阅读说明：本技术 制备n-(氨基亚氨基甲基)-2-氨基乙酸的亚稳晶体变体的方法(iv) (Process (IV) for preparing metastable crystal modifications of N- (aminoiminomethyl) -2-aminoacetic acid ) 是由 T·古斯纳 F·塔尔哈麦尔 J·桑斯 于 2020-06-25 设计创作，主要内容包括：本发明涉及制备含有热力学亚稳晶体变体形式的N-(氨基亚氨基甲基)-2-氨基乙酸的N-(氨基亚氨基甲基)-2-氨基乙酸的方法。(The invention relates to a method for producing N- (aminoiminomethyl) -2-aminoacetic acids containing N- (aminoiminomethyl) -2-aminoacetic acid in the form of thermodynamically metastable crystal modifications.)

1. a process for the preparation of N- (aminoiminomethyl) -2-aminoacetic acids containing N- (aminoiminomethyl) -2-aminoacetic acid in the form of thermodynamically metastable crystal modifications, characterized in that N- (aminoiminomethyl) -2-aminoacetic acid is crystallized from an aqueous solution in the presence of at least one guanidine compound according to formula (I), where for formula (I) it applies

Wherein for the group R in formula (I)¹、R²And an index m¹、m²Independently of one another, the following apply:

R¹、R²independently of one another hydrogen or C1-to C4-alkyl,

m¹、m²1, 2 or 3 independently of each other.

2. The method of claim 1, wherein the aqueous solution contains at least 40 wt% water (based on the total weight of the solution).

3. The process according to claim 1 or 2, characterized in that N- (aminoiminomethyl) -2-aminoacetic acid is dissolved in water or an aqueous solution in a first process step and N- (aminoiminomethyl) -2-aminoacetic acid containing N- (aminoiminomethyl) -2-aminoacetic acid in the form of thermodynamically metastable crystal modifications is crystallized in a second process step from the solution prepared in the first process step in the presence of the guanidine compound of the formula (I).

4. The process according to claim 1 or 2, characterized in that N- (aminoiminomethyl) -2-aminoacetic acid is prepared in a first process step from cyanamide and glycine in water or in an aqueous solution, and that N- (aminoiminomethyl) -2-aminoacetic acid containing N- (aminoiminomethyl) -2-aminoacetic acid in the form of thermodynamically metastable crystal modifications is crystallized in a second process step from the reaction mixture prepared in the first process step in the presence of the guanidine compound of the formula (I).

5. The process according to any one of the preceding claims, characterized in that in the first process step N- (aminoiminomethyl) -2-aminoacetic acid is dissolved or prepared in aqueous solution at a temperature in the range from 20 to 100 ℃ at normal pressure.

6. The method according to any one of the preceding claims, characterized in that the guanidine compound of formula (I) is used in an amount corresponding to 80% of the amount that can be maximally dissolved in water at 25 ℃ under normal pressure.

7. The method according to any of the preceding claims, characterized in that the thermodynamically metastable crystal modification has the strongest reflection bands at 2 Θ -20.2 ° and 23.3 ° and 23.8 ° and 25.3 ° with a measurement accuracy of +/-0.2 ° in its X-ray powder diffraction pattern using Cu-ka radiation.

8. The method according to any of the preceding claims, wherein said thermodynamically metastable crystal modification has an orthogonal space group P2₁2₁2₁Wherein Z is 8, at 105 Kelvin and atHaving a lattice constant at measurement accuracyAnd

Drawings

In the drawings, there is shown in the drawings,

figure 1 shows the X-ray powder diffraction pattern of N- (aminoiminomethyl) -2-aminoacetic acid form a from example 1.

Figure 2 shows the X-ray powder diffraction pattern of N- (aminoiminomethyl) -2-aminoacetic acid form B from example 2.

FIG. 3 shows a micrograph (image width 8mm) of N- (aminoiminomethyl) -2-aminoacetic acid form A prepared according to example 1.

FIG. 4 shows a micrograph (image width 8mm) of spherical aggregates of N- (aminoiminomethyl) -2-aminoacetic acid type B prepared by recrystallization from a solution of N, N' -guanidinodiacetic acid according to example 2.

FIG. 5 shows the solubility curve of N- (aminoiminomethyl) -2-aminoacetic acid form A or B in water.

