Method for preparing guanidinoacetic acid

Abstract

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

Description

[0001] Guanidine acetic acid (GAA) is a colorless crystalline organic compound used as an animal feed additive (e.g., WO2005120246 A1 and US2011257075 A1). GAA is a natural precursor of creatine (e.g., Humm et al., Biochem. J. (1997) 322, 771-776). Therefore, supplementation of GAA allows for optimal creatine supply in the organism.

[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 production of GAA by adding cyanamide to glycine was first described in 1861 (M. Strecker, comptesrendus 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 publications also include reaction conditions using sodium hydroxide, sodium bicarbonate or sodium carbonate as base to set the pH value (e.g. CN 102329250 A and CN 101462983 A).

[0004] Alkaline environment (pH 8-10) is necessary for the production of GAA from cyanamide and glycine. In an alkaline environment, undesirable cyanamide byproducts such as dicyandiamide, ammonia and urea (Buchanan and Barsky, J.Am.Chem.Soc.Vol.52,195,1930) are also formed. Excessive glycine can be used for inhibition. Two GAA production methods carried out by cyanamide and glycine are described in the document:

[0005] A) Adding the cyanamide solution to the alkaline glycine solution (batch feed; Figure 1 )

[0006] B) adding glycine and cyanamide to a continuously operating reaction system and circulating the mother liquor containing glycine continuously after product separation. In this process, the glycine concentration is set to be higher than the cyanamide concentration ( Figure 2 ).

[0007] A) Batch feeding: Large amounts of base are required to adjust the pH, since the glycine provided has an unfavorable pH buffering effect. However, during the reaction, the glycine is consumed and the buffering effect weakens, the pH rises too high and the yield and selectivity deteriorate. This undesirable effect can be prevented by adding acid, but this has not yet been described. Controlling the pH with acid leads to a generally high rate of salt formation.

[0008] B) Continuously operated reaction system: For technical reasons, continuous operation allows only a small excess of glycine in the reactor (usually: glycine: cyanamide = 2: 1), otherwise the loop becomes too large. This leads to poor selectivity. At the same time, by-products must leave the circulation, otherwise there is a risk of accumulation. However, such a purge stream also removes a large amount of glycine, which is then lost.

[0009] Both proposed process variants have disadvantages. High selectivities can only be achieved in a batch process, but relatively high amounts of base are required for good reaction performance.

[0010] The problem to be solved by the present invention is to provide a process for preparing guanidinoacetic acid (GAA) by reacting cyanamide with glycine in an aqueous reaction mixture in the presence of a base, which avoids high molar amounts of base or acid to control the pH value while maintaining the reaction selectivity and product yield.

[0011] This is achieved by a process for preparing guanidinoacetic acid (GAA) from cyanamide and glycine, wherein cyanamide and glycine are added continuously to a premixed aqueous solution comprising glycine and a base, characterized in that the addition rates of cyanamide and glycine are adjusted so that the molar ratio of base to glycine in the reaction mixture remains constant at 0.1 to 0.4 during the entire reaction.

[0012] Suitable bases for the process according to the invention are, for example, hydroxides, bicarbonates or carbonates of potassium or sodium.

[0013] In the method according to the invention as described above, glycine is used as both a reagent and an acid regulator. Therefore, further addition of alkali, such as sodium hydroxide (NaOH), is avoided. Due to this special reaction control, a very high glycine: cyanamide molar ratio allows high selectivity. For the reaction according to the invention, at the moment when cyanamide and glycine are added to the reaction mixture, a typical glycine: cyanamide ratio is up to 100: 1, while in a conventional continuous process, at the moment when cyanamide and glycine are added to the reaction mixture, a glycine: cyanamide ratio is lower than 5: 1, thereby causing unwanted by-products such as dicyandiamide, ammonia and trimerization cyanamide.

[0014] In a particular embodiment of the process according to the invention, cyanamide is reacted with a total equimolar amount of glycine, wherein in a subsequent step ("stage II" of the reaction), the remaining molar amount of cyanamide is added continuously to the reaction mixture containing glycine in the absence of glycine while the pH of the reaction mixture is kept below 10 by adding acid.

[0015] The pH of the reaction mixture can be measured by an electronic pH meter or by pH test paper.

[0016] Reaction stage II allows complete conversion not only of cyanamide but also of glycine (see Example 9).

[0017] The acid added to the reaction mixture for pH control may be sulfurous acid, acetic acid, hydrochloric acid, carbonic acid, formic acid or phosphorous acid, with acetic acid and sulfurous acid being preferred.

