RU2425025C1 - Method of producing beta-glycine - Google Patents

Abstract

FIELD: chemistry. ^ SUBSTANCE: invention relates to the chemical and pharmaceutical industry, specifically to a method of producing beta-glycine, having wide application in engineering, medicine and food industry. The method involves fast cooling of aqueous glycine solution to liquid nitrogen temperature, wherein the cooled aqueous glycine solution has concentration of 15-33 wt % and cooling is carried out at a rate of not less than 800 degrees per minute, after which the obtained mixture of beta-glycine and ice is put into an evacuated chamber (less than 0.3 mm Hg) at temperature not higher than -30C, where the mixture is heated to -30C and then held at this temperature until complete removal of ice, and then heated to room temperature. The chamber is filled with dry gas and the sample is extracted. Fast cooling of the initial glycine solution is preferably carried out by spraying it into a vessel with liquid nitrogen or by spraying it into the surface of a metal plate which is cooled to liquid nitrogen temperature. ^ EFFECT: obtaining pure beta-glycine using a simple and efficient method. ^ 3 cl, 2 ex

Description

The invention relates to the pharmaceutical industry, in particular to methods for producing beta glycine, which is widely used in technology, medicine and the food industry.

Of all the polymorphic modifications of glycine, alpha glycine (α glycine) has received the greatest use. An example of the use of α glycine is the method of treating acute ischemic stroke, protected by RF patent No. 2082398 [1], based on the use of glycine as an inhibitor, which is a natural inhibitory mediator that helps to normalize the balance between excitatory and inhibitory neurotransmitter systems, which allows acute cerebral ischemia significantly limit the activity of exciting aminacidergic mediators (glutamate, aspartate) and prevent the "shock" opening of calcium channels.

Known methods for producing α glycine. For example, RF patents 2009122 and 2009123 [2], [3] protect the technology for producing α glycine from monochloracetic acid and gaseous ammonia in the presence of hexamethylenetetramine in methanol containing 10% water, with the additional introduction of chloroform into the reaction mass. The yield of the finished product is 98.5-99%.

Of the other glycine modifications, the gamma form (γ glycine) is also stable, some of which is often present in commercially available glycine.

At the same time, the glycine beta form (β glycine), which is unstable, can remain indefinitely in a dry atmosphere, quickly transforming into the alpha form in the presence of water vapor (“Crystal Structural Study of the Metastable β-Modification of Glycine and its Transition to α-Modification.” Zhurn Structural Chem., 43 (No. 5), pp. 899-907, 2002 [4]).

It has been established that the structure of β glycine has features that distinguish it from the structure of stable modification of glycine (α glycine), (P21 space group, NH ... O hydrogen bonds connect the zwitterions in the form of which glycine molecules exist into layers that contain β glycine modifications are combined in a three-dimensional grid, rather than paired, unlike α glycine), which suggests the presence of properties that make β glycine a more effective drug.

Currently, the following methods for producing beta glycine are known: by recrystallization from a water-alcohol solution of glycine (“The crystal structure of β-glycine” Acta Cryst., 13, pp. 35-45, 1960 [5] and cooling a saturated solution of glycine, containing β-glycine acetic acid Acta Cryst, E58, pp.o634-o636, 2002 [6]).

The disadvantage of these methods is the often observed precipitation of alpha glycine modification as well, in which case beta modification crystals must be manually separated under a microscope.

The third method consists in salting out with acetone a saturated solution of α glycine in a mixture of glacial acetic acid and water (2: 1) (previously synthesized in a sealed vessel for two weeks at room temperature) (Synthesis and calorimetric investigation of unstable β- glycine "Journal of Cryst. Growth, 241, pp. 266-268, 2002 [7]). Precipitated small crystals must be quickly filtered and dried under vacuum. In this way, about 1 gram of beta glycine can be obtained in one synthesis, it is difficult to scale the process, moreover, even with strict observance of the synthesis conditions, the gamma form of glycine crystallizes.

The disadvantages of this method are the need for a long aging of the solution, the need to filter out the precipitated glycine precipitate (due to the difference in the solubility of glycine at 80 ° C and 20 ° C) before adding acetone, the need to quickly add a volume of acetone comparable to the volume of the initial solution and quickly separate the resulting precipitate. Also significant disadvantages of this method are the need to work with small amounts of glycine and the possible crystallization of the gamma form of glycine under all synthesis conditions.

All of the above methods require significant efforts and costs for the development of industrial technologies based on them.

The prototype of the proposed method was the established fact of the formation of a mixture of beta glycine and ice, obtained by spraying an aqueous solution of glycine in a container with liquid nitrogen ("Phase transitions of glycine in frozen water solutions and during freeze-drying" Pharmaceutical Research., 18 (No. 10), pp.1448-1454, 2001 [8]. The resulting mixture under the conditions described in the article leads to the appearance of gamma modification impurities.

