CN114591203A - Preparation method of high-purity creatine - Google Patents
Preparation method of high-purity creatine Download PDFInfo
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- CN114591203A CN114591203A CN202210138752.9A CN202210138752A CN114591203A CN 114591203 A CN114591203 A CN 114591203A CN 202210138752 A CN202210138752 A CN 202210138752A CN 114591203 A CN114591203 A CN 114591203A
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- CVSVTCORWBXHQV-UHFFFAOYSA-N creatine Chemical compound NC(=[NH2+])N(C)CC([O-])=O CVSVTCORWBXHQV-UHFFFAOYSA-N 0.000 title claims abstract description 120
- 229960003624 creatine Drugs 0.000 title claims abstract description 59
- 239000006046 creatine Substances 0.000 title claims abstract description 59
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- ZUFONQSOSYEWCN-UHFFFAOYSA-M sodium;2-(methylamino)acetate Chemical compound [Na+].CNCC([O-])=O ZUFONQSOSYEWCN-UHFFFAOYSA-M 0.000 claims abstract description 43
- 108010077895 Sarcosine Proteins 0.000 claims abstract description 41
- 229940048098 sodium sarcosinate Drugs 0.000 claims abstract description 41
- 238000006243 chemical reaction Methods 0.000 claims abstract description 38
- 239000012535 impurity Substances 0.000 claims abstract description 38
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 claims abstract description 31
- 239000007864 aqueous solution Substances 0.000 claims abstract description 24
- 239000000203 mixture Substances 0.000 claims abstract description 22
- 238000004519 manufacturing process Methods 0.000 claims abstract description 19
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical group OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 10
- 238000001035 drying Methods 0.000 claims abstract description 9
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims abstract description 7
- 238000001816 cooling Methods 0.000 claims abstract description 7
- 238000010438 heat treatment Methods 0.000 claims abstract description 7
- 238000006482 condensation reaction Methods 0.000 claims abstract description 3
- 238000001914 filtration Methods 0.000 claims abstract description 3
- 238000003756 stirring Methods 0.000 claims abstract description 3
- 238000005406 washing Methods 0.000 claims abstract description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 36
- 239000000243 solution Substances 0.000 claims description 17
- 229960004826 creatine monohydrate Drugs 0.000 claims description 14
- MEJYXFHCRXAUIL-UHFFFAOYSA-N 2-[carbamimidoyl(methyl)amino]acetic acid;hydrate Chemical compound O.NC(=N)N(C)CC(O)=O MEJYXFHCRXAUIL-UHFFFAOYSA-N 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 239000008213 purified water Substances 0.000 claims description 6
- 238000004321 preservation Methods 0.000 claims description 5
- VXMDOKODOQETRU-UHFFFAOYSA-N 2-[(4-amino-2,5-dihydro-1H-1,3,5-triazin-6-ylidene)-methylazaniumyl]acetate Chemical compound C\[N+](CC([O-])=O)=C1\NCN=C(N)N1 VXMDOKODOQETRU-UHFFFAOYSA-N 0.000 abstract description 38
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 30
- 239000000047 product Substances 0.000 description 22
- 239000002994 raw material Substances 0.000 description 14
- 238000012360 testing method Methods 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 238000000967 suction filtration Methods 0.000 description 5
- 238000007605 air drying Methods 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000007599 discharging Methods 0.000 description 4
- 238000002386 leaching Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- -1 nitrogen-containing organic acid Chemical class 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000010586 diagram Methods 0.000 description 3
- QGBSISYHAICWAH-UHFFFAOYSA-N dicyandiamide Chemical compound NC(N)=NC#N QGBSISYHAICWAH-UHFFFAOYSA-N 0.000 description 3
- 235000010265 sodium sulphite Nutrition 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 230000000711 cancerogenic effect Effects 0.000 description 2
- 231100000315 carcinogenic Toxicity 0.000 description 2
- 238000000855 fermentation Methods 0.000 description 2
- 230000004151 fermentation Effects 0.000 description 2
- BPMFZUMJYQTVII-UHFFFAOYSA-N guanidinoacetic acid Chemical compound NC(=N)NCC(O)=O BPMFZUMJYQTVII-UHFFFAOYSA-N 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 2
- 235000016709 nutrition Nutrition 0.000 description 2
- 229940071089 sarcosinate Drugs 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 1
- 229940106681 chloroacetic acid Drugs 0.000 description 1