[0018] In a further embodiment, cyanamide and glycine are added simultaneously to the reaction mixture in the form of a mixture comprising both cyanamide and glycine.

[0019] Experimental Section

[0020] General information

[0021] Suppliers and equipment used in Experiment 1:

[0022] - Glycine for analysis: Merck KGaA, Darmstadt (Germany)

[0023] - Hydrochloric acid (aqueous solution): Merck KGaA, Darmstadt (Germany)

[0024] - Formic acid: Merck KGaA, Darmstadt (Germany)

[0025] -50% cyanamide in H 2 O solution: ABCR GmbH, Karlsruhe (Germany)

[0026] -Sodium hydroxide: Merck KGaA, Darmstadt (Germany)

[0027] -Diaphragm pump Fink Ritmo R05

[0028] -Piston pump Ismatec

[0029] -KPG mixer

[0030] Suppliers used for all other experiments:

[0031] - Glycine for analysis: Evonik Rexim (Nanning) Pharmaceutical Co. Ltd., Nanning (China)

[0032] -50% NaOH 2 O solution: VWR International, Radnor (USA)

[0033] -50% cyanamide in H 2 O solution: Brenntag, Essen (Germany)

[0034] analyze:

[0035] -GAA analysis via Agilent HPC

[0036] οDerivatization: No

[0037] ο Column: Zorbax SB-phenyl; Column temperature: 30°C

[0038] οUV detection at 200nm

[0039] οEluent: 1780 g H 2 O + 68 g of 85 wt% orthophosphoric acid H 2 O solution

[0040] οFlow rate: 0.4mL / min

[0041] οRetention time: 15.1 minutes

[0042] -The pH of the reaction mixture can be measured by an electronic pH meter or by pH test paper.

[0043] Example 1

[0044] Determining the optimal pH value for the reaction of cyanamide with glycine to form guanidinoacetic acid (GAA)

[0045] Semi-batch experiments were conducted to determine the optimal pH for the synthesis of guanidine acetic acid (GAA). For these experiments, a solution of glycine (32 g, 0.42 mol, 2.0 eq.) in water (variable amount to adjust total glycine concentration) was placed in a 250 mL four-necked flask equipped with a condenser, KPG stirrer, thermometer, and pH electrode. The pH was determined by evaporation of the mixture with an aqueous solution of NaOH (in H 2 The pH was carefully adjusted with 40 wt % glycine in 2% MgSO (40 wt %), NaOH, HCl (aq.) or formic acid to give a final total glycine concentration of 30 wt %.

[0046] With stirring, cyanamide (in H 2 O) (50 wt%, 18 g, 0.21 mol, 1.0 eq.) (v=1 mL / min, t=about 24 min. After 2 h at 75° C., the resulting suspension was filtered and the wet cake was dried. The dry cake was subjected to HPLC analysis to determine the purity of GAA and calculate the yield.

[0047] Table 1 shows the results for different pH values.

[0048] Table 1:

[0049] pH GAA yield [%] 8.0 63.6 9.0 81.6 9.6 82.9 10.0 78.8 11.0 45.0

[0050] The yield was very low at pH < 8 or pH > 11 (not shown).

[0051] Example 2

[0052] 19GLY-Mol-% Semi-batch under NaOH

[0053] In a 50L reaction apparatus, cyanamide (in H 2 O (50 wt%, 4.5 kg, 54 mol, 1.0 eq., 24 mL / min for 178 min) was added to glycine (5.8 kg, 77 mol, 1.4 eq.) and sodium hydroxide (H 2 After stirring for a further 2 hours at 82° C., the GAA yield was determined by HPLC analysis of the resulting suspension.

[0054] GAA yield: 88% (5.6 kg).

[0055] NaOH molar content relative to glycine: 19%

[0056] The pH value at the beginning of the reaction was 9, and the pH value at the end of the reaction was 10.

[0057] Example 3

[0058] 13GLY-Mol-% Semi-batch under NaOH

[0059] In a 50L reaction apparatus, cyanamide (in H 2 O (50 wt%, 4.5 kg, 54 mol, 1.0 eq., 24 mL / min for 178 min) was added to glycine (5.8 kg, 77 mol, 1.4 eq.) and sodium hydroxide (H 2 O (50% by weight, 0.77 kg, 9.7 mol) in aqueous solution (17 kg, glycine content of the solution: 25% by weight). After stirring for a further 2 hours at 82° C., the GAA yield was determined by HPLC analysis of the resulting suspension.

