CN112759667A

CN112759667A - Preparation method of triacetyl-beta-cyclodextrin

Info

Publication number: CN112759667A
Application number: CN202110008545.7A
Authority: CN
Inventors: 崔丽艳; 许维成; 王哲; 王丽萍; 毕方玉
Original assignee: Zibo Qianhui Biotechnology Co ltd
Current assignee: Zibo Qianhui Biotechnology Co ltd
Priority date: 2021-01-05
Filing date: 2021-01-05
Publication date: 2021-05-07

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a method for preparing triacetyl-beta-cyclodextrin, wherein the acylation reaction adopts a solvent-free reaction, the reaction efficiency is high, the post-treatment is simple, the environment is friendly, and the method is suitable for industrial production; iodine or DMAP is used as an acylation catalyst, the reaction can be carried out at room temperature, the reaction speed is high, the utilization rate of an acylation reagent is high, and the purity of a final product is high.

Description

Preparation method of triacetyl-beta-cyclodextrin

Technical Field

The invention belongs to the technical field of organic synthesis, and particularly relates to a method for preparing triacetyl-beta-cyclodextrin.

Background

Beta-cyclodextrin has special inclusion effect on many medicines and has important application in pharmaceutical excipients, but the application is limited due to the defects of solubility and some physical properties. Some of the chemical properties of cyclodextrins can be improved by acetylation, methylation, hydroxypropylation.

Acetyl cyclodextrin obtained by the prior art is basically a partially substituted acylation product, and completely substituted cyclodextrin has fewer documents. Acetic anhydride is used as an acylation reagent and pyridine is used as a solvent in the conventional acetylation reaction of beta-cyclodextrin. This method is not suitable for industrial production because pyridine has toxicity and unpleasant odor. In the prior art, acetic anhydride is used as an acylation reagent to perform catalytic reaction in ionic liquid, the method needs the ionic liquid to perform catalytic reaction, the production cost is increased, and a fully-substituted product is not synthesized. Acetic acid is used as an acylation solvent in Rolff-Herson Kone, post-treatment is complicated, and the utilization rate of acetic anhydride is low.

Disclosure of Invention

In order to overcome the defects in the prior art and prepare the fully-substituted triacetyl-beta-cyclodextrin, the invention provides a preparation method of the triacetyl-beta-cyclodextrin.

The scheme provided by the invention is as follows:

a preparation method of triacetyl-beta-cyclodextrin comprises the following steps:

s1: weighing the acylation reagent and beta-cyclodextrin in reaction amount, wherein the molar ratio of the acylation reagent to the beta-cyclodextrin is 21-30: 1, and preferably 22-26: 1.

Specifically, the acylating agent is one of acetic anhydride or acetyl chloride.

S2: mixing a part of acylation reagent with a reaction amount with beta-cyclodextrin, adding a reaction amount of catalyst, and uniformly stirring to obtain a reaction solution, wherein the mass of the acylation reagent used in the step is 30-80% of the total mass of the acylation reagent; meanwhile, the optimal adding mode of the catalyst is that the catalyst is added in several batches within 10-30min, the stirring state is maintained during the adding, and the adding is generally selected to be carried out for 3-5 times.

Specifically, the catalyst is one of iodine and 4-dimethylaminopyridine (hereinafter, DMAP).

S3: dripping the residual reaction amount of the acylating reagent in the S2 into the first reaction liquid within 10-30min within a certain time, keeping stirring during dripping, and continuously reacting for 4-12h after all dripping to obtain a crude product solution, namely a crude product of triacetyl-beta-cyclodextrin;

s4: and filtering the second reaction solution, washing the filtered filter cake with water for three times, dissolving the filter cake by using a purification solvent, slowly pouring the dissolved solution into purified water, filtering, and drying in vacuum to obtain the final product triacetyl-beta-cyclodextrin.

Specifically, the purification solvent is one or more of methanol, ethanol or acetone, and the dosage of the purification solvent is 10-25% of the total mass of the acylation reagent and the beta-cyclodextrin.

Compared with the prior art, the invention has the advantages that:

1. the synthetic process of the invention does not need organic solvent, avoids environmental pollution and has simple post-treatment.

2. The method adopts iodine or DMAP as an acylation catalyst, can react at room temperature, and has the advantages of high reaction speed, high utilization rate of an acylation reagent and high purity of a final product.

3. The method has the advantages of simple process, mild and easily controlled operating conditions and suitability for industrial production.

Drawings

FIG. 1 shows the nuclear magnetic spectrum of triacetyl- β -cyclodextrin in example 1 of the present invention.

FIG. 2 is an IR spectrum of triacetyl- β -cyclodextrin of example 1 of the present invention.

Detailed Description

The present invention is further illustrated by the following examples.

All materials used in the examples are commercially available, except where specifically indicated.

Example 1

100g of beta-cyclodextrin and 198g of acetic anhydride are weighed out.

