CN103736402B - A kind of sodium alginate chirality cross linking membrane and application thereof - Google Patents

Abstract

The invention discloses a sodium alginate chiral cross-linked membrane and an application thereof. Weigh sodium alginate and dissolve it in acetic acid aqueous solution, ultrasonically remove aggregated particle molecules, and let it stand for defoaming; pour the casting solution on a clean and smooth glass plate at room temperature, scrape the film with a scraper, and dry it for 4 days; The membrane is immersed in an acetone crosslinking agent containing glutaraldehyde and hydrochloric acid for crosslinking; after the crosslinked membrane is washed with a large amount of acetone and ultrapure water in sequence until neutral, the desired chiral crosslinked membrane is obtained. The cross-linked membrane is installed in a conventional dialysis device, and the aqueous solution of D, L-p-hydroxyphenylglycine racemate is separated under the drive of concentration difference, and the enantiomeric purity of p-hydroxyphenylglycine in the permeate is above 60%. The film-making raw material of the invention is cheap, and the obtained single enantiomer has high purity and large throughput, energy saving, environmental protection, low cost, and easy continuous operation and large-scale industrial production.

Description

A kind of sodium alginate chiral cross-linked membrane and its application

technical field

The invention belongs to the technical field of separation of chiral polymer membranes, and in particular relates to a sodium alginate chiral crosslinked membrane. At the same time, the invention also relates to the application of the chiral cross-linked membrane in the resolution of D,L-p-hydroxyphenylglycine racemate.

Background technique

Chirality is a common phenomenon in nature, and there are a large number of chiral molecules in nature and living organisms. The problem of chirality of drugs arises from the chiral properties of nature to the chirality of compounds. A chiral drug refers to a drug composed of a chiral compound with pharmacological activity, and the molecular structure of the drug and its mirror image cannot be superimposed on each other, and they are drug structural enantiomers in a mirror image relationship. Because the in vivo pharmacokinetic process of the two enantiomers of chiral drugs is different, there are often significant differences in the pharmacological activity, metabolic process, metabolic rate and toxicity of the two enantiomers of chiral drugs in vivo. The following four situations: (1) only one enantiomer has the required pharmacological activity, while the other enantiomer has no pharmacological activity; (2) one of the two enantiomers has the required pharmacological activity, The other enantiomer has other toxic and side effects pharmacological activities; (3) The pharmacological activities of each enantiomer are the same but not equal. (4) The two enantiomers have different pharmacological activities. Due to the lack of understanding of chiral drugs, many painful lessons have been learned, such as the "reactin" teratogenic event in the 1960s, which made people realize that chiral drugs must pay attention to their different configurations.

The production of chiral compounds is generally through four major ways: natural sources, chiral source synthesis, asymmetric synthesis and racemate resolution. Chiral synthesis is currently used in a narrow range, and the enantiomeric excess value (e.e.%) is often low; chiral resolution techniques include mechanical resolution, crystal seeding resolution, biological resolution, chemical resolution , chromatographic resolution, molecularly imprinted polymer resolution and membrane resolution, etc., but it is suitable for large-scale production, energy saving, environmental protection, and low cost is the chiral polymer membrane resolution method.

The single enantiomer D-p-hydroxyphenylglycine is the raw material for the production of antibiotic side chains, but most of the synthesized p-hydroxyphenylglycine is racemic, and my country is a big country in the production and demand of antibiotics, semi-synthetic cephalosporins and Semi-synthetic penicillin drugs have become the focus and focus of the pharmaceutical industry. Therefore, it is of great significance to the chiral resolution of D, L-p-hydroxyphenylglycine.

So far, there has been no public report on the chiral crosslinked membrane of sodium alginate and its application in the resolution of D,L-p-hydroxyphenylglycine racemate.

Contents of the invention

The purpose of the present invention is to provide a sodium alginate chiral cross-linked membrane prepared from sodium alginate and a multifunctional group compound to address the deficiencies of the prior art.

The purpose of the present invention is also to provide the application of the sodium alginate chiral cross-linked membrane in the resolution of D,L-p-hydroxyphenylglycine racemate.

