Synthetic process for water soluble sulfoalkyl ether-beta-cyclic dextrine

Abstract

The present invention relates to synthesis process of water soluble sulfoalkyl ether-beta-cyclodextrin. The process includes dissolving certain amount of beta-cyclodextrin in anhydrous dioxane solvent, adding certain amount of metal sodium for complete reaction, dropping certain amount of sulfo butyrolactone or sulfo propiolactone slowly into the reaction system, refluxing at certain temperature for etherification reaction, separating out amorphous solid after finishing the reaction, washing with methanol for several times, drying, dissolving the dried solid in deionized water, neutralization with acid to pH 8, desalting purification, concentrating the filtrate, and freeze drying to obtain white or yellowish water soluble sulfobutyl ether-beta-cyclodextrin or sulfopropyl ether-beta-cyclodextrin.

Description

technical field

[0001] The invention relates to a new synthesis process of a water-soluble sulfoalkyl ether-β-cyclodextrin, and belongs to the technical field of synthesis of pharmaceutical auxiliary materials. Background technique

[0002] Cyclodextrin (CD for short) is a cyclic oligosaccharide of D-glucose, which is isolated from the reaction of starch cyclodextrin glycosyltransferase, and is formed by β-glucopyranose in chair conformation through α-(1,4) It is connected by glycosidic bonds and has a special non-polar tire-like ring structure. Its chemical structure is as follows:

[0003]

[0004] Natural cyclodextrins include 6 (n=4, also known as α-CD), 7 (n=5, also known as β-CD), 8 (n=6, also known as γ-CD) chair conformations β-glucopyranose ring. In the field of pharmaceutical formulations, cyclodextrin and its derivatives are known as the perfect "host" body, which can encapsulate various organic and inorganic guest molecules and form non-covalent host-guest c...

Examples

Embodiment 1

[0021]Under stirring, dissolve 10 grams of β-cyclodextrin (8.8 mmol) in 20 mL of anhydrous dioxane solvent, and add 0.24 grams of sodium metal (10.6 mmol) in batches until the sodium metal is completely reacted, and add to the above reaction system 1.8 g of sultone (13.2 mmol) was slowly added dropwise, and the etherification reaction was carried out under reflux at 70° C. for 3 hours. After the reaction was complete, the amorphous solid was separated, washed with methanol three times, and dried. After drying, the solid was dissolved in 100 ml of deionized water, neutralized with 1N hydrochloric acid to pH 8, desalted and purified through a Sephadex column (G-25), the filtrate was concentrated, and freeze-dried to obtain white water-soluble sulfobutyl Ether-β-cyclodextrin 4.7 g (yield about 41%). The average molecular weight is 1307, elemental analysis: measured value C42.75%, H5.96%, S2.71%, Na1.93, C / S=15.77, calculated value (substitution degree is 1.1) C / S=15.7.

Embodiment 2

[0023] Under stirring, dissolve 10 grams of β-cyclodextrin (8.8 mmol) in 20 mL of anhydrous dioxane solvent, add 0.97 grams of sodium metal (42.3 mmol) in batches until the sodium metal is completely reacted, and then add to the above reaction system Slowly add 7.2 g of sultone (52.8 mmol) dropwise, and carry out etherification reaction at 90° C. for 3 hours under reflux reaction. After the reaction is complete, an amorphous solid is separated, washed with methanol three times, and dried. After drying, the solid was dissolved in 150 ml of deionized water, neutralized with 1N sulfuric acid to pH 8, desalted and purified through a Sephadex column (G-25), the filtrate was concentrated, and freeze-dried to obtain white water-soluble sulfobutyl Ether-β-cyclodextrin 8.3 g (yield about 52%). The average molecular weight is 1813, elemental analysis: measured value C39.35%, H5.65%, S7.49%, Na5.52, C / S=5.25, calculated value (substitution degree is 4.3) C / S=5.26.

