METHOD FOR PREPARING GUANIDINO ACETIC ACID

Abstract

A modified method for preparing guanidino acetic acid (GAA) involves reacting cyanamide with an excess molar amount of glycine in an aqueous reaction mixture, in the presence of a base. The method avoids high molar amounts of base or acid for pH control, and maintains the reaction selectivity and product yields.

Claims

1. A method for preparing guanidino acetic acid (GAA) from cyanamide and glycine, the method comprising: continuously adding the cyanamide and the glycine to a pre-mixed aqueous solution comprising the glycine and a base, wherein a rate of addition of the cyanamide and the glycine is adjusted such that a molar ratio of base to glycine within a reaction mixture is kept constant at 0.1 to 0.4 over an entire reaction period.

2. The method of claim 1, wherein the cyanamide is reacted with an overall equimolar amount of the glycine, and wherein subsequently, a remaining molar amount of the cyanamide without glycine is continuously added to a glycine containing reaction mixture while maintaining a pH of the reaction mixture below 10 by adding an acid.

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

Description

EXPERIMENTAL PART

General Information

[0019] Suppliers and devices used in experiment 1: [0020] Glycine, p.a.: Merck KGaA, Darmstadt (Germany) [0021] Hydrochloric acid (aq.): Merck KGaA, Darmstadt (Germany) [0022] Formic acid: Merck KGaA, Darmstadt (Germany) [0023] Cyanamide 50% in H.sub.2O: ABCR GmbH, Karlsruhe (Germany) [0024] Sodium hydroxide: Merck KGaA, Darmstadt (Germany) [0025] Membrane pump Fink Ritmo R05 [0026] Piston pump Ismatec [0027] KPG Stirrer

[0028] Suppliers used for all other experiments: [0029] Glycine, p.a.: Evonik Rexim (Nanning) Pharmaceutical Co. Ltd., Nanning (China) [0030] Sodium hydroxide 50% in H.sub.2O: VWR International, Radnor (USA) [0031] Cyanamide 50% in H.sub.2O: Brenntag, Essen (Germany)

[0032] Analytics: [0033] GAA analysis via Agilent HPC [0034] Derivatization: none [0035] Column: Zorbax SB-Phenyl; column temperature: 30° C. [0036] UV-Detection at 200 nm [0037] Eluent: 1780 g H.sub.2O + 68 g ortho-phosphoric acid 85 wt.-% in H.sub.2O [0038] Flow: 0.4 mL/min [0039] Retention time: 15.1 min [0040] The pH of the reaction mixture may be measured by means of an electronic pH meter or by means of pH indicator paper.

Example 1

[0041] Identification of best pH-value for the reaction of cyanamide with glycine to form guanidino acetic acid (GAA)

[0042] Semi-batch trials were conducted to identify the best pH-value for the synthesis of guanidino acetic acid (GAA). For these experiments, glycine (32 g, 0.42 mol, 2.0 equiv.) 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-value was carefully adjusted by either NaOH aqueous solution (40 wt-% in H2O), NaOH, HCl (aq.), or formic acid, thereby ending up with a total glycine concentration of 30 wt-%.

[0043] Cyanamide (50 wt-% in H.sub.2O, 18 g, 0.21 mol, 1.0 equiv.) was added dropwise (v = 1 mL/min, t = ca. 24 min) at 80° C. under stirring. After 2 h at 75° C., the formed suspension was filtered, and the wet cake was dried. HPLC analysis of the dry cake was performed to determine the GAA purity, and to calculate the yield.

[0044] The results for different pH values are shown in Table 1.

TABLE-US-00001 pH value yield GAA [%] 8.0 63.6 9.0 81.6 9.6 82.9 10.0 78.8 11.0 45.0

[0045] Very poor yields were obtained with pH values < 8 or pH values > 11 (not shown).

Example 2

[0046] Semi-Batch at 19 GLY-Mol-% NaOH

[0047] In a 50 L reaction device, cyanamide (50 wt-% in H.sub.2O, 4.5 kg, 54 mol, 1.0 equiv., 24 mL/min for 178 min) was added to a solution of glycine (5.8 kg, 77 mol, 1.4 equiv.) and sodium hydroxide (50 wt-% in H.sub.2O, 1.2 kg, 15 mol) in water (16 kg, glycine content of solution: 25 wt-%) at 82° C. under stirring. After stirring for another 2 h at 82° C. the GAA yield was determined by HPLC analysis of the formed suspension.

[0048] GAA yield: 88% (5.6 kg).

[0049] NaOH molar content in respect of glycine: 19%

[0050] pH value at reaction start: 9, pH value at reaction end: 10.