- QPJDMGCKMHUXFD-UHFFFAOYSA-N cyanogen chloride Chemical compound ClC#N QPJDMGCKMHUXFD-UHFFFAOYSA-N 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 210000000663 muscle cell Anatomy 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical class [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of high-purity creatine, which comprises the following steps: s1, adding an impurity removing agent into the sodium sarcosinate aqueous solution, and stirring until the impurity removing agent is completely dissolved; s2, adjusting the pH value of the mixture obtained in the step S1 to 9-11, heating the mixture to 50-70 ℃, and then slowly adding cyanamide aqueous solution for condensation reaction for 1-4 h; s3, cooling, crystallizing, filtering, washing and drying the mixture reacted in the step S2 to obtain a finished product; in step S1, the impurity removing agent is sulfurous acid, sulfite or bisulfite; the mass content of the impurity removing agent in the whole reaction system is 0.01-1 wt%. On the basis of ensuring that the existing best creatine production process is adopted, the dihydrotriazine in the product is not detected, and the method has the advantages of low production cost, high product yield and high purity.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, and particularly relates to a preparation method of high-purity creatine.
Background
Creatine (Creatine) chemical name: n-methyl guanidinoacetic acid, is a nitrogen-containing organic acid with chemical formula C4H9N3O2Naturally occurring in the vertebrate body, and can assist in providing energy to muscle and nerve cells. It can quickly increase muscle strength, accelerate fatigue recovery, and improve explosive force, and can be widely used by athletes and bodybuilders。
In GB24154-2015, the types and daily usage of nutritional ingredients in various sports item products are as follows: creatine 1-3 g/day, a relatively high-volume variety of nutritional food additives, is used in an amount of more than 1 million tons per year globally, is a main market for creatine consumption in the United states and countries and regions of Europe, and is included in the United states pharmacopoeia Commission in 2020, which is incorporated into the United states pharmacopoeia USP43-NF38-4920, and is administered in 11/01/2020, meaning that the creatine quality standards entering the United states market after the administration date of the pharmacopoeia must meet the requirements of the United states pharmacopoeia.
Dihydrotriazine, chemical name 2- [ (4-amino-2, 5-dihydro-1H-1, 3, 5-triazin-6-ylidene) -methylammonium ] acetate, abbreviated as english: dihydrotriazine. The dihydrotriazine compounds are by-products of the creatine production process and, because they are carcinogenic, the united states pharmacopoeia has made near rigorous control over them, providing a creatine product with a dihydrotriazine content of less than 0.0005% (5 ppm). Therefore, there is a need to control the creatine reaction process from the source, thereby achieving the purpose of controlling the quality of creatine products.
However, the creatine production processes described in the prior art do not address the control of the dihydrotriazine impurity. For example, patent WO2004/031133A1, which describes the preparation of cyanamide from virulent chlorocyanogen followed by reaction with sodium sarcosinate to produce creatine, does not mention the control of dihydrotriazine impurity, but because of the residual formaldehyde in sodium sarcosinate, dihydrotriazine impurity must be produced during the synthesis of creatine. Patent CN1140707A, which describes the production of creatine by the process of sodium sarcosinate and cyanamide, also does not mention impurity control of dihydrotriazine. Patent CN1240207A, which uses chloroacetic acid to react with methylamine to produce sodium sarcosinate, which contains no formaldehyde and thus does not produce dihydrotriazine as an impurity when synthesizing creatine, but sodium sarcosinate produced in this way has poor quality and thus produces low content of creatine and more impurities when synthesizing creatine by subsequent reaction with cyanamide, which is not an optimal process. Patent CN1253945A describes a process for the preparation of creatine or creatine monohydrate, although the yield of creatine is high, no mention is made of the control of the dihydrotriazine impurity. Patent CN101415672A describes a method for preparing creatine, creatine monohydrate or guanidinoacetic acid, which uses metal-catalyzed dehydrogenation of ethanolamine to prepare sarcosinate, and then prepare creatine, wherein the prepared sarcosinate contains no formaldehyde, so that the final synthetic creatine contains no dihydrotriazine impurity, but the method uses high-pressure equipment and metal catalyst, and different substituents exist in raw material alcohol amine, so that the content of other impurities in the generated creatine product is high, and the content of heavy metals in the creatine is easily over-determined. Patent CN 106065411A discloses a fermentation method for producing creatine, which, although the product does not contain dihydrotriazine, the fermentation concentration can only be 61g/L, and since the product contains many organic impurities, the produced product needs to pass through a resin exchange column, resulting in unsatisfactory production efficiency and cost of the product.
