CN109438268B - Choline bitartrate and preparation method thereof - Google Patents
Choline bitartrate and preparation method thereof Download PDFInfo
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- CN109438268B CN109438268B CN201811212079.9A CN201811212079A CN109438268B CN 109438268 B CN109438268 B CN 109438268B CN 201811212079 A CN201811212079 A CN 201811212079A CN 109438268 B CN109438268 B CN 109438268B
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- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/24—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one carboxyl group bound to the carbon skeleton, e.g. aspartic acid
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Abstract
The invention relates to choline bitartrate and a preparation method thereof, belonging to the technical field of chemical synthesis. The preparation method of the choline bitartrate comprises the steps of firstly reacting tartaric acid and trimethylamine in a molar ratio of 0.8-1.2: 2 to generate trimethylamine tartrate, then adding ethylene oxide into the trimethylamine tartrate according to a molar ratio of the trimethylamine tartrate to the ethylene oxide of 1:2 to generate choline bitartrate, then adding tartaric acid into the choline bitartrate according to a molar ratio of the choline bitartrate to the tartaric acid of 1: 0.8-1.2, and finally concentrating, crystallizing and drying to obtain a white or colorless choline bitartrate finished product. The production process of the invention does not use methanol, thereby avoiding the emission of Volatile Organic Compounds (VOC) in the production process, and the product does not contain toxic and harmful substances such as methanol and the like. The method has the advantages of easily available raw materials, stable reaction, environmental protection, yield higher than 98.1%, uniform product appearance, good stability and wide application value in the fields of food nutrition enhancers, medicines and feed additives.
Description
Technical Field
The invention relates to choline and a preparation method thereof, in particular to choline bitartrate and a preparation method thereof, and belongs to the technical field of chemical synthesis.
Background
Choline (C)5H15NO2) Is an unstable strong base, is first separated from pig bile by Streker in 1894, and is formally named choline in 1962. Is a component of all biological membranes and precursors of acetylcholine in cholinergic neurons. Plays an important role in the process of organism nerve conduction and membrane growth, and is widely applied to the fields of food nutrition enhancers, medicines and feed additives.
The choline applied to the food nutrition enhancer can promote brain development and memory ability, ensure information transfer, promote fat metabolism, promote in vivo transmethylation metabolism and reduce serum cholesterol. Can be used for treating fatty liver and liver cirrhosis, can be used as intermediate of nervous system drug, and is important component of lecithin in biological cell. The low molecular organic compound is used as feed additive to maintain the physiological function of animal, regulate fat metabolism and conversion, prevent liver and kidney and other tissue degeneration caused by fat deposition, promote amino acid regeneration and raise the utilization of amino acid, especially methionine.
The choline salt which is widely applied at present mainly comprises choline chloride and choline bitartrate (also called choline bitartrate), wherein the choline chloride is mainly prepared by the reaction of trimethylamine hydrochloride and ethylene oxide through concentration and refining, and the catalyst is difficult to separate and contains chloride ions with stronger reducibility, so the catalyst can be used as medicine and feed only through purification, and the application of the choline chloride in the two fields is influenced. Choline bitartrate is a relatively stable dibasic acid choline salt, is used as a vitamin product and is widely applied to medicines, health products and food nutrition additives.
Currently, the preparation method of choline bitartrate mainly comprises an ion resin exchange method, a choline chloride method and an ethylene oxide method, wherein the ion resin exchange method has high cost and potential safety hazard of the choline chloride method, so that the preparation method of choline bitartrate in the prior art is widely applied to the ethylene oxide method, choline is obtained by reacting high-concentration ethylene oxide aqueous solution with trimethylamine at normal temperature, then the choline is dissolved in methanol, tartaric acid is added for neutralization according to a molar ratio, and the choline is refined by concentration, drying, acetone recrystallization and the like. In the method, choline generated by the reaction of trimethylamine and ethylene oxide is unstable organic strong base, and is easy to generate side reaction to generate aldehyde products and other polymers; and under the strong alkaline environment, ethylene oxide which is subsequently added generates ethylene glycol and ethylene oxide polymers in a large amount. The components in the system are complex, so that the yield is low, and the target product choline bitartrate cannot be crystallized and separated out in an aqueous solution containing a lot of impurities. Therefore, the target product with higher purity can be obtained only by using organic solvents such as methanol and the like. GB 2760-. The emission of volatile organic compounds in the production process causes environmental pollution and reduces the safety of the production process. Methanol residue exists in the product, and the production and the application of the product are limited to a great extent.
