阅读说明：本技术 一种利用重结晶制备粉末状甘氨酸的方法 (Method for preparing powdery glycine by recrystallization ) 是由 陈昀 李立标 郑爱 林文龙 徐新 王秀 于 2020-11-27 设计创作，主要内容包括：本发明提供了一种利用重结晶制备粉末状甘氨酸的方法,所述方法包括：将甘氨酸溶液滴加至第二溶剂中,然后降温结晶,得到所述粉末状甘氨酸；其中,所述甘氨酸在所述第二溶剂中的溶解度小于1g/100g。本发明提供的方法结晶条件温和,方法简单易行,且最后得到的甘氨酸收率较高,纯度较高且呈粉末状,具有适宜的松密度以便于应用。(The invention provides a method for preparing powdery glycine by recrystallization, which comprises the following steps: dropwise adding a glycine solution into a second solvent, and then cooling and crystallizing to obtain powdery glycine; wherein the solubility of the glycine in the second solvent is less than 1g/100 g. The method provided by the invention has the advantages of mild crystallization conditions, simplicity and easiness, higher yield of the finally obtained glycine, higher purity, powdery shape and proper bulk density, and is convenient to apply.)

1. A method for preparing powdered glycine by recrystallization, the method comprising: dropwise adding a glycine solution into a second solvent, and then cooling and crystallizing to obtain powdery glycine;

wherein the solubility of the glycine in the second solvent is less than 1g/100 g.

2. The method according to claim 1, wherein the second solvent comprises any one or a combination of at least two of anhydrous ethanol, diethyl ether or acetone, preferably anhydrous ethanol;

and/or the temperature of the second solvent is 5-65 ℃, preferably 5-10 ℃;

and/or the mass ratio of the glycine to the second solvent is 1 (4-5), preferably 1: 4.8.

3. The method according to claim 1 or 2, wherein the dropping rate is 55-65 g/min;

preferably, the dropwise addition is carried out under stirring.

4. A method according to any one of claims 1 to 3, wherein the rate of cooling is from 10 to 30 ℃/h;

and/or the temperature of the crystallization is below 10 ℃, preferably 5-10 ℃, and the crystallization is preferably carried out in a stirring state;

and/or the crystallization time is 0.5-1 h.

5. The method of any one of claims 1 to 4, wherein the glycine solution is selected from aqueous glycine solutions.

6. The method according to claim 5, wherein the mass ratio of glycine to water in the glycine aqueous solution is 1 (2-2.5), preferably 1: 2.4.

7. The method according to claim 5 or 6, wherein the preparation method of the glycine aqueous solution comprises: mixing glycine with water, heating and dissolving to obtain a glycine aqueous solution;

preferably, the temperature for dissolving by heating is 60-65 ℃.

8. The method according to any one of claims 1 to 7, further comprising cooling crystallization, filtering and drying.

9. Glycine in powder form obtainable by the process according to any one of claims 1 to 8.

10. Powdered glycine according to claim 9, characterized in that its loose-most density is 0.21-0.49g/mL, preferably 0.23-0.31 g/mL; the tightest bulk is 0.35-0.65g/mL, preferably 0.38-0.54 g/mL.

Technical Field

The invention belongs to the technical field of compound purification, and relates to a method for preparing powdery glycine.

Background

Glycine (Gly for abbreviation) also known as aminoacetic acid, of formula C₂H₅NO. Glycine is a constituent amino acid of the endogenous antioxidant, reduced glutathione, and is often exogenously supplemented when the body is severely stressed, sometimes also referred to as a semi-essential amino acid. The solid glycine is white monoclinic or hexagonal crystal or white crystal powder, has no odor and no toxicity, is easily soluble in water, and is hardly soluble in ethanol or diethyl ether. It is the only amino carboxyl aliphatic amino acid with simple structure and no optical rotation in natural alpha-amino acid. Glycine is widely used in medicine, organic synthesis, food, feed additive and biochemical reagent.

Aspirin-lysine glycine mixed powder is a typical application of glycine in the field of medicine. Because the single-component aspirin-lysine for injection is unstable to moisture, heat and light, the aspirin-lysine is easy to partially decompose into free salicylic acid in the storage period, and the drug effect is reduced. Glycine is added into the aspirin-lysine to inhibit the generation of free salicylic acid of a decomposition product, so that the stability of the aspirin-lysine for injection in the storage period can be improved; and the irritation to the muscle is remarkably reduced. Aspirin-lysine is a powdered solid with a maximum bulk density of about 0.20g/mL and a maximum bulk density of about 0.38 g/mL.

