Method for producing guanidinoacetic acid

Abstract

The present invention relates to an improved process for the preparation of guanidinoacetic acid (GAA) by reacting cyanamide with a molar excess of glycine in an aqueous reaction mixture in the presence of a base, which avoids high molar amounts of base or acid for pH control while maintaining reaction selectivity and product yield.

Description

[Technical Field]

[0001] Guanidinoacetic acid (GAA) is a colorless, crystalline organic compound used as an animal feed additive (e.g., International Publication No. 2005120246 and U.S. Patent Application Publication No. 2011257075). GAA is a natural precursor of creatine (e.g., Humm et al., Biochem. J. (1997) 322, 771-776). Therefore, supplementation with GAA can optimize the supply of creatine in the body.

[0002] The present invention relates to an improved process for the preparation of guanidinoacetic acid (GAA) by reacting cyanamide with glycine in an aqueous reaction mixture in the presence of a base.

[0003] The preparation of GAA by adding cyanamide to glycine was first described in 1861 (M. Strecker, comptes rendus 1861, 52, 1212; cited in Ber. Chem. Ges. (now: Eur. J. Inorg. Chem.) 1908, 41, 4385). A weakly alkaline aqueous ammonia solution was used as the reaction medium. More recent literature also describes reaction conditions using sodium hydroxide, sodium bicarbonate, or sodium carbonate as a base for pH adjustment (e.g., CN102329250 and CN101462983).

[0004] To produce GAA from cyanamide and glycine, an alkaline environment (pH 8-10) is required. In an alkaline environment, unwanted by-products of cyanamide, such as dicyandiamide, ammonia, and urea, are also produced (Buchanan and Barsky, J. Am. Chem. Soc. Vol. 52, 195, 1930). Excess glycine can be used for inhibition. Two methods for producing GAA from cyanamide and glycine have been described in the literature: A) Method of adding cyanamide solution to alkaline glycine solution (fed-batch; Figure 1). B) Glycine and cyanamide are added to a continuous reaction system, and the mother liquor containing glycine is continuously recycled after product separation. In this method, the glycine concentration is set higher than the cyanamide concentration (Figure 2).

[0005] A) Fed-batch: The provided glycine has poor pH buffering properties, so a large amount of base is required to adjust the pH value. However, as glycine is consumed during the reaction, the buffering effect decreases, causing the pH to rise excessively, resulting in reduced yield and selectivity. This undesirable effect can be prevented by adding acid, but this has not yet been described. pH control by acid increases the overall rate of salt production.

[0006] B) Continuously operated reaction systems: For technical reasons, in continuous operation only a small excess of glycine is permitted in the reactor (usually glycine:cyanamide = 2:1), otherwise the circulation section would be too large, resulting in low selectivity. At the same time, by-products must be purged from the cycle, otherwise there is a risk of accumulation. However, in such purge streams, a large amount of glycine is also removed and lost.

[0007] Both process variants shown have drawbacks: high selectivities can only be achieved in batch processes, while relatively large amounts of base are required for good reaction performance.

[0008] The problem to be solved by the present invention is to provide a method for producing guanidinoacetic acid (GAA) by reacting cyanamide with glycine in the presence of a base in an aqueous reaction mixture, which avoids the use of high molar amounts of base or acid for pH control, while maintaining reaction selectivity and product yield.

[0009] This is achieved by a process for producing guanidinoacetic acid (GAA) from cyanamide and glycine, in which cyanamide and glycine are continuously added to a premixed aqueous solution containing glycine and a base, and the addition rates of cyanamide and glycine are adjusted so that the molar ratio of base to glycine in the reaction mixture is maintained constant at 0.1 to 0.4 throughout the reaction period.

[0010] Suitable bases for the process according to the invention are, for example, potassium or sodium hydroxides, bicarbonates or carbonates.

[0011] In the process according to the present invention, glycine is used both as a reagent and an acid regulator. Therefore, the additional addition of a base such as sodium hydroxide (NaOH) is avoided. This unique reaction control allows for a very high molar glycine:cyanamide ratio, resulting in high selectivity. While the typical glycine:cyanamide ratio in the reaction according to the present invention is up to 100:1 when cyanamide and glycine are added to the reaction mixture, in conventional continuous processes, the glycine:cyanamide ratio when cyanamide and glycine are added to the reaction mixture is 5:1 or less, resulting in the generation of undesirable by-products such as dicyandiamide, ammonia, and melamine.