FIG. 6 shows a schematic representation of two crystallographically independent molecules of N- (aminoiminomethyl) -2-aminoacetic acid from single crystal X-ray structural analysis.

FIG. 7 shows a schematic of the molecular packing of crystal-bound N- (aminoiminomethyl) -2-aminoacetic acid. The viewing direction is along the a-axis. Molecular chains parallel to the a-axis and the b-axis, which are arranged independently of one another, perpendicular to one another, and linked by H bridges, are clearly visible. The chains are stacked along the c-axis.

Fig. 8 shows the bulk density as a function of type B concentration.

Fig. 9 shows the calibration curve fractions for form B and form a.

Figure 10 shows the DSC of N- (aminoiminomethyl) -2-aminoacetic acid form a.

Figure 11 shows the DSC of N- (aminoiminomethyl) -2-aminoacetic acid form B.

Examples

Guanidine compounds for use

1) N, N-guanidinodiacetic acid

Preparation of N, N-guanidinodiacetic acid (CAS 94324-66-0)

The synthesis was carried out analogously to T.S.Leyh, Biochemistry 1985,24, 308-316. 65.15g (1.55mol) of cyanamide were dissolved in 65.15g of water, to which 171.6g (1.29mol) of iminodiacetic acid and 325ml of a 25% ammonia solution were mixed and stirred at 22 ℃ for 96 hours. The pH was then adjusted from 10.63 to 5.00 with 628.7g 96% acetic acid. The thick suspension obtained is stirred overnight, then filtered off with suction and washed with water. After drying at 40 ℃ 103.8g of N, N-guanidinodiacetic acid with correct elemental analysis were obtained. The yield thereof was found to be 46.1%. NMR data in d⁶-in DMSO:¹H:3.991ppm，¹³171.2ppm (carboxylate), 157.5ppm (guanidine), 54.6ppm (CH)₂)。

2) N, N' -guanidinodiacetic acid

Preparation of N, N' -guanidinodiacetic acid

2a.) 1242g of 20% caustic soda solution (6.21mol) are placed at 20 ℃. A total of 246g (2.12mol) of thiohydantoin were stirred in portions and hydrolyzed at 20 ℃ for 24 hours. The reaction mixture was diluted with 650g of water, cooled to 5 ℃ and precipitated with 638ml of 32% hydrochloric acid (6.55mol) within 45 minutes. The precipitated solid is filtered off with suction and washed 2 times with cold water at 5 ℃ and 1 time with cold ethanol at 5 ℃. 202g (71%) of thioureidoacetic acid are obtained after drying in vacuo at 40 ℃ in the form of a yellowish solid. Purity according to HPLC > 99%. The product had the following elemental composition: 26.95% C, 4.40% H, 20.90% N. The melting point at decomposition was 170 ℃.

2b.) 167.8g (1.25mol) of thioureidoacetic acid from example 2a) are placed in 210ml of methanol at 40 ℃. 221.8g (1.563mol) of methyl iodide were added dropwise over 2 hours and stirred at 40 ℃ for a further 1 hour. The obtained orange-yellow clear reaction mixture was completely evaporated in vacuo at 40 ℃. 345.13g (1.25mol) of S-methyl-isothioureido acetic acid hydroiodide are obtained in the form of a brown, viscous melt. The yield was quantitative. The reaction product was further reacted without analysis.

2c.) 345.13g (1.25mol) of S-methyl-isothioureido acetate hydroiodide from example 2b) were dissolved in 300ml of water. 225g (3.00mol) glycine was dissolved in 400ml water in a reaction flask and 1253ml of 25% aqueous ammonia solution (16.7mol) was mixed in. A solution of S-methyl-isothioureido acetate hydroiodide is metered into this glycine solution at 20 ℃ over a period of 4 hours. Then stirred for a further 16 hours at 20 ℃. A white suspension of pH 11.0 was obtained, which was cooled to 5 ℃. 1948g of 32% hydrochloric acid (17.1mol) are now metered in at 5 ℃ to adjust the pH to 3.0. The white suspension obtained is filtered off with suction, washed with water and ethanol and dried at 40 ℃ in vacuo. 140.6g of N, N' -guanidinodiacetic acid are obtained in the form of a white solid. The yield thereof was found to be 64.2%. The purity by HPLC was 96%. The element composition is as follows: 34.07% C, 5.49% H, 23.20% N. Chloride content was 0.26%, water content < 0.1%. This material does not have a melting point but decomposes and turns black starting from 230 ℃.