The purpose of the present invention is achieved through the following technical solutions.

Unless otherwise specified, the percentages used in the present invention are all mass percentages.

A sodium alginate chiral cross-linked membrane is characterized in that: sodium alginate is dissolved in acetic acid aqueous solution to directly spread the film, and the dry film is cross-linked with a multifunctional group compound to obtain the required chiral cross-linked membrane.

Specifically prepared by the following method:

(1) Put sodium alginate in 2wt.% acetic acid aqueous solution, stir and dissolve, and the concentration of sodium alginate in the final solution is 5wt.%;

(2) Ultrasound for 30 minutes to remove aggregated particle molecules, stand still for defoaming, and obtain casting solution;

(3) Pour the casting solution on a smooth glass plate at room temperature, scrape the film with a scraper, and dry at room temperature for 4 days;

(4) The dry film is cross-linked with multifunctional group compounds;

(5) Rinse and wash with acetone and water in turn until neutral to obtain the desired chiral cross-linked sodium alginate membrane.

The multifunctional group compound is one of polyaldehyde, polyisocyanate, polyacyl chloride or polyanhydride, or contains two or more functional groups of aldehyde, isocyanate, acid chloride or acid anhydride. Because the effective body of sodium alginate cross-linked chiral film is sodium alginate, but there are a large number of hydroxyl groups in the molecular structure of sodium alginate, therefore, polyhydric aldehydes, polyisocyanates, polyacyl chlorides or polyanhydrides, or contain more than two The functional group of aldehyde, isocyanate, acid chloride or acid anhydride can be used as a crosslinking agent to achieve the same chiral separation effect.

The described multifunctional group compound is preferably an acetone solution containing 5% glutaraldehyde and 0.1% hydrochloric acid.

Application of the sodium alginate chiral cross-linked membrane in the resolution of D,L-p-hydroxyphenylglycine racemate.

Specifically: the sodium alginate chiral cross-linked membrane is loaded into a conventional dialysis device, and the aqueous solution of D, L-p-hydroxyphenylglycine racemate is separated under the drive of a concentration difference of 0-0.8 mg/mL.

Compared with the prior art, the present invention has the advantages of:

1. The enantiomeric purity (e.e.%) obtained by using the sodium alginate-glutaraldehyde chiral cross-linked membrane of the present invention to resolve D, L-p-hydroxyphenylglycine racemate can reach more than 60%, which can realize Separation of higher enantiomeric purity;

2. No new chemical reagents are added during the membrane splitting process, which is environmentally friendly and low in cost;

3. Membrane splitting is carried out at close to normal temperature, no phase change occurs, and low energy consumption;

4. Membrane separation is easy for continuous operation and large-scale industrial production.

Description of drawings

Fig. 1 is the molecular structural formula of sodium alginate;

Fig. 2 is the detection spectrum of enantiomer sample passing through the chiral high-performance liquid chromatography.

detailed description:

The content of the present invention will be further described in detail below in conjunction with the accompanying drawings and embodiments. However, the drawings and embodiments are not limitations to the technical solution of the present invention.

Example 1

Commercial sodium alginate was used as raw material, dissolved in 2wt.% acetic acid aqueous solution to make the concentration 5wt.%; stirred and dissolved, ultrasonicated for 30 minutes to remove aggregated particle molecules, and left to defoam; at room temperature, pour the casting solution on a smooth surface Scrape the film with a scraper on a glass plate and dry it at room temperature for 4 days; cross-link the dry film with an acetone cross-linking agent containing 5% glutaraldehyde and 0.1% hydrochloric acid; properties; that is, to obtain the desired sodium alginate chiral cross-linked membrane.

Application Example 1

Put the sodium alginate chiral cross-linked membrane prepared in Example 1 into a conventional dialysis device, drive at a concentration difference of 0.8 mg/mL, and resolve racemization of D,L-p-hydroxyphenylglycine with a concentration of 0.8 mg/mL body water solution.

