A preparation method for continuously producing high-purity creatine monohydrate

Abstract

This invention provides a continuous method for preparing high-purity creatine monohydrate, comprising the following steps: a) adding chloroacetic acid aqueous solution dropwise to an aqueous methylamine solution, stirring at room temperature for 2 hours after the addition is complete; b) heating to 50-60°C and holding for 1 hour to remove most of the methylamine, then heating to 95°C to evaporate the methylamine aqueous solution for 1 hour; c) adding sodium hydroxide solution dropwise to the solution from step b) at 95°C, then heating to 105°C and concentrating under reduced pressure for 1.5 hours to approximately half the original volume, obtaining a creatine solution with a concentration of 30%-40%; d) cooling the solution from step c) to 40-60°C and adding a catalyst; e) drying to obtain pure creatine monohydrate. This invention reduces the methylamine equivalent, saving costs, and eliminates the need for purifying creatine for direct use in the next reaction; it can simultaneously lower the system reaction temperature and pH value to inhibit the formation of byproducts dicyandiamide and creatinine, and eliminates the need for debittering agents for purification and debittering, thus saving production costs.

Description

Technical Field

[0001] This invention belongs to the field of chemical production technology and relates to a method for the continuous synthesis of creatine monohydrate. Background Technology

[0002] Creatine monohydrate, also known as N-methylguanidinoacetic acid, is a pharmaceutical raw material and health supplement additive. It can inhibit the production of factors that cause muscle fatigue, reduce fatigue and tension, restore physical strength, accelerate protein synthesis in the human body, make muscles stronger, and enhance muscle elasticity. Creatine is present in small amounts in fish and meat products; it is difficult to obtain the required daily intake for muscle growth entirely from food. Because creatine is not a hormone, it does not interfere with or damage the human endocrine system and does not cause drug dependence or physiological side effects. It is hailed as one of the most effective nutritional supplements and has become increasingly popular in recent years.

[0003] There are several existing methods for producing creatine monohydrate: 1) reacting S-methylisothiourea with an aqueous solution of sodium or potassium sarcosinate to prepare creatine; 2) reacting cyanamide with an aqueous solution of sodium or potassium sarcosinate to prepare creatine monohydrate; 3) preparing sarcosinate from chloroacetic acid and methylamine, and then reacting it with an aqueous solution of cyanamide to prepare creatine monohydrate. High-purity sarcosinate is expensive, making it difficult to reduce the production cost of the first and second methods. Furthermore, the process reported in US Patent 6326513B1, which involves reacting S-methylisothiourea with an aqueous solution of sodium or potassium sarcosinate to prepare creatine, produces an equimolar amount of methanethiol as a byproduct with a particularly unpleasant odor. The exhaust gas is difficult to absorb fully with alkaline solutions, easily causing air pollution. It also requires repeated washing of the product with ethanol, resulting in a long process and high cost. In contrast, the third method synthesizes sarcosinate from inexpensive chloroacetic acid and methylamine. The byproduct sodium chloride does not affect the subsequent reaction, and creatine precipitates from the aqueous phase after reacting with cyanamide, significantly reducing the production cost of creatine monohydrate.

[0004] Chinese invention patent CN98110909.8 uses a molar ratio of chloroacetic acid to methylamine of 1:8 to 1:12, requiring a high methylamine equivalent to synthesize creatine. When cyanamide is added, the pH of the reaction solution is 9 to 12, and the reaction temperature is 70-80℃, which are relatively high. This method produces a product with a large amount of dicyandiamide as a byproduct, which has an intolerable bitter taste. A single water wash is insufficient to completely remove the bitterness; debittering agents such as sodium thiosulfate are needed to obtain a high-purity creatine monohydrate product. The process is cumbersome. Summary of the Invention

[0005] The purpose of this invention is to further study and improve the above-mentioned production process of creatine monohydrate, and to develop an economical and effective method for producing high-purity creatine monohydrate.

[0006] The technical solution adopted in this invention is: a method for the continuous production of high-purity creatine monohydrate, comprising the following steps:

[0007] a) Prepare an aqueous solution of chloroacetic acid, add the aqueous solution of chloroacetic acid dropwise to the aqueous solution of methylamine, and stir at room temperature for 2 hours after the addition is complete;

[0008] b) Heat to 50-60℃ and hold for 1 hour to drive out most of the methylamine, then heat to 95℃ to evaporate the methylamine aqueous solution for 1 hour;

[0009] c) Add sodium hydroxide solution dropwise to the solution from step b) at 95°C, then heat to 105°C and concentrate under reduced pressure for 1.5 hours to about half of the original volume to obtain a sarcosine solution with a concentration of 30%-40%.