At d₆Dissolution in DMSO gave the following NMR spectra¹³C: 170.08ppm (COOH), 157.11ppm (guanidine C), 54.40ppm (CH)₂)；¹H7.2 ppm (Width, NH), 4.00ppm (CH)₂). At D₂Dissolved in O and mixed with an equimolar amount of NaOD (i.e. as the monosodium salt), gives the following NMR data:¹³175.44ppm (COOH), 156.32ppm (guanidine C), 44.96ppm (CH)₂)；¹H: about 7ppm (very broad, NH), 4.80ppm (CH)₂)。

3) N' -carboxymethyl-3-guanidinopropionic acid

69.0g (0.25mol) of S-methyl-isothioureido acetate hydroiodide from Synthesis example 2b.) are dissolved in 300ml of water. In a reaction flask 53.4g (0.6mol) beta-alanine was dissolved in 400ml water and mixed into 250ml 25% ammonia solution (3.34 mol). S-methyl-isothioureido acetate hydroiodide is metered into the beta-alanine solution at 20 ℃ over a period of 4 hours. Then stirred for a further 16 hours at 20 ℃. A white suspension of pH 10.9 was obtained, which was cooled to 5 ℃. 391g of 32% hydrochloric acid (3.43mol) are now metered in at 5 ℃ in order to adjust the pH of 3.0. The white suspension obtained is filtered off with suction, washed with water and ethanol and dried at 40 ℃ in vacuo. 21.6g of N' -carboxymethyl-3-guanidinopropionic acid are obtained in the form of a white solid. The yield thereof was found to be 45.7%. The purity by HPLC was 94%.

4) N' -carboxymethyl-4-guanidinobutyric acid

69.0g (0.25mol) of S-methyl-isothioureido acetate hydroiodide from Synthesis example 2b.) are dissolved in 300ml of water. 61.8g (0.6mol) of 4-aminobutyric acid were suspended in 400ml of water in a reaction flask and 250ml of 25% aqueous ammonia solution (3.34mol) was mixed in, in this case, to form a solution. S-methyl-isothioureido acetate hydroiodide is metered into the solution of 3-aminobutyric acid at 20 ℃ over a period of 4 hours. Then stirred for a further 16 hours at 20 ℃. A white suspension of pH 10.8 was obtained, which was cooled to 5 ℃. 386g of 32% hydrochloric acid (3.39mol) are now metered in at 5 ℃ in order to adjust the pH of 3.0. The white suspension obtained is filtered off with suction, washed with water and ethanol and dried at 40 ℃ in vacuo. 23.7g of N' -carboxymethyl-4-guanidinobutyric acid are obtained in the form of a white solid. The yield thereof was found to be 46.7%. The purity by HPLC was 92%.

X-ray powder diffraction measurements

In the context of the present examples, X-ray powder diffraction measurements were carried out using a powder diffractometer Bruker D2 Phaser, having a theta/2 theta geometry, LYNXEYE detector, wavelengthCu-ka radiation, acceleration voltage 30kV and anode current 10mA, nickel filter and step value of 0.02 °. The samples provided for the study were ground in an agate mortar and pressed onto a sample pan according to the manufacturer's instructions and the surface was smoothed.

X-ray radiographic measurement of A/B type fractionFixed calibration line

XRD data were determined using a mechanical mixture of pure samples GAA of form a and B. The peak heights at 20.7 ° and 20.2 ° were used for quantitative evaluation of peak heights. The calibration curve thus determined (calibration straight line) with a very good correlation coefficient was used for unknown samples to determine the share of type a/B (see table 1 and fig. 9).

