CN112574050B - Method for preparing powdery glycine by recrystallization - Google Patents
Method for preparing powdery glycine by recrystallization Download PDFInfo
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- CN112574050B CN112574050B CN202011363579.XA CN202011363579A CN112574050B CN 112574050 B CN112574050 B CN 112574050B CN 202011363579 A CN202011363579 A CN 202011363579A CN 112574050 B CN112574050 B CN 112574050B
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- glycine
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- recrystallization
- aqueous solution
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- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 title claims abstract description 174
- 239000004471 Glycine Substances 0.000 title claims abstract description 85
- 238000000034 method Methods 0.000 title claims abstract description 28
- 238000001953 recrystallisation Methods 0.000 title claims abstract description 15
- 239000002904 solvent Substances 0.000 claims abstract description 20
- 238000001816 cooling Methods 0.000 claims abstract description 10
- 238000002425 crystallisation Methods 0.000 claims abstract description 10
- 230000008025 crystallization Effects 0.000 claims abstract description 10
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 15
- 239000007864 aqueous solution Substances 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 230000000052 comparative effect Effects 0.000 description 15
- 239000004472 Lysine Substances 0.000 description 9
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- 239000007787 solid Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 4
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 4
- 238000003860 storage Methods 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 229960004889 salicylic acid Drugs 0.000 description 2
- 108010024636 Glutathione Proteins 0.000 description 1
- 150000001370 alpha-amino acid derivatives Chemical class 0.000 description 1
- 235000008206 alpha-amino acids Nutrition 0.000 description 1
- -1 amino carboxyl Chemical group 0.000 description 1
- 239000003674 animal food additive Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 239000011812 mixed powder Substances 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000011056 performance test Methods 0.000 description 1
- YIBOMRUWOWDFLG-ONEGZZNKSA-N rilpivirine Chemical compound CC1=CC(\C=C\C#N)=CC(C)=C1NC1=CC=NC(NC=2C=CC(=CC=2)C#N)=N1 YIBOMRUWOWDFLG-ONEGZZNKSA-N 0.000 description 1
- 229960002814 rilpivirine Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003883 substance clean up Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
- C07C227/42—Crystallisation
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention provides a process for preparing powdered glycine by recrystallization, the process comprising: dropwise adding glycine solution into a second solvent, and then cooling and crystallizing to obtain the powdery glycine; wherein the solubility of glycine in the second solvent is less than 1g/100g. The method provided by the invention has mild crystallization conditions, is simple and easy to implement, and the finally obtained glycine has higher yield, higher purity and powdery shape, and has proper bulk density so as to be convenient to apply.
Description
Technical Field
The invention belongs to the technical field of compound purification, and relates to a method for preparing powdery glycine.
Background
Glycine (abbreviated Gly) is also known as Glycine and has the chemical formula C 2 H 5 NO. Glycine is a constituent amino acid of the endogenous antioxidant, reduced glutathione, and is frequently exogenously supplemented when severe stress occurs in the body, sometimes also called semi-essential amino acid. The solid glycine is white monoclinic or hexagonal crystal or white crystal powder, has no odor and toxicity, is easy to dissolve in water, and is almost insoluble in ethanol or diethyl ether. It is the only amino carboxyl fatty amino acid with simple structure and no optical activity in natural alpha-amino acid. Glycine is widely used in medicine, organic synthesis, food, feed additive and biochemical reagent.
The lysine-piprolin glycine mixed powder is a typical application of glycine in the field of medicine. Because the single-component lysine-piperalin for injection is unstable to humidity, heat and light, the single-component lysine-piperalin is easy to be partially decomposed into free salicylic acid during the storage period, and the drug effect is reduced. Glycine is added into the lysine-piprolin, and the glycine can inhibit the generation of free salicylic acid which is a decomposition product, so that the stability of the lysine-piprolin for injection in the storage period can be improved; and the irritation to the muscle is remarkably reduced. Lysipin is a powdered solid having a bulk at maximum of about 0.20g/mL and a bulk at maximum of about 0.38g/mL.
In order to ensure that the mixing powder of the lysine and the mixing powder of the lysine are uniformly mixed and cannot generate layering phenomenon after transportation, glycine is required to be a powdery solid, and the bulk density of the glycine is close to that of the lysine.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention aims to provide a method for preparing powdery glycine by recrystallization, which has the advantages of mild crystallization condition, simple and easy operation, and the obtained glycine has higher purity and powdery shape and proper bulk density so as to be convenient for application.
To achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, the present invention provides a process for preparing powdered glycine by recrystallization, the process comprising: dropwise adding glycine solution into a second solvent, and then cooling and crystallizing to obtain the powdery glycine;
wherein the solubility of glycine in the second solvent is less than 1g/100g (second solvent).
