CN114591203B - Preparation method of high-purity creatine - Google Patents
Preparation method of high-purity creatine Download PDFInfo
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- CN114591203B CN114591203B CN202210138752.9A CN202210138752A CN114591203B CN 114591203 B CN114591203 B CN 114591203B CN 202210138752 A CN202210138752 A CN 202210138752A CN 114591203 B CN114591203 B CN 114591203B
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- creatine
- aqueous solution
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- cyanamide
- sodium sarcosinate
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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 115
- 229960003624 creatine Drugs 0.000 title claims abstract description 56
- 239000006046 creatine Substances 0.000 title claims abstract description 56
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 108010077895 Sarcosine Proteins 0.000 claims abstract description 44
- 229940048098 sodium sarcosinate Drugs 0.000 claims abstract description 42
- ZUFONQSOSYEWCN-UHFFFAOYSA-M sodium;2-(methylamino)acetate Chemical compound [Na+].CNCC([O-])=O ZUFONQSOSYEWCN-UHFFFAOYSA-M 0.000 claims abstract description 42
- 239000012535 impurity Substances 0.000 claims abstract description 38
- 238000006243 chemical reaction Methods 0.000 claims abstract description 37
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 claims abstract description 30
- 239000007864 aqueous solution Substances 0.000 claims abstract description 24
- 239000000203 mixture Substances 0.000 claims abstract description 23
- 238000004519 manufacturing process Methods 0.000 claims abstract description 17
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 13
- 238000001035 drying Methods 0.000 claims abstract description 11
- 238000001816 cooling Methods 0.000 claims abstract description 7
- 238000010438 heat treatment Methods 0.000 claims abstract description 7
- 238000003756 stirring Methods 0.000 claims abstract description 6
- 238000006482 condensation reaction Methods 0.000 claims abstract description 3
- 238000001914 filtration 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
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 33
- 229960004826 creatine monohydrate Drugs 0.000 claims description 14
- 239000000243 solution Substances 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
- 238000000034 method Methods 0.000 claims description 10
- 230000008569 process Effects 0.000 claims description 8
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical group [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 230000001105 regulatory effect Effects 0.000 claims description 7
- 238000002386 leaching Methods 0.000 claims description 6
- 238000005086 pumping Methods 0.000 claims description 6
- 239000008213 purified water Substances 0.000 claims description 6
- 235000010265 sodium sulphite Nutrition 0.000 claims description 4
- 238000000967 suction filtration Methods 0.000 claims description 2
- 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 34
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical group OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 abstract description 15
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 abstract description 4
- 239000000047 product Substances 0.000 description 22
- 239000002994 raw material Substances 0.000 description 15
- -1 nitrogen-containing organic acid Chemical class 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical compound C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 230000001276 controlling effect Effects 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 238000007599 discharging Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 231100000331 toxic Toxicity 0.000 description 4
- 230000002588 toxic effect Effects 0.000 description 4
- 238000007664 blowing Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- QGBSISYHAICWAH-UHFFFAOYSA-N dicyandiamide Chemical compound NC(N)=NC#N QGBSISYHAICWAH-UHFFFAOYSA-N 0.000 description 3
- GRWZHXKQBITJKP-UHFFFAOYSA-L dithionite(2-) Chemical compound [O-]S(=O)S([O-])=O GRWZHXKQBITJKP-UHFFFAOYSA-L 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 238000005755 formation reaction Methods 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 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 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 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
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 235000016709 nutrition Nutrition 0.000 description 2
- 229940071089 sarcosinate Drugs 0.000 description 2
- 229940043230 sarcosine Drugs 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 206010007269 Carcinogenicity Diseases 0.000 description 1
- 229920000877 Melamine resin Polymers 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
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 231100000260 carcinogenicity Toxicity 0.000 description 1
- 230000007670 carcinogenicity Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 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
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- MGNCLNQXLYJVJD-UHFFFAOYSA-N cyanuric chloride Chemical compound ClC1=NC(Cl)=NC(Cl)=N1 MGNCLNQXLYJVJD-UHFFFAOYSA-N 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 235000015872 dietary supplement Nutrition 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
- JDSHMPZPIAZGSV-UHFFFAOYSA-N melamine Chemical compound NC1=NC(N)=NC(N)=N1 JDSHMPZPIAZGSV-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 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
- 238000004321 preservation Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 235000014268 sports nutrition Nutrition 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
Classifications
-
- 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
Abstract
The invention discloses a preparation method of high-purity creatine, which comprises the following steps: s1, adding a impurity removing agent into a sodium sarcosinate aqueous solution, and stirring until the impurity removing agent is completely dissolved; s2, adjusting the pH value of the mixture in the step S1 to 9-11, heating the mixture to 50-70 ℃, and then slowly adding a cyanamide aqueous solution to perform condensation reaction for 1-4h; s3, cooling, crystallizing, filtering, washing and drying the mixture reacted in the step S2 to obtain a finished product; in the step S1, the impurity removing agent is sulfurous acid, sulfite or bisulphite; the mass content of the impurity removing agent in the whole reaction system is 0.01-1wt%. On the basis of ensuring that the existing optimal creatine production process is adopted, the dihydro-triazine in the product is not detected, the production cost is low, and the product yield and purity are high.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a preparation method of high-purity creatine.