Table 1:calibration curve share for form a to form B

To quantify the ratio of form B to N- (aminoiminomethyl) -2-aminoacetic acid of form a, a mechanical mixture of powdery samples of the respective pure forms was prepared and measured on an X-ray powder diffractometer. The mixing ratio was 100:0, 95:5, 90:10, 80:20, 67:33, 50:50, 33:67, 20:80, 10:90, 5:95 and 0: 100. The signal height (count rate) at 2 theta 20.2 deg. (type B) is related to the sum of the signal heights at 2 theta 20.7 deg. (type a) and 2 theta 20.2 deg. (type B) and a calibration line is determined therefrom. The following linear relationship was found using a corrected correlation coefficient R2 of 0.998:

this formula was used in the subsequent examples to determine the respective proportions of form a and form B.

Single crystal X-ray structural analysis

Suitable crystals are prepared by diluting an aqueous solution of N- (aminoiminomethyl) -2-aminoacetic acid in the presence of N, N' -guanidinodiacetic acid. Single crystal measurements were performed at 105K on crystals with a size of 0.02 x 0.09mm using a wavelength ofFor monochromatic Mo-K α (molybdenum-K- α) radiation, using a two-circuit diffractometer Bruker D8 Venture TXS. Using 2072 independent reflected X-ray crystal countsAccording to optimization, the R value (F) is up to 0.0381_obs) The least variance method is performed. The positions of the NH hydrogen atoms and OH hydrogen atoms are optimized, which fixes the CH hydrogen atoms in the calculated positions. The results of the X-ray single crystal structure analysis are illustrated in fig. 6 and 7. The powder diffraction pattern recalculated from the single crystal structure analysis exactly matches the measured powder diffraction pattern according to fig. 2.

Example 1(comparative) -recrystallization of N- (Aminoiminomethyl) -2-aminoacetic acid from water

400g of water are initially taken at 80 ℃ and 11.66g in total of N- (aminoiminomethyl) -2-aminoacetic acid present in form A in an amount of 99.0% are dissolved in one spoon, the last portion of which is above the solubility limit. Then filtered at 80 ℃, 100g of water was mixed into the filtrate, and heated to 80 ℃. A barely saturated clear solution formed. N- (Aminoiminomethyl) -2-aminoacetic acid is crystallized by slow cooling to 20 ℃ over 4 hours. The precipitated crystals were filtered off and dried in vacuo at 60 ℃. 6.51g of N- (aminoiminomethyl) -2-aminoacetic acid are obtained with a content of 99.1%.

The product obtained is in the form of fine needle-like crystals. Fine needle crystals were investigated by microscopy (see fig. 3). X-ray powder diffraction measurements gave the powder diffraction pattern shown in figure 1, which indicates the well-known form a.

Example 2-crystallization of N- (aminoiminomethyl) -2-aminoacetic acid from a solution of N, N' -guanidinodiacetic acid

A1% solution was prepared from 5g of N, N' -guanidinodiacetic acid from Synthesis example 2c) and 495g of water. To 400g of this solution were added N- (aminoiminomethyl) -2-aminoacetic acid of the same composition as in example 1 in portions at 80 ℃. The solubility limit was exceeded at an addition level of 20.38 g. The small solid portion is filtered off at 80 ℃, the remaining 100g of a 1% solution of N, N' -guanidinodiacetic acid are mixed into the filtrate and stirred for 1 hour at 80 ℃. A clear colorless solution was obtained. N- (Aminoiminomethyl) -2-aminoacetic acid is crystallized by slow cooling to 20 ℃ over 4 hours. The precipitated crystalline aggregate was filtered off, washed 3 times with water at 20 ℃ and dried at 60 ℃. 11.67g of N- (aminoiminomethyl) -2-aminoacetic acid having a content of 99.4% are obtained. The amounts obtained are significantly greater than in example 1, owing to the increased solubility of N- (aminoiminomethyl) -2-aminoacetic acid, which is enhanced by the presence of N, N' -guanidinodiacetic acid.

A similarly recorded powder diffraction pattern (see fig. 2) shows form B, which is unknown to date. Polygonal, nearly circular crystal aggregates were studied microscopically (see fig. 4).

