阅读说明：本技术 一种HMB-Ca的制备方法 (Preparation method of HMB-Ca ) 是由 石亚楠 洪永德 王碧 李阳 吴文忠 于 2019-09-30 设计创作，主要内容包括：一种HMB-Ca的制备方法,包括下述步骤：(1)氯仿反应：将40-60wt％的双丙酮醇水溶液均分2～3份后分次匀速滴加入10-25wt％氧化剂水溶液中,于18-28℃环境下搅拌反应0.5-1h；(2)产物精制纯化：反应液原液酸化至PH为7-8后,以100-200道尔顿的纳滤膜浓缩除盐至浓缩液体积为原液的45％,膜操作压力为1.5～2.25MPa；继而于60℃进行真空蒸馏继续浓缩至原液质量的10-20％；冷却至室温,搅拌0.5-1h后过滤；向滤液中加入2-3倍质量的洗脱剂,搅拌1h后过滤,烘干得到的HMB-Ca。本发明缩短了工艺路径,提高了转化率；生产过程清洁、环保、安全,成本低廉。(A preparation method of HMB-Ca comprises the following steps: (1) and (3) chloroform reaction: uniformly dripping 2-3 parts of 40-60 wt% diacetone alcohol aqueous solution into 10-25 wt% oxidant aqueous solution at constant speed for several times, and stirring and reacting for 0.5-1h at the temperature of 18-28 ℃; (2) and (3) refining and purifying a product: acidifying the reaction liquid stock solution until the pH value is 7-8, and concentrating and desalting by using a nanofiltration membrane of 100-; then vacuum distillation is carried out at 60 ℃ and concentration is continued until the mass of the stock solution is 10-20%; cooling to room temperature, stirring for 0.5-1h, and filtering; adding eluent with the mass of 2-3 times of the filtrate, stirring for 1h, filtering, and drying to obtain the HMB-Ca. The invention shortens the process path and improves the conversion rate; the production process is clean, environment-friendly, safe and low in cost.)

1. A preparation method of HMB-Ca comprises the following steps:

(1) and (3) chloroform reaction:

uniformly dripping 2-3 parts of 40-60 wt% diacetone alcohol aqueous solution into 10-25 wt% oxidant aqueous solution at constant speed for several times, and stirring and reacting for 0.5-1h at the temperature of 18-28 ℃;

(2) refining and purifying the product

Acidifying the reaction liquid stock solution in the step (1) until the pH value is 7-8, concentrating and desalting by using a nanofiltration membrane of 100 and 200 daltons until the volume of the concentrated solution is 45% of that of the stock solution, and the membrane operating pressure is 1.5-2.25 MPa; then vacuum distillation is carried out at 60 ℃ and concentration is continued until the mass of the stock solution is 10-20%; cooling to room temperature, stirring for 0.5-1h, and filtering; adding eluent with the mass of 2-3 times of the filtrate, stirring for 1h, filtering, and drying to obtain the HMB-Ca.

2. The method of claim 1 wherein said oxidizing agent is selected from the group consisting of calcium hypochlorite, sodium hypoiodate, sodium hypobromite, and calcium hypoiodate.

3. The method of claim 2 wherein said aqueous oxidant solution has a concentration of 15 to 20 wt%.

4. The method of claim 1, wherein said aqueous diacetone alcohol solution has a concentration of 50 wt%.

5. The method of claim 1, wherein the diacetone alcohol aqueous solution is added dropwise at a flow rate of 0.3 to 0.6ml/min in step (1).

6. The method of claim 1, wherein the molar ratio of diacetone alcohol to oxidant is from 1:2 to 4.

7. The method of claim 1, wherein the eluent is selected from the group consisting of methanol, ethanol, and ethyl acetate.

8. The method of claim 1, wherein the acidification in step (2) is sulfuric acid, hydrochloric acid or nitric acid.

9. The method of claim 1, further comprising the steps of: preparing the obtained HMB-Ca into 30-50 wt% aqueous solution, adding 2-3 times of eluent, stirring for 1 hr, and filtering.

Technical Field

The invention relates to a preparation method of beta-hydroxy-beta-methylbutanoic acid calcium salt (HMB-Ca), belonging to the technical field of synthesis and refining of organic compounds.

Background

HMB is collectively known as beta-hydroxy-beta-methylbutyrate and is an intermediate metabolite of leucine. HMB was first discovered by doctor Steven Nissen in 1988, and the effects of increasing lean body mass and reducing the decomposition degree of protein molecules were firstly found in animal experiments, and HMB has the functions of increasing fatty acid oxidation and reducing fat of experimental animals.

HMB has been used more widely as a sports supplement and has been a matter of the 21 st century. HMB has a very large number of functions, such as promoting recovery, increasing strength, relieving stress, etc., which are seen in publicity, but it primarily acts on the handler in two ways, namely, promoting protein synthesis and helping to increase muscle; secondly, the protein decomposition is inhibited, and the fat reduction is helped. Both muscle building and fat reduction, and are therefore preferred by the market.