Embodiment 3

[0025] Under stirring, dissolve 10 grams of β-cyclodextrin (8.8 mmol) in 20 mL of anhydrous dioxane solvent, and add 1.70 grams of sodium metal (73.9 mmol) in batches until the sodium metal is completely reacted, and then add to the above reaction system 12.57 g of sultone (92.4 mmol) was slowly added dropwise, and the reaction was carried out under reflux at 105° C. for etherification for 3 hours. After the reaction was complete, an amorphous solid was separated, washed with methanol three times, and dried. After drying, the solid was dissolved in 200 ml of deionized water, neutralized with 1N hydrochloric acid to pH 8, desalted and purified by ultrafiltration membrane permeation (500 MWCO fiber ester membrane), the filtrate was concentrated, and freeze-dried to obtain a slightly yellow water-soluble sulfonate Butyl ether-β-cyclodextrin 11.4 g (yield about 57%). The average molecular weight is 2271, elemental analysis: measured value C37.44%, H5.32%, S10.21%, Na7.26, C / S=3.67...

technical field

[0001] The invention relates to a new synthesis process of a water-soluble sulfoalkyl ether-β-cyclodextrin, and belongs to the technical field of synthesis of pharmaceutical auxiliary materials. Background technique

[0002] Cyclodextrin (CD for short) is a cyclic oligosaccharide of D-glucose, which is isolated from the reaction of starch cyclodextrin glycosyltransferase, and is formed by β-glucopyranose in chair conformation through α-(1,4) It is connected by glycosidic bonds and has a special non-polar tire-like ring structure. Its chemical structure is as follows:

[0003]

[0004] Natural cyclodextrins include 6 (n=4, also known as α-CD), 7 (n=5, also known as β-CD), 8 (n=6, also known as γ-CD) chair conformations β-glucopyranose ring. In the field of pharmaceutical formulations, cyclodextrin and its derivatives are known as the perfect "host" body, which can encapsulate various organic and inorganic guest molecules and form non-covalent host-guest c...

Examples

Embodiment 1

[0021]Under stirring, dissolve 10 grams of β-cyclodextrin (8.8 mmol) in 20 mL of anhydrous dioxane solvent, and add 0.24 grams of sodium metal (10.6 mmol) in batches until the sodium metal is completely reacted, and add to the above reaction system 1.8 g of sultone (13.2 mmol) was slowly added dropwise, and the etherification reaction was carried out under reflux at 70° C. for 3 hours. After the reaction was complete, the amorphous solid was separated, washed with methanol three times, and dried. After drying, the solid was dissolved in 100 ml of deionized water, neutralized with 1N hydrochloric acid to pH 8, desalted and purified through a Sephadex column (G-25), the filtrate was concentrated, and freeze-dried to obtain white water-soluble sulfobutyl Ether-β-cyclodextrin 4.7 g (yield about 41%). The average molecular weight is 1307, elemental analysis: measured value C42.75%, H5.96%, S2.71%, Na1.93, C / S=15.77, calculated value (substitution degree is 1.1) C / S=15.7.

Embodiment 2

[0023] Under stirring, dissolve 10 grams of β-cyclodextrin (8.8 mmol) in 20 mL of anhydrous dioxane solvent, add 0.97 grams of sodium metal (42.3 mmol) in batches until the sodium metal is completely reacted, and then add to the above reaction system Slowly add 7.2 g of sultone (52.8 mmol) dropwise, and carry out etherification reaction at 90° C. for 3 hours under reflux reaction. After the reaction is complete, an amorphous solid is separated, washed with methanol three times, and dried. After drying, the solid was dissolved in 150 ml of deionized water, neutralized with 1N sulfuric acid to pH 8, desalted and purified through a Sephadex column (G-25), the filtrate was concentrated, and freeze-dried to obtain white water-soluble sulfobutyl Ether-β-cyclodextrin 8.3 g (yield about 52%). The average molecular weight is 1813, elemental analysis: measured value C39.35%, H5.65%, S7.49%, Na5.52, C / S=5.25, calculated value (substitution degree is 4.3) C / S=5.26.

Embodiment 3

[0025] Under stirring, dissolve 10 grams of β-cyclodextrin (8.8 mmol) in 20 mL of anhydrous dioxane solvent, and add 1.70 grams of sodium metal (73.9 mmol) in batches until the sodium metal is completely reacted, and then add to the above reaction system 12.57 g of sultone (92.4 mmol) was slowly added dropwise, and the reaction was carried out under reflux at 105° C. for etherification for 3 hours. After the reaction was complete, an amorphous solid was separated, washed with methanol three times, and dried. After drying, the solid was dissolved in 200 ml of deionized water, neutralized with 1N hydrochloric acid to pH 8, desalted and purified by ultrafiltration membrane permeation (500 MWCO fiber ester membrane), the filtrate was concentrated, and freeze-dried to obtain a slightly yellow water-soluble sulfonate Butyl ether-β-cyclodextrin 11.4 g (yield about 57%). The average molecular weight is 2271, elemental analysis: measured value C37.44%, H5.32%, S10.21%, Na7.26, C / S=3.67...

Images