[0060] GAA yield: 76% (4.8 kg).

[0061] NaOH molar content relative to glycine: 13%

[0062] The pH value at the beginning of the reaction was 9, and the pH value at the end of the reaction was 9.5.

[0063] Example 4

[0064] 9GLY-Mol-% Semi-batch under NaOH

[0065] In a 50L reaction apparatus, cyanamide (in H 2 O (50 wt%, 4.5 kg, 54 mol, 1.0 eq., 24 mL / min for 178 min) was added to glycine (5.8 kg, 77 mol, 1.4 eq.) and sodium hydroxide (H 2 O (50% by weight, 0.56 kg, 7.0 mol) in aqueous solution (17 kg, glycine content of the solution: 25% by weight). After stirring for a further 2 hours at 82° C., the GAA yield was determined by HPLC analysis of the resulting suspension.

[0066] GAA yield: 63% (4.0 kg).

[0067] NaOH molar content relative to glycine: 9%

[0068] The pH value at the beginning of the reaction was 8.9, and the pH value at the end of the reaction was 9.3.

[0069] Example 5

[0070] In the case of a 20% glycine content in the reactor at the start

[0071] The method according to the invention at 5 GLY-Mol-% NaOH

[0072] In a 50L reaction apparatus, cyanamide (in H 2 O (50 wt%, 4.5 kg, 54 mol, 1.0 eq., 24 mL / min for 178 min), and glycine (4.6 kg, 62 mol, 1.1 eq.) in aqueous solution (14 kg, glycine content of the solution: 25 wt%, at a total of 107 mL / min for 178 min) were added to glycine (1.2 kg, 15 mol, 0.28 eq.) and sodium hydroxide (H 2 After stirring for a further 2 hours at 82° C., the GAA yield was determined by HPLC analysis of the resulting suspension.

[0073] GAA yield: 89% (5.7 kg).

[0074] NaOH molar content relative to glycine: 5%

[0075] The pH value at the beginning of the reaction was 9.5, and the pH value at the end of the reaction was 8.9.

[0076] Example 6

[0077] In the case of a 30% glycine content in the reactor at the start

[0078] The method according to the invention with 6 GLY-Mol-% NaOH

[0079] In a 50L reaction apparatus, cyanamide (in H 2 O (50 wt%, 4.5 kg, 54 mol, 1.0 eq., 24 mL / min for 178 min), and an aqueous solution of glycine (4.0 kg, 54 mol, 1.0 eq.) (12 kg, glycine content of the solution: 25 wt%, at a total of 93 mL / min for 178 min) were added to glycine (1.7 kg, 23 mol, 0.42 eq.) and sodium hydroxide (H 2 O (50% by weight, 0.35 kg, 4.4 mol) in aqueous solution (4.8 kg, glycine content of the solution: 25% by weight). After stirring for a further 2 hours at 82° C., the GAA yield was determined by HPLC analysis of the resulting suspension.

[0080] GAA yield: 93% (5.9 kg).

[0081] NaOH molar content relative to glycine: 6%

[0082] The pH value at the beginning of the reaction was 9.3, and the pH value at the end of the reaction was 9.0.

[0083] Example 7

[0084] At the beginning, the reactor had a H content of 20% glycine, 30% by weight of cyanamide. 2 In the case of O solution

[0085] The method according to the invention at 9 GLY-Mol-% NaOH

[0086] In a 50L reaction apparatus, cyanamide (in H 2 O 30 wt%, 7.6 kg, 54 mol, 1.0 eq, 42 mL / min for 178 min), and glycine (4.6 kg, 62 mol, 1.1 eq) and sodium hydroxide (in H 2 O (50 wt%, 0.24 kg, 3.0 mol) in water (14 kg, glycine content of the solution: 25 wt%, at a total of 107 mL / min for 178 min) was added to glycine (1.2 kg, 15 mol, 0.28 eq) and sodium hydroxide (H 2After stirring for a further 2 hours at 82° C., the GAA yield was determined by HPLC analysis of the resulting suspension.

[0087] GAA yield: 93% (5.9 kg).

[0088] NaOH molar content relative to glycine: 9%

[0089] The pH value at the beginning of the reaction: 9.1, the pH value at the end of the reaction: 9.1.