Background
Creatine (Creatine) chemical name: n-methyl guanidinoacetic acid is a nitrogen-containing organic acid, and has the chemical formula of C 4 H 9 N 3 O 2 Naturally present in vertebrates, can assist in providing energy to muscles and nerve cells. It can quickly increase muscle strength, accelerate fatigue recovery and improve explosive force, and is widely used by athletes and body-building people.
In general rule of food safety national standard sports nutrition food, GB24154-2015, the types and daily usage amount of the nutritional ingredients in various sports products are as follows: creatine 1-3 g/day is a relatively large variety of nutritional food additives, the global consumption of the creatine is more than 1 ten thousand tons each year, the United states and European countries and regions are main markets for creatine consumption, the United states pharmacopoeia Commission records the creatine in United states pharmacopoeia USP43-NF38-4920 in 2020, and the creatine is listed in dietary supplements and implemented on month 11 and 01 in 2020, which means that the quality standard of the creatine entering the United states market after the implementation day of the pharmacopoeia must meet the requirements of the United states pharmacopoeia.
Dihydro-triazines, chemical name 2- [ (4-amino-2, 5-dihydro-1H-1, 3, 5-triazin-6-ylidene) -methyl ammonium ] acetate, english abbreviation: dihydrotriazine. The dihydrotriazine compound is a by-product in the preparation process of the creatine product, and because the dihydrotriazine compound is a cancerogenic substance, the dihydrotriazine compound is controlled by United states pharmacopoeia in a near-harsh way, and the content of the dihydrotriazine compound in the creatine product is regulated to be lower than 0.0005 percent (5 ppm). Therefore, the creatine reaction process needs to be controlled from the source, so that the purpose of controlling the quality of the creatine product is achieved.
However, the control of the dihydrotriazine impurity is not mentioned in the creatine production process described in the prior art. For example, patent WO2004/031133A1, which describes the preparation of melamine from highly toxic cyanuric chloride and then creatine by reaction with sodium sarcosinate, does not mention dihydrotriazine impurity control, but since formaldehyde remains in sodium sarcosinate, the production of dihydrotriazine impurities is necessarily expected in the synthesis of creatine. Patent CN1140707a, which describes the production of creatine using the sodium sarcosinate and cyanamide process, also does not mention dihydrotriazine impurity control. Patent CN1240207A, which uses chloroacetic acid to react with methylamine to produce sodium sarcosinate, does not contain formaldehyde, and therefore does not produce dihydrotriazine impurities during the synthesis of creatine, but sodium sarcosinate produced in this way is of poor quality, and therefore produces low levels of creatine and a lot of other impurities when creatine is synthesized by subsequent reaction with cyanamide, which is not the optimal process. Patent CN1253945a describes a process for preparing creatine or creatine monohydrate, although the creatine yield is high, no mention is made of control of dihydrotriazine impurities. Patent CN101415672a describes a process for the preparation of creatine, creatine monohydrate or guanidinoacetic acid by catalytic dehydrogenation of ethanolamine metal to prepare sarcosinate and then to prepare creatine, wherein although the prepared sarcosinate contains no formaldehyde, the final synthesized creatine contains no dihydrotriazine impurity, but the process uses high pressure equipment, metal catalyst, and different substituents are present in the raw material alcohol amine, the produced creatine product contains more other impurities, and the heavy metal content in the creatine is easily out of standard. In the patent CN 106065411A, creatine is produced by adopting a fermentation method, and the product does not contain dihydrotriazine, but the fermentation concentration can only reach 61g/L, and the produced product is required to pass through a resin exchange column due to the fact that organic impurities in the product are more, so that the production efficiency and the cost of the product are not ideal.