Example 3Recrystallization of N- (aminoiminomethyl) -2-aminoacetic acid from aqueous solutions of guanidine compounds

Aqueous solutions of different guanidine compounds were prepared analogously to example 2, each at a given concentration (C). In 400g of the respective solutions, in each case a given amount (M) of N- (aminoiminomethyl) -2-aminoacetic acid is dissolved at 80 ℃. After filtration at 80 ℃, a further 100g of a given aqueous solution of the respective guanidine compound was added and the clear solution was stirred at 80 ℃ for 1 hour. N- (Aminoiminomethyl) -2-aminoacetic acid is crystallized by slow cooling to 20 ℃ over 4 hours. The precipitated crystalline aggregate was filtered off, washed 3 times with water at 20 ℃ and dried at 60 ℃. N- (Aminoiminomethyl) -2-aminoacetic acid is obtained in each given amount (A) with a content (G) (see Table 2 a/b).

The powder diffraction pattern of each product was recorded and the presence of each form was checked, wherein the amount shares of form a and B were determined using the formula given above.

Table 2 a:recrystallization of guanidine compounds (not according to the invention) from aqueous solutions

Table 2 b:recrystallization from an aqueous solution of a guanidine compound according to formula (I) — according to the invention

The guanidine compounds according to formula (I) according to the invention induce an induction upon crystallization of N- (aminoiminomethyl) -2-aminoacetic acid and thus preferably induce form B, wherein in some cases mixtures with form a also occur (see table 2B). Additional guanidines not according to the invention do not do this (see table 2 a).

Example 4(comparative) -Synthesis of N- (Aminoiminomethyl) -2-aminoacetic acid from Glycine and cyanamide in aqueous solution

112.6g (1.5mol) of glycine are dissolved in 300g of water. To this solution was mixed 21.6g (0.27mol) of 50% caustic soda solution, which gave a pH of 8.4. A solution of 42.04g (1.0mol) of cyanamide in 42g of water is metered in at 80 ℃ over 4 hours. The post reaction was allowed to proceed for another 1 hour at 80 ℃. The suspension obtained is cooled to 20 ℃, filtered, washed with water and dried at 60 ℃. 100.6g of N- (aminoiminomethyl) -2-aminoacetic acid are obtained with a content of 99.1%. The yield thereof was found to be 85.9%.

The powder diffraction pattern of the fine needle crystals obtained showed the presence of form a alone (100% form a).

Example 5(according to the invention) Synthesis of N- (Aminoiminomethyl) -2-aminoacetic acid from Glycine and cyanamide in 2% solution of N, N' -guanidinodiacetic acid

A solution was prepared from 6g N, N' -guanidinodiacetic acid and 294g of water. 112.6g (1.5mol) of glycine were dissolved therein and the pH of 8.4 was adjusted with 22.7g (0.28mol) of 50% caustic soda solution. A solution of 42.04g (1.0mol) of cyanamide in 42g of water is metered in at 80 ℃ over 4 hours. The post reaction was allowed to proceed for another 1 hour at 80 ℃. The suspension obtained is cooled to 20 ℃, filtered, washed with water and dried at 60 ℃. 99.6g of N- (aminoiminomethyl) -2-aminoacetic acid are obtained with a content of 99.3%. The yield thereof was found to be 85.0%.

The powder diffraction pattern of the crystals obtained showed the presence of only N- (aminoiminomethyl) -2-aminoacetic acid of form B (100% form B).

Example 6(comparative) Synthesis of N- (Aminoiminomethyl) -2-aminoacetic acid from Glycine and cyanamide in solutions of different substances

Stock solution a was prepared from a mixture of different substances. This includes:

30g N-cyanoguanidine

30g of ureidoacetic acid

10g of urea

5g diglycine

5g of guanidinoacetic lactam

0.5g of melamine

These materials were dissolved in water and the mixture was made up to a total weight of 1000 g.

To 300g of this stock solution A, 112.6g (1.5mol) of glycine were dissolved and the pH value of 8.4 was adjusted with 20.9g (0.26mol) of 50% caustic soda solution. A solution of 42.04g (1.0mol) of cyanamide in 42g of water is metered in at 80 ℃ over 4 hours. The post reaction was allowed to proceed for another 1 hour at 80 ℃. The suspension obtained is cooled to 20 ℃, filtered, washed with water and dried at 60 ℃. 100.5g of N- (aminoiminomethyl) -2-aminoacetic acid are obtained with a content of 99.0%. The yield thereof was found to be 85.8%.

The powder diffraction pattern of the crystals obtained showed the presence of only form a.