Example 3

[0051] Semi-Batch at 13 GLY-Mol-% NaOH

[0052] In a 50 L reaction device, cyanamide (50 wt-% in H.sub.2O, 4.5 kg, 54 mol, 1.0 equiv., 24 mL/min for 178 min) was added to a solution of glycine (5.8 kg, 77 mol, 1.4 equiv.) and sodium hydroxide (50 wt-% in H.sub.2O, 0.77 kg, 9.7 mol) in water (17 kg, glycine content of solution: 25 wt-%) at 82° C. under stirring. After stirring for another 2 h at 82° C. the GAA yield was determined by HPLC analysis of the formed suspension.

[0053] GAA yield: 76% (4.8 kg).

[0054] NaOH molar content in respect of glycine: 13%

[0055] pH value at reaction start: 9, pH value at reaction end: 9.5.

Example 4

[0056] Semi-Batch at 9 GLY-Mol-% NaOH

[0057] In a 50 L reaction device, cyanamide (50 wt-% in H.sub.2O, 4.5 kg, 54 mol, 1.0 equiv., 24 mL/min for 178 min) was added to a solution of glycine (5.8 kg, 77 mol, 1.4 equiv.) and sodium hydroxide (50 wt-% in H.sub.2O, 0.56 kg, 7.0 mol) in water (17 kg, glycine content of solution: 25 wt-%) at 82° C. under stirring. After stirring for another 2 h at 82° C. the GAA yield was determined by HPLC analysis of the formed suspension.

[0058] GAA yield: 63% (4.0 kg).

[0059] NaOH molar content in respect of glycine: 9%

[0060] pH value at reaction start: 8.9, pH value at reaction end: 9.3.

Example 5

Method According to the Present Invention at 5 GLY-Mol-% NaOH, With 20% Glycine Content in Reactor at Start

[0061] In a 50 L reaction device, both cyanamide (50 wt-% in H.sub.2O, 4.5 kg, 54 mol, 1.0 equiv., 24 mL/min for 178 min) and a solution of glycine (4.6 kg, 62 mol, 1.1 equiv.) in water (14 kg, glycine content of solution: 25 wt-%, in total 107 mL/min for 178 min) were added to a solution of glycine (1.2 kg, 15 mol, 0.28 equiv.) and sodium hydroxide (50 wt-% in H.sub.2O, 0.30 kg, 3.8 mol) in water (3.2 kg, glycine content of solution: 25 wt-%) at 82° C. under stirring. After stirring for another 2 h at 82° C. the GAA yield was determined by HPLC analysis of the formed suspension.

[0062] GAA yield: 89% (5.7 kg).

[0063] NaOH molar content in respect of glycine: 5%

[0064] pH value at reaction start: 9.5, pH value at reaction end: 8.9.

Example 6

Method According to the Present Invention at 6 GLY-Mol-% NaOH, With 30% Glycine Content in Reactor at Start

[0065] In a 50 L reaction device, both cyanamide (50 wt-% in H.sub.2O, 4.5 kg, 54 mol, 1.0 equiv., 24 mL/min for 178 min) and a solution of glycine (4.0 kg, 54 mol, 1.0 equiv.) in water (12 kg, glycine content of solution: 25 wt-%, in total 93 mL/min for 178 min) were added to a solution of glycine (1.7 kg, 23 mol, 0.42 equiv.) and sodium hydroxide (50 wt-% in H.sub.2O, 0.35 kg, 4.4 mol) in water (4.8 kg, glycine content of solution: 25 wt-%) at 82° C. under stirring. After stirring for another 2 h at 82° C. the GAA yield was determined by HPLC analysis of the formed suspension.

[0066] GAA yield: 93% (5.9 kg).

[0067] NaOH molar content in respect of glycine: 6%

[0068] pH value at reaction start: 9.3, pH value at reaction end: 9.0.

Example 7

Method According to the Present Invention at 9 GLY-Mol-% NaOH, With 20% Glycine Content in Reactor at Start, Cyanamide 30 wt-% in H.SUB.2.O

[0069] In a 50 L reaction device, both cyanamide (30 wt-% in H.sub.2O, 7.6 kg, 54 mol, 1.0 equiv., 42 mL/min for 178 min) and a solution of glycine (4.6 kg, 62 mol, 1.1 equiv.) and sodium hydroxide (50 wt-% in

[0070] H.sub.2O, 0.24 kg, 3.0 mol) in water (14 kg, glycine content of solution: 25 wt-%, in total 107 mL/min for 178 min) were added to a solution of glycine (1.2 kg, 15 mol, 0.28 equiv.) and sodium hydroxide (50 wt-% in H.sub.2O, 0.30 kg, 3.8 mol) in water (3.2 kg, glycine content of solution: 25 wt-%) at 82° C. under stirring. After stirring for another 2 h at 82° C. the GAA yield was determined by HPLC analysis of the formed suspension.

[0071] GAA yield: 93% (5.9 kg).

[0072] NaOH molar content in respect of glycine: 9%

[0073] pH value at reaction start: 9.1, pH value at reaction end: 9.1.

