CN111153829A - Preparation method of N-acetyl-L-tyrosine - Google Patents
Preparation method of N-acetyl-L-tyrosine Download PDFInfo
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- CN111153829A CN111153829A CN201911365457.1A CN201911365457A CN111153829A CN 111153829 A CN111153829 A CN 111153829A CN 201911365457 A CN201911365457 A CN 201911365457A CN 111153829 A CN111153829 A CN 111153829A
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- C07—ORGANIC CHEMISTRY
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- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
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- C07—ORGANIC CHEMISTRY
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- C07C2523/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group C07C2521/00
- C07C2523/02—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group C07C2521/00 of the alkali- or alkaline earth metals or beryllium
- C07C2523/04—Alkali metals
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Abstract
The invention discloses a preparation method of N-acetyl-L-tyrosine, which comprises the steps of synthesizing a crude product by using sodium hydroxide as a catalyst, and purifying and refining the crude product by using acetone. The invention has the beneficial effects that: the invention adopts sodium hydroxide as a catalyst, has high L-tyrosine conversion rate, has high N-acetyl-L-tyrosine content in a crude product, can effectively remove L-tyrosine impurities by using acetone for dissolution and refining, and obtains a product with high purity which reaches the pharmaceutical grade.
Description
Technical Field
The invention relates to preparation of amino acid, in particular to a preparation method of N-acetyl-L-tyrosine.
Background
The compound amino acid can regulate human body functions as a nutritional supplement, wherein the L-tyrosine has the function of stimulating the pituitary gland to release growth hormone, and the growth hormone is gradually reduced along with the increase of age, so that the compound amino acid has multiple benefits for regulating the body of the old.
L-tyrosine has low solubility and is not easy to absorb, so that the substitution of N-acetyltyrosine is widely applied to clinic. Researches show that the increase of the proportion of the N-acetyl-L-tyrosine has better nutrition supplement effect, and has better effects on improving the metabolic disorder of amino acid and inhibiting catabolism.
In general, water is used as a solvent and acetic anhydride is used as an acylating agent for heating reaction when preparing N-acetyl-L-tyrosine, and alkali is not used as a catalyst, so that incomplete L-tyrosine reaction is easily caused, the yield is low, the main impurity is an L-tyrosine raw material and is insoluble in acetone, the solubility of N-acetyl-L-tyrosine acetone is high, and the L-tyrosine cannot be effectively removed due to the fact that the purification process adopts hot water for dissolution and then crystallization.
Disclosure of Invention
The invention provides a preparation method of N-acetyl-L-tyrosine, aiming at the problem that L-tyrosine impurity is not easy to remove in the process of preparing N-acetyl-L-tyrosine.
The technical scheme for solving the technical problems is as follows: a preparation method of N-acetyl-L-tyrosine comprises the following steps:
1) crude product synthesis: taking 1 weight part of L-tyrosine, mixing 1.5-2 weight parts of purified water and 2.5-3 weight parts of 8% sodium hydroxide solution, adding L-tyrosine under stirring, cooling to 0-5 ℃, simultaneously adding 12-15 weight parts of 8% sodium hydroxide solution and 1-1.5 weight parts of acetic anhydride, slowly heating to 20-25 ℃, preserving heat for 40-60min for reaction, cooling to 0-5 ℃ after the reaction is finished, dropwise adding 6-7 weight parts of 40 wt% sulfuric acid, standing for 12h at the temperature of 0-5 ℃, centrifuging, filtering by a stainless steel laminated filter to be clear, concentrating the filtrate under reduced pressure at 50-60 ℃, adding the concentrated solution into 4-5 weight parts of acetone, stirring for 20-30min at 40-45 ℃, centrifuging, concentrating the centrifuged solution under reduced pressure at 50-55 ℃, adding 1.5-2.0 parts by weight of purified water, stirring at 50-55 ℃ for 10-20min, transferring to a crystallization tank, stirring at 0-5 ℃ until the mixture is turbid, standing for crystallization for 12h, centrifuging, washing a filter cake with 0-5 ℃ purified water, drying at 50-55 ℃ under the vacuum degree of less than or equal to-0.06 MPa for 6h to obtain a crude product of the N-acetyl-L-tyrosine;
2) and (3) refining a crude product: taking 1 weight part of the crude product of the N-acetyl-L-tyrosine obtained in the step 1), putting the crude product into 4 to 5 weight parts of acetone, adding 0.02 weight part of activated carbon, stirring for 15 to 20min at the temperature of 40 to 45 ℃, filtering, concentrating the filtrate under reduced pressure at the temperature of 50 to 55 ℃, evaporating to remove the acetone, adding 2 to 3 weight parts of purified water, stirring for 10 to 20min at the temperature of 50 to 55 ℃, filtering by a stainless steel disc filter to a fine crystallization tank, cooling to 0 to 5 ℃, stirring to turbidity, standing for 12h for crystallization, uniformly stirring the feed liquid after crystallization, centrifuging to obtain a refined wet product of the acetyl-L-tyrosine, and drying the wet product at the temperature of 50 to 55 ℃ and under the vacuum degree of less than or equal to-0.06 MPa for 10 to 12h to obtain the acetyl-L-tyrosine.