The experimental results show that: the sodium alginate chiral cross-linked membrane of the present invention is used to resolve D, L-p-hydroxyphenylglycine racemate, and the p-hydroxyphenylglycine enantiomer sample obtained after passing through the membrane is analyzed by high performance liquid chromatography. It shows that its purity is above 60%, which can realize the separation of high enantiomeric purity; since the membrane separation is carried out at close to normal temperature, no phase change occurs, so the energy consumption is low; since the membrane separation process does not add new chemical reagents , so it is environmentally friendly and low in cost; membrane separation is easy for continuous operation and large-scale industrial production.

The effect of chiral separation is shown in Figure 2. The raw materials for chiral membrane resolution are racemic compounds. In racemic compounds, the concentrations of left-handed and right-handed enantiomers are equal. Therefore, if a membrane without chiral resolution capability is used to resolve racemates , it should be reflected in Figure 2 as two peaks with equal areas. And we can see from Fig. 2 that there is an obvious difference in the areas of the two peaks, so it shows that the sodium alginate chiral crosslinked membrane of the present invention has obvious selectivity to the left-handed and right-handed enantiomers. The high performance liquid chromatography of the enantiomer sample of p-hydroxyphenylglycine obtained after passing through the membrane shows that its purity is above 60%, which can realize the separation of high enantiomeric purity.

Example 2

Commercial sodium alginate was used as raw material, dissolved in 2wt.% acetic acid aqueous solution to make the concentration 5wt.%; stirred and dissolved, ultrasonicated for 30 minutes to remove aggregated particle molecules, and left to defoam; at room temperature, pour the casting solution on a smooth surface On a glass plate, scrape the film with a scraper and dry it at room temperature for 4 days; cross-link the dry film with a 6.7% 1,6-hexamethylene diisocyanate n-heptane solution; rinse with a large amount of heptane, acetone, and water in sequence To neutral; that is, to obtain the desired sodium alginate chiral cross-linked membrane.

Application Example 2

Put the sodium alginate chiral cross-linked membrane prepared in Example 2 into a conventional dialysis device, drive at a concentration difference of 0.4 mg/mL, and resolve racemization of D,L-p-hydroxyphenylglycine with a concentration of 0.4 mg/mL body water solution.

The experimental results show that: the sodium alginate chiral cross-linked membrane of the present invention is used to resolve D, L-p-hydroxyphenylglycine racemate, and the p-hydroxyphenylglycine enantiomer sample obtained after passing through the membrane is analyzed by high performance liquid chromatography. It shows that its purity is above 55%, which can realize the separation of higher enantiomeric purity; since the membrane separation is carried out at close to normal temperature, no phase change occurs, so the energy consumption is low; since the membrane separation process does not add new chemical Reagents are environmentally friendly and low in cost; membrane separation is easy for continuous operation and large-scale industrial production.

Claims (2)

1. A sodium alginate chiral cross-linked membrane, characterized in that it is prepared by the following method: (1) Sodium alginate is placed in 2wt.% acetic acid aqueous solution, stirred and dissolved, and the concentration of sodium alginate in the final solution is 5wt.%; (2) Ultrasound for 30 minutes to remove aggregated particle molecules, stand still for defoaming, and obtain the casting solution; (3) Pour the casting solution on a smooth glass plate at room temperature, scrape the film with a scraper, and dry at room temperature for 4 days; (4) The dry film is cross-linked with a multifunctional group compound, and the multifunctional group compound is an acetone solution containing 5% glutaraldehyde and 0.1% hydrochloric acid; (5) Rinse and wash with acetone and water in sequence until neutral, and obtain the desired chiral crosslinked sodium alginate membrane. 2. the application of the sodium alginate chiral cross-linked membrane described in claim 1 in the resolution of D, L-p-hydroxyphenylglycine racemate, specifically: the described sodium alginate chiral cross-linked membrane is loaded into a conventional In the dialysis device, the aqueous solution of D, L-p-hydroxyphenylglycine racemate is resolved under the drive of the concentration difference of 0-0.8mg/mL.