In summary, the main route for global production of creatine is to use sodium sarcosinate as raw material, and then react with cyanamide to produce creatine, but the above synthetic route is the best route in terms of product quality, production cost, etc., but intensive studies on the above reaction mechanism show that sodium sarcosinate contains formaldehyde, so that impurities of dihydrotriazine are generated when creatine is synthesized by using the above synthetic route, and the concentration of the impurities of dihydrotriazine is 3-25 ppm. With the intensive research on the toxicity of impurities, the dihydrotriazine is found to be carcinogenic, so that a process for producing creatine without the toxic impurities of the dihydrotriazine needs to be researched.
Disclosure of Invention
In order to solve the problems in the background art, the invention provides a preparation method of high-purity creatine, which ensures that the dihydrotriazine in the product is not detected on the basis of adopting the existing best creatine production process, and has the advantages of low production cost, high product yield and high purity.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a preparation method of high-purity creatine, which comprises the following steps:
s1, adding an impurity removing agent into the sodium sarcosinate aqueous solution, and stirring until the impurity removing agent is completely dissolved;
s2, adjusting the pH value of the mixture obtained in the step S1 to 9-11, heating the mixture to 50-70 ℃, and then slowly adding cyanamide aqueous solution for condensation reaction for 1-4 h;
s3, cooling, crystallizing, filtering, washing and drying the mixture reacted in the step S2 to obtain a finished product;
in step S1, the impurity removing agent is sulfurous acid, sulfite, or bisulfite.
Sulfites or bisulfites include, but are not limited to, sodium, potassium, ammonium salts.
The applicant of the application finds that in the directional synthesis research of the dihydrotriazine, creatine and dicyandiamide react under certain conditions to prepare guanidyl creatine, and the dihydrotriazine with high yield and high purity can be prepared by reacting the guanidyl creatine and formaldehyde under certain conditions. The applicant of the present application has found that the synthetic route for producing creatine by reacting sodium sarcosinate with cyanamide results in formation of dihydrotriazine impurities, and the concentration of dihydrotriazine impurities is 3-25 ppm. Based on the research of the directed synthesis of the dihydrotriazine. The applicant of the present application has experimentally concluded that the mechanism of the dihydrotriazine impurity generation reaction is shown in fig. 1: this is because the purchased raw material, sodium sarcosinate, usually contains formaldehyde impurities and dicyandiamide is produced as a by-product in the reaction of sodium sarcosinate with cyanamide, so that dicyandiamide reacts with sodium sarcosinate to produce guanidino creatine, which reacts with formaldehyde to produce dihydrotriazine.
According to the summarized reaction mechanism of the impurity generation of the dihydrotriazine, the aim can be achieved by only removing formaldehyde in the sodium sarcosinate raw material and not generating the dihydrotriazine when the sodium sarcosinate reacts with the cyanamide. The principle of removing formaldehyde from the sodium sarcosinate raw material is shown in figure 2.
The reaction principle for producing creatine by reacting sodium sarcosinate with cyanamide in the present application is shown in fig. 3.
Specifically, the mass content of the impurity removing agent in the whole reaction system is 0.01-1 wt%.
