阅读说明：本技术 一种双极膜法制备d-泛解酸内酯的工艺 (Process for preparing D-pantolactone by bipolar membrane method ) 是由 李博 张琳 寿高锋 杨赛 王钰 陈亚君 王玉岗 于 2019-10-08 设计创作，主要内容包括：本发明公开了一种双极膜法制备D-泛解酸内酯的工艺,该工艺包括：D-泛解酸盐溶液经双极膜电渗析装置进行解离,得到D-泛解酸内酯水溶液和碱液,D-泛解酸内酯水溶液经过萃取和结晶得到D-泛解酸内酯产品。本发明主要是解决现有技术中需要强酸酸化、产品光学活性不易保持的问题,提供一种采用双极膜电渗析技术转化D-泛解酸盐制备D-泛解酸内酯的方法,该方法具有不需强酸酸化、产品光学纯度高的优点。(The invention discloses a process for preparing D-pantoic acid lactone by a bipolar membrane method, which comprises the following steps: and dissociating the D-pantoate solution by a bipolar membrane electrodialysis device to obtain a D-pantolactone aqueous solution and alkali liquor, and extracting and crystallizing the D-pantolactone aqueous solution to obtain a D-pantolactone product. The invention mainly solves the problems that strong acid is needed for acidification and the optical activity of the product is not easy to maintain in the prior art, and provides a method for preparing D-pantolactone by converting D-pantoate by adopting a bipolar membrane electrodialysis technology.)

1. A process for preparing D-pantolactone by a bipolar membrane method is characterized by comprising the following steps: and dissociating the D-pantoate solution by a bipolar membrane electrodialysis device to obtain a D-pantolactone aqueous solution and alkali liquor, and extracting and crystallizing the D-pantolactone aqueous solution to obtain a D-pantolactone product.

2. The process for preparing D-pantolactone by using the bipolar membrane method of claim 1, wherein the bipolar membrane electrodialysis device is operated at a constant voltage and the current density is controlled to be 10 to 100mA/cm²Preferably 40-70mA/cm²；

The running time of the bipolar membrane electrodialysis device is 2-8h, and preferably 4-7 h.

3. The process for preparing D-pantolactone by the bipolar membrane process of claim 1 wherein the solution of said D-pantoate is passed into the acid compartment of said bipolar membrane electrodialysis device at the time of dissociation in a concentration of 10 to 50% by weight, preferably 15 to 25% by weight.

4. The bipolar membrane process for preparing D-pantolactone according to claim 1, wherein the linear flow rate of the solution flowing through the electrode compartment, the alkali compartment and the acid compartment is controlled by a peristaltic pump to be 3 to 10cm/s during the operation of the bipolar membrane electrodialysis device.

5. The process for preparing D-pantoic acid lactone by bipolar membrane process of claim 1, characterized in that the extractant used for extraction is dichloromethane, 1, 2-dichloroethane, ethyl acetate, n-butyl acetate, isobutyl acetate, diethyl ether, isopropyl ether or methyl tert-butyl ether, preferably the extractant is dichloromethane or ethyl acetate.

6. The process for preparing D-pantolactone by the bipolar membrane process of any one of claims 1 to 5, wherein the reaction temperature of the acid compartment of the bipolar membrane electrodialysis device is 30 to 50 ℃, preferably 35 to 40 ℃.

7. The process for preparing D-pantolactone by the bipolar membrane method according to any one of claims 1 to 5, wherein the preparation of the D-pantolactone solution comprises: d, L-pantolactone is subjected to hydrolysis reaction under the action of D-pantolactone hydrolase, the pH value is controlled to be 6.8-7.2 by using an alkaline substance in the reaction process, and the D, L-pantolactone is subjected to post-treatment after the reaction is finished.