In summary, the main route for producing creatine worldwide is currently that sodium sarcosinate is adopted as a raw material, and is reacted with cyanamide to produce creatine, and the synthetic route is the best route in terms of product quality, production cost and the like, but through intensive study on the reaction mechanism, the fact that formaldehyde is contained in sodium sarcosinate is found, so that the production of the creatine by adopting the synthetic route can generate dihydrotriazine impurities, and the concentration of the dihydrotriazine impurities is 3-25ppm. With the intensive research on the toxicity of impurities, the dihydrotriazine is found to have carcinogenicity, so that the research on a creatine production process without the toxic impurities of the dihydrotriazine is needed.
Disclosure of Invention
In order to solve the problems in the prior 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 optimal creatine production process, and has low production cost, high product yield and high purity.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
the invention provides a preparation method of high-purity creatine, which comprises the following steps:
s1, adding a impurity removing agent into a sodium sarcosinate aqueous solution, and stirring until the impurity removing agent is completely dissolved;
s2, adjusting the pH value of the mixture in the step S1 to 9-11, heating the mixture to 50-70 ℃, and then slowly adding a cyanamide aqueous solution to perform condensation reaction for 1-4h;
s3, cooling, crystallizing, filtering, washing and drying the mixture reacted in the step S2 to obtain a finished product;
in the 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 the reaction of the sarcosine and the dicyandiamide under a certain condition is adopted to prepare the guanidyl creatine in the research of directional synthesis of the dihydrotriazine, and the reaction of the guanidyl creatine and the formaldehyde under a certain condition is adopted to prepare the dihydrotriazine with high yield and high purity. The applicant of the present application found that the production of creatine by reaction of sodium sarcosinate with cyanamide all resulted in the formation of dihydrotriazine impurities at concentrations of 3-25ppm. Based on the research of directional synthesis of dihydrotriazine. The applicant of the present application has experimentally summarized the mechanism of the dihydrotriazine impurity formation reaction, as shown in fig. 1: this is because the raw material sodium sarcosinate purchased usually contains formaldehyde impurities, and dicyandiamide by-products are formed during the reaction of sodium sarcosinate with cyanamide, so dicyandiamide reacts with sodium sarcosinate to form guanidyl creatine, which reacts with formaldehyde to form dihydrotriazine.
According to the research on the reaction mechanism of the produced dihydrotriazine impurity, formaldehyde in the raw material of sodium sarcosinate is only required to be removed, the dihydrotriazine is not produced when the sodium sarcosinate reacts with cyanamide, and the applicant of the application discovers through the experimental process that the purpose can be achieved by mixing the sodium sarcosinate with sulfurous acid, sulfite or hydrosulfite. The formaldehyde removal principle in the specific sarcosine sodium raw material is shown in figure 2.
The reaction principle of creatine production by reaction of sodium sarcosinate and cyanamide is shown in figure 3.
Specifically, the mass content of the impurity removing agent in the whole reaction system is 0.01-1wt%.
Specifically, the mass content of the impurity removing agent in the whole reaction system is 0.05-0.15wt%.
Specifically, in the step S3, the mixture after the reaction in the step S2 is cooled to 20-30 ℃, the pH value of the mixture is regulated to 6-7, then the mixture is subjected to heat preservation and crystallization for 1-4 hours at 20-30 ℃, and then the creatine monohydrate is obtained through suction filtration, purified water leaching, pumping and drying treatment.
Specifically, the creatine monohydrate prepared in the step S3 is subjected to drying treatment to obtain anhydrous creatine with the water content less than or equal to 1%.
Specifically, in the step S2, hydrochloric acid is used to adjust the pH value of the reaction solution, and in the process of adding the aqueous solution of cyanamide, hydrochloric acid is continuously used to adjust the pH value of the reaction solution to 9-11, 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 dihydro-triazine toxic impurities, which is based on the existing optimal creatine production process (namely, a synthetic route for producing creatine by reacting sodium sarcosinate raw material with cyanamide is still adopted), only sulfurous acid, sulfite or bisulphite is needed to be added and mixed with the sodium sarcosinate raw material so as to remove formaldehyde impurities in the sodium sarcosinate raw material, and the dihydro-triazine impurities are not generated when the sodium sarcosinate reacts with cyanamide, so that the whole preparation process is simple to operate, equipment is not needed to be added, and other technological parameters of the original preparation process are not needed to be changed; the product prepared by the preparation process has the advantages of no detected dihydrotriazine, high product yield and purity, important significance for improving the quality of creatine products and protecting the health of consumers, large supply of sulfurous acid, sulfite or hydrosulfite in markets, readily available raw materials and low price.