Example 7(according to the invention) Synthesis of N- (Aminoiminomethyl) -2-aminoacetic acid from Glycine and cyanamide in solution of different substances comprising the guanidine Compound according to the invention

Stock solution B was prepared from a mixture of different substances. This includes:

30g N-cyanoguanidine

30g of ureidoacetic acid

10g of urea

5g diglycine

5g of guanidinoacetic lactam

0.5g of melamine

15g N, N' -guanidinodiacetic acid

These materials were dissolved in water and the mixture was made up to a total weight of 1000 g. Compared to the stock solution a, the stock solution B therefore contains a further 1.5% by weight of N, N' -guanidinodiacetic acid.

To 300g of this stock solution B, 112.6g (1.5mol) of glycine were dissolved and the pH of 8.4 was adjusted with 21.3g (0.27mol) of 50% caustic soda solution. A solution of 42.04g (1.0mol) of cyanamide in 42g of water is metered in at 80 ℃ over 4 hours. The post reaction was allowed to proceed for another 1 hour at 80 ℃. The suspension obtained is cooled to 20 ℃, filtered, washed with water and dried at 60 ℃. 100.7g of N- (aminoiminomethyl) -2-aminoacetic acid are obtained with a content of 99.2%. The yield thereof was found to be 86.0%.

The powder diffraction pattern of the crystals obtained showed the presence of only form B.

The presence of N, N' -guanidinodiacetic acid therefore serves to crystallize N- (aminoiminomethyl) -2-aminoacetic acid into the form B in complex substance mixtures.

Example 8Recrystallization of N- (Aminoiminomethyl) -2-aminoacetic acid from stock solutions B of different concentrations

Different starting concentrations were prepared from x g stock solutions a or B from examples 10 or 11, respectively, and y g water (see table). To 400g of each of these solutions were added N- (aminoiminomethyl) -2-aminoacetic acid in portions at 80 ℃. The amounts (S) respectively required to reach the saturation limit are given in the table. Then filtered at 80 ℃, an additional 100g of each solution was mixed into the filtrate and stirred at 80 ℃ for 1 hour. N- (Aminoiminomethyl) -2-aminoacetic acid is crystallized by slow cooling to 20 ℃ over 4 hours. The precipitated product was filtered off, washed with water and dried at 60 ℃. The respective weights (A) of the N- (aminoiminomethyl) -2-aminoacetic acids are given in the table.

The crystalline form of the powdery product was investigated by means of powder diffraction. The results are summarized in Table 3.

Table 3:recrystallization from stock solution B

The results clearly show that the N, N' -guanidinodiacetic acid additionally contained in the stock solution B acts to crystallize N- (aminoiminomethyl) -2-aminoacetic acid into form B. At higher dilutions, such effects gradually disappear.

Example 9Physico-chemical characterization of N- (aminoiminomethyl) -2-aminoacetic acids of the type-A and type-BCharacterization of

9.1 melting Point or decomposition Point

A Mettler DSC 3+ instrument with a 40 μ l aluminum crucible was used for dynamic Differential Scanning Calorimetry (DSC). The heating rate was 10 kelvin per minute at a temperature range of 30 to 350 ℃. Approximately 1.4mg of product from examples 1 and 2 were each weighed into an aluminum crucible and measured at atmospheric pressure (960mbar, 500m altitude at standard zero).

The sample from example 1(═ a type N- (aminoiminomethyl) -2-aminoacetic acid) shows a starting point (inflection point of the melting curve projected on the base line) of 280.5 ℃ and a peak temperature of the melting curve of 286.3 ℃. The total endothermic heat of fusion was 887J/g (FIG. 10). The product changes color from white to brown when melted.

The sample from example 2(═ N- (aminoiminomethyl) -2-aminoacetic acid form B) was measured analogously. It showed an onset of 272.5 ℃ and a peak at 280.4 ℃ with a heat of fusion of 860J/g and the same discoloration (see FIG. 11).

Form B thus melts about 6 to 8 kelvin lower than form a and has a heat of fusion lower than 27J/g or a lattice energy higher than 27J/g. In other words, form B requires 27J/g less energy than form A to achieve the same energy melting conditions. Form B is thus a metastable crystal form of N- (aminoiminomethyl) -2-aminoacetic acid or a polymorph in the energetic position under atmospheric and ambient conditions.