8. The process for preparing D-pantolactone by the bipolar membrane process of claim 7, wherein the D-pantolactone hydrolase is added in the form of a strain producing D-pantolactone hydrolase;

the post-treatment comprises filtering and recovering the strain, and then extracting with an extractant, wherein the obtained water phase is the D-pantoate solution, and the extractant used for extraction is dichloromethane, 1, 2-dichloroethane, ethyl acetate, n-butyl acetate, isobutyl acetate, diethyl ether, isopropyl ether or methyl tert-butyl ether; preferably, the extractant is dichloromethane or ethyl acetate.

9. The process for preparing D-pantolactone by the bipolar membrane process of claim 8 wherein the alkaline substance for adjusting pH is an alkaline solution obtained by dissociation in a bipolar membrane electrodialysis device; or one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate and ammonia water which are independently added are mixed, and sodium hydroxide is preferred.

10. The process for preparing D-pantolactone by the bipolar membrane process of claim 9, wherein the strain producing D-pantolactone hydrolase is one or more of Fusarium Fusarium, Gibberella Gibberella, Gliocladium, Aspergillus terreus, Rhizopus, preferably Fusarium verticillium Verticillioides.

11. The process for preparing D-pantolactone by the bipolar membrane process of claim 10, wherein the strain used in the hydrolysis reaction may be free mycelium obtained by direct filtration after the end of fermentation or immobilized mycelium; preferably, immobilized mycelium is used.

12. The process for preparing D-pantolactone by the bipolar membrane process of claim 11, wherein the organic phase obtained by extraction contains L-pantolactone, and the L-pantolactone is subjected to racemization by heating under an alkaline condition for recycling.

Technical Field

The invention relates to a novel synthesis process of D-pantolactone, belonging to the technical field of chemical engineering.

Background

Calcium D-pantothenate, also known as vitamin B5, is an essential trace substance for maintaining normal physiological functions in humans and animals. It can be converted into pantothenic acid to synthesize coenzyme A, has the function of promoting the metabolism of carbohydrate, fat and protein, and can be widely applied to the fields of medicines, foods, feed additives and the like. The synthesis and chiral resolution technology of D-Pantolactone (D-Pantolactone) is a key technology for producing products such as D-calcium pantothenate, D-panthenol and D-pantethine.

The chemical resolution method for preparing D-pantoic acid lactone needs to use expensive chiral resolution reagent, has too high production cost and also has the defects of complex process and poor optical purity of products. At present, the method for producing D-pantoic acid lactone at home and abroad is mainly based on a biological resolution method, namely D-pantoic acid lactone in D, L-pantoic acid lactone is selectively hydrolyzed by microbial enzyme to obtain D-pantoic acid (salt) with high optical purity, and the D-pantoic acid (salt) is lactonized and converted into the D-pantoic acid lactone again.

Patent CN 1313402A adopts Neurospora moniliforme to ferment and produce D-pantoic acid lactone hydrolase, which is used for hydrolyzing D-pantoic acid lactone to produce D-pantoic acid, a large amount of ammonia water is used to maintain PH in the hydrolysis process, and then hydrochloric acid is used to acidify (PH 1) D-pantoic acid ammonium salt solution, thus a large amount of ammonia water and hydrochloric acid are consumed while lactonization is realized; patents CN 101392278B and CN107446966A used a similar strategy, still maintaining PH using ammonia, to hydrolyze D-pantoic acid lactone to D-pantoic acid ammonium salt, but using concentrated sulfuric acid for acidification lactonization. The methods all need to use a large amount of strong acid for lactonization, and the lactonization under the acid and high temperature can cause racemization of D-pantoic acid or lactone thereof, which is not beneficial to maintaining the optical purity of D-pantoic acid lactone products.

Bipolar membrane electrodialysis is a green, environment-friendly and energy-saving membrane separation technology and can separate water into H under low voltage⁺And OH^-Can convert organic and inorganic salts into corresponding acids and alkalis in one stepHas no chemical reagent consumption and no by-product generation, and has wide application prospect in chemical industry, environmental protection, biological separation, energy and pharmaceutical industry. However, until now, no process study for preparing D-pantolactone by converting D-pantoate by bipolar membrane electrodialysis has been known.

