized water dialysis method; obtaining a 6-hydroxypropyl substituted beta-cyclodextrin functional monomer crude product by a freeze drying method; then separating and purifying to obtain 6-hydroxypropyl substituted-beta-cyclodextrin.
- 2. The method according to claim 1, wherein the beta-cyclodextrin is dissolved completely in the reaction medium and then placed in a salt bath of ice salt to be maintained at-5 to 4%oAnd C.
- 3. The preparation method according to claim 1, wherein the propylene oxide is added dropwise by slowly and dropwise adding the propylene oxide into the reaction system through a constant pressure dropping funnel.
- 4. The method according to claim 1, wherein the main product is 6-monohydroxypropyl-substituted- β -cyclodextrin or 6-polyhydroxypropyl-substituted- β -cyclodextrin obtained by controlling the amount ratio of propylene oxide to β -cyclodextrin added dropwise.
- 5. The process according to claim 4, wherein the molar ratio of the propylene oxide to the β -cyclodextrin to be added dropwise is controlled to be not more than 10.5:1, and the main product is 6-monohydroxypropyl-substituted- β -cyclodextrin or 6-polyhydroxypropyl-substituted- β -cyclodextrin.
- 6. The preparation method according to claim 5, wherein the molar ratio of the added propylene oxide to the beta-cyclodextrin is controlled not to exceed 1.5:1, and the main product is 6-position mono-hydroxypropyl substituted-beta-cyclodextrin; or controlling the molar ratio of the added propylene oxide to the beta-cyclodextrin to be more than 1.5N: 1 and not more than 1.5 (N + 1): 1, preparing a main product of 6-N hydroxypropyl substituted-beta-cyclodextrin, wherein N is a positive integer not more than 6.
- 7. The method according to claim 1, wherein the concentration is-5 to 4 times the concentration after the dropwise additionoAnd C, reacting for 12-24 h at constant temperature.
- 8. The preparation method of claim 1, wherein the purification of the 6-hydroxypropyl substituted- β -cyclodextrin is performed by using sephadex G-25 as a carrier and deionized water as an eluent, and the 6-hydroxypropyl substituted- β -cyclodextrin is obtained by separating and purifying a crude product of a 6-hydroxypropyl substituted- β -cyclodextrin functional monomer.
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