According to the invention, the glycine solution is recrystallized in a dropwise adding mode, so that the finally obtained glycine is ensured to be in a powder form, the product purity is higher, and the bulk density is moderate.
As a preferred embodiment of the present invention, the second solvent includes any one or a combination of at least two of absolute ethanol, diethyl ether, and acetone, preferably absolute ethanol.
The second solvent of the present invention has a temperature of 5 to 65℃such as 10℃15℃20℃25℃30℃35℃40℃45℃50℃55℃60℃and preferably 5 to 10℃such as 6℃7℃8℃9 ℃.
When the temperature of the second solvent is 5-10 ℃, the subsequent process can be carried out without further cooling, and the crystallization can be directly carried out at the temperature, so that the bulk density of the finally obtained glycine powder is the smallest and is closest to that of the lysine.
As 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, etc., preferably 1:4.8.
In order to give glycine having a relatively good bulk density, the rate of the dropwise addition is 55-65g/min, for example 60g/min.
As a preferable embodiment of the present invention, the dropping is performed in a stirred state.
As a preferable 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 is performed at a temperature of 10℃or lower, for example, 9℃8℃6℃4℃2℃and the like, preferably 5 to 10℃and preferably in a stirred state.
As a preferred embodiment of the present invention, the crystallization time is 0.5 to 1h, for example, 0.6h, 0.8h, 0.9h, etc.
The invention is preferably carried out in a stirring state, such that the dripping, cooling and subsequent heat preservation crystallization are carried out in a stirring state, the final glycine is ensured to be in powder form, the bulk density of the glycine is ensured to be low, and the bulk density of the lysine is conveniently and well matched.
The glycine solution according to 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 glycine amount can be ensured to 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 glycine aqueous solution.
As a preferable embodiment of the present invention, the temperature of the heated dissolution is 60 to 65℃such as 61℃and 62℃and 63℃and 64 ℃.
The method also comprises the steps of cooling, crystallizing, filtering and drying.
In a second aspect, the present invention provides powdered glycine obtained by the process of the first aspect.
As 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 density is 0.35-0.69g/mL, preferably 0.38-0.54g/mL, such as 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, has the bulk density close to that of the lysine and can be well mixed with the lysine, and layering phenomenon is not easy to occur after uniform mixing.
Compared with the prior art, the invention has the following beneficial effects:
according to the invention, the glycine solution is dripped into a slightly or indissolvable glycine solvent, and the finally obtained glycine is in a powder form by controlling the dripping temperature, the dripping speed, the cooling crystallization temperature and the like, and the most loose density of the glycine are close to those of the lysine and can be well mixed with the lysine for application; meanwhile, the method provided by the invention has the advantages of mild reaction conditions, simple working procedures, easiness in control and extremely high purity of the finally obtained glycine.
Detailed Description
The technical scheme of the invention is further described by the following specific embodiments. It should be apparent to those skilled in the art that the detailed description is merely provided to aid in understanding the invention and should not be taken as limiting the invention in any way.
Example 1
This example provides a method for preparing powdered glycine using recrystallization.
(1) To a 500mL three-necked flask, 50.0g of glycine and 120.0g of purified water were added, and stirring was started, and the temperature was raised to 65℃to dissolve all glycine solids.
(2) In addition, 240.0g of absolute ethyl alcohol is added into a 500mL three-port bottle, the temperature is raised to 65 ℃, the aqueous solution of glycine is dropwise added into the absolute ethyl alcohol at 65 ℃ under the stirring state at the dropwise adding rate of 60g/min, the temperature is reduced to 5 ℃ at the cooling rate of-20 ℃/h after the dropwise adding, the temperature is kept for 0.5h, and then the crystalline powdery glycine is obtained after filtering and drying.
Examples 2 to 4
This example provides a method for preparing powdered glycine using recrystallization.
The difference from example 1 is that the absolute ethanol in step (2) has a temperature of 25 ℃ (example 2), 10 ℃ (example 3), 5 ℃ (example 4).
Example 5
This example provides a method for preparing powdered glycine using recrystallization.
(1) To a 500mL three-necked flask, 50.0g of glycine and 110.0g of purified water were added, and stirring was started, and the temperature was raised to 60℃to dissolve all glycine solids.
(2) 200.0g of diethyl ether is added into a 500mL three-necked flask, the temperature of the three-necked flask is kept at 10 ℃, the aqueous solution of glycine is dripped into the diethyl ether at the temperature of 10 ℃ under the stirring state at the dripping rate of 60g/min, the three-necked flask is stirred for 0.5h under the condition of heat preservation after dripping, and then the three-necked flask is filtered and dried to obtain crystalline powdery glycine.
Comparative example 1
This comparative example provides a process for preparing powdered glycine using recrystallization.