Disclosure of Invention

The invention mainly solves the problems of strong acid acidification and low product optical purity in the prior art, and provides a method for preparing D-pantolactone by converting D-pantoate by adopting a bipolar membrane electrodialysis technology.

In order to solve the problems, the technical scheme adopted by the invention is as follows:

a process for preparing D-pantolactone by bipolar membrane method includes such steps as dissociating the D-pantolactone solution by bipolar membrane electrodialysis to obtain D-pantolactone aqueous solution and alkali solution, and extracting and crystallizing the D-pantolactone aqueous solution to obtain D-pantolactone product.

The process for preparing D-pantolactone by the bipolar membrane method comprises the steps of introducing a D-pantoate solution into an acid chamber in a bipolar membrane electrodialysis membrane stack, and introducing deionized water into an alkali chamber in the bipolar membrane electrodialysis membrane stack; h produced by bipolar membrane dissociation under the action of direct current⁺Combines with D-pantoate anion in the acid chamber to generate D-pantoic acid, and under the action of self-acid catalysis, the D-pantoate lactone is closed to form cation (such as Na) in the acid chamber⁺) Is transferred to the alkali chamber through the cation exchange membrane to dissociate from the bipolar membrane in the alkali chamber to generate OH^-The combination produces a base (e.g., NaOH).

In the process for preparing D-pantoic acid lactone by using the bipolar membrane method, the bipolar membrane material in the bipolar membrane device is Neosepta BP-1 of ASTOM company. The anode and the cathode of the bipolar membrane electrodialysis device are made of corrosion-resistant titanium-coated ruthenium; the compartment between adjacent ion exchange membranes comprises the alkali chamber and the acid chamber and is composed of a gasket with a flow channel and a grid, and the thickness of the gasket is 0.8 mm.

The preparation of D-The process of pantoic acid lactone, in the course of bipolar membrane electrodialysis operation, constant voltage operation, current density is set to 10-100mA/cm²Preferably 40-70mA/cm²。

In the process for preparing D-pantolactone by the bipolar membrane method, the running time of a bipolar membrane electrodialysis device, namely the reaction time for preparing D-pantolactone by membrane separation is 2-8h, and preferably, the reaction time is 4-7 h.

The process for preparing D-pantolactone by the bipolar membrane method has the advantages that the concentration of D-pantoate solution introduced into an acid chamber is 10-50 wt%, and preferably, the concentration of D-pantoate is 15-25 wt%.

In the process for preparing D-pantoic acid lactone by the bipolar membrane method, before electrodialytic dissociation, the feed liquid of each compartment is circulated for 5-30 minutes by a peristaltic pump, and bubbles in a membrane stack are discharged. In the operation process, the peristaltic pump is used for controlling the linear flow rate of the flowing solutions in the electrode chamber, the alkali chamber and the acid chamber to be 3-10cm/s, so that the concentration polarization phenomenon is avoided.

According to the process for preparing D-pantolactone by the bipolar membrane method, the conversion rate of D-pantolactone sodium in the bipolar membrane electrodialysis conversion process can be up to 99%, and the content of metal cations (such as sodium ions) can be reduced to below 300 mg/L.

In the process for preparing D-pantoic acid lactone by the bipolar membrane method, an extracting agent adopted by extraction is dichloromethane, 1, 2-dichloroethane, ethyl acetate, n-butyl acetate, isobutyl acetate, diethyl ether, isopropyl ether or methyl tert-butyl ether, and preferably, the extracting agent is dichloromethane or ethyl acetate.

In the process for preparing D-pantolactone by the bipolar membrane method, the acid chamber of the bipolar membrane electrodialysis device is kept at the reaction temperature of 30-50 ℃ by using a water bath, and preferably, the reaction temperature is 35-40 ℃.