The new metastable crystal modification of type B is stable up to its melting point. No solid transition from form B to form a or reversible solid transition from form a/B could be observed. Thus, type B represents an example of a single degeneration polymorphism.

9.2 determination of the Water solubility

100g of water at 5 ℃ are placed in advance. The product from example 1(═ N- (aminoiminomethyl) -2-aminoacetic acid of form a) was dissolved therein until saturation and the amount dissolved was determined by reverse weighing. The temperature was then increased to 20 ℃ and so much sample was added until the saturation point was reached again. The same repetition was carried out at other temperatures, up to 95 ℃. Similar measurements were carried out with the product from example 2(═ N- (aminoiminomethyl) -2-aminoacetic acid form B). The solubility data obtained for both products is graphically summarized in fig. 5.

Both crystal forms of N- (aminoiminomethyl) -2-aminoacetic acid are better soluble in water with increasing temperature. The N- (aminoiminomethyl) -2-aminoacetic acid form B according to the invention dissolves approximately 20% better than the known form A at any temperature.

9.3 determination of Density

The N- (aminoiminomethyl) -2-aminoacetic acid crystals of form a from example 1 were introduced at 20 ℃ into carbon tetrachloride, which here floated on the surface. The density of the liquid medium was reduced by dropwise addition of dichloromethane until the crystals were just suspended in the liquid without rising and without settling. The density of the liquid phase was measured in a densitometer. The measured value was 1.50+/-0.03g/cm³。

The treatment was carried out analogously with crystals of form B from example 2. The density at 20 ℃ was determined to be 1.41+/-0.03g/cm³。

Thus, form B has a 6% lower density than form a. This is associated with the low lattice energy of type B mentioned above. The measured crystal density furthermore corresponds to the X-ray crystal density calculated from the individual lattice constants.

9.4 determination of the dust content

The product from example 1 was sieved through a sieve having a sieve width of 63 μm (equal to a 230 mesh sieve size). A fine fraction of 46% by weight is obtained. The sample from example 2 consisting of polygonal, near-circular aggregates of crystals was similarly processed. Fine fractions of less than 3% by weight were determined here. Low-dust and therefore safe-to-handle materials should have a dust fraction of less than 10% (i.e. particle fraction <63 μm). The product from example 2 (N- (aminoiminomethyl) -2-aminoacetic acid of form B) is satisfactory, whereas comparative example 1 (N- (aminoiminomethyl) -2-aminoacetic acid of form A) is not.

9.5 determination of the pile Angle

The product from example 1, consisting of needle-shaped crystals felted into one another, was poured onto a flat plane by means of a funnel using a device according to DIN ISO 4324. After removal of the funnel, the angle of inclination of the cone obtained was determined with an angle measuring device. It is about 45 °. N- (aminoiminomethyl) -2-aminoacetic acid form A therefore shows poor flow behavior. The granular product from example 2 was measured similarly. An inclination angle of about 25 ° is obtained here. N- (aminoiminomethyl) -2-aminoacetic acid form B therefore exhibits excellent flow behavior.

9.6 determination of bulk Density

A weighed amount of the product from example 1 was placed in a measuring cylinder and partially compacted by hard tapping twice on a laboratory bench. The bulk density, determined from the filling height of the graduated cylinder, was 0.37g/cm³. The product from example 2 was treated similarly. A bulk density of 0.62g/cm3 was determined. N- (aminoiminomethyl) -2-aminoacetic acid form B therefore has a significantly increased bulk density, which is advantageous for the packaging, transport and handling of the products.

9.7 thermal stability of N- (Aminoiminomethyl) -2-aminoacetic acid of type B

a) Form B of N- (aminoiminomethyl) -2-aminoacetic acid from example 2 is left for 6 hours at 120 ℃ in a drying cabinet. The crystalline form is subsequently determined by means of X-ray powder diffraction. It remains unchanged as pure form B.

b) Form B of N- (aminoiminomethyl) -2-aminoacetic acid from example 2 was wetted with 20% water, incubated at 65 ℃ for 6 hours in a closed vessel and then dried. The X-ray powder diffraction pattern shows no change, and the B form is kept stable.

c) The N- (aminoiminomethyl) -2-aminoacetic acid form B from example 2 was transferred into a 10% suspension in water. The suspension was stirred at 80 ℃ for 2 hours. Then cooled, the solid filtered off and dried. X-ray powder diffraction shows the presence of a mixture consisting of forms a and B.

d) N- (Aminoiminomethyl) -2-aminoacetic acid form B from example 2 is dissolved in water at 80 ℃ and largely recrystallised by cooling the solution, filtered off and dried. Pure form a was shown by X-ray powder diffraction.