The invention has the beneficial effects that: the invention adopts sodium hydroxide as a catalyst, has high L-tyrosine conversion rate, has high N-acetyl-L-tyrosine content in a crude product, can effectively remove L-tyrosine impurities by using acetone for dissolution and refining, and obtains a product with high purity which reaches the pharmaceutical grade.
Drawings
FIG. 1 is a HPLC chart of the finished product of N-acetyl-L-tyrosine obtained in example 1;
FIG. 2 is a HPLC chart of the N-acetyl-L tyrosine product obtained in example 2.
Detailed Description
The present invention is described below with reference to examples, which are provided for illustration only and are not intended to limit the scope of the present invention.
Example 1
A preparation method of N-acetyl-L-tyrosine comprises the following steps: adding 37.5kg of purified water and 62.5kg of 8% sodium hydroxide solution into a glass lining tank, stirring, adding 25.0 kgL-tyrosine, cooling to 0-5 ℃, dropwise adding 300.0kg of 8% sodium hydroxide solution and 30.0kg of acetic anhydride, and controlling the temperature in the dropwise adding process to be 0-5 ℃. After the dripping is finished, slowly heating to 20 ℃, keeping the temperature for 40min, cooling to 0-5 ℃, dripping 150.0kg of sulfuric acid solution, controlling the dripping temperature to be 0-5 ℃, stirring for 5min after the dripping is finished, stopping stirring, and standing for 12h at 0-5 ℃. Centrifuging, and filtering with stainless steel filter until it is clear. Collecting the filtrate in a glass-lined jar, concentrating at 50-60 deg.C and vacuum degree of not less than-0.095 MPa, and evaporating to remove water and acetic acid. 100.0kg of acetone and 0.5kg of medicinal charcoal are added dropwise. Keeping the temperature at 45 ℃, stirring for 20min, centrifuging, washing filter residues with 9.0kg of acetone, collecting filtrate, transferring the centrifugate into a glass lined tank, concentrating at a temperature of not higher than 50-55 ℃ and a vacuum degree of not lower than-0.09 MPa, evaporating to remove the acetone, adding 25.0kg of purified water, stirring for 10min at 50 ℃, transferring to a crude crystallization tank, cooling to 0-5 ℃, stirring until the mixture is turbid, and standing for crystallization for 12 h. Centrifuging at 50-55 deg.C and vacuum degree of not less than-0.06 MPa, and drying for 6 hr to obtain N-acetyl-L-tyrosine crude product; adding 51.0kg of acetone into a glass lining tank, adding 17.0kg of crude N-acetyl-L-tyrosine, dissolving at 40 ℃, cooling to room temperature, adding 0.34kg of active carbon, stirring for 15min, filtering with a stainless steel disc filter, and collecting the filtrate. Concentrating at 50-55 deg.C and vacuum degree not lower than-0.09 MPa, and distilling off acetone. Adding 17.0kg of purified water, stirring for 10min at 50 ℃, filtering the solution to a clean area through a stainless steel disc filter, filtering the solution entering the clean area through the stainless steel disc filter to a fine crystallization tank, cooling to 0-5 ℃, stirring to be turbid, standing for crystallization for 12h, uniformly stirring the solution after crystallization, centrifuging to obtain an acetyl-L-tyrosine refined wet product, drying for 10h at 50-55 ℃ under the vacuum degree of not less than-0.06 MPa to obtain 15.2kg of an N-acetyl-L-tyrosine refined dry product.
