CN1240207A - Production process of high-purity creatine and its monohydrate - Google Patents
Production process of high-purity creatine and its monohydrate Download PDFInfo
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Abstract
The production process of high-purity creatine and its monohydrate includes the following steps: making the aqueous solutions of chloroactic acid and methylamine take part in reaction to produce sarcosine solution, heating, removing methylamine, concentrating, adding aqueous solution of cyanamine, stirring while introducing ammonia to pH9-12, automatically heating reaction solution to 70-80 deg.c, reacting for 0.5-1.5 hr. centrifugal separation to obtain crude monohydrated creatine, then suspending said crude product the aqueous solution of sodium thiosulfate, as bitter-removing agent, stirring and washing for 2-4 hr, centrifugal filtering, washing filter cake with deionized water, and oven-drying to obtain high-purity (over 99.5%) bitter-free monohydrated creatine (water content is less than or equal to 12%) or anhydrous creatine (water content is less than or equal to 1%).
Description
The present invention relates to a process for producing high-purity creatine and its monohydrate.
Creatine, also known as sarcomere, is a component of blood, muscle and fish, has the function of repairing cells, can be used for manufacturing medicaments, can also be used as a supplement for human energy, accelerates the synthesis of human protein, supplements creatine with a proper amount, can increase the strength and tolerance of human bodies and delays the generation of fatigue. Creatine is also a raw material for synthetic perfumes and is used for perfume production. Creatine can be used as food additive for food and beverage production. In the prior art, creatine synthesis by reacting sarcosine with cyanamide has been reported, but this method cannot be developed into an economical creatine production process because sarcosine is expensive and yield of creatine is not ideal.
European patent EP 0754679 discloses a method for preparing creatine by reacting a creatine sodium aqueous solution and a cyanamide aqueous solution, wherein the reaction temperature is 20-150 ℃, the pH value is 9-10, the pH value of a reaction solution is adjusted by inorganic acid hydrochloric acid or organic acid sarcosine, acetic acid and formic acid, and the reaction product creatine is cleaned by dechlorinated ion water and recrystallized to obtain anhydrous creatine (the water content is less than or equal to 1 percent) or creatine monohydrate (the water content is less than or equal to 12 percent). The reaction is carried out under the condition of weak alkalinity (pH 9-10), and the pH value of the reaction is adjusted by adding inorganic acid hydrochloric acid or organic acid sarcosine, acetic acid or formic acid because the sarcosine sodium aqueous solution is strong alkalinity. Inorganic acid or organic acid is used for adjusting the pH value, and corresponding inorganic acid salt or organic acid salt impurities are introduced. Furthermore, it is impossible to adjust the strong basicity of the sodium sarcosinate solution with sarcosine, because the sarcosine solution itself is weak basic. In addition, the production cost of creatine by using sodium sarcosinate and cyanamide is higher. Creatine produced from cyanamide has an intolerable bitter taste in mouthfeel due to the fact that while creatine is produced by reaction, cyanide-containing impurities including dicyandiamide are also produced, and the bitter taste is unacceptable and toxic and must be removed. When the creatine is washed by the dechlorinated ion aqueous solution at room temperature, the creatine is difficult to remove the bitter taste at one time, and the creatine product is dissolved and lost greatly after repeated washing, so that the yield is reduced. The hot water recrystallization method is used for debitterizing, the effect is poor, and under the condition that the creatine is heated in a water phase, the obvious deamination phenomenon and side reactions such as dehydration into creatinine are generated, and the product yield is influenced.
The invention aims to provide a production process for preparing high-purity creatine and a monohydrate thereof by directly reacting a sarcosine aqueous solution generated by reacting chloroacetic acid with methylamine in a water phase with a cyanamide aqueous solution, which omits the step of purifying sarcosine or sodium sarcosine and then reacting with cyanamide in the background technology and saves the production cost. The creatine monohydrate is refined and debittered with water solution of debittering agent such as sodium thiosulfate to obtain high purity creatine product capable of being taken orally.
