CN110878028A - Preparation method of amino acid ester hydrochloride solution - Google Patents
Preparation method of amino acid ester hydrochloride solution Download PDFInfo
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- CN110878028A CN110878028A CN201911288744.7A CN201911288744A CN110878028A CN 110878028 A CN110878028 A CN 110878028A CN 201911288744 A CN201911288744 A CN 201911288744A CN 110878028 A CN110878028 A CN 110878028A
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- amino acid
- ester hydrochloride
- hydrochloric acid
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- acid ester
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- 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
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
- C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
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- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to compound synthesis, in particular to a preparation method of an amino acid ester hydrochloride solution. Refluxing and dividing water of concentrated hydrochloric acid by stirring with n-heptane to obtain dehydrated hydrochloric acid; stirring and refluxing the dehydrated hydrochloric acid and alcohol at 80-150 ℃ for esterification reaction to obtain the amino acid ester hydrochloride. The esterification reaction directly utilizes concentrated hydrochloric acid to carry out reaction, thereby avoiding inconvenience and potential safety hazard caused by using gaseous hydrogen chloride; in addition, n-heptane is used for dehydrating concentrated hydrochloric acid in the esterification reaction process, and the dehydration of the molecular sieve is combined, so that the problem that the esterification reaction is inhibited due to the overlarge water content in the concentrated hydrochloric acid is solved.
Description
Technical Field
The invention relates to compound synthesis, in particular to a preparation method of an amino acid ester hydrochloride solution.
Background
At present, the proton acid method is most widely applied in the preparation method of synthetic amino acid ester salt. Most of them are used for synthesizing amino acid ester sulfate, but the disadvantages of difficult separation of product mixture, low yield and the like exist. In the synthesis of the amino acid ester hydrochloride, the existence of water can inhibit the esterification reaction due to the problem of large water content of concentrated hydrochloric acid, so the conversion rate is low; furthermore, most of the methods mainly adopt direct introduction of hydrogen chloride gas, but hydrogen chloride is volatile and has strong corrosivity, so that a preparation method which is simple in process and beneficial to industrial production is needed.
The resin catalysis method and the zeolite catalysis method which are started in recent years respectively use strong acid type cation resin and ultrastable zeolite to realize normal temperature esterification and can be repeatedly used, but have the defects of low yield and long processing time of processes such as reaction, elution and the like.
Disclosure of Invention
The invention aims to provide a preparation method of an amino acid ester hydrochloride solution.
In order to achieve the purpose, the invention adopts the technical scheme that:
a preparation method of amino acid ester hydrochloride solution comprises refluxing concentrated hydrochloric acid with n-heptane under stirring for water separation to obtain dehydrated hydrochloric acid; stirring and refluxing the dehydrated hydrochloric acid and alcohol at 80-150 ℃ for esterification reaction to obtain the amino acid ester hydrochloride.
The weight volume (g/ml) ratio of the n-heptane, the concentrated hydrochloric acid and the alcohol is 1:1-3: 8-10.
The concentrated hydrochloric acid is dehydrated into: dropping concentrated hydrochloric acid into amino acid, stirring and dissolving at 30-80 deg.C, adding n-heptane after dissolving, mixing, placing in a water separator, heating to 80-100 deg.C, stirring n-heptane and water, azeotropy, condensing, refluxing, and separating water for 2 hr to obtain dehydrated hydrochloric acid.
The dehydrated hydrochloric acid and alcohol are stirred and refluxed at the temperature of 60-130 ℃ for esterification reaction for 10-20h to obtain amino acid ester hydrochloride; wherein, molecular sieve is added in the esterification reaction to remove water so as to ensure that the esterification reaction is complete.
And adding a molecular sieve in the esterification reaction process, wherein the addition amount of the molecular sieve is 2-4 times of the mass of the amino acid.
The adding amount of the n-heptane is 0.5-4 times of the mass of the amino acid; wherein the amino acid is aliphatic, aromatic or heterocyclic amino acid; the mass ratio of the amino acid to the concentrated hydrochloric acid is 1: 1-2.
The amino acid is alanine, glycine, valine, isoleucine, leucine, phenylalanine or tyrosine.
After refluxing and water separation, the mixture is further concentrated and distilled at the temperature of 60-80 ℃ to obtain n-heptane for reuse.
The concentration of the concentrated hydrochloric acid is 36-38%.
The alcohol is methanol, ethanol or isopropanol; the molecular sieve is a 3A type molecular sieve or a 4A type molecular sieve.
The invention has the advantages that:
1. the esterification reaction directly utilizes concentrated hydrochloric acid to carry out reaction, thereby avoiding inconvenience and potential safety hazard caused by using gaseous hydrogen chloride; the concentrated hydrochloric acid is dehydrated by using n-heptane, so that the problem that the esterification reaction is inhibited due to the overlarge water content in the concentrated hydrochloric acid is solved.