Specifically, the mass content of the impurity removing agent in the whole reaction system is 0.05-0.15 wt%.
Specifically, in the step S3, the mixture reacted in the step S2 is cooled to 20 to 30 ℃, the pH value of the mixture is adjusted to 6 to 7, and then the mixture is crystallized at 20 to 30 ℃ for 1 to 4 hours, and then the creatine monohydrate is obtained after suction filtration, rinsing with purified water, suction drying and drying treatment.
Specifically, the creatine monohydrate obtained in step S3 is dried to obtain anhydrous creatine having a water content of 1% or less.
Specifically, in step S2, hydrochloric acid is used to adjust the pH of the reaction solution, hydrochloric acid is continuously used to adjust the pH of the reaction solution to 9-11 during the addition of the aqueous solution of cyanamide, and the temperature of the reaction solution is controlled to 50-70 ℃.
Specifically, the mass fraction of the hydrochloric acid is 10-20%.
Specifically, the mass content of sodium sarcosinate in the sodium sarcosinate aqueous solution is 35-45%, the mass content of cyanamide in the cyanamide aqueous solution is 25-35%, and the mass ratio of sodium sarcosinate in the sodium sarcosinate aqueous solution to cyanamide in the cyanamide aqueous solution is (2-3): 1.
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a preparation method of creatine without dihydrotriazine toxic impurities, which is characterized in that on the basis of the existing best creatine production process (namely, a synthetic route for producing creatine by reacting a sodium sarcosinate raw material with cyanamide is still adopted), only sulfurous acid, sulfite or bisulfite needs to be added and mixed with the sodium sarcosinate raw material to remove formaldehyde impurities in the sodium sarcosinate raw material, and dihydrotriazine impurities can not be generated when the sodium sarcosinate reacts with the cyanamide; the product prepared by the preparation process has no detectable dihydrotriazine, high yield and high purity, has important significance for improving the quality of creatine products and protecting the health of human bodies of consumers, and has abundant supply of sulfurous acid, sulfite or bisulfite in markets, easily obtained raw materials and low price.
Drawings
The invention is described in further detail below with reference to specific embodiments and with reference to the following drawings.
FIG. 1 is a reaction mechanism diagram of formation of dihydrotriazine impurity in the present invention;
FIG. 2 is a reaction diagram illustrating the removal of formaldehyde from a sodium sarcosinate feedstock according to the present invention;
FIG. 3 is a schematic diagram of the reaction of sodium sarcosinate with cyanamide to produce creatine in accordance with the present invention;
FIG. 4 is an IR test spectrum of a finally obtained product in example 1;
FIG. 5 is a HPLC test pattern of the finally prepared product in example 1.
Fig. 6 is an HPLC test pattern of the finally prepared product in comparative example 1.
Detailed Description
The following description of the preferred embodiments of the present invention is provided for the purpose of illustration and description, and is in no way intended to limit the invention.
The raw materials of sodium sarcosinate and cyanamide used in each example and comparative example are the same batch.
Example 1
230g of 40.8 wt% sodium sarcosinate aqueous solution with the pH value of 13.38 is added into a 500mL four-mouth bottle, and 0.3g of sodium sulfite is added into the bottle and stirred to be dissolved;
dropwise adding 20 wt% hydrochloric acid, adjusting the pH value of the mixture in the four-mouth bottle to 10.60, heating to 55-60 ℃, slowly dropwise adding 115g of 30.11 wt% cyanamide aqueous solution, continuously adjusting the pH value of the reaction solution to 10-11 by using 20 wt% hydrochloric acid, controlling the temperature of the reaction solution to 55-60 ℃, after dropwise adding, and keeping the temperature for reaction for 2 hours;
then cooling the mixture after reaction in the four-mouth bottle to about 25 ℃, dropwise adding 20 wt% hydrochloric acid, adjusting the pH value to 6.5-7.0, carrying out heat preservation and crystal growth at 20-25 ℃ for 1h, carrying out suction filtration, leaching twice with 100mL of purified water, carrying out suction drying, carrying out forced air drying on the material at 60 ℃ for 4h, and discharging to obtain 108.6g of a product.