The process for preparing D-pantoic acid lactone by the bipolar membrane method comprises the steps of carrying out hydrolysis reaction on D, L-pantoic acid lactone under the action of D-pantoic acid lactone hydrolase, controlling the pH value to be 6.8-7.2 by using an alkaline substance in the reaction process, and carrying out post-treatment after the reaction is finished.

The process for preparing D-pantolactone by the bipolar membrane method, wherein the D-pantolactone hydrolase is added in the form of a strain for producing the D-pantolactone hydrolase;

the post-treatment comprises filtering and recovering the strain, and then extracting with an extractant, wherein the obtained water phase is a D-pantoate solution, the extractant is dichloromethane, 1, 2-dichloroethane, ethyl acetate, n-butyl acetate, isobutyl acetate, diethyl ether, isopropyl ether or methyl tert-butyl ether, and preferably, the extractant is dichloromethane or ethyl acetate.

The process for preparing D-pantolactone by the bipolar membrane method is characterized in that an alkaline substance for adjusting pH is an alkali liquor obtained by dissociation of a bipolar membrane electrodialysis device, and one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, ammonia water and the like can be independently added for mixing, preferably sodium hydroxide.

In the process for preparing D-pantolactone by the bipolar membrane method, the strain producing D-pantolactone hydrolase can be one or a mixture of more of Fusarium, Gibberella, Gliocladium, Aspergillus terreus, Rhizopus rhizogenes and other strains producing D, L-pantolactone hydrolase. Preferably, Fusarium verticillium vertetillioides is adopted as the strain for producing the D-pantoic acid lactone hydrolase, which is collected and separated from soil near New Changjiang county of New Changjiang province by the company of the inventor, and the preservation number is CGMCC NO. 14552.

In the process for preparing D-pantolactone by the bipolar membrane method, the strain for hydrolysis reaction can be free mycelium obtained by direct filtration after fermentation or immobilized mycelium. Preferably, immobilized mycelium is used.

According to the process for preparing the D-pantoic acid lactone by the bipolar membrane method, the organic phase obtained by extraction contains the L-pantoic acid lactone, and the L-pantoic acid lactone is heated, racemized and recycled under the alkaline condition.

After hydrolysis of D, L-pantoic acid lactone is completed, a bipolar membrane electrodialysis technology is adopted to separate D-pantoate solution, corresponding alkali and D-pantoic acid can be generated, and the D-pantoic acid is unstable and can be directly lactonized into the D-pantoic acid lactone under the catalysis of self acidity. The whole process does not need strong acid acidification, D-pantoic acid or racemization of D-pantoic acid lactone is not easy to occur, the product yield is high, the purity is more than or equal to 98 percent, and the optical purity is as follows: ee. is more than or equal to 98 percent, and the quality index of the synthesized D-calcium pantothenate and D-panthenol is fully satisfied.

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

1) the invention adopts the bipolar membrane electrodialysis technology to convert D-pantoate into D-pantoic acid and generate D-pantoic acid lactone in situ, does not need strong acid for acidification, has mild reaction conditions, is not easy to racemize an intermediate, is beneficial to maintaining optical activity, and has high optical purity of the obtained product.

2) The alkali liquor generated by bipolar membrane separation can be continuously used for enzyme hydrolysis reaction to regulate and control PH, and the whole process flow does not generate obvious three wastes, so that the method is more green, economic and environment-friendly compared with the prior art.

3) The process of the invention greatly reduces the production cost and equipment investment on the basis of improving the optical purity of the product, avoids the generation of a large amount of waste salt and is more environment-friendly.

Detailed Description

The present invention is further illustrated by, but is not limited to, the following examples.

The immobilized fusarium verticillium mycelium adopted in the embodiment of the invention is from fusarium verticillium ioides with the preservation number of CGMCC NO.14552, and meanwhile, the strain and the corresponding immobilization method are disclosed in Chinese patent application with the publication number of CN 108004291A.