2. In the esterification reaction process, the dehydrated HCl is introduced into the mixture of amino acid and alcohol, the reflux reaction has good reproducibility, the reaction period is short, the product is easy to separate, and meanwhile, the operability of industrial production is improved by further directly using concentrated hydrochloric acid.
3. In the reaction process, n-heptane and water are subjected to azeotropy, and water is separated by using a water separator, so that the aim of reducing the water content in a system can be fulfilled, and the requirement of an esterification reaction can be met; in the reaction process, water is removed once through the water carried by the n-heptane, repeated concentration and water removal are not needed in the esterification step, and only heating, stirring and refluxing are needed.
4. In the reaction process, the reaction mixture after water removal is directly subjected to n-heptane removal and then stirred and refluxed, so that the process of concentrating, removing alcohol and replenishing for many times is omitted, the operation steps are reduced, and the reaction efficiency is improved.
5. And a molecular sieve is used for removing water in the esterification reaction process, so that the esterification reaction is more nearly complete, and higher yield is obtained.
Detailed Description
The following examples are presented to further illustrate embodiments of the present invention, and it should be understood that the embodiments described herein are for purposes of illustration and explanation only and are not intended to limit the invention.
Example 1
Mixing 20g L-alanine with 28.6g concentrated hydrochloric acid, stirring at 60 deg.C to dissolve, weighing 10mL n-heptane, adding into reaction kettle, stirring at 80 deg.C under reflux to dehydrate, and maintaining for 2 h. Concentration was then continued and n-heptane was distilled off. Adding 80g of methanol into the reaction kettle, heating to 80 ℃, and stirring and refluxing for reaction for 10 hours. After concentration, a solution of L-alanine methyl ester hydrochloride is obtained. The conversion of L-alanine methyl ester hydrochloride by HPLC was 96.8%.
Example 2
Mixing 20g L-alanine with 28.6g concentrated hydrochloric acid, stirring at 60 deg.C to dissolve, weighing 10mL n-heptane, adding into reaction kettle, stirring at 80 deg.C under reflux to dehydrate, and maintaining for 2 h. Concentration was then continued and n-heptane was distilled off. Adding 100g of ethanol into the reaction kettle, heating to 100 ℃, and stirring and refluxing for reaction for 10 hours. After concentration, a solution of L-alanine methyl ester hydrochloride is obtained. The conversion of L-alanine methyl ester hydrochloride by HPLC was 95.46%.
Example 3
Mixing 20g L-alanine with 28.6g concentrated hydrochloric acid, stirring at 60 deg.C to dissolve, weighing 10mL n-heptane, adding into reaction kettle, stirring at 80 deg.C under reflux to dehydrate, and maintaining for 2 h. Concentration was then continued and n-heptane was distilled off. Adding 80g of methanol into a reaction kettle, hanging a rectifying column filled with 50g of 3A type molecular sieve, heating to 80 ℃, and stirring and refluxing for reaction for 10 hours. After concentration, a solution of L-alanine methyl ester hydrochloride is obtained. The conversion of L-alanine methyl ester hydrochloride by HPLC was 99.24%.
The L-alanine in the above examples was substituted with the amino acids shown in the following table to prepare other various amino acid methyl ester hydrochloride solutions, and the conversion rates were as shown in the following table.
| Kind of amino acid | Conversion (%) |
| L-glycine | 99.17 |
| L-valine | 99.09 |
| L-isoleucine | 99.32 |
| L-leucine | 98.96 |
| L-phenylalanine | 99.03 |
| L-tyrosine | 99.15 |
Example 4
Mixing 20g L-alanine with 28.6g concentrated hydrochloric acid, stirring at 60 deg.C to dissolve, weighing 10mL n-heptane, adding into reaction kettle, stirring at 80 deg.C under reflux to dehydrate, and maintaining for 2 h. Concentration was then continued and n-heptane was distilled off. Adding 100g of isopropanol into the reaction kettle, heating to 120 ℃, and stirring and refluxing for reaction for 12 hours. After concentration, a solution of L-alanine methyl ester hydrochloride is obtained. The conversion of L-alanine methyl ester hydrochloride by HPLC was 95.14%.
Comparative example
Adding 20g L-alanine and 28.6g concentrated hydrochloric acid into a reaction kettle, stirring at 60 ℃ to dissolve, adding 80g methanol, stirring at 80 ℃ and refluxing, and reacting for 10 h. After concentration, a solution of L-alanine methyl ester hydrochloride is obtained. The conversion of L-alanine methyl ester hydrochloride by HPLC was 80.65%.