And (3) carrying out IR (infrared) characterization test on the prepared product, wherein a test spectrum is shown in figure 4, and the prepared product is the target compound creatine monohydrate.
The creatine monohydrate obtained by HPLC (liquid chromatograph) test shows in figure 5, has a yield of 86.2% and a purity of 99.77%, and no dihydrotriazine is detected in the sample.
Example 2
268.11g of 35 wt% sodium sarcosinate aqueous solution with the pH value of 12.9 is added into a 500mL four-mouth bottle, and 0.23g of sodium sulfite is added into the solution and stirred to be dissolved;
dropwise adding 20 wt% hydrochloric acid, adjusting the pH value of the mixture in the four-mouth bottle to 9.5, heating to 50-55 ℃, slowly dropwise adding 187.68g of 25 wt% cyanamide aqueous solution, continuously adjusting the pH value of the reaction solution to 9-10 by using 20 wt% hydrochloric acid, controlling the temperature of the reaction solution to 50-55 ℃, keeping the temperature and reacting for 4 hours after dropwise adding;
then cooling the mixture after reaction in the four-mouth bottle to about 25 ℃, dropwise adding 20 wt% hydrochloric acid, adjusting the pH value to 6-6.5, carrying out heat preservation and crystal growth at 25-30 ℃ for 2h, carrying out suction filtration, leaching twice with 100mL of purified water, carrying out suction drying, carrying out forced air drying on the material at 60 ℃ for 4h, discharging to obtain 107.6g of creatine monohydrate, wherein the yield of the creatine monohydrate is 85.4% and the purity is 99.85% through HPLC (high performance liquid chromatography) tests, and no dihydrotriazine is detected in the sample.
Example 3
208.53g of 45 wt% sodium sarcosinate aqueous solution with the pH value of 13.6 is added into a 500mL four-mouth bottle, 4.5g of sodium sulfite is added into the solution, and the solution is stirred and dissolved;
dropwise adding 20 wt% hydrochloric acid, adjusting the pH value of the mixture in the four-mouth bottle to 10.60, heating to 60-70 ℃, slowly dropwise adding 89.37g of 35 wt% cyanamide aqueous solution, continuously adjusting the pH value of the reaction solution to 10-11 by using 20 wt% hydrochloric acid, controlling the temperature of the reaction solution to 60-70 ℃, and keeping the temperature for reaction for 2 hours after dropwise adding;
then cooling the mixture after reaction in the four-mouth bottle to about 25 ℃, dropwise adding 20 wt% hydrochloric acid, adjusting the pH value to 6.5-7.0, carrying out heat preservation and crystal growth at 20-25 ℃ for 1h, carrying out suction filtration, leaching twice with 100mL of purified water, carrying out suction drying, carrying out forced air drying on the material at 80 ℃ for 4h, discharging to obtain 107.95gg creatine monohydrate, and testing by HPLC (high performance liquid chromatography) that the yield of the creatine monohydrate is 85.7%, the purity is 99.82%, wherein dihydrotriazine is not detected in the sample.
Comparative example 1
Comparative example 1 is a comparative example to example 1, and the specific procedure is as follows:
230g of 40.8 wt% sodium sarcosinate aqueous solution is added into a 500mL four-mouth bottle, and the pH value is 13.38;
dropwise adding 20 wt% hydrochloric acid, adjusting the pH value of the mixture in the four-mouth bottle to 10.60, heating to 55-60 ℃, slowly dropwise adding 115g of 30.11 wt% cyanamide aqueous solution, continuously adjusting the pH value of the reaction solution to 10-11 by using 20 wt% hydrochloric acid, controlling the temperature of the reaction solution to 55-60 ℃, after dropwise adding, and keeping the temperature for reaction for 2 hours;
then cooling the mixture after reaction in the four-mouth bottle to about 25 ℃, dropwise adding 20 wt% hydrochloric acid, adjusting the pH value to 6.5-7.0, carrying out heat preservation and crystal growth at 20-25 ℃ for 1h, carrying out suction filtration, leaching twice with 100mL of purified water, carrying out suction drying, carrying out forced air drying on the material at 60 ℃ for 4h, and discharging to obtain 108.5g of creatine monohydrate.