[0012] In a particular embodiment of the method according to the invention, cyanamide is reacted with an overall equimolar amount of glycine, and in a subsequent step ("Stage II" of the reaction), the remaining molar amount of cyanamide is added continuously to the glycine-containing reaction mixture without glycine, while the pH of the reaction mixture is maintained below 10 by the addition of acid.

[0013] The pH of the reaction mixture can be measured by an electronic pH meter or pH paper.

[0014] Reaction step II allows not only complete conversion of cyanamide but also complete conversion of glycine (see Example 9).

[0015] The acid added to the reaction mixture to control the pH may be sulfurous acid, acetic acid, hydrochloric acid, carbonic acid, formic acid or phosphoric acid, preferably acetic acid and sulfurous acid.

[0016] In a further embodiment, the cyanamide and glycine are added simultaneously to the reaction mixture in the form of a mixture containing both cyanamide and glycine. [Brief explanation of the drawings]

[0017] [Figure 1] FIG. 1 illustrates fed-batch. [Figure 2] FIG. 1 is a diagram showing a continuously operated reaction system. [Figure 3] FIG. 1 illustrates a fed-batch concept in accordance with the present invention. [Figure 4] FIG. 1 shows the overall results of Examples 2 to 9.

[0018] Experimental section General Information Suppliers and equipment used in Experiment 1: - Glycine (pa): Merck KGaA, Darmstadt (Germany) - Hydrochloric acid (aq.): Merck KGaA, Darmstadt (Germany) - Formic acid: Merck KGaA, Darmstadt (Germany) - Cyanamide, 50% in H2O: ABCR GmbH, Karlsruhe (Germany) - Sodium hydroxide: Merck KGaA, Darmstadt (Germany) - Fink Ritmo R05 membrane pump - Piston pump Ismatec - KPG stirrer

[0019] Suppliers used for all other experiments: - Glycine (pa): Evonik Rexim (Nanning) Pharmaceutical Co. Ltd., Nanning (China) - Sodium hydroxide, 50% in H2O: VWR International, Radnor (USA) - Cyanamide, 50% in H2O: Brenntag, Essen (Germany)

[0020] Analytical equipment: - GAA analysis with Agilent HPC Derivatization: None Column: Zorbax SB-Phenyl; Column temperature: 30°C UV detection at 200nm Eluent: 1780 g H2O + 68 g orthophosphoric acid, 85 wt% in H2O ·Flow rate: 0.4mL / min ·Holding time: 15.1 minutes The pH of the reaction mixture can be measured by an electronic pH meter or pH paper.

[0021] Example 1 Identification of the best pH value for the production of guanidinoacetic acid (GAA) by the reaction of cyanamide with glycine Semibatch experiments were conducted to identify the optimal pH value for the synthesis of guanidinoacetic acid (GAA). In these experiments, a 250 mL four-neck flask equipped with a condenser, KPG stirrer, thermometer, and pH electrode was charged with glycine (32 g, 0.42 mol, 2.0 equiv.) in water (variable amount to adjust total glycine concentration). The pH was carefully adjusted with aqueous NaOH (40 wt.% in HO), NaOH, HCl (aq.), or formic acid to achieve a final total glycine concentration of 30 wt.%.

[0022] Cyanamide (50 wt% in HO, 18 g, 0.21 mol, 1.0 equiv.) was added dropwise with stirring at 80 °C (v = 1 mL / min, t = approx. 24 min). After 2 h at 75 °C, the formed suspension was filtered and the wet cake was dried. HPLC analysis of the dried cake was performed to determine GAA purity and calculate the yield.

[0023] The results for each pH value are shown in Table 1.

[0024] [Table 1]

[0025] At pH values ​​<8 or >11, the yields were very low (not shown).

[0026] Example 2 Semi-batch with 19GLY mol% NaOH In a 50 L reactor, cyanamide (50 wt% in HO, 4.5 kg, 54 mol, 1.0 eq, 24 mL / min in 178 min) was added to a stirred aqueous solution of glycine (5.8 kg, 77 mol, 1.4 eq) and sodium hydroxide (50 wt% in HO, 1.2 kg, 15 mol) (16 kg water, glycine content of the solution: 25 wt%) at 82 °C. After stirring for an additional 2 h at 82 °C, the GAA yield was determined by HPLC analysis of the formed suspension.