[0010] d) Cool the solution from step c) to 40-60℃, add the catalyst 1-methylimidazolium or dimethylaminopyridine, adjust the pH of the sarcosine solution to 7.5-8.0 with sodium hydroxide solution, add cyanamide solution dropwise, and keep the reaction at the temperature for 4-8 hours after the addition is complete. Then cool the solution to 25℃ and adjust the pH with hydrochloric acid.

[0011] e) Filter the solution from step d) above at 25°C, wash with water to obtain crude product, heat and stir the crude product in deionized water for 2 hours, cool to 5-10°C, filter, wash with deionized water, and dry to obtain pure creatine monohydrate.

[0012] Preferably, the concentration of the methylamine solution is 40%, and the molar ratio of methylamine to chloroacetic acid is 5:1 to 8:1.

[0013] Preferably, the concentration of the sodium hydroxide solution is 30 wt%.

[0014] Preferably, the system temperature during step a) when adding chloroacetic acid aqueous solution to methylamine aqueous solution is 5-15℃.

[0015] Preferably, the mass content of the catalyst 1-methylimidazolium or dimethylaminopyridine in step c) is 0.02-0.15 wt%.

[0016] Preferably, in step d), the cyanamide solution is added over a time of 1.5-2 hours, and the pH value is monitored and adjusted to 7.5-8.0 during the addition process.

[0017] Preferably, in step d), 15-20 wt% hydrochloric acid is used to adjust the pH to 8.0.

[0018] Preferably, the deionized water stirring temperature in step e) is 50°C.

[0019] The beneficial effects obtained by this invention are as follows: The production process conditions for preparing high-purity creatine monohydrate by reacting chloroacetic acid and methylamine to generate sarcosine first, and then reacting it with cyanamide aqueous solution are optimized: the first step reduces the methylamine equivalent to save costs, and sarcosine can be directly used in the next step without purification; by adding water-soluble catalyst 1-MI or DMAP to catalyze the second step reaction, the reaction temperature and pH value of the system can be reduced at the same time to inhibit the generation of byproducts dicyandiamide and creatinine, and debittering agents are not needed for purification and debittering, thus saving production costs.

[0020] The reaction equation of this invention is as follows:

[0021] Detailed Implementation

[0022] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments.

[0023] A method for the continuous production of high-purity creatine monohydrate comprises the following steps:

[0024] a) Prepare an aqueous solution of chloroacetic acid, add the aqueous solution of chloroacetic acid dropwise to the aqueous solution of methylamine, and stir at room temperature for 2 hours after the addition is complete;

[0025] b) Heat to 50-60℃ and hold for 1 hour to drive out most of the methylamine, then heat to 95℃ to evaporate the methylamine aqueous solution for 1 hour;

[0026] c) Add sodium hydroxide solution dropwise to the solution from step b) at 95°C, then heat to 105°C and concentrate under reduced pressure for 1.5 hours to about half of the original volume to obtain a sarcosine solution with a concentration of 30%-40%.

[0027] d) Cool the solution from step c) to 40-60℃, add the catalyst 1-methylimidazolium or dimethylaminopyridine, adjust the pH of the sarcosine solution to 7.5-8.0 with sodium hydroxide solution, add cyanamide solution dropwise, and keep the reaction at the temperature for 4-8 hours after the addition is complete. Then cool the solution to 25℃ and adjust the pH with hydrochloric acid.

[0028] e) Filter the solution from step d) above at 25°C, wash with water to obtain crude product, heat and stir the crude product in deionized water for 2 hours, cool to 5-10°C, filter, wash with deionized water, and dry to obtain pure creatine monohydrate.

[0029] The concentration of the methylamine solution is 40%, and the molar ratio of methylamine to chloroacetic acid is 5:1 to 8:1. The concentration of the sodium hydroxide solution is 30 wt%. In step a), the system temperature during the dropwise addition of the chloroacetic acid aqueous solution to the methylamine aqueous solution is 5-15°C. In step c), the mass content of the catalyst 1-methylimidazolium or dimethylaminopyridine is 0.02-0.15 wt%. In step d), the dropwise addition time of the cyanamide solution is controlled at 1.5-2 hours, and the pH value of the reaction is monitored during the dropwise addition and adjusted to pH = 7.5-8.0. In step d), 15-20 wt% hydrochloric acid is used to adjust the pH to 8.0. In step e), the stirring temperature of the deionized water is 50°C.