The chemical reaction equation of the invention is as follows:
1、
the invention is realized by the following steps of the production process of the high-purity creatine and monohydrate thereof (the following aqueous solution concentrations are all in percentage by weight):
a. reacting chloroacetic acid aqueous solution with methylamine aqueous solution at 10-30 ℃ to generate sarcosine solution, wherein the reaction time is 8-12 hours;
b. heating at 50-95 ℃ for 1-3 hours to expel methylamine out of the reaction solution;
c. adding sodium hydroxide solution to neutralizeand decompose the by-product methylamine chloride in the reaction solution;
d. concentrating under reduced pressure for 1-2 hours at 105-110 ℃ to obtain 30-40% creatine aqueous solution;
e. filtering to remove impurities (precipitates) to obtain a sarcosine aqueous solution, adding the cyanamide aqueous solution into the sarcosine aqueous solution, stirring, introducing ammonia to adjust the pH of the reaction solution to 9-12, and stirring to react at 70-80 ℃ for 0.5-1.0 hour to generate white emulsion creatine;
f. cooling the reaction liquid to 5-15 ℃, stirring for 1-7 hours to generate creatine crystals, centrifugally filtering, leaching a filter cake with deionized water, and spin-drying to obtain crude creatine monohydrate with the purity of 98.5% and the water content of 18%;
g. the coarse creatine monohydrate is treated through suspension, stirring, washing or re-crystallization with deionized water solution of debittering agent to obtain creatine monohydrate with purity over 99.5% and no bitter taste, and the debittering agent may be selected from thiosulfate, sulfite, hypohalite and hypophosphorous acid salt.
The concentration of the methylamine solution is 35-40%, the mol ratio of chloroacetic acid to methylamine is 1: 8-1: 12, preferably 1: 9-1: 10.
The concentration of the sodium hydroxide solution is 30%, and the molar ratio of the sodium hydroxide to the chloroacetic acid is 1.0: 1-1.1: 1.
In the present invention, the mixed solution of the aqueous sarcosine solution and the aqueous cyanamide solution is preferably adjusted to pH9 by adding ammonia.
The concentration of the cyanamide aqueous solution is 25-35%.
The molar ratio of cyanamide to chloroacetic acid is 0.7: 1-1.2: 1, preferably 0.8: 1-1.1: 1.
The concentration of the debitterizing agent aqueous solution is 5-15%.
The suspension stirring washing treatment of the rough creatine monohydrate by the debitterized agent aqueous solution is to suspend the rough creatine monohydrate in the debitterized agent aqueous solution and stir for 2-4 hours, then to carry out centrifugal filtration, to wash out the residual debitterized agent by deionized water from the filter cake, and to dry the filter cake to obtain the creatine monohydrate.
The aqueous solution recrystallization treatment of the debitterized agent for the rough creatine monohydrate is to add deionized water into the rough creatine monohydrate, heat and dissolve the rough creatine monohydrate, add the debitterized agent, stir for 20 to 40 minutes, cool and recrystallize, centrifugally spin-filter, wash out residual debitterized agent by using deionized water in a filter cake, and dry the filter cake to obtain the creatine monohydrate.
The non-bitter creatine monohydrate (the water content is less than or equal to 12%) with the purity of more than 99.5% can be dried to prepare the non-bitter creatine (the water content is less than or equal to 1%).
Dropwise adding chloroacetic acid aqueous solution into methylamine aqueous solution under stirring to react for 8-12 hours, and then carrying out methylamine driving and reduced pressure concentration to obtain aqueous solution containing sarcosine with the concentration of 30-40%. In order to inhibit side reactions from generating di-substituted methyliminodiacetic acid or hydrolyzing the di-substituted methyliminodiacetic acid into glycolic acid, the reaction temperature is required to be as low as possible, the concentration of methylamine is required to be as high as possible, the molar ratio of methylamine to chloroacetic acid isrequired to be as large as possible, and the reaction temperature is determined to be 10-30 ℃; the concentration of methylamine is within the range of 35-40%, and the molar ratio of methylamine to chloroacetic acid is 8-12, thereby achieving satisfactory results. In order to fully recover methylamine, at the later stage of removing methylamine under normal pressure, sodium hydroxide aqueous solution is dripped to decompose methylamine in byproduct ammonium chloride and remove methylamine. The amount of sodium hydroxide added is such that the substitution is complete and not so much excessive that some of the sodium sarcosinate formed polymerizes at high temperatures. The molar ratio of sodium hydroxide to chloroacetic acid is preferably 1.0: 1 to 1.1: 1. The pH value of the obtained 30-40% sarcosine concentrated solution is below 8. The expelled methylamine is condensed and absorbed by a condenser for recycling.