N- (aminoiminomethyl) -2-aminoacetic acid form B is therefore very stable in solid form, but has a tendency to transform into form a via aqueous solutions. This behavior also confirms the metastable crystal structure of form B.

9.8 physical Properties of mixtures of types A and B

In example 9.6, the bulk density of the GAA form was determined to be 0.37g/cm3 and the bulk density of the GAA B form was determined to be 0.62g/cm 3. Starting from pure samples of GAA type a and type B species, the two forms of the mixture were weighed and mixed by shaking (no grinding or use of a mortar |). The bulk density of the crystal mixture thus prepared was measured.

Table 4:bulk density in crystal mixture

Type A weight fraction	Type B weight fraction	Bulk density
			100％	0％	0.62g/cm3
75％	25％	0.59g/cm3
			50％	50％	0.53g/cm3
25％	75％	0.41g/cm3
			0％	100％	0.37g/cm3

It can be seen that the bulk density increases with increasing GAA form B fraction, with the bulk density advantageously exceeding the arithmetic mean of the two last terms, starting from 50% form B (see also fig. 8).

The claims (modification according to treaty clause 19)

1. Method for producing an N- (aminoiminomethyl) -2-aminoacetic acid containing N- (aminoiminomethyl) -2-aminoacetic acid in the form of a thermodynamically metastable crystal modification, wherein the thermodynamically metastable crystal modification has the strongest reflection bands at 2 Θ ═ 20.2 ° and 23.3 ° and 23.8 ° and 25.3 ° with measurement accuracy using Cu-ka radiation in the X-ray powder diffraction pattern of the crystal modification, characterized in that N- (aminoiminomethyl) -2-aminoacetic acid is crystallized from an aqueous solution in the presence of at least one guanidine compound according to formula (I), wherein the same applies for formula (I)

Wherein for the group R in formula (I)¹、R²And an index m¹、m²Independently of one another, the following apply:

R¹、R²independently of one another hydrogen or C1-to C4-alkyl,

m¹、m²independently of one another 1, 2 or 3,

wherein the guanidine compound of formula (I) is used in an amount of at least 0.01 wt. -%, based on the total weight of the solution.

2. The method of claim 1, wherein the aqueous solution contains at least 40 wt% water (based on the total weight of the solution).

3. The process according to claim 1 or 2, characterized in that N- (aminoiminomethyl) -2-aminoacetic acid is dissolved in water or an aqueous solution in a first process step and N- (aminoiminomethyl) -2-aminoacetic acid containing N- (aminoiminomethyl) -2-aminoacetic acid in the form of thermodynamically metastable crystal modifications is crystallized in a second process step from the solution prepared in the first process step in the presence of the guanidine compound of the formula (I).

4. The process according to claim 1 or 2, characterized in that N- (aminoiminomethyl) -2-aminoacetic acid is prepared in a first process step from cyanamide and glycine in water or in an aqueous solution, and that N- (aminoiminomethyl) -2-aminoacetic acid containing N- (aminoiminomethyl) -2-aminoacetic acid in the form of thermodynamically metastable crystal modifications is crystallized in a second process step from the reaction mixture prepared in the first process step in the presence of the guanidine compound of the formula (I).

5. The process according to any one of the preceding claims, characterized in that in the first process step N- (aminoiminomethyl) -2-aminoacetic acid is dissolved or prepared in aqueous solution at a temperature in the range from 20 to 100 ℃ at normal pressure.

6. The method according to any one of the preceding claims, characterized in that the guanidine compound of formula (I) is used in an amount corresponding to 80% of the amount that can be maximally dissolved in water at 25 ℃ under normal pressure.

7. The method according to any of the preceding claims, wherein said thermodynamically metastable crystal modification has an orthogonal space group P2₁2₁2₁Wherein Z is 8, at 105 Kelvin and atMeasuringHaving a lattice constant at precisionAnd