[0030] Example 1

[0031] (1) Cool 40% methylamine solution (622 kg) to 5-10℃, dissolve chloroacetic acid (95 kg) in 40 kg of deionized water to prepare an aqueous solution, add the prepared 70% chloroacetic acid solution dropwise to the methylamine solution, control the dropping rate and ensure that the temperature does not exceed 15℃, and after the dropping is completed, raise the temperature to room temperature and stir the reaction for 2 hours.

[0032] (2) Heat the above solution to 50-60℃ and hold for 1 hour to remove most of the methylamine. Then heat to 95℃ and hold for 1 hour. Add 30% sodium hydroxide solution (140 kg) dropwise and heat to 105℃ and hold for 1.5 hours. Then concentrate under reduced pressure (~20 mbar) to half of the original volume (all steps fully recover methylamine for reuse) to obtain a 30%-40% sarcosine solution.

[0033] (3) Heat the above solution to 50°C, add the catalyst DMAP (50g), adjust the pH of the solution to 8.0 with 30% sodium hydroxide solution, and then slowly add 120kg of 30% cyanamide aqueous solution to the reaction solution dropwise. During the dropwise addition, pay attention to adjusting the pH of the reaction solution to 8.0 with 18% hydrochloric acid. After the dropwise addition is completed, keep the reaction at the temperature for 8 hours. After the reaction is completed, gradually cool down to 25°C and adjust the pH to about 8.0 with hydrochloric acid.

[0034] (4) Filter the above solution at about 25°C, rinse with 100 kg of deionized water, and dry to obtain crude creatine monohydrate.

[0035] (5) The crude product was suspended in 160 kg of deionized water, stirred at 50°C for 2 h, slowly cooled to room temperature, cooled to 5-10°C with ice-salt water, filtered, washed with 100 kg of deionized water, and dried at 60°C to obtain 81.44 kg of high-purity creatine monohydrate product, with a yield of 54.6% (calculated as chloroacetic acid). HPLC purity >99%, no catalyst DMAP, byproducts dicyandiamide and creatinine were detected. ICP-MS analysis showed that the contents of arsenic, lead, mercury, and chromium in the sample were 0.0049 mg / kg, 0.0071 mg / kg, 0.0341 mg / kg, and 0.0120 mg / kg, respectively. ICP-OES analysis showed that the iron content in the sample was 5.19 mg / kg, which met the requirements.

[0036] Example 2

[0037] (1) Cool 40% methylamine solution (389 kg) to 5-10℃, dissolve chloroacetic acid (95 kg) in 40 kg of deionized water to prepare an aqueous solution, add the prepared 70% chloroacetic acid solution dropwise to the methylamine solution, control the dropping rate and ensure that the temperature does not exceed 15℃, and after the dropping is completed, raise the temperature to room temperature and stir the reaction for 4 hours.

[0038] (2) Heat the above solution to 50-60℃ and hold for 1 hour to remove most of the methylamine. Then heat to 95℃ and hold for 1 hour. Add 30% sodium hydroxide solution (140 kg) dropwise and heat to 105℃ and hold for 1.5 hours. Then concentrate under reduced pressure (~20 mbar) to half of the original volume (all steps fully recover methylamine for reuse) to obtain a 30%-40% sarcosine solution.

[0039] (3) Heat the above solution to 60°C, add 1-MI (50g), adjust the pH of the solution to 7.8 with 30% sodium hydroxide solution, and then slowly add 110kg of 30% cyanamide aqueous solution to the reaction solution. During the addition, pay attention to adjusting the pH of the reaction solution to 7.8 with 18% hydrochloric acid. After the addition is complete, keep the reaction at the temperature for 4 hours. After the reaction is completed, gradually cool down to 25°C and adjust the pH to about 8.0 with hydrochloric acid.

[0040] (4) Filter the above solution at about 25°C, rinse with 100 kg of deionized water, and dry to obtain crude creatine monohydrate.

[0041] (5) The crude product was suspended in 160 kg of deionized water, stirred at 50°C for 2 h, slowly cooled to room temperature, cooled to 5-10°C with ice-salt water, filtered, rinsed with 100 kg of deionized water, and dried at 60°C to obtain 75.3 kg of high-purity creatine monohydrate product, with a yield of 50.5% (calculated as chloroacetic acid). HPLC purity >99%, no catalyst 1-MI, byproducts dicyandiamide and creatinine were detected. ICP-MS analysis showed that the contents of arsenic, lead, mercury, and chromium in the sample were 0.0006 mg / kg, 0.0139 mg / kg, 0.0933 mg / kg, and 0.0139 mg / kg, respectively. ICP-OES analysis showed that the iron content in the sample was 6.64 mg / kg, which met the requirements.