In the step of reacting an aqueous solution of sarcosine with an aqueous solution of cyanamide, the greater the concentration of the aqueous solution of cyanamide used, the more advantageous the reaction. However, since the price of cyanamide rapidly increases with the increase in concentration and more impurities may be dissolved in a high-concentration cyanamide aqueous solution, it is not always economical to pursue a high concentration, and it is determined that the concentration of the cyanamide aqueous solution is reasonable from 25 to 35%. The molar ratio of the amount of cyanamide to the amount of chloroacetic acid in the reaction is 0.7: 1 to 1.2: 1, preferably 0.8: 1 to 1.1: 1. While the condensation reaction of sarcosine with cyanamide may actually occur, a number of competing side reactions may occur, including the self-polymerization of cyanamide into dicyandiamide and even polymers; cyanamide is hydrated into urea; the polymerization of creatine and the deamination decomposition and dehydration of creatine itself to creatinine. The success of this processis based on the fact that creatine is condensed with cyanamide in the main reaction, which is much faster than the side reactions. In terms of process conditions, the advantages of the main reaction are ensured, the temperature rising speed is high, and the main reaction is completed as soon as possible. The time for keeping at high temperature is short so as to prevent the generated creatine from being further converted and decomposed. Therefore, the reaction and high temperature holding time for automatically raising the temperature to 70 to 80 ℃ is preferably 0.5 to 1.0 hour.
The purity of the crude creatine is about 98.5%, the water content is about 18%, and the creatine has obvious bitter taste. Suspension, stirring, washing or recrystallizing with de-bittering agent solution of deionized water to obtain creatine monohydrate (water content less than or equal to 12%) with purity of 99.5% and no bitter taste, and oven drying to obtain anhydrous creatine (water content less than or equal to 1%).
Compared with the prior art, the invention has the following advantages: firstly, the process of preparing creatine by directly reacting sarcosine solution generated by reacting chloroacetic acid and methylamine in water phase with cyanamide is adopted, so that the production cost is reduced. Secondly, the creatine monohydrate prepared by the process of suspending, stirring and washing crude creatine monohydrate by adopting aqueous solution of debitterizing agent such as sodium thiosulfate and the like or the process of recrystallizing the crude product by using the aqueous solution of the debitterizing agent has no bitter taste. Overcomes the defect that the creatine produced by the reaction of taking cyanamide as a raw material in the prior art has intolerable bitter taste for a long time. The high purity creatine and its monohydrate prepared by the present invention are suitable for all uses including oral administration. Compared with the debitterizing treatment of the crude creatine monohydrate by using the water washing process and the hot water recrystallization process, the process has good debitterizing effect, and the product yield is improved by about 1 time compared with the product yield by using the water recrystallization method.
In order to better practice the invention, the following examples are given to further illustrate the invention, but the examples are not intended to limit the invention.
Example 1
At 1M3700 kg (9kmol) of 40% methylamine aqueous solution is pumped into an enamel reaction kettle with an end face sealed stirring and a high-level dropping storage tank by a material conveying pump. The jacket was cooled with ice brine to below 10 ℃ with stirring. From the head tank, 95 kg (1kmol) of chloroacetic acid was added with 40 kg of dissolved chloroacetic acid in water. Controlling the dropping speed, ensuring the reaction temperature to be 10-30 ℃, standing for 8-12 hours at room temperature after dropping, and transferring into a container with the volume of 1M3Stirring and heating to expel methylamine in an enamel kettle with end face sealed stirring, a high-level sodium hydroxide solution storage tank and a distillation opening connected with a condenser, and heating by adopting a method of gradually raising the temperature: keeping the temperature at 50-60 ℃ for about 1 hour to remove most of methylamine, heating to 95 ℃ to steam methylamine water solution for 1 hour, dropping 140 kg of sodium hydroxide solution (30%), heating to 105 ℃ and concentrating for 1.5 hours. At the moment, the materials in the kettle are concentrated to half of the original volume, and the expelled methylamine is condensed and absorbed by a condenser for recycling. Sucking the concentrated material into 0.5M3With sealed stirring end face,distillation opening and condenser (cooling area 5M)2) The enamel concentration kettle is further decompressed and concentrated (30-50 mbar) until half of the original volume is required for 1-2 hours, the feed liquid in the kettle is carefully filtered to remove sodium chloride and iron-containing impurities, and the precipitate is obtained, so that 250 liters of sarcosine filtrate with the concentration of 30-40% is obtained. The filtrate is sucked into an enamel condensation kettle, 130 kg (0.93kmol) of cyanamide aqueous solution with the concentration of 30% is added under stirring, and ammonia is introduced until the pH value is 9, so that the reaction occurs automatically. The temperature rises rapidly and the material is white emulsion due to product precipitation. After 30 minutes the temperature had risen to 75 ℃ at which temperatureKeeping for 30 minutes, injecting cold water into the jacket to cool to 40 ℃, cooling to 15 ℃ by using ice brine, and stirring for 2 hours to ensure that crystallization is complete. Centrifugal filtration, washing the filter cake with deionized water (total washing water amount is 60 kg), and drying to obtain crude creatine monohydrate 110 kg with water content of 18%, purity 98.5% (HPLC), and heavy bitter taste. It was suspended in sodium thiosulfate (Na)2S2O3·10H2O)64 kg of deionized water, 350 kg of deionized water, stirring for 3 hours at room temperature, and centrifuging and filtering. The filter cake was rinsed with deionized water (total water usage 60 kg). 78 kg of white fine crystals with the water content of 18 percent are obtained after spin-drying, and the white fine crystals are dried until the monohydrate (the water content is 11 percent) weighs 72.5 kg, the purity is 99.8 percent (HPLC), the product has no bitter taste, and the yield is 48.7 percent (calculated according to chloroacetic acid).