HMB-Ca was GRAS approved by the U.S. food and drug administration in 1995 and was used in the range of medical nutrition and special meals. For the last 20 years, HMB-Ca has been widely used in dairy products, chocolate products, beverages, energy bars and other various food products in the US market. Especially widely applied in the sports nutrition field of the United states, the commodities are widely circulated, and the sports nutritional health-care food is particularly popular among professional athletes and bodybuilders.

Compared with the overseas market, the development time of HMB-Ca in the Chinese market is later. The data show that the demand of the 2016 national market on HMB-Ca raw materials is only 2 tons, and reaches about 20 tons in 2017, and the market demand is estimated to break through 1000 tons in 2025. Of course, the success of HMB-Ca in the Japanese market will continue to encourage the development of products related to domestic brands. Since 2015, domestic enterprises have successively introduced HMB products, such as Likekang high-energy solid beverages introduced by Xianlibang; special force products pushed by Shanghai compound stars; the cornbit HMB muscle building powder enriched type, etc., which have previously been concentrated on sports nutrition foods and special foods sold in hospital channels due to limited use of new food materials. After the technology source group in 2017 finishes the application expansion, HMB-Ca can be used for almost all common food formulations (see 2017.5.31 Wei Shun Notice). This undoubtedly brings unprecedented historical opportunities for numerous food and health product research and development enterprises.

A preparation method of HMB calcium salt belongs to the technical field of organic compound preparation. The preparation route commonly used in the industry is generally based on the reaction of 4-methyl-4-hydroxy-2-pentanone (diacetone alcohol) with an oxidizing agent, and salifying and refining the reaction product to obtain the calcium salt of HMB. In recent years, the application range of HMB is gradually expanding, and many biomedical enterprises have introduced HMB-related products, but there are few reports on methods for synthesizing HMB. In a typical HMB-Ca preparation method, diacetone alcohol and an oxidant are used as reaction raw materials to carry out haloform reaction, then the reaction raw materials are acidified and extracted by an organic solvent to obtain HMB (beta-hydroxy-beta-methylbutyric acid), and then the HMB and the calcium reagent form salt to obtain HMB-Ca, wherein the oxidant is divided into hypohalite and peracetic acid; the organic solvent mostly adopts ethyl acetate, isobutanol and the like; calcium reagents mostly adopt calcium chloride and calcium hydroxide. (CN02151042 and CN 201711166893). However, the synthesis conversion rate of the existing method is low and is not more than 60%, wherein the Yapei company adopts a small-test optimization to mix pure diacetone alcohol and sodium hypochlorite at a low temperature of 3 ℃ for 12.8min and then convert the pure diacetone alcohol and the sodium hypochlorite into 64-78% after flowing out by adopting a continuous tubular reactor, which shows the pyrolysis characteristic of the diacetone alcohol and the essence of the heat release of the chloroform reaction, and the industrial low-temperature controllable continuity and the corrosivity of the raw material sodium hypochlorite have high requirements on equipment, personnel, energy consumption and conditions of the company, so the method is not suitable for the industrial production of small and medium-sized enterprises. And the reaction liquid of the oxidant and the diacetone alcohol which are subjected to the chloroform reaction has large salt content after acidification, and most manufacturers need to adopt an organic solvent extraction method for separation and purification.

Disclosure of Invention

The invention aims to provide a more efficient and environment-friendly HMB-Ca production process.

Based on the purpose, the invention provides a preparation method of HMB-Ca, which comprises the following steps:

(1) and (3) chloroform reaction:

uniformly dripping 2-3 parts of 40-60 wt% diacetone alcohol aqueous solution into 10-25 wt% oxidant aqueous solution at constant speed for several times, and stirring and reacting for 0.5-1h at the temperature of 18-28 ℃;

(2) refining and purifying the product

Acidifying the reaction liquid stock solution in the step (1) until the pH value is 7-8, concentrating and desalting by using a nanofiltration membrane of 100 and 200 daltons until the volume of the concentrated solution is 45% of that of the stock solution, and the membrane operating pressure is 1.5-2.25 MPa; then vacuum distillation is carried out at 60 ℃ and concentration is continued until the mass of the stock solution is 10-20%; cooling to room temperature, stirring for 0.5-1h, and filtering; adding eluent with the mass of 2-3 times of the filtrate, stirring for 1h, filtering, and drying to obtain the HMB-Ca.

The production method of HMB-Ca is practically based on the property of HMB-Ca, adopts a direct synthesis process, and directly synthesizes HMB-Ca without an intermediate of HMB-Na. The traditional synthesis process is changed, the process path is shortened, and the conversion rate is improved to more than 70%; in addition, the use of an organic solvent is effectively avoided in the refining and purification process of the product at the later stage, and high-purity HMB-Ca is obtained; the production process is clean, environment-friendly and safe, and the cost is effectively reduced.