[0090] Example 8

[0091] At the beginning, the reactor had a H content of 20% glycine, 30% by weight of cyanamide. 2 In the case of O solution

[0092] The method according to the invention at 8 GLY-Mol-% NaOH

[0093] In a 50L reaction apparatus, cyanamide (in H 2 O 30 wt%, 7.6 kg, 54 mol, 1.0 eq, 42 mL / min for 178 min), and glycine (4.6 kg, 62 mol, 1.1 eq) and sodium hydroxide (in H 2 An aqueous solution of 50 wt%, 0.20 kg, 2.5 mol) in 2% O (14 kg, glycine content of the solution: 25 wt%, at a total of 107 mL / min for 178 min) was added to glycine (1.2 kg, 15 mol, 0.28 eq) and sodium hydroxide (H 2 After stirring for a further 2 hours at 82° C., the GAA yield was determined by HPLC analysis of the resulting suspension.

[0094] GAA yield: 85% (5.4 kg).

[0095] NaOH molar content relative to glycine: 8%

[0096] The pH value at the beginning of the reaction was 8.5, and the pH value at the end of the reaction was 9.5.

[0097] The results of Examples 5 to 8 are shown in Table 3 and FIG. 6 .

[0098] Example 9

[0099] Process according to the invention with 40% glycine content in the reactor at the start at 11 GLY-Mol-% NaOH + reaction stage II (addition of further cyanamide to a final GLY:CA ratio of 1:1)

[0100] Reaction Phase I:

[0101] In a 50L reaction apparatus, cyanamide (in H 2 O (50 wt%, 4.5 kg, 54 mol, 0.70 equiv., 24 mL / min for 178 min), and glycine (3.5 kg, 46 mol, 0.60 equiv.) in aqueous solution (11 kg, glycine content of the solution: 25 wt%, at a total of 79 mL / min for 178 min) were added to glycine (2.3 kg, 31 mol, 0.40 equiv.) and sodium hydroxide (H 2 O, 50% by weight, 0.66 kg, 8.3 mol) aqueous solution (6.5 kg, glycine content of the solution: 24% by weight).

[0102] Reaction Phase II:

[0103] Immediately after reaction stage I, cyanamide (in H 2 O 50 wt%, 1.9 kg, 23 mol, 0.30 eq, 24 mL / min for 74 min) and by adding H 2 SO 4 (10% in water, threshold: pH<=10) The pH of the reaction was controlled. After stirring for a further 5 hours at 82°C, the GAA yield was determined by HPLC analysis of the resulting suspension.

[0104] GAA yield based on cyanamide: 76% (5.9 kg GAA), GAA yield based on glycine: 76%.

[0105] NaOH molar content relative to glycine: 11%

[0106] The pH value at the beginning of the reaction: 10, the pH value at the end of the reaction: 10.

[0107] Final GLY concentration in the process: 1.3 wt% (the aim of this experiment was to keep the yield high and to minimize this value).

[0108] Table 2: Results of Examples 2-9

[0109]

[0110] Example 2-4: Fed-Batch Feed.

[0111] Example 5-8: New method,

[0112] Example 9: New method + Phase II.

[0113] Compared to the new process, the batch feed experiments had relatively high base: feed ratios, but at the same time did not have improved yields. Instead, the yields actually improved, which can be attributed to better control of pH. This applies to both - the yield based on cyanamide and the yield based on glycine.

[0114] "New process + stage II" (see Example 9) means that a complete conversion of the starting compound is observed (by using glycine and cyanamide in a 1:1 ratio based on the overall reaction), wherein in a subsequent step, the remaining molar amount of cyanamide is continuously added to the reaction mixture containing glycine without glycine, under the condition that the pH of the reaction mixture is kept below 10 by adding acid. This is only possible with the help of the new process, because the pH value can still be controlled.

[0115] The results of Examples 2-9 are also as follows Figure 4 shown.

Claims

1. A method for preparing guanidinoacetic acid (GAA) from cyanamide and glycine, wherein cyanamide and glycine are continuously added to a premixed aqueous solution containing glycine and a base, characterized in that The addition rates of cyanamide and glycine are adjusted so that the molar ratio of base to glycine in the reaction mixture remains constant at 0.1 to 0.4 during the entire reaction period, wherein the base is a hydroxide, bicarbonate or carbonate of potassium or sodium.

2. The process according to claim 1, wherein cyanamide is reacted with a total equimolar amount of glycine and wherein in a subsequent step, the remaining molar amount of cyanamide is continuously added to the reaction mixture containing glycine in the absence of glycine while the pH of the reaction mixture is kept below 10 by adding an acid.

3. The process according to claim 1 or 2, wherein cyanamide and glycine are added simultaneously to the reaction mixture in the form of a mixture comprising both cyanamide and glycine.

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