[0042] Example 3

[0043] (1) Cool 40% methylamine solution (544 kg) to 5-10℃, dissolve chloroacetic acid (95 kg) in 40 kg of deionized water to prepare an aqueous solution, add the prepared 70% chloroacetic acid solution dropwise to the methylamine solution, control the dropping rate and ensure that the temperature does not exceed 15℃, and after the dropping is completed, raise the temperature to room temperature and stir the reaction for 2 hours.

[0044] (2) Heat the above solution to 50-60℃ and hold for 1 hour to remove most of the methylamine. Then heat to 95℃ and hold for 1 hour. Add 30% sodium hydroxide solution (140 kg) dropwise and heat to 105℃ and hold for 1.5 hours. Then concentrate under reduced pressure (~20 mbar) to half of the original volume (all steps fully recover methylamine for reuse) to obtain a 30%-40% sarcosine solution.

[0045] (3) Heat the above solution to 55°C, add 1-MI (50g), adjust the pH of the solution to 7.8 with 30% sodium hydroxide solution, and then slowly add 110kg of 30% cyanamide aqueous solution to the reaction solution. During the addition, pay attention to adjusting the pH of the reaction solution to 7.8 with 18% hydrochloric acid. After the addition is complete, keep the reaction at the temperature for 8 hours. After the reaction is completed, gradually cool down to 25°C and adjust the pH to about 8.0 with hydrochloric acid.

[0046] (4) Filter the above solution at about 25°C, rinse with 100 kg of deionized water, and dry to obtain crude creatine monohydrate.

[0047] (5) The crude product was suspended in 160 kg of deionized water, stirred at 50°C for 2 h, slowly cooled to room temperature, cooled to 5-10°C with ice-salt water, filtered, rinsed with 100 kg of deionized water, and dried at 60°C to obtain 71.59 kg of high-purity creatine monohydrate product, with a yield of 48.0% (calculated as chloroacetic acid). HPLC purity >99%, no catalyst 1-MI, byproducts dicyandiamide and creatinine were detected. ICP-MS analysis showed that the contents of arsenic, lead, mercury, and chromium in the sample were 0.0015 mg / kg, 0.0079 mg / kg, 0.0323 mg / kg, and 0.0110 mg / kg, respectively. ICP-OES analysis showed that the iron content in the sample was 4.39 mg / kg, which met the requirements.

[0048] Comparative Example 1

[0049] A method for synthesizing creatine monohydrate, characterized by comprising the following steps: without a catalyst, at a reaction temperature of 60°C and a pH of 8.0.

[0050] (1) Prepare aqueous solutions of methylamine and chloroacetic acid. Add chloroacetic acid solution dropwise to the methylamine solution (the molar ratio of chloroacetic acid to methylamine is 1:8). Control the dropping rate and ensure that the temperature does not exceed 30°C. After the addition is complete, stir at room temperature for 2 hours. (2) Heat the above solution to 50-60°C and hold for 1 hour to expel most of the methylamine. Then raise the temperature to 95°C and hold for 1 hour. Add sodium hydroxide solution dropwise and raise the temperature to 105°C and hold for 1.5 hours. Then concentrate under reduced pressure to half of the original volume to obtain a 30%-40% sarcosine solution.

[0051] (3) Heat the above solution to 60°C, add sodium hydroxide solution to adjust the pH to 8.0, and then slowly add cyanamide aqueous solution dropwise to the reaction solution. During the dropwise addition, adjust the pH to 8.0 with hydrochloric acid. After the dropwise addition is complete, keep the reaction at the temperature for 8 hours. After the reaction is complete, gradually cool down to 25°C and add hydrochloric acid dropwise to adjust the pH to about 8.0.

[0052] (4) Filter the above solution at about 25°C, rinse with 100 kg of deionized water, and dry to obtain crude creatine monohydrate.

[0053] (5) The crude product was suspended in 160 kg of deionized water, stirred at 50°C for 2 h, slowly cooled to room temperature, cooled to 5-10°C with ice-salt water, filtered, washed with 100 kg of deionized water, and dried in a forced-air oven at 60°C to obtain creatine monohydrate product with a yield of 35.46% (calculated as chloroacetic acid), which was significantly reduced.

[0054] Comparative Example 2

[0055] A method for synthesizing creatine monohydrate, characterized by comprising the following steps: reducing the equivalent of methylamine to 4.0 eq., reacting at 60°C, and setting the pH to 8.0.