In order to ensure that the aspirin-lysine mixed powder is uniformly mixed and does not generate a layering phenomenon after transportation, glycine is required to be powdery solid, and the bulk density of the glycine is close to that of the aspirin-lysine.

Disclosure of Invention

Aiming at the defects in the prior art, the invention aims to provide the method for preparing the powdery glycine by recrystallization, the method provided by the invention has the advantages of mild crystallization conditions, simplicity and easiness in operation, and the finally obtained glycine has high purity, is powdery and has proper bulk density so as to be convenient to apply.

In order to achieve the purpose, the invention adopts the following technical scheme:

in a first aspect, the present invention provides a method for preparing glycine in powder form using recrystallization, the method comprising: dropwise adding a glycine solution into a second solvent, and then cooling and crystallizing to obtain powdery glycine;

wherein the solubility of the glycine in the second solvent is less than 1g/100g (second solvent).

The method provided by the invention is used for recrystallizing the glycine solution in a dropwise manner, so that the finally obtained glycine is in a powdery state, the product purity is high, and the bulk density is moderate.

In a preferred embodiment of the present invention, the second solvent includes one or a combination of at least two of absolute ethyl alcohol, diethyl ether and acetone, preferably absolute ethyl alcohol.

The temperature of the second solvent of the present invention is 5 to 65 deg.C, such as 10 deg.C, 15 deg.C, 20 deg.C, 25 deg.C, 30 deg.C, 35 deg.C, 40 deg.C, 45 deg.C, 50 deg.C, 55 deg.C, 60 deg.C, etc., preferably 5 to 10 deg.C, such as 6 deg.C, 7 deg.C, 8 deg.C, 9.

When the temperature of the second solvent is 5-10 ℃, further cooling is not needed subsequently, direct heat preservation and crystallization can be carried out at the temperature, and the finally obtained glycine powder has the smallest bulk density which is closest to that of aspirin-lysine.

In a preferred embodiment of the present invention, the mass ratio of glycine to the second solvent is 1 (4-5), for example, 1:4.2, 1:4.5, 1:4.8, preferably 1: 4.8.

In order to obtain glycine having a suitable bulk density, the rate of addition is from 55 to 65g/min, for example 60 g/min.

In a preferred embodiment of the present invention, the dropwise addition is carried out under stirring.

As a preferred technical scheme of the invention, the cooling rate is 10-30 ℃/h, such as 15 ℃/h, 20 ℃/h, 25 ℃/h and the like.

In a preferred embodiment of the present invention, the crystallization temperature is 10 ℃ or less, for example, 9 ℃, 8 ℃, 6 ℃, 4 ℃, 2 ℃, etc., preferably 5 to 10 ℃, and the crystallization is preferably carried out under stirring.

In a preferred embodiment of the present invention, the crystallization time is 0.5 to 1 hour, for example, 0.6 hour, 0.8 hour, 0.9 hour, etc.

The dropwise adding, cooling and subsequent heat preservation crystallization are preferably carried out in a stirring state, so that the finally obtained glycine is powdery, the low bulk density of the glycine is ensured, and the bulk density of the lysine aspirin can be better matched.

The glycine solution of the present invention is selected from aqueous glycine solutions.

In the glycine aqueous solution, the mass ratio of glycine to water is 1:2-2.5, preferably 1: 2.4. The glycine aqueous solution is a saturated aqueous solution, so that the waste of unnecessary solvents can be avoided, and the amount of glycine can be maximized when the aqueous solution is dripped into the second solvent.

The preparation method of the glycine aqueous solution comprises the following steps: mixing glycine with water, and heating to dissolve to obtain the glycine aqueous solution.

In a preferred embodiment of the present invention, the temperature for the heating and dissolution is 60 to 65 ℃, for example, 61 ℃, 62 ℃, 63 ℃, 64 ℃.

The method also comprises the steps of cooling, crystallizing, filtering and drying.

In a second aspect, the present invention provides glycine in powder form obtained by the process of the first aspect.

In a preferred embodiment of the present invention, the powdered glycine has a bulk density of 0.21 to 0.49g/mL, preferably 0.21 to 0.31g/mL, for example, 0.25g/mL, 0.27g/mL, 0.28g/mL, 0.30g/mL, etc.; the tightest bulk is 0.35-0.69g/mL, preferably 0.38-0.54g/mL, e.g., 0.4g/mL, 0.42g/mL, 0.44g/mL, 0.46g/mL, 0.48g/mL, 0.50g/mL, 0.52g/mL, etc.