Example 2
A preparation method of N-acetyl-L-tyrosine comprises the following steps: adding 50.0kg of purified water and 75.0kg of 8% sodium hydroxide solution into a glass lining tank, stirring, adding 25.0 kgL-tyrosine, cooling to 0-5 ℃, dropwise adding 375.0kg of 8% sodium hydroxide solution and 37.5kg of acetic anhydride, and controlling the temperature in the dropwise adding process to be 0-5 ℃. After the dripping is finished, slowly heating to 25 ℃, keeping the temperature for 60min, cooling to 0-5 ℃, dripping 175.0kg of sulfuric acid solution, controlling the dripping temperature to be 0-5 ℃, stirring for 5min after the dripping is finished, stopping stirring, and standing for 12h at 0-5 ℃. Centrifuging, and filtering with stainless steel filter until it is clear. Collecting the filtrate in a glass-lined jar, concentrating at 50-60 deg.C and vacuum degree of not less than-0.095 MPa, and evaporating to remove water and acetic acid. 125.0kg of acetone and 0.5kg of medicinal charcoal are added dropwise. Keeping the temperature at 45 ℃, stirring for 20min, centrifuging, washing filter residues with 9.0kg of acetone, collecting filtrate, transferring the centrifugate into a glass lined tank, concentrating at the temperature of not higher than 50-55 ℃ and the vacuum degree of not lower than-0.09 MPa, evaporating to remove the acetone, adding 50.0kg of purified water, stirring for 10min at 55 ℃, transferring to a crude crystallization tank, cooling to 0 ℃, stirring until the mixture is turbid, and standing for crystallization for 12 h. Centrifugation, 9.0kg, washing with purified water at 0-5 ℃. Drying at 50-55 deg.C and vacuum degree not lower than-0.06 MPa for 6 hr to obtain N-acetyl-L-tyrosine crude product; adding 69.6kg of acetone into a glass lining tank, adding 17.4kg of crude N-acetyl-L-tyrosine, dissolving at 45 ℃, cooling to room temperature, adding 0.35kg of active carbon, stirring for 15min, filtering with a stainless steel disc filter, and collecting the filtrate. Concentrating at 50-55 deg.C and vacuum degree not lower than-0.09 MPa, and distilling off acetone. Adding 34.8kg of purified water, stirring for 10min at 55 ℃, filtering the material liquid in a clean area through a stainless steel disc filter, filtering the material liquid in the clean area through the stainless steel disc filter, sending the material liquid to a fine crystallization tank, cooling to 0-5 ℃, stirring until the material liquid is turbid, standing for crystallization for 12h, uniformly stirring the material liquid after crystallization, centrifuging to obtain an acetyl-L-tyrosine refined wet product, drying for 10h at 50-55 ℃ under the vacuum degree of not less than-0.06 MPa to obtain 16.2kg of an N-acetyl-L-tyrosine refined dry product.
FIG. 1 is a HPLC chart of the finished product of N-acetyl-L-tyrosine obtained in example 1, wherein the purity of N-acetyl-L-tyrosine is 99.97%; FIG. 2 is the HPLC chart of the finished product of N-acetyl-L-tyrosine obtained in example 2, and the purity of the obtained N-acetyl-L-tyrosine is 99.97%.
The products obtained in examples 1 and 2 were subjected to a correlation test as shown in table 1. As can be seen from the detection results in Table 1, the indexes of the N-acetyl-L-tyrosine prepared by the method of the invention are all within the standard regulation.
TABLE 1 detection results of the products obtained in examples 1 and 2
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (1)
1. A preparation method of N-acetyl-L-tyrosine is characterized by comprising the following steps:
1) crude product synthesis: taking 1 weight part of L-tyrosine, mixing 1.5-2 weight parts of purified water and 2.5-3 weight parts of 8% sodium hydroxide solution, adding L-tyrosine under stirring, cooling to 0-5 ℃, simultaneously adding 12-15 weight parts of 8% sodium hydroxide solution and 1-1.5 weight parts of acetic anhydride, slowly heating to 20-25 ℃, preserving heat for 40-60min for reaction, cooling to 0-5 ℃ after the reaction is finished, dropwise adding 6-7 weight parts of 40 wt% sulfuric acid, standing for 12h at the temperature of 0-5 ℃, centrifuging, filtering by a stainless steel laminated filter to be clear, concentrating the filtrate under reduced pressure at 50-60 ℃, adding the concentrated solution into 4-5 weight parts of acetone, stirring for 20-30min at 40-45 ℃, centrifuging, concentrating the centrifuged solution under reduced pressure at 50-55 ℃, adding 1.5-2.0 parts by weight of purified water, stirring at 50-55 ℃ for 10-20min, transferring to a crystallization tank, stirring at 0-5 ℃ until the mixture is turbid, standing for crystallization for 12h, centrifuging, washing a filter cake with 0-5 ℃ purified water, drying at 50-55 ℃ under the vacuum degree of less than or equal to-0.06 MPa for 6h to obtain a crude product of the N-acetyl-L-tyrosine;
2) and (3) refining a crude product: taking 1 weight part of the crude product of the N-acetyl-L-tyrosine obtained in the step 1), putting the crude product into 4 to 5 weight parts of acetone, adding 0.02 weight part of activated carbon, stirring for 15 to 20min at the temperature of 40 to 45 ℃, filtering, concentrating the filtrate under reduced pressure at the temperature of 50 to 55 ℃, evaporating to remove the acetone, adding 2 to 3 weight parts of purified water, stirring for 10 to 20min at the temperature of 50 to 55 ℃, filtering by a stainless steel disc filter to a fine crystallization tank, cooling to 0 to 5 ℃, stirring to turbidity, standing for 12h for crystallization, uniformly stirring the feed liquid after crystallization, centrifuging to obtain a refined wet product of the acetyl-L-tyrosine, and drying the wet product at the temperature of 50 to 55 ℃ and under the vacuum degree of less than or equal to-0.06 MPa for 10 to 12h to obtain the acetyl-L-tyrosine.
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN116098884A (en) * | 2022-12-12 | 2023-05-12 | 山东大学 | Application of