Detailed Description

The invention aims to provide an efficient and environment-friendly HMB-Ca production method. The invention has the advantages of improving the conversion rate of reaction substrates, improving the product quality, reducing the generation of polluting organic solvents and the like.

The preparation method of HMB-Ca is based on the basic production route of chloroform reaction-product fine purification HMB-Ca in the prior art. In the chloroform reaction, the chloroform reaction of the substrate diacetone alcohol and the oxidant is still involved. But in the adding mode of the product, beneficial innovation is carried out, namely, 2-3 parts of 40-60 wt% diacetone alcohol aqueous solution are uniformly dripped into 10-25 wt% oxidant aqueous solution in a sub-step manner at a constant speed, and the mixture is stirred and reacted for 0.5-1h at the temperature of 18-28 ℃.

In order to achieve the technical object of the invention, in particular a sufficient conversion of the substrate, it is a primary technical feature to set a suitable mode of product addition. The specific scheme provided by the invention is that the diacetone alcohol aqueous solution is added in a plurality of times and slowly. In the whole reaction process, the diacetone alcohol aqueous solution serving as a reaction substrate is uniformly divided into 2-3 parts, and the diacetone alcohol aqueous solution is dripped into a reaction system at a constant speed in several times. The dropping speed is 0.3-0.6 ml/min, preferably 0.5 ml/min. The adding time point is selected to ensure that the interval of the starting time points of two adjacent adding times is not less than 15 min. In the scheme of adding for 2 times, the first adding is carried out at the beginning of the reaction, namely the reaction is carried out for 0 min; the second addition is preferably carried out during a reaction time of 30-60 min. Based on the improved technical scheme, the haloform reaction provided by the invention has the advantages that under the condition that the feeding molar ratio of the oxidant to the diacetone alcohol is 2-4:1, the conversion rate of the substrate diacetone alcohol can reach 70% or higher, and under the same technical condition, the value generally does not exceed 60%.

In the chloroform reaction, the oxidant can be selected according to the prior art in the field, and in the invention, calcium hypochlorite, sodium hypoiodate, sodium hypobromite and calcium hypoiodate can be selected but not limited. For sufficient conversion of the reaction substrate, the concentration of the aqueous oxidant solution is 15-20 wt%, wherein wt% refers to mass percent concentration. Also for the purpose of increasing the substrate conversion, the concentration of the aqueous diacetone alcohol solution in our invention is selected to be 50% by weight. However, this is a setting for obtaining the most prominent advantageous effect and is not a limiting condition parameter.

On the basis of improving the conversion rate of the substrate, the technical scheme improvement on the other hand focuses on the purification of the product. The invention replaces the widely adopted organic solvent scheme in the prior art with a solvent-free alternative route: adjusting the pH of the haloform reaction solution to be neutral by acid, and then adding an eluent to wash and crystallize to directly separate and purify the HMB-Ca, so that an HMB-Ca product with the purity of over 95 percent can be obtained, and the yield is 96 percent. The total purity-reduced yield of HMB-Ca in the whole process is over 75 percent. In the specific technical scheme, the product is refined and purified by acidifying the reaction liquid stock solution after the chloroform reaction to the pH value of 7-8, and then concentrating and desalting by using a nanofiltration membrane of 100 and 200 daltons until the volume of the concentrated solution is 45% of that of the stock solution, and the membrane operating pressure is 1.5-2.25 MPa; then vacuum distillation is carried out at 60 ℃ and concentration is continued until the mass of the stock solution is 10-20%; cooling to room temperature, stirring for 0.5-1h, and filtering to obtain filtrate containing HMB-Ca 40-60 wt%; adding eluent with the mass of 2-3 times of the filtrate, stirring for 1h, filtering, and drying to obtain the HMB-Ca. In the step, sulfuric acid, hydrochloric acid or nitric acid is selected as an acidifying agent for acidification; the choice and amount of acidifying agent ensures that the reaction system suppresses salt singleness and ensures that the HMB-Ca is not acidified to HMB. The eluent is selected from methanol, ethanol and ethyl acetate. Ethanol is preferably used. The product obtained by adopting the refining and purifying scheme still does not reach the product with satisfactory purity, and the steps of repeated dissolution-elution can be added to obtain the HMB-Ca product with higher quality label. The repeated dissolution-elution is to prepare the obtained HMB-Ca into 30-50 wt% aqueous solution, add 2-3 times of eluent, stir for 1h and filter. The selection of the eluent is consistent with the scheme so as to ensure the singleness of the solvent and be beneficial to the recovery processing and the reutilization.

The invention is further illustrated by the following non-limiting examples.

In the present specification, unless otherwise specified: and (4) measuring the conversion rate and the HMB-Ca purity by adopting high performance liquid chromatography.

And (3) measuring the effective oxidability of the raw material by adopting a sodium thiosulfate titration method.

Wt% is used herein to denote the mass concentration of the solution.