Product analysis: purity 99.8% (HPLC)
Heavy metal (calculated as iron) is less than or equal to 10ppm
Not detected arsenic
Non-detection of cyano group
The water content is 11%
0.01 percent of ignition residue
Example 2
The amounts of the raw materials, the steps and the products were the same as in example 1, except that the amounts of the raw materials and the yields of the products were different from those in example 1.
Raw materials: 850 kg (11kmol) of 40% methylamine aqueous solution and 170 kg (1.2kmol) of 30% cyanamide aqueous solution.
The product is as follows: the crude creatine monohydrate preparation, containing 18% water, was obtained in the amount of 121 kg (purity 98.5%), which was suspended in sodium thiosulfate (Na)2S2O3·10H2O)128 kg of deionized water and 350 kg of deionized water, stirring for 3 hours at room temperature, and centrifuging and filtering. The filter cake was rinsed with deionized water (total water usage 60 kg). 86 kg of white fine crystals with the water content of 18 percent are obtained after spin-drying, and the white fine crystals are dried until the weight of the monohydrate (the water content is 11 percent) is 79.9 kg and the purity is 99.8 percent (HPLC) without bitter taste. The yield was 53.6% (calculated as chloroacetic acid).
The product analysis was the same as in example 1.
Example 3
The amounts of the raw materials, the steps and the products were the same as in example 1, except that the amounts of the raw materials and the yields of the products were different from those in example 1.
Raw materials: 620 kg (8kmol) of 40% methylamine aqueous solution and 98 kg (0.7kmol) of 30% cyanamide aqueous solution.
The product is as follows: the crude creatine monohydrate preparation, containing 18% water, was obtained in the form of 105 kg (purity 98.5%), which was suspended in sodium thiosulfate (Na)2S2O3·10H2O)43 kg of deionized water 350 kg, stirring for 3 hours at room temperature, and centrifuging and filtering. The filter cake was rinsed with deionized water (total water usage 60 kg). Drying to obtain 74.8 kg of white fine crystals with the water content of 18 percent, and drying until the monohydrate (the water content is 11 percent) weighs 69.5 kg and the purity is 99.8 percent (HPLC) without bitter taste. The yield was 46.6% (calculated as chloroacetic acid).
The product analysis was the same as in example 1.
Example 4
The raw material amount, procedure and crude product yield were the same as in example 1. The same procedure as in example 1 was followed to obtain 110 kg (98.5% purity, 18% water content) of the crude creatine, which was dissolved in 6 times the amount of deionized water, followed by addition of sodium thiosulfate (Na)2S2O3·10H2O)30 kg is stirred for 20 minutes and filtered while the solution is hot, the filtrate is cooled to below 15 ℃ and stirred for 4 hours, centrifugal filtration is carried out, filter cakes are rinsed by deionized water (the total water content is 50 kg) to obtain 63 kg of white fine grains (the water content is 18 percent) without bitter taste, and the white fine grains are dried to obtain 58 kg of creatine monohydrate (the purity is 99.7 percent, the water content is 11 percent) and the yield is 38.3 percent (calculated according to chloroacetic acid).
Comparative example 1
The raw material amount, procedure and crude product yield were the same as in example 1. 110 kg of creatine crude product (purity 98.5% and water content 18%) is obtained by the same process as in example 1, 6 times of deionized water is added for heating and dissolving, the solution is filtered while hot, the filtrate is cooled to below 15 ℃, the solution is stirred for 4 hours and centrifuged, the filtrate is filtered, and filter cakes (total washing amount is 30 kg) are leached by deionized water to obtain 70 kg of white crystals (water content 18%) with slight bitterness. Recrystallizing with 6 times of water by the same method to obtain 48 kg (water content 18%) without bitter taste, and oven drying to obtain 33 kg of creatine monohydrate (water content 11%, purity 99.8%) with yield of only 22.1% (calculated on chloroacetic acid).