As can be seen from the above, after a part of water in the concentrated hydrochloric acid is removed by using the azeotropic principle of n-heptane and water, the concentrated hydrochloric acid is used as a catalyst to carry out the esterification reaction for synthesizing a series of amino-acid ester salts, and the conversion rate is greatly improved. Wherein, the step of further removing water by adding the molecular sieve in the esterification reaction in the embodiment 3 ensures that the conversion rate reaches a very high level, and meanwhile, the whole process is simple, the operation is safe, and the method is suitable for industrial scale-up production.
Claims (10)
1. A preparation method of an amino acid ester hydrochloride solution is characterized by comprising the following steps: refluxing and dividing water of concentrated hydrochloric acid by stirring with n-heptane to obtain dehydrated hydrochloric acid; stirring and refluxing the dehydrated hydrochloric acid and alcohol at 80-150 ℃ for esterification reaction to obtain the amino acid ester hydrochloride.
2. A process for the preparation of the amino acid ester hydrochloride solution according to claim 1, characterized in that: the weight volume (g/ml) ratio of the n-heptane, the concentrated hydrochloric acid and the alcohol is 1:1-3: 8-10.
3. A process for the preparation of the amino acid ester hydrochloride solution according to claim 1 or 2, characterized in that: the concentrated hydrochloric acid is dehydrated into: dropping concentrated hydrochloric acid into amino acid, stirring at 30-80 deg.C for dissolving, adding n-heptane after dissolving, mixing with water separator at 80-100 deg.C, stirring with n-heptane and water, azeotropy condensing, refluxing, and separating water for 2 hr to obtain dehydrated hydrochloric acid.
4. A process for the preparation of the amino acid ester hydrochloride solution according to claim 3, characterized in that: and (3) stirring and refluxing the dehydrated hydrochloric acid and alcohol at the temperature of 60-130 ℃ for esterification reaction for 10-20h to obtain the amino acid ester hydrochloride.
5. A process for the preparation of the amino acid ester hydrochloride solution according to claim 4, characterized in that: and adding a molecular sieve in the esterification reaction process, wherein the addition amount of the molecular sieve is 2-4 times of the mass of the amino acid.
6. The process for the preparation of the amino acid ester hydrochloride solution according to claim 4, characterized in that: the adding amount of the n-heptane is 0.5-4 times of the mass of the amino acid; wherein the amino acid is aliphatic, aromatic or heterocyclic amino acid; the mass ratio of the amino acid to the concentrated hydrochloric acid is 1: 1-2.
7. The process for the preparation of the amino acid ester hydrochloride solution according to claim 6, characterized in that: the amino acid is alanine, glycine, valine, isoleucine, leucine, phenylalanine or tyrosine.
8. The process for the preparation of the amino acid ester hydrochloride solution according to claim 4, characterized in that: after refluxing and water separation, the mixture is further concentrated and distilled at the temperature of 60-80 ℃ to obtain n-heptane for reuse.
9. A process for the preparation of the amino acid ester hydrochloride solution according to claim 4, characterized in that: the concentration of the concentrated hydrochloric acid is 36-38%.
10. A process for the preparation of the amino acid ester hydrochloride solution according to claim 4, characterized in that: the alcohol is methanol, ethanol or isopropanol; the molecular sieve is a 3A type molecular sieve or a 4A type molecular sieve.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112979485A (en) * | 2021-03-25 | 2021-06-18 | 齐鲁工业大学 | Application of 3A type molecular sieve in synthesis of N- (4-acetylene benzene carbonyl) amino acid ester |
| CN115160164A (en) * | 2022-05-06 | 2022-10-11 | 大连医诺生物股份有限公司 | Preparation method and application of composite alanine methyl ester hydrochloride |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4898966A (en) * | 1987-10-24 | 1990-02-06 | Hoechst Aktiengesellschaft | Process for the preparation of phenylalanine n-propyl ester hydrochloride |
| CN101891637A (en) * | 2009-05-19 | 2010-11-24 | 李其奎 | Method for synthesizing glycine ester hydrochloride and processing mother liquid thereof |
-
2019
- 2019-12-12 CN CN201911288744.7A patent/CN110878028A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4898966A (en) * | 1987-10-24 | 1990-02-06 | Hoechst Aktiengesellschaft | Process for the preparation of phenylalanine n-propyl ester hydrochloride |
| CN101891637A (en) * | 2009-05-19 | 2010-11-24 | 李其奎 | Method for synthesizing glycine ester hydrochloride and processing mother liquid thereof |
Non-Patent Citations (1)
| Title |
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| 高锐等: "氯化氢催化法合成氨基酸酯盐酸盐", 《化学反应工程与工艺》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112979485A (en) * | 2021-03-25 | 2021-06-18 | 齐鲁工业大学 | Application of 3A type molecular sieve in synthesis of N- (4-acetylene benzene carbonyl) amino acid ester |
| CN115160164A (en) * | 2022-05-06 | 2022-10-11 | 大连医诺生物股份有限公司 | Preparation method and application of composite alanine methyl ester hydrochloride |
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Application publication date: 20200313 |