By HPLC test, the test pattern is shown in figure 6, the yield of creatine monohydrate is 86.1%, the purity is 98.82%, and t is 4.308min represents dihydrotriazine, the content is 870ppm, which is far greater than the maximum limit value of 0.0005% specified by the United states pharmacopoeia.
In conclusion, the invention provides a preparation method of creatine without the toxic impurities of the dihydrotriazine, which is characterized in that on the basis of the existing optimal creatine production process (namely, a synthetic route for producing creatine by reacting a sodium sarcosinate raw material with cyanamide is still adopted), only sulfurous acid, sulfite or bisulfite needs to be added and mixed with the sodium sarcosinate raw material to remove formaldehyde impurities in the sodium sarcosinate raw material, and the dihydrotriazine impurities can not be generated when the sodium sarcosinate reacts with the cyanamide, so that the whole preparation process is simple to operate, equipment does not need to be added, and other process parameters of the original preparation process do not need to be changed; the product prepared by the preparation process has no detectable dihydrotriazine, high yield and high purity, has important significance for improving the quality of creatine products and protecting the health of human bodies of consumers, and has abundant supply of sulfurous acid, sulfite or bisulfite in markets, easily obtained raw materials and low price.
The present invention has been described in terms of specific examples, which are provided to aid understanding of the invention and are not intended to be limiting. For a person skilled in the art to which the invention pertains, several simple deductions, modifications or substitutions may be made according to the idea of the invention.
Claims (8)
1. A preparation method of high-purity creatine is characterized by comprising the following steps:
s1, adding an impurity removing agent into the sodium sarcosinate aqueous solution, and stirring until the impurity removing agent is completely dissolved;
s2, adjusting the pH value of the mixture obtained in the step S1 to 9-11, heating the mixture to 50-70 ℃, and then slowly adding cyanamide aqueous solution for condensation reaction for 1-4 h;
s3, cooling, crystallizing, filtering, washing and drying the mixture reacted in the step S2 to obtain a finished product;
in step S1, the impurity removing agent is sulfurous acid, sulfite, or bisulfite.
2. The method for producing high-purity creatine according to claim 1, wherein the mass content of the impurity-removing agent in the entire reaction system is 0.01 to 1 wt%.
3. The method for producing high-purity creatine according to claim 2, wherein the mass content of the impurity-removing agent in the entire reaction system is 0.05 to 0.15 wt%.
4. The method for preparing high-purity creatine according to claim 1, wherein in step S3, the mixture obtained after the reaction in step S2 is cooled to 20-30 ℃ and the pH thereof is adjusted to 6-7, and then the mixture is crystallized at 20-30 ℃ for 1-4h under heat preservation, and then filtered, rinsed with purified water, drained and dried to obtain creatine monohydrate.
5. The method for producing high purity creatine according to claim 4, wherein the creatine monohydrate obtained in step S3 is dried to obtain anhydrous creatine having a water content of 1% or less.
6. The method for producing high-purity creatine according to claim 1, wherein the pH of the reaction solution is adjusted by hydrochloric acid in step S2, the pH of the reaction solution is continuously adjusted to 9-11 by hydrochloric acid during the addition of the aqueous solution of cyanamide, and the temperature of the reaction solution is controlled to 50-70 ℃.
7. The method for producing high-purity creatine according to claim 6, wherein the hydrochloric acid is contained in an amount of 10 to 20% by mass.
8. The method for producing high-purity creatine according to claim 1, wherein the mass content of sodium sarcosinate in the aqueous solution of sodium sarcosinate is 35 to 45%, the mass content of cyanamide in the aqueous solution of cyanamide is 25 to 35%, and the mass ratio of sodium sarcosinate in the aqueous solution of sodium sarcosinate to cyanamide in the aqueous solution of cyanamide is (2-3): 1.
Priority Applications (1)
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