100g of beta-cyclodextrin and 66g of acetic anhydride are mixed and stirred, the temperature in a reaction bottle is controlled to be 40 ℃, 0.9g of iodine is added into the reaction bottle for three times in 10min, the rest 132g of acetic anhydride is slowly dripped into the reaction bottle, and the mixture is completely dripped into the bottle for about 30 min. The reaction was continued for 4 h. After the reaction is finished, pouring the feed liquid into 800ml of purified water, filtering, washing a filter cake for three times, dissolving the filter cake with 50ml of ethanol, slowly pouring the dissolved filter cake into 1000ml of purified water, filtering, and drying in vacuum to obtain the triacetyl-beta-cyclodextrin, wherein the yield is 85.2%. The product was analyzed by high performance liquid chromatography and the triacetyl- β -cyclodextrin content was 95.0%.

Example 2

100g of beta-cyclodextrin and 216g of acetic anhydride are weighed.

100g of beta-cyclodextrin and 108g of acetic anhydride are mixed and stirred, the temperature in a reaction bottle is controlled to be 30 ℃, 1.6g of DMAP is added in batches within 15min, the remaining 108g of acetic anhydride is slowly dripped into the reaction bottle, and the acetic anhydride is completely dripped into the bottle within about 25 min. The reaction was continued for 6 h. After the reaction is finished, pouring the feed liquid into 800ml of purified water, filtering, washing a filter cake for three times, dissolving the filter cake by 40ml of methanol, slowly pouring the dissolved filter cake into 1000ml of purified water, filtering, and drying in vacuum to obtain the triacetyl-beta-cyclodextrin, wherein the yield is 87.3%. The product was analyzed by high performance liquid chromatography and the triacetyl- β -cyclodextrin content was 96.4%.

Example 3

100g of beta-cyclodextrin and 173g of acetyl chloride were weighed out.

100g of beta-cyclodextrin and 86.5g of acetyl chloride are mixed and stirred, the temperature in the reaction bottle is controlled to be 20 ℃, 1.6g of iodine is added into the reaction bottle in 15min in batches, and 86.5g of the rest acetyl chloride is slowly dripped into the reaction bottle for about 30 min. The reaction was continued for 8 h. After the reaction is finished, pouring the feed liquid into 800ml of purified water, filtering, washing a filter cake for three times, dissolving the filter cake by 70ml of acetone, slowly pouring the dissolved filter cake into 1000ml of purified water, filtering, and drying in vacuum to obtain the triacetyl-beta-cyclodextrin, wherein the yield is 84.0%. The product was analyzed by high performance liquid chromatography and the triacetyl- β -cyclodextrin content was 94.8%.

Example 4

100g of beta-cyclodextrin and 233.8g of acetic anhydride are weighed.

100g of beta-cyclodextrin and 187g of acetic anhydride are mixed and stirred, the temperature in the reaction bottle is controlled at 30 ℃, 2.6g of iodine is added in batches within 30min, the rest 46.8g of acetic anhydride is slowly dropped into the reaction bottle, and the mixture is completely dropped into the bottle within about 10 min. The reaction was continued for 12 h. After the reaction is finished, pouring the feed liquid into 800ml of purified water, filtering, washing a filter cake for three times, dissolving the filter cake with 50ml of ethanol, slowly pouring the solution into 1000ml of purified water, filtering, and drying in vacuum to obtain the triacetyl-beta-cyclodextrin with the yield of 87.8%. The product was analyzed by high performance liquid chromatography and the triacetyl- β -cyclodextrin content was 97.6%.

Claims

1. A preparation method of triacetyl-beta-cyclodextrin is characterized by comprising the following steps:

s1: weighing acylation reagent and beta-cyclodextrin in reaction amount;

s2: mixing a part of reaction amount of acylation reagent with reaction amount of beta-cyclodextrin, uniformly stirring, and adding reaction amount of catalyst to obtain reaction liquid;

s3: dripping the residual reaction amount of the acylating reagent in the S2 into the first reaction liquid within a certain time, keeping stirring during dripping, and continuously reacting for 4-12h to obtain a crude product solution;

s4: and filtering, washing, purifying and drying the crude product solution to obtain the triacetyl-beta-cyclodextrin.

2. The method for preparing triacetyl-beta-cyclodextrin according to claim 1, wherein the molar ratio of the acylating agent to beta-cyclodextrin in S1 is 21-30: 1.

3. The method of claim 1, wherein the amount of the partially reacted acylating agent in S2 is 30-80% of the mass of the reacted acylating agent in S1.

4. The method of claim 1, wherein the partial reaction amount of the acylating agent in S2 is added dropwise for 10-30 min.

5. The method for preparing triacetyl- β -cyclodextrin according to claim 1, wherein the catalyst in S2 is added in the following manner: maintaining the stirring state, and adding the catalyst for several times within 10-30 min.

6. The method for preparing triacetyl- β -cyclodextrin according to any one of claims 1 to 3, wherein the acylating agent is one of acetic anhydride or acetyl chloride.

7. The method of claim 1 or 5, wherein the catalyst is one of iodine or 4-dimethylaminopyridine.

8. The method for preparing triacetyl- β -cyclodextrin as claimed in claim 1, wherein the purification process in S4 is: and dissolving the filter cake of the washed crude product solution into a purification solvent, slowly pouring the dissolved solution into purified water, and filtering.

9. The method of claim 8, wherein the purification solvent is one or more of methanol, ethanol, and acetone.

10. The method according to claim 8 or 9, wherein the amount of the purification solvent is 10-25% of the total mass of the acylating agent and the beta-cyclodextrin.