[0027] GAA yield: 88% (5.6 kg) NaOH molar content to glycine: 19% pH value at the start of the reaction: 9, pH value at the end of the reaction: 10

[0028] Example 3 Semi-batch with 13GLY mol% NaOH In a 50 L reactor, cyanamide (50 wt% in HO, 4.5 kg, 54 mol, 1.0 eq, 24 mL / min in 178 min) was added to a stirred aqueous solution of glycine (5.8 kg, 77 mol, 1.4 eq) and sodium hydroxide (50 wt% in HO, 0.77 kg, 9.7 mol) (17 kg water, glycine content of the solution: 25 wt%) at 82 °C. After stirring for an additional 2 h at 82 °C, the GAA yield was determined by HPLC analysis of the formed suspension.

[0029] GAA yield: 76% (4.8 kg) NaOH molar content to glycine: 13% pH value at the start of the reaction: 9, pH value at the end of the reaction: 9.5

[0030] Example 4 Semi-batch with 9GLY mol% NaOH In a 50 L reactor, cyanamide (50 wt% in HO, 4.5 kg, 54 mol, 1.0 eq, 24 mL / min in 178 min) was added to a stirred aqueous solution of glycine (5.8 kg, 77 mol, 1.4 eq) and sodium hydroxide (50 wt% in HO, 0.56 kg, 7.0 mol) (17 kg water, glycine content of the solution: 25 wt%) at 82 °C. After stirring for an additional 2 h at 82 °C, the GAA yield was determined by HPLC analysis of the formed suspension.

[0031] GAA yield: 63% (4.0 kg) NaOH molar content to glycine: 9% pH value at the start of the reaction: 8.9, pH value at the end of the reaction: 9.3

[0032] Example 5 Method according to the invention 5GLY mol% NaOH, glycine content in the reactor at the start 20% In a 50 L reactor, an aqueous solution of cyanamide (50 wt% in HO, 4.5 kg, 54 mol, 1.0 eq, 24 mL / min in 178 min) and glycine (4.6 kg, 62 mol, 1.1 eq) (14 kg water, glycine content of the solution: 25 wt%, total 107 mL / min in 178 min) was added to an aqueous solution of glycine (1.2 kg, 15 mol, 0.28 eq) and sodium hydroxide (50 wt% in HO, 0.30 kg, 3.8 mol) (3.2 kg water, glycine content of the solution: 25 wt%) at 82 °C with stirring. After stirring for an additional 2 h at 82 °C, the GAA yield was determined by HPLC analysis of the formed suspension.

[0033] GAA yield: 89% (5.7 kg) NaOH molar content to glycine: 5% pH value at the start of the reaction: 9.5, pH value at the end of the reaction: 8.9

[0034] Example 6 Method according to the invention 6GLY mol% NaOH, glycine content in the reactor at the start 30% In a 50 L reactor, both aqueous solutions of cyanamide (50 wt% in HO, 4.5 kg, 54 mol, 1.0 equiv, 24 mL / min in 178 min) and glycine (4.0 kg, 54 mol, 1.0 equiv) (12 kg water, glycine content of the solution: 25 wt%, 93 mL / min total in 178 min) were added to an aqueous solution of glycine (1.7 kg, 23 mol, 0.42 equiv) and sodium hydroxide (50 wt% in HO, 0.35 kg, 4.4 mol) (4.8 kg water, glycine content of the solution: 25 wt%) at 82 °C with stirring. After stirring for an additional 2 h at 82 °C, the GAA yield was determined by HPLC analysis of the formed suspension.

[0035] GAA yield: 93% (5.9 kg) NaOH molar content to glycine: 6% pH value at the start of the reaction: 9.3, pH value at the end of the reaction: 9.0

[0036] Example 7 Method according to the invention 9GLY mol% NaOH, 20% glycine content in the starting reactor, 30% by weight cyanamide in HO In a 50 L reactor, cyanamide (30 wt% in HO, 7.6 kg, 54 mol, 1.0 eq, 42 mL / min in 178 min) and an aqueous solution of glycine (4.6 kg, 62 mol, 1.1 eq) and sodium hydroxide (50 wt% in HO, 0.24 kg, 3.0 mol) (14 kg water, glycine content of the solution: 25 wt%, 107 mL / min total in 178 min) were both added with stirring to an aqueous solution of glycine (1.2 kg, 15 mol, 0.28 eq) and sodium hydroxide (50 wt% in HO, 0.30 kg, 3.8 mol) (3.2 kg water, glycine content of the solution: 25 wt%) at 82 °C. After stirring for an additional 2 h at 82 °C, the GAA yield was determined by HPLC analysis of the formed suspension.