The glycine obtained by the recrystallization method provided by the invention is powdery solid, the bulk density of the glycine is close to that of aspirin lysine, the glycine can be well mixed with the aspirin lysine, and the layering phenomenon is not easy to generate after the glycine is uniformly mixed.

Compared with the prior art, the invention has the following beneficial effects:

the glycine solution is dripped into a solvent of slightly soluble or insoluble glycine, and the finally obtained glycine is powdery by controlling the dripping temperature, the dripping speed, the cooling crystallization temperature and the like, and the loose bulk density and the tight bulk density of the glycine are close to those of aspirin lysine, so that the glycine can be well mixed with aspirin for application; meanwhile, the method provided by the invention has the advantages of mild reaction conditions, simple process and easiness in control, and the finally obtained glycine has extremely high purity.

Detailed Description

The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the specific embodiments are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.

Example 1

This example provides a process for the preparation of powdered glycine by recrystallization.

(1) 50.0g of glycine and 120.0g of purified water were added to a 500mL three-necked flask, and stirring was started, and the temperature was raised to 65 ℃ to dissolve all glycine solids.

(2) And adding 240.0g of absolute ethyl alcohol into another 500mL three-necked bottle, heating to 65 ℃, dropwise adding the glycine aqueous solution into the 65 ℃ absolute ethyl alcohol in a stirring state at a dropwise adding rate of 60g/min while the solution is hot, cooling to 5 ℃ at a cooling rate of-20 ℃/h after dropwise adding, keeping the temperature and stirring for 0.5h, filtering, and drying to obtain crystalline powdery glycine.

Examples 2 to 4

This example provides a process for the preparation of powdered glycine by recrystallization.

The difference from example 1 is that the temperature of absolute ethanol in step (2) is 25 deg.C (example 2), 10 deg.C (example 3), and 5 deg.C (example 4).

Example 5

This example provides a process for the preparation of powdered glycine by recrystallization.

(1) 50.0g of glycine and 110.0g of purified water were added to a 500mL three-necked flask, and stirring was started, and the temperature was raised to 60 ℃ to completely dissolve the glycine solid.

(2) And adding 200.0g of diethyl ether into another 500mL three-necked bottle, keeping the temperature at 10 ℃, dropwise adding the glycine aqueous solution into the 10 ℃ diethyl ether in a stirring state at the dropwise adding speed of 60g/min, keeping the temperature and stirring for 0.5h after dropwise adding, filtering, and drying to obtain crystalline powdery glycine.

Comparative example 1

This comparative example provides a process for the preparation of glycine in powder form by recrystallization.

The difference from example 1 is that in this comparative example, anhydrous ethanol was added dropwise to an aqueous glycine solution to obtain powdery glycine.

Comparative example 2

This comparative example provides a process for the preparation of glycine in powder form by recrystallization.

The difference from example 1 is that in this comparative example, the aqueous glycine solution was directly mixed with anhydrous ethanol without mixing by dropwise addition to obtain powdery glycine.

Comparative examples 3 to 5

This comparative example provides a process for the preparation of glycine in powder form by recrystallization.

The difference from example 1 is that in this comparative example, anhydrous ethanol was replaced with 95% ethanol (comparative example 3), 90% ethanol (comparative example 4), 85% ethanol (comparative example 5) and added dropwise to an aqueous glycine solution to obtain powdery glycine.

The yield, the tightest bulk density, etc. of the powdered glycine prepared in the examples and comparative examples were calculated, and the results are shown in table 1:

TABLE 1

The embodiment and the performance test show that the glycine obtained by the method provided by the invention is powdery, the yield is high and can reach more than 94.3%, the most loose density is 0.21-0.49g/mL, the most tight density is 0.35-0.69g/mL, when the recrystallization method is in the preferable range of the invention, the most loose density of the finally obtained glycine is 0.23g/mL, the most tight density is 0.38g/mL, the density is very close to that of aspirin lysine, and the glycine and the aspirin are uniformly mixed, so that the glycine cannot be layered in the transportation and storage processes, and the stability is high.

As can be seen from the comparison of example 1 with comparative examples 1-2, only the recrystallization method of the present invention provides glycine in powder form with a higher yield and a bulk density closer to that of aspirin lysine. As can be seen from a comparison of example 1 and comparative examples 3-5, the second solvent of the present invention is preferably absolute ethanol.

Although the invention has been described in detail hereinabove by way of general description, specific embodiments and experiments, it will be apparent to those skilled in the art that many modifications and improvements can be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.