The difference from example 1 is that in this comparative example, absolute ethanol was added dropwise to an aqueous glycine solution to obtain glycine in powder form.
Comparative example 2
This comparative example provides a process for preparing powdered glycine using recrystallization.
The difference from example 1 is that in this comparative example, glycine aqueous solution was directly mixed with absolute ethanol to obtain powdered glycine without mixing by dropping.
Comparative examples 3 to 5
This comparative example provides a process for preparing powdered glycine using 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) was added dropwise to glycine aqueous solution to obtain glycine in powder form.
The powdered glycine prepared in examples and comparative examples was calculated for its yield, the tightest bulk and the tightest bulk, etc., and the results are shown in Table 1:
TABLE 1
As shown in the examples and performance tests, the glycine obtained by the method provided by the invention is powdery, the yield is higher and can reach more than 94.3%, the maximum bulk density is 0.21-0.49g/mL, the maximum bulk density is 0.35-0.69g/mL, when the recrystallization method is in the preferred range of the invention, the maximum bulk density of the finally obtained glycine is 0.23g/mL, the maximum bulk density is 0.38g/mL, the glycine is very similar to the bulk density of the lisinopilin, and the glycine and the lisinopilin can not be layered in the transportation and storage process after being uniformly mixed, and the glycine has higher stability.
As is evident from the comparison of example 1 and comparative examples 1-2, only the recrystallization method of the present invention was used to prepare powdered glycine with a higher yield and a bulk density closer to that of rilpivirine. 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.
While the invention has been described in detail in the foregoing general description, embodiments and experiments, it will be apparent to those skilled in the art that modifications and improvements can be made thereto. Accordingly, such modifications or improvements may be made without departing from the spirit of the invention and are intended to be within the scope of the invention as claimed.
Claims (8)
1. A process for preparing powdered glycine by recrystallization, the process comprising: dropwise adding glycine aqueous solution into a second solvent, cooling, crystallizing, filtering and drying to obtain the powdery glycine;
wherein the solubility of the glycine in the second solvent is less than 1g/100 g;
the second solvent comprises any one or a combination of at least two of absolute ethyl alcohol, diethyl ether and acetone, and the temperature of the second solvent is 5-10 ℃;
in the glycine aqueous solution, the mass ratio of glycine to water is 1: (2-2.5);
the dripping is carried out in a stirring state, and the dripping speed is 55-65 g/min;
the temperature of the crystallization is 5-10 ℃, and the cooling rate is 10-30 ℃/h.
2. The method according to claim 1, wherein the mass ratio of glycine to the second solvent is 1: (4-5).
3. The method of claim 1 or 2, wherein the second solvent comprises absolute ethanol; and/or, the mass ratio of glycine to the second solvent is 1:4.8.
4. the method according to claim 1 or 2, wherein the time of crystallization is 0.5-1 h.
5. The method according to claim 1, wherein the crystallization is performed in a stirred state.
6. The method according to claim 1, wherein the mass ratio of glycine to water is 1:2.4.
7. the method according to claim 1, wherein the preparation method of the glycine aqueous solution comprises: mixing glycine with water, and heating to dissolve to obtain glycine aqueous solution.
8. The method of claim 7, wherein the heated dissolution temperature is 60-65 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011363579.XA CN112574050B (en) | 2020-11-27 | 2020-11-27 | Method for preparing powdery glycine by recrystallization |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202011363579.XA CN112574050B (en) | 2020-11-27 | 2020-11-27 | Method for preparing powdery glycine by recrystallization |
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| CN112574050A CN112574050A (en) | 2021-03-30 |
| CN112574050B true CN112574050B (en) | 2024-02-02 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1237327A (en) * | 1959-06-19 | 1960-07-29 | Prod Chim Ind Soc D | Amino Acid Preparation Process |
| CN1283101A (en) * | 1997-10-29 | 2001-02-07 | 高露洁-棕榄公司 | Improved antiperspiration agent activition and prescription compounded by it |
| CN1288884A (en) * | 1999-09-22 | 2001-03-28 | 苏州市永达精细化工有限公司 | Glycine purifying and closed production process |
-
2020
- 2020-11-27 CN CN202011363579.XA patent/CN112574050B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1237327A (en) * | 1959-06-19 | 1960-07-29 | Prod Chim Ind Soc D | Amino Acid Preparation Process |
| CN1283101A (en) * | 1997-10-29 | 2001-02-07 | 高露洁-棕榄公司 | Improved antiperspiration agent activition and prescription compounded by it |
| CN1288884A (en) * | 1999-09-22 | 2001-03-28 | 苏州市永达精细化工有限公司 | Glycine purifying and closed production process |
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| CN112574050A (en) | 2021-03-30 |
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