In order to guarantee the safety and the quality of food and medicine for people, the choline bitartrate and the preparation method thereof have the advantages of easily available raw materials, stable reaction, environmental protection and high yield, and toxic and harmful substances such as methanol and the like are not added in the production process.
Disclosure of Invention
In order to overcome the defects of low yield of the preparation method of choline bitartrate and residual toxic and harmful substances such as methanol in the product in the prior art, the invention provides choline bitartrate and the preparation method thereof, wherein the raw materials are easy to obtain, the reaction is stable, the method is green and environment-friendly, the yield is high, and no toxic and harmful substances such as methanol are added in the production process.
In order to achieve the purpose, the technical scheme adopted by the invention for solving the technical problems is as follows:
a choline bitartrate characterized by: the choline bitartrate is any one of L + choline bitartrate, DL choline bitartrate or D-choline bitartrate with different specific optical rotation.
A preparation method of choline bitartrate comprises the following steps:
1) adding tartaric acid into water, stirring and mixing uniformly, adding trimethylamine, stirring while adding, cooling to 20-50 ℃, and carrying out heat preservation reaction for 2-6 hours to obtain trimethylamine tartrate;
2) adding ethylene oxide into the trimethylamine tartrate prepared in the step (A), controlling the temperature to be 30-70 ℃ and controlling the pH to be = 8-9, and generating choline bitartrate;
3) adding tartaric acid into the prepared choline tartrate to generate choline bitartrate, controlling the temperature to be 40-70 ℃, and filtering;
4) and concentrating and crystallizing: and (3) carrying out reduced pressure heating, evaporation and concentration on the filtrate prepared in the step, then cooling to obtain a large amount of white or colorless choline bitartrate crystals, and centrifuging and drying to obtain a finished product of choline bitartrate.
Preferably, the molar ratio of tartaric acid to trimethylamine in step 1) is 0.8-1.2: 2.
Preferably, the trimethylamine used in the step 1) is a 30-40% trimethylamine aqueous solution or 99% liquefied trimethylamine.
Preferably, the temperature reduction in the step 1) is cooling water temperature reduction or ice water circulating cooling temperature reduction, and the temperature is reduced to 30-40 ℃.
Preferably, the molar ratio of the trimethylamine tartrate salt to the ethylene oxide in the step 2) is 1: 2.
Preferably, the ethylene oxide described in step 2) is liquefied ethylene oxide at a concentration of 99%.
Preferably, the molar ratio of the choline bitartrate and the tartaric acid in the step 3) is 0.8-1.2: 1, wherein the molar ratio of the total amount of the tartaric acid added in the step 1) and the step 3) to the trimethylamine added in the step 1) and the ethylene oxide added in the step 2) is 1:1: 1-1.08.
Preferably, tartaric acid is added to the choline tartrate prepared in the step 2) in the step 3) when the temperature is 40-70 ℃.
Preferably, the reduced-pressure heating evaporation concentration temperature in the step 4) is 70-95 ℃.
Preferably, the concentration of the aqueous solution obtained in the step 4) is reduced by heating under reduced pressure, evaporating and concentrating until the concentration of the aqueous solution is 50-95%, and then cooling to 40-20 ℃.
In the method, the reaction process is as follows:
(1) reacting tartaric acid and trimethylamine to generate trimethylamine tartrate:
(2) reacting the trimethylamine tartrate with ethylene oxide to generate the choline tartrate:
(3) reacting the choline bitartrate with tartaric acid to generate choline bitartrate:
the invention has the beneficial technical effects that:
(1) the preparation and production process of the choline bitartrate does not use toxic and harmful substances such as methanol and the like, thereby putting an end to the emission of Volatile Organic Compounds (VOC) in the production process and effectively avoiding the substitution of the toxic and harmful substances such as methanol and the like in the product.
(2) The preparation method of the choline bitartrate does not use methanol in the production process, avoids the strong alkaline environment of the system in the reaction process, effectively reduces the probability of side reaction of the ethylene oxide, and has stable reaction and the yield higher than 98.1 percent.
(3) The preparation method of the choline bitartrate has the advantages of easily available raw materials, economy, safety, environmental protection, uniform appearance and good stability of the prepared choline bitartrate product, and has wide application value in the fields of food nutrition enhancers, medicines and feed addition.
Drawings
FIG. 1 is an X-ray diffraction (XRD) pattern of L + choline bitartrate prepared in example 1 of the present invention.
Fig. 2 is an X-ray diffraction (XRD) pattern of DL choline bitartrate prepared in example 2 of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are some, but not all, embodiments of the present invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without any inventive work belong to the protection scope of the present invention, and the detailed description does not limit the present invention.