Example 8

Method According to the Present Invention at 8 GLY-Mol-% NaOH, With 20% Glycine Content in Reactor at Start, Cyanamide 30 wt-% in H.SUB.2.O

[0074] In a 50 L reaction device, both cyanamide (30 wt-% in H.sub.2O, 7.6 kg, 54 mol, 1.0 equiv., 42 mL/min for 178 min) and a solution of glycine (4.6 kg, 62 mol, 1.1 equiv.) and sodium hydroxide (50 wt-% in H.sub.2O, 0.20 kg, 2.5 mol) in water (14 kg, glycine content of solution: 25 wt-%, in total 107 mL/min for 178 min) were added to a solution of glycine (1.2 kg, 15 mol, 0.28 equiv.) and sodium hydroxide (50 wt-% in H.sub.2O, 0.30 kg, 3.8 mol) in water (3.2 kg, glycine content of solution: 25 wt-%) at 82° C. under stirring. After stirring for another 2 h at 82° C. the GAA yield was determined by HPLC analysis of the formed suspension.

[0075] GAA yield: 85% (5.4 kg).

[0076] NaOH molar content in respect of glycine: 8%

[0077] pH value at reaction start: 8.5, pH value at reaction end: 9.5.

[0078] The results of Examples 5 to 8 are shown in Table 3 and in FIG. 6.

Example 9

Method According to the Present Invention at 11 GLY-Mol-% NaOH, With 40% Glycine Content in Reactor at Start + Reaction Phase II (Add Additional Cyanamide to a Final GLY:CA Ration of 1:1)

Reaction Phase I

[0079] In a 50 L reaction device, both cyanamide (50 wt-% in H.sub.2O, 4.5 kg, 54 mol, 0.70 equiv., 24 mL/min for 178 min) and a solution of glycine (3.5 kg, 46 mol, 0.60 equiv.) in water (11 kg, glycine content of solution: 25 wt-%, in total 79 mL/min for 178 min) were added to a solution of glycine (2.3 kg, 31 mol, 0.40 equiv.) and sodium hydroxide (50 wt-% in H.sub.2O, 0.66 kg, 8.3 mol) in water (6.5 kg, glycine content of solution: 24 wt-%) at 82° C. under stirring.

Reaction Phase II

[0080] Immediately after reaction phase I, cyanamide (50 wt-% in H.sub.2O, 1.9 kg, 23 mol, 0.30 equiv., 24 mL/min for 74 min) was added under stirring at 82° C. and the pH-value of the reaction was controlled by addition of H.sub.2SO.sub.4 (10% 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.

[0081] GAA yield based on Cyanamide: 76% (5.9 kg GAA), GAA yield based on Glycine: 76%.

[0082] NaOH molar content in respect of glycine: 11%

[0083] pH value at reaction start: 10, pH value at reaction end: 10

[0084] Final GLY-concentration in process: 1.3 wt-% (aim of this experiment to keep yield high, and to minimize this value).

TABLE-US-00002 Results of Examples 2-9 Ex. No. Overall Cyanamide [mol] Overall Glycine [mol] Overall Base [mol] GAA [mol] molar ratio Base : Glycine molar ratio Base : Cyanamide Yield based on Cyanamide Yield based on Glycine Molar ratio Glycine : Cyanamide 2 54 77 15.0 47.8 0.19 0.28 89% 62% 1.4 3 54 77 9.7 41.0 0.13 0.18 76% 53% 1.4 4 54 77 7.0 34.2 0.09 0.13 63% 44% 1.4 5 54 77 3.8 48.2 0.05 0.07 89% 63% 1.4 6 54 77 4.4 50.4 0.06 0.08 93% 65% 1.4 7 54 77 6.8 50.4 0.09 0.13 93% 65% 1.4 8 54 77 6.3 46.1 0.08 0.12 85% 60% 1.4 9 77 77 8.3 58.9 0.11 0.11 77% 77% 1.0 Examples 2-4: Fed batch. Examples 5-8: New method, Example 9: New method + Phase II.

[0085] Compared to the new method, the fed-batch tests have relatively high base: raw material ratios, but at the same time no improved yields. On the contrary, the yield actually improves, which can be attributed to better control of the pH value. This applies to both, the yield based on cyanamide and glycine.

[0086] “New method + Phase II” (cf. Example 9) means that attention was paid to full conversion of the starting compounds by using glycine and cyanamide in a ratio of 1: 1 based on the overall reaction, wherein in a subsequent step the remaining molar amount of cyanamide without glycine is continuously added to the glycine containing reaction mixture under maintaining the pH of the reaction mixture below 10 by adding an acid This was only made possible with the help of the new method, since the pH value can still be controlled.

[0087] The results of Examples 2-9 are also depicted in FIG. 4.