Synthetic method of specific average degree of substitution sulfobutyl ether-β-cyclodextrin

Abstract

The invention discloses a synthesis method of sulfobutyl ether-beta-cyclodextrin with a specific average substitution degree. The synthesis method comprises the following steps: (1) dissolving beta-cyclodextrin into NaOH solution while stirring, wherein the use amount of NaOH solution is 1.6-6.5 times as much as the molar quantity of beta-cyclodextrin; (2) dropwise adding 1,4-butyl sultone and performing reflux etherification; when pH value drops to 8.8, adding NaOH solution to adjust the pH value to be between 8.80-9.70 until the pH value does not change; and then adding all residual NaOH aqueous solution into a reaction container from a sample injector; and (3) when detecting that the mass of residual beta-cyclodextrin in the reaction container is 1% or below, adding NaOH solution, wherein the use amount of NaOH solution is 0.4-1.5 times as much as the molar quantity of beta-cyclodextrin. By the synthesis method, a sulfobutyl ether-beta-cyclodextrin product with a specific average substitution degree can be obtained and the yield is high; in addition, the specific average substitution degree range of the synthesis product is concentrated and the composition of the product is in strict normal distribution; the reaction conditions are mild and post-treatment is simple.

Description

technical field [0001] The invention relates to a synthesis method of sulfobutyl ether-beta-cyclodextrin, and belongs to the fields of synthesis of cyclodextrin derivatives, molecular recognition, chiral resolution and pharmaceutical auxiliary materials. Background technique [0002] Cyclodextrin (CD for short) is a cyclic oligosaccharide formed by the action of cyclodextrin glycosyltransferase on starch. It has a hydrophilic appearance and a hydrophobic inner cavity. The shape is wide at the top and narrow at the bottom. The spatial structure of the three-dimensional configuration of the ring-shaped hollow cone barrel with two ends open. This unique molecular structure enables cyclodextrin to form supramolecular inclusion complexes with guest molecules and change the physical and chemical properties of guest molecules. Therefore, cyclodextrin has become a cheap, easy-to-obtain and biocompatible compound in supramolecular chemistry. It is an important host molecule and is w...

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Problems solved by technology

The synthesis method of sulfobutyl ether-β-cyclodextrin has been reported at present: U.S. Patent US5134127 adopts the method for synthesizing sulfobutyl ether-β-cyclodextrin in water solvent for the first time, utilizes the glucose unit of β-cyclodextrin The hydroxyl groups on the 2, 3, and 6 carbons undergo substitution reactions with 1,4-butane sultone in alkaline solutions to obtain products with a single degree of substitution and multiple degrees of substitution. The disadvantage lies in the degree of substitution of products with multiple substitutions The scope is wide; U.S. Patent US6153746 improves this method, obtains the product that the degree of substitution is 6.6-7.1, and the yield is 50-80%, and its disadvantage is that the yield of the product is low and unstable; Chinese patent CN1858071A uses Metal sodium captures the hydrogen on the hydroxyl group of β-cyclodextrin in the organic solvent 1,4-dioxane to produce more basic sodium alkoxide, which undergoes a nucleophilic substitution reaction with 1,4-butane sultone to obtain Mono-substitution and multi-substitution products, the yield is between 50-60%, the disadvantage is that the yield of the product is low, and metal sodium is a dangerous active metal, the reaction conditions are harsh, and the organic solvent is expensive , high toxicity, may cause environmental pollution; Chinese patent CN103694376A improves the above two methods, introduces one of the organic solvent tetrahydrofuran, 1,4-dioxane or 2-methyltetrahydrofuran into the alkaline aqueous solution, and improves the The solubility of 1,4-butane sultone, the average substitution degree is 6.7 sulfobutyl ether-β-cyclodextrin, the yield is between 75-80%, the disadvantage is the use of organic solvents and electrophoresis The peaks corresponding to each degree of substitution in the figure do not show the law of strict normal distribution

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