Example 1: preparation of L + choline bitartrate
Adding 85kg of water into a reaction kettle, then adding 30kg of L + tartaric acid, completely dissolving the L + tartaric acid, introducing 29.5kg of liquefied trimethylamine with the purity of 99%, stirring while adding, cooling the cooled water to 30 ℃, carrying out heat preservation reaction for 2 hours, and obtaining L + tartaric acid trimethylamine salt. And continuously adding 22kg of ethylene oxide into the reaction kettle, controlling the pH value to be 8-9 and the temperature to be 50 ℃, and stirring while adding to generate the L + choline tartrate. Adding 45kg of L + tartaric acid into the reaction kettle to generate L + choline bitartrate; and (4) carrying out suction filtration, heating the filtrate under reduced pressure, evaporating and concentrating the filtrate until the concentration is 85%, then cooling the filtrate to room temperature to separate out a large amount of colorless L + choline bitartrate crystals, and centrifuging and drying the crystals to obtain the L + choline bitartrate finished product.
124.1kg of sample is obtained (126.5 kg should be obtained by theoretical calculation), the yield is 98.1%, the purity of the sample to be inspected is 99.8%, other indexes meet the standards of food nutrition enhancers, medicines and feed additives, and specific detection results are shown in table 1.
Table 1 example 1L + choline bitartrate assay results
Example 2: preparation of DL choline bitartrate
Adding 150kg of deionized water into a reaction kettle, then adding 70kg of DL tartaric acid which can not be completely dissolved, introducing 59kg of liquefied trimethylamine with the purity of 99%, stirring while adding, cooling the temperature to 30 ℃, carrying out heat preservation reaction for 2h, and obtaining DL tartaric acid trimethylamine salt. And continuously adding 44kg of ethylene oxide into the reaction kettle, controlling the pH value to be 8-9 and the temperature to be 50 ℃, and stirring while adding to generate DL-choline tartrate. Adding 80kg of DL tartaric acid into the reaction kettle to generate DL choline bitartrate; and (4) carrying out suction filtration, heating the filtrate under reduced pressure, evaporating and concentrating the filtrate until the concentration of the solution is 90%, then cooling the solution to room temperature to separate out a large amount of white DL choline bitartrate crystals, and centrifuging and drying the crystals to obtain a DL choline bitartrate finished product.
250.2kg of sample is obtained (253.0 kg should be obtained by theoretical calculation), the yield is 98.9%, the purity of the sample to be inspected is 99.3%, other indexes all meet the standards of food nutrition enhancers, medicines and feed additives, and specific detection results are shown in table 2.
Table 2 example 2 DL choline bitartrate assay results
Example 3: preparation of DL choline bitartrate
Adding 340kg of water into a reaction kettle, then adding 150kg of DL tartaric acid, leading 118kg of trimethylamine aqueous solution with the purity of 99 percent into the reaction kettle, stirring the mixture while adding, cooling the mixture to 40 ℃, carrying out heat preservation reaction for 6 hours, and obtaining DL tartaric acid trimethylamine salt. And continuously adding 88kg of ethylene oxide into the reaction kettle, controlling the pH value to be 8-9 and the temperature to be 55 ℃, and stirring while adding to generate DL-choline tartrate. Adding 150kg of DL tartaric acid into the reaction kettle to generate DL choline bitartrate; and (3) carrying out suction filtration, heating the filtrate under reduced pressure, evaporating and concentrating the filtrate until the concentration of the solution is 50%, then cooling to 5 ℃, separating out a large amount of colorless DL choline bitartrate crystals, and centrifuging and drying to obtain a DL choline bitartrate finished product.
501.5kg of sample (506 kg should be obtained by theoretical calculation) is obtained, the yield is 99.1%, the purity of the sample for submission is 98.8%, other indexes all meet the standards of food nutrition enhancers, medicines and feed additives, and specific detection results are shown in table 3.
Table 3 example 3 DL choline bitartrate assay results
Example 4: preparation of D-choline bitartrate
Adding 170kg of deionized water into a reaction kettle, then adding 60kg of D-tartaric acid, completely dissolving the D-tartaric acid, introducing 59kg of liquefied trimethylamine with the purity of 99%, stirring while adding, cooling the temperature to 30 ℃, carrying out heat preservation reaction for 2 hours, and obtaining the D-tartaric acid trimethylamine salt. And continuously adding 44kg of ethylene oxide into the reaction kettle, controlling the pH value to be 8-9 and the temperature to be 55 ℃, and stirring while adding to generate the D-choline tartrate. Then 90kg of D-tartaric acid is added into the reaction kettle to generate D-choline bitartrate; and (4) carrying out suction filtration, heating the filtrate under reduced pressure, evaporating and concentrating the filtrate until the concentration of the solution is 70%, then cooling the solution to-5 ℃, separating out a large amount of colorless D-choline bitartrate crystals, and centrifuging and drying the crystals to obtain a D-choline bitartrate finished product.