The objective of the present invention is to develop a simpler, effective and technologically advanced method for producing pure β glycine, which can be stored for a long time in a dry atmosphere.

The problem is solved by rapidly cooling aqueous solutions of glycine with a concentration of 15-33 wt.% To a temperature of liquid nitrogen at a rate of at least 800 ° C per minute, for example, by spraying the solution into a container with liquid nitrogen or onto a copper plate cooled in liquid nitrogen, after of this, ice is removed from the resulting mixture of beta glycine and ice by sublimation, for which the mixture is placed in an evacuated (vacuum of less than 0.3 mm Hg) chamber at a temperature not exceeding -30 ° C, in which the mixture is then heated to -30 ° C and at this temperature can withstand olnogo icing. The time required to remove ice is calculated based on the known mass of water in the sample and pump performance. After removing the ice, the sample chamber is warmed to room temperature, filled with dry gas (nitrogen, argon) and the sample is removed.

It was experimentally found that beta glycine under the conditions of the proposed method is obtained at any of its concentrations in the initial aqueous solutions, but the concentration range suitable for this method is from 15 to 33 wt.%. At concentrations of the initial solutions <15%, the relative fraction of ice, which must be removed by sublimation, significantly increases, and when using glycine solutions in the concentration range above 33 wt.%, Firstly, to dissolve the entire mass of glycine, it is necessary to mix for a long time while heating to the boiling temperature of the solution and secondly, an admixture of alpha glycine modification appears upon cooling of the resulting solution.

The temperature and pressure for the proposed method for producing beta glycine were selected based on the position of the sublimation curve of ice in the phase diagram of water and taking into account the limitations associated with polymorphic transformations of glycine.

The fact of obtaining beta modification of glycine under these conditions is confirmed by the identification of the final product by x-ray phase analysis.

The proposed method is simple to implement, relatively easily can be converted into a technological process on an industrial scale.

Method implementation examples

Example 1

5 ml of a 15% alpha glycine solution was sprayed into a vessel with liquid nitrogen. The resulting mixture of solid phases (ice and beta glycine) was placed in a vacuum (10 ^-2 mm Hg vacuum) chamber at a temperature of -120 ° C. Then the chamber was heated to -30 ° C and kept at this temperature until the ice was completely removed. (The time required to remove ice was calculated based on the known mass of water in the sample and pump performance). After that, the chamber with the sample was warmed to room temperature, filled with argon and the sample was taken out. X-ray phase analysis showed that the obtained sample was pure beta glycine.

Similarly to the described example, experiments were carried out with aqueous solutions at glycine concentrations wt.%: 20, 30, 33.

The result was pure beta glycine.

Example 2

The mixture of solid phases of ice and beta glycine, obtained by spraying 5 ml of a 15% solution of alpha glycine on a copper plate cooled to the temperature of liquid nitrogen, was placed in a vacuum chamber at a temperature of -80 ° C; further steps are similar to example 1.

Information sources

1. RF patent No. 2082398 dated 06/27/1997.

2. RF patent No. 2009122 of 05.20.1991.

3. RF patent No. 2009123 of 05.20.1991.

4. "Crystal structure study of metastable β-modification of glycine and its transition to α-modification." Zhurn. structure Chem., 43 (No. 5), pp. 899-907, 2002.

5. "The crystal structure of β-glycine" Acta Cryst., 13, pp. 35-45, 1960.

6. "β-glycine" Acta Cryst., E58, pp.o634-o636, 2002.

7. "Synthesis and calorimetric investigation of unstable β-glycine" Journal of Cryst. Growth, 241, pp. 266-268, 2002.

8. "Phase transitions of glycine in frozen aqueous solutions and during freeze-drying" Pharmaceutical Research., 18 (No. 10), pp. 1448-1454, 2001.

Claims (3)

1. The method of producing beta glycine by rapidly cooling an aqueous solution of glycine to a temperature of liquid nitrogen, characterized in that cooling is subjected to an aqueous solution of glycine with a concentration of 15-33 wt.%, Cooling is performed at a speed of at least 800 deg / min, after which the resulting mixture beta glycine and ice are placed at a temperature not exceeding -30 ° C in a vacuum (less than 0.3 mm Hg) chamber, in which the mixture is heated to -30 ° C and at this temperature is maintained until the ice is completely removed, then heated to room temperature fill chamber with dry gas and extract the sample. 2. The method according to claim 1, characterized in that the rapid cooling of the initial glycine solution is carried out by spraying it into a vessel with liquid nitrogen. 3. The method according to claim 1, characterized in that the rapid cooling of the initial glycine solution is carried out by spraying it on the surface of a metal plate, cooled to a temperature of liquid nitrogen.