Claims (10)
1. The production process of high-purity creatine and its monohydrate is characterized by that (the concentration of its aqueous solution is weight percentage):
a. reacting chloroacetic acid aqueous solution with methylamine aqueous solution at 10-30 ℃ to generate sarcosine solution, wherein the reaction time is 8-12 hours,
b. heating at 50-95 deg.C for 1-3 hr to remove methylamine from the reaction solution,
c. adding sodium hydroxide solution to neutralize and decompose the by-product methylamine chloride in the reaction solution,
d. concentrating under reduced pressure for 1-2 hours at 105-110 ℃ to obtain a sarcosine aqueous solution with the concentration of 30-40%,
e. filtering to remove impurities (precipitates), adding cyanamide aqueous solution into the obtained sarcosine aqueous solution, adding ammonia under stirring to adjust the pH of the solution to 9-12, stirring and reacting for 0.5-1.0 hour at 70-80 ℃ to generate white emulsion creatine,
f. cooling the reaction liquid to 5-15 ℃, stirring for 1-7 hours to generate creatine crystals, centrifugally filtering, leaching filter cakes with deionized water, spin-drying to obtain crude creatine monohydrate with the purity of 98.5% and the water content of 18%,
g. the coarse creatine monohydrate is treated through suspension, stirring, washing or re-crystallization with debitterizing agent solution of deionized water to obtain creatine monohydrate with purity over 99.5% and no bitter taste, and the debitterizing agent may be selected from thiosulfate, sulfite, hypohalite and hypophosphorous acid salt.
2. The process for producing high purity creatine and monohydrate thereof according to claim 1, wherein the concentration of the methylamine solution is 35 to 40%, and the molar ratio of chloroacetic acid to methylamine is 1: 8 to 1: 12, preferably 1: 9 to 1: 10.
3. The process for producing high purity creatine and monohydrate thereof according to claim 1, wherein the concentration of the sodium hydroxide solution is 30% and the molar ratio of sodium hydroxide to chloroacetic acid is 1.0: 1 to 1.1: 1.
4. The process for producing high purity creatine and monohydrate thereof according to claim 1, wherein the mixture of aqueous sarcosine solution and aqueous cyanamide solution is adjusted to pH9 by adding ammonia.
5. The process for producing high purity creatine and monohydrate thereof according to claim 1, wherein the concentration of the aqueous solution of cyanamide is 25 to 35%.
6. The process for producing high purity creatine and monohydrate thereof according to claim 1, wherein the molar ratio of cyanamide to chloroacetic acid is 0.7: 1 to 1.2: 1, preferably 0.8: 1 to 1.1: 1.
7. The process for producing high purity creatine and monohydrate thereof according to claim 1, wherein the concentration of the aqueous solution of the debittering agent is 5-15%.
8. The process for producing high purity creatine and its monohydrate according to claim 1, wherein the suspension stirring washing treatment of the creatine monohydrate is prepared by suspending the creatine monohydrate in the aqueous solution of debittering agent, stirring for 2-4 hours, centrifugal filtration, washing off the residual debittering agent from the filter cake with deionized water, and drying.
9. The process for producing high purity creatine and its monohydrate according to claim 1, wherein the said process for recrystallizing creatine monohydrate is carried out by dissolving creatine monohydrate in deionized water under heating, adding debitterizing agent, stirring for 20-40 min, cooling, recrystallizing, centrifugal filtering, washing filter cake with deionized water to remove residual debitterizing agent, and drying.
10. The process for producing a high purity creatine and monohydrate thereof according to claim 1, 7, 8 or 9, wherein the non-bitter creatine monohydrate having a purity of 99.5% or more (water content: 12%) is dried to produce anhydrous creatine (water content: 1%).
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| DE19526236A1 (en) * | 1995-07-18 | 1997-01-23 | Sueddeutsche Kalkstickstoff | Process for the production of creatine or creatine monohydrate |
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- 1998-06-19 CN CN98110909A patent/CN1097578C/en not_active Expired - Fee Related
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| CN113603618A (en) * | 2021-07-13 | 2021-11-05 | 无锡贝塔医药科技有限公司 | Preparation method of creatine-D3 |
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