[0037] GAA yield: 93% (5.9 kg) NaOH molar content to glycine: 9% pH value at the start of the reaction: 9.1, pH value at the end of the reaction: 9.1

[0038] Example 8 Method according to the invention 8GLY mol% NaOH, 20% glycine content in the starting reactor, 30% by weight cyanamide in HO In a 50 L reactor, cyanamide (30 wt% in HO, 7.6 kg, 54 mol, 1.0 eq, 42 mL / min in 178 min) and an aqueous solution of glycine (4.6 kg, 62 mol, 1.1 eq) and sodium hydroxide (50 wt% in HO, 0.20 kg, 2.5 mol) (14 kg water, glycine content of the solution: 25 wt%, 107 mL / min total in 178 min) were both added with stirring to an aqueous solution of glycine (1.2 kg, 15 mol, 0.28 eq) and sodium hydroxide (50 wt% in HO, 0.30 kg, 3.8 mol) (3.2 kg water, glycine content of the solution: 25 wt%) at 82 °C. After stirring for an additional 2 h at 82 °C, the GAA yield was determined by HPLC analysis of the formed suspension.

[0039] GAA yield: 85% (5.4 kg) NaOH molar content to glycine: 8% pH value at the start of the reaction: 8.5, pH value at the end of the reaction: 9.5

[0040] The results of Examples 5 to 8 are shown in Table 3 and FIG.

[0041] Example 9 Method according to the invention 11 GLY mole % NaOH, glycine content in the reactor at the start 40% + Reaction Step II (addition of additional cyanamide to achieve a final GLY:CA ratio of 1:1) Reaction Step I: In a 50 L reactor, an aqueous solution of cyanamide (50 wt% in HO, 4.5 kg, 54 mol, 0.70 equiv, 24 mL / min in 178 min) and glycine (3.5 kg, 46 mol, 0.60 equiv) (11 kg water, glycine content of the solution: 25 wt%, 79 mL / min total in 178 min) was added to an aqueous solution of glycine (2.3 kg, 31 mol, 0.40 equiv) and sodium hydroxide (50 wt% in HO, 0.66 kg, 8.3 mol) (6.5 kg water, glycine content of the solution: 24 wt%) at 82 °C with stirring.

[0042] Reaction Step II: Immediately after reaction step I, cyanamide (50 wt% in H2O, 1.9 kg, 23 mol, 0.30 equiv., 24 mL / min in 74 min) was added under stirring at 82 °C, and the pH value of the reaction was controlled by adding H2SO4 (10 wt% in water, threshold: pH ≤ 10). After stirring for another 5 h at 82 °C, the GAA yield was determined by HPLC analysis of the formed suspension.

[0043] GAA yield relative to cyanamide: 76% (5.9 kg of GAA), GAA yield relative to glycine: 76% NaOH molar content to glycine: 11% pH value at the start of the reaction: 10, pH value at the end of the reaction: 10 Final GLY concentration in this method: 1.3% by weight (the aim of this experiment is to minimize this value while keeping the yield high).

[0044] [Table 2]

[0045] Compared to the new process, the fed-batch test has a relatively high base:feedstock ratio, but at the same time the yield is not improved. In contrast, the yield is actually improved, which can be attributed to better control of the pH value. This applies to both the yield for cyanamide and the yield for glycine.

[0046] "New method + step II" (see Example 9) means that attention was paid to the complete conversion of the starting compounds by using glycine and cyanamide in a 1:1 ratio based on the entire reaction, and in a subsequent step the remaining molar amount of cyanamide is added continuously to the glycine-containing reaction mixture without glycine, while the pH of the reaction mixture is kept below 10 by adding acid. This was only possible with the new method, because the pH value could still be controlled.

[0047] The results of Examples 2 to 9 are also shown in FIG.

Claims

1. A method for producing guanidinoacetic acid (GAA) from cyanamide and glycine, comprising continuously adding cyanamide and glycine to a premixed aqueous solution containing glycine and a base to react them, the method comprising adjusting the addition rates of cyanamide and glycine so that the molar ratio of base to glycine in the reaction mixture is maintained constant at 0.1 to 0.4 throughout the reaction period.

2. 2. The method of claim 1, wherein cyanamide is reacted with an equimolar amount of glycine, and in a subsequent step, only additional cyanamide is continuously added to the reaction mixture while maintaining the pH of the reaction mixture at 10 or less by the addition of acid.

3. 3. The method of claim 1, wherein the cyanamide and glycine are added simultaneously to the reaction mixture in the form of a mixture containing both cyanamide and glycine.

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