[0056] (1) Prepare aqueous solutions of methylamine and chloroacetic acid. Add chloroacetic acid solution dropwise to the methylamine solution (the molar ratio of chloroacetic acid to methylamine is 1:4). Control the dropping rate and ensure that the temperature does not exceed 30°C. After the addition is complete, stir at room temperature for 2 hours. (2) Heat the above solution to 50-60°C and hold for 1 hour to expel most of the methylamine. Then raise the temperature to 95°C and hold for 1 hour. Add sodium hydroxide solution dropwise and raise the temperature to 105°C and hold for 1.5 hours. Then concentrate under reduced pressure to half of the original volume to obtain a 30%-40% sarcosine solution.

[0057] (3) Heat the above solution to 60°C, add sodium hydroxide solution to adjust the pH to 8.5, add 1-MI (50g), and then slowly add cyanamide aqueous solution dropwise to the reaction solution. During the dropwise addition, adjust the pH to 8.0 with hydrochloric acid. After the dropwise addition is complete, keep the reaction at the temperature for 8 hours. After the reaction is complete, gradually cool down to 25°C and add hydrochloric acid dropwise to adjust the pH to about 8.0.

[0058] (4) Filter the above solution at about 25°C, rinse with 100 kg of deionized water, and dry to obtain crude creatine monohydrate.

[0059] (5) The crude product was suspended in 160 kg of deionized water, stirred at 50°C for 2 h, slowly cooled to room temperature, cooled to 5-10°C with ice-salt water, filtered, washed with 100 kg of deionized water, and dried in a forced-air oven at 60°C to obtain creatine monohydrate product with a yield of 30.46% (calculated as chloroacetic acid), which greatly reduced the yield.

[0060] It should be noted that the above examples are merely some specific embodiments of the present invention. Obviously, the present invention is not limited to the above embodiments and other modifications are possible. All modifications directly or indirectly derived by those skilled in the art from the disclosure of the present invention should be considered within the scope of protection of the present invention.

Claims

1. A method for the continuous production of creatine monohydrate, characterized in that, Prepared by the following steps: a) Prepare an aqueous solution of chloroacetic acid, add the aqueous solution of chloroacetic acid dropwise to the aqueous solution of methylamine, and stir at room temperature for 2 hours after the addition is complete; b) Heat to 50-60℃ and hold for 1 hour to drive out most of the methylamine, then heat to 95℃ to evaporate the methylamine aqueous solution for 1 hour; c) Add sodium hydroxide solution dropwise to the solution from step b) above at 95°C, then heat to 105°C and concentrate under reduced pressure for 1.5 h to half the original volume to obtain a sarcosine solution with a concentration of 30%-40%. d) Cool the solution from step c) to 40-60℃, add the catalyst 1-methylimidazolium or dimethylaminopyridine, adjust the pH of the sarcosine solution to 7.5-8.0 with sodium hydroxide solution, add cyanamide solution dropwise, and keep the reaction at the temperature for 4-8 h after the addition is complete. Then cool to 25℃ and adjust the pH with hydrochloric acid. e) Filter the solution from step d) above at 25°C, rinse with water to obtain crude product, heat and stir the crude product in deionized water for 2 hours, cool to 5-10°C, filter, wash with deionized water, and dry to obtain pure creatine monohydrate.

2. The method for preparing creatine monohydrate as described in claim 1, characterized in that, The concentration of the methylamine solution is 40%, and the molar ratio of methylamine to chloroacetic acid is 5:1 to 8:

1.

3. The method for preparing creatine monohydrate as described in claim 1, characterized in that, The concentration of the sodium hydroxide solution is 30 wt%.

4. The method for preparing creatine monohydrate as described in claim 1, characterized in that, In step a), the system temperature during the dropwise addition of chloroacetic acid aqueous solution to the methylamine aqueous solution is 5-15℃.

5. The method for preparing creatine monohydrate as described in claim 1, characterized in that, In step c), the mass content of the catalyst 1-methylimidazolium or dimethylaminopyridine is 0.02-0.15 wt%.

6. The method for preparing creatine monohydrate as described in claim 1, characterized in that, In step d), the cyanamide solution is added over a time of 1.5-2 hours, and the pH value is monitored and adjusted to 7.5-8.0 during the addition process.

7. The method for preparing creatine monohydrate as described in claim 1, characterized in that, In step d), the pH is adjusted to 8.0 using 15-20 wt% hydrochloric acid.

8. The method for preparing creatine monohydrate as described in claim 1, characterized in that, In step e), the temperature of the deionized water during stirring is 50°C.

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