251.4kg of sample is obtained (253.0 kg should be obtained by theoretical calculation), the yield is 99.4%, the purity of the sample for inspection is 98.2%, other indexes all meet the standards of food nutrition enhancers, medicines and feed additives, and specific detection results are shown in Table 4.
Table 4 example 4D-choline bitartrate assay results
The actual measurement data of the censorship prove that the preparation method of the choline bitartrate of the invention has high yield and purity, does not contain methanol, and other indexes all meet the standards of food nutrition enhancers, medicines and feed additives.
It should be noted that the above-mentioned preferred embodiments are merely illustrative of the technical concepts and features of the present invention, and are intended to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
Claims (7)
1. A preparation method of choline bitartrate is characterized by comprising the following steps:
1) adding tartaric acid into water, stirring and mixing uniformly, adding trimethylamine, stirring while adding, cooling to 20-50 ℃, and reacting for 2-6 hours to obtain trimethylamine tartrate;
2) adding ethylene oxide into the trimethylamine tartrate prepared in the step (A), controlling the temperature to be 30-70 ℃ and controlling the pH to be = 8-9, and generating choline bitartrate;
3) adding tartaric acid into the prepared choline tartrate to generate choline bitartrate, controlling the temperature to be 40-70 ℃, and filtering;
4) and concentrating and crystallizing: heating the filtrate obtained in the above steps under reduced pressure, evaporating, concentrating, cooling to separate out choline bitartrate crystals, centrifuging, and drying to obtain choline bitartrate finished product;
the trimethylamine in the step 1) is trimethylamine aqueous solution with the concentration of 30-40% or liquefied trimethylamine with the concentration of 99%;
the ethylene oxide in the step 2) is liquefied ethylene oxide with the concentration of 99 percent.
2. The method for preparing choline bitartrate according to claim 1, wherein: the molar ratio of the tartaric acid to the trimethylamine in the step 1) is 0.8-1.2: 2.
3. The method for preparing choline bitartrate according to claim 1, wherein: the temperature reduction in the step 1) is cooling water or ice water circulation cooling, and the temperature is reduced to 30-40 ℃.
4. The method for preparing choline bitartrate according to claim 1, wherein: the molar ratio of the tartaric acid trimethylamine salt to the ethylene oxide in the step 2) is 1: 2.
5. The method for preparing choline bitartrate according to claim 1, wherein: the molar ratio of the choline bitartrate to the tartaric acid in the step 3) is 0.8-1.2: 1, wherein the molar ratio of the total amount of the tartaric acid added in the step 1) and the step 3) to the amount of trimethylamine added in the step 1) and the amount of ethylene oxide added in the step 2) is 1:1: 1-1.08.
6. The method for preparing choline bitartrate according to claim 1, wherein: the reduced pressure heating evaporation concentration temperature in the step 4) is 70-95 ℃.
7. The method for preparing choline bitartrate according to any one of claims 1 or 6, wherein: and 4) carrying out reduced pressure heating, evaporation and concentration until the concentration of the aqueous solution is 50-95%, and then cooling to 40-20 ℃.
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| CN113214093B (en) * | 2021-05-21 | 2022-11-29 | 济南亚西亚药业有限公司 | Method for recovering choline chloride and tartrate from choline bitartrate waste mother liquor |
| CN118344260A (en) * | 2024-05-20 | 2024-07-16 | 济南久安酯类化工有限公司 | Preparation method of choline nitrate crystal |
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| WO2017165287A1 (en) * | 2016-03-22 | 2017-09-28 | Balchem Corporation | Compositions comprising choline |
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| CN108707082A (en) * | 2018-07-10 | 2018-10-26 | 天津辰力工程设计有限公司 | A kind of choline bitartrate preparation method |
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| 酒石酸与胆碱反应机理的研究-一种新的分子复合物;胡惟孝 等;《浙江工学院学报》;19910702(第2期);第27页式（3） * |
| 重酒石酸胆碱的合成研究;胡惟孝 等;《浙江工学院学报》;19900702(第2期);第55页第2段 * |
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