Drawings
The invention will be described in further detail with reference to the drawings and the specific embodiments.
FIG. 1 is a diagram of the mechanism of the dihydrotriazine impurity formation reaction in the present invention;
FIG. 2 is a schematic diagram of the reaction for removing formaldehyde from sodium sarcosinate raw material in the present invention;
FIG. 3 is a schematic diagram showing the reaction of sodium sarcosinate with cyanamide to produce creatine according to the present invention;
FIG. 4 is an IR test chart of the final product obtained in example 1;
fig. 5 is an HPLC test pattern of the final product prepared in example 1.
Fig. 6 is an HPLC test pattern of the final product prepared 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 explanation only and is not intended to limit the present invention.
The raw materials of sodium sarcosinate and cyanamide used in each example and comparative example were all the same batch.
Example 1
In a 500mL four-necked flask, 230g of 40.8wt% sodium sarcosinate aqueous solution having a pH of 13.38 was added, and 0.3g of sodium sulfite was added thereto and dissolved by stirring;
dropwise adding 20wt% hydrochloric acid, regulating the pH value of the mixture in the four-mouth bottle to 10.60, heating to 55-60 ℃, slowly dropwise adding 115g of 30.11wt% cyanamide aqueous solution, continuously using 20wt% hydrochloric acid to regulate the pH value of the reaction solution to 10-11, controlling the temperature of the reaction solution to 55-60 ℃, and preserving the heat for 2h after the dropwise adding is finished;
then cooling the mixture after reaction in the four-mouth bottle to about 25 ℃, dropwise adding 20wt% hydrochloric acid, adjusting the pH value to 6.5-7.0, preserving heat and growing crystal for 1h at 20-25 ℃, leaching for two times by using 100mL of purified water, pumping, drying the material in a blowing way for 4h at 60 ℃ and discharging to obtain 108.6g of product.
The prepared product is subjected to IR (infrared) characterization test, the test chart is shown in figure 4, and the prepared product is the target compound creatine monohydrate.
HPLC (liquid chromatograph) test shows that the test chart is shown in figure 5, the yield of the prepared creatine monohydrate is 86.2%, the purity is 99.77%, and no dihydrotriazine is detected in the sample.
Example 2
Into a 500mL four-necked flask, 268.11g of 35wt% sodium sarcosinate aqueous solution having a pH of 12.9 was added, and 0.23g of sodium sulfite was added thereto and dissolved by stirring;
dropwise adding 20wt% hydrochloric acid, regulating the pH value of the mixture in the four-mouth bottle to 9.5, heating to 50-55 ℃, slowly dropwise adding 187.68g of 25wt% cyanamide aqueous solution, continuously using 20wt% hydrochloric acid to regulate the pH value of the reaction solution to 9-10, controlling the temperature of the reaction solution to 50-55 ℃, and preserving the heat for 4 hours after the dropwise adding is completed;
then cooling the mixture after reaction in the four-mouth bottle to about 25 ℃, dropwise adding 20wt% hydrochloric acid, adjusting the pH value to 6-6.5, preserving heat at 25-30 ℃ for 2h, leaching twice with 100mL of purified water, pumping, drying the material in a blowing way for 4h at 60 ℃, discharging to obtain 107.6g of creatine monohydrate, and carrying out HPLC test, wherein the yield of the creatine monohydrate is 85.4%, the purity is 99.85%, and no dihydrotriazine is detected in the sample.
Example 3
In a 500mL four-necked flask, 208.53g of 45wt% sodium sarcosinate aqueous solution having a pH of 13.6 was added, and 4.5g of sodium sulfite was added thereto and dissolved by stirring;
dropwise adding 20wt% hydrochloric acid, regulating the pH value of the mixture in the four-mouth bottle to 10.60, heating to 60-70 ℃, slowly dropwise adding 89.37g of 35wt% cyanamide aqueous solution, continuously using 20wt% hydrochloric acid to regulate the pH value of the reaction solution to 10-11, controlling the temperature of the reaction solution to 60-70 ℃, and preserving the heat for 2h after the dropwise adding is finished;
then cooling the mixture after reaction in the four-mouth bottle to about 25 ℃, dropwise adding 20wt% hydrochloric acid, adjusting the pH value to 6.5-7.0, preserving heat at 20-25 ℃ for crystal growth for 1h, leaching twice with 100mL of purified water, pumping, drying the material in an air blast manner for 4h at 80 ℃, discharging to obtain 107.95gg creatine monohydrate, wherein the yield of the creatine monohydrate is 85.7%, the purity is 99.82%, and no dihydrotriazine is detected in the sample through HPLC test.
Comparative example 1
Comparative example 1 is a comparative experimental example of example 1, which was prepared as follows:
in a 500mL four-necked flask, 230g of a 40.8wt% aqueous solution of sodium sarcosinate was added thereto, and the pH thereof was 13.38;
dropwise adding 20wt% hydrochloric acid, regulating the pH value of the mixture in the four-mouth bottle to 10.60, heating to 55-60 ℃, slowly dropwise adding 115g of 30.11wt% cyanamide aqueous solution, continuously using 20wt% hydrochloric acid to regulate the pH value of the reaction solution to 10-11, controlling the temperature of the reaction solution to 55-60 ℃, and preserving the heat for 2h after the dropwise adding is finished;
then cooling the mixture after reaction in the four-mouth bottle to about 25 ℃, dropwise adding 20wt% hydrochloric acid, adjusting the pH value to 6.5-7.0, preserving heat and growing crystal for 1h at 20-25 ℃, leaching twice by using 100mL of purified water, pumping, drying the material in a blowing way for 4h at 60 ℃ and discharging to obtain 108.5g creatine monohydrate.
The HPLC test shows that the yield of creatine monohydrate is 86.1%, the purity is 98.82%, t= 4.308min represents dihydrotriazine, the content is 870ppm, and the maximum limit value is far greater than 0.0005% specified in United states pharmacopoeia.
In summary, the invention provides a preparation method of creatine without dihydrotriazine toxic impurities, which is based on the existing optimal creatine production process (namely, a synthetic route for producing creatine by reacting sodium sarcosinate raw material with cyanamide is still adopted), only sulfurous acid, sulfite or bisulfite is needed to be added to be mixed with the sodium sarcosinate raw material so as to remove formaldehyde impurities in the sodium sarcosinate raw material, and the dihydrotriazine impurities are not generated when the sodium sarcosinate reacts with cyanamide, so that the whole preparation process is simple to operate, equipment is not needed to be added, and other process parameters of the original preparation process are not needed to be changed; the product prepared by the preparation process has the advantages of no detected dihydrotriazine, high product yield and purity, important significance for improving the quality of creatine products and protecting the health of consumers, large supply of sulfurous acid, sulfite or hydrosulfite in markets, readily available raw materials and low price.
The foregoing description of the invention has been presented for purposes of illustration and description, and is not intended to be limiting. Several simple deductions, modifications or substitutions may also be made by a person skilled in the art to which the invention pertains, based on the idea of the invention.
Claims (3)
1. The preparation method of the high-purity creatine is characterized by comprising the following steps of:
s1, adding a impurity removing agent into a sodium sarcosinate aqueous solution, and stirring until the impurity removing agent is completely dissolved;
s2, adjusting the pH value of the mixture in the step S1 to 9-11, heating the mixture to 50-70 ℃, and then slowly adding a cyanamide aqueous solution to perform condensation reaction for 1-4h;
s3, cooling, crystallizing, filtering, washing and drying the mixture reacted in the step S2 to obtain a finished product;
in the step S1, the impurity removing agent is sodium sulfite;
the mass content of the impurity removing agent in the whole reaction system is 0.05-0.15wt%;
in the step S2, hydrochloric acid is adopted to adjust the pH value of the reaction solution, hydrochloric acid is continuously used to adjust the pH value of the reaction solution to 9-11 in the process of adding the cyanamide aqueous solution, and the temperature of the reaction solution is controlled to 50-70 ℃;
in the step S3, the mixture after the reaction in the step S2 is cooled to 20-30 ℃, the pH value of the mixture is regulated to 6-7, then the mixture is crystallized for 1-4 hours at the temperature of 20-30 ℃, and then the creatine monohydrate is obtained through suction filtration, purified water leaching, pumping and drying treatment; 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;
the sodium sarcosinate contains formaldehyde.
2. The method for producing high-purity creatine according to claim 1, wherein the creatine monohydrate produced in step S3 is subjected to a drying treatment to obtain anhydrous creatine having a water content of 1% or less.
3. The method for preparing high-purity creatine according to claim 1, wherein the mass fraction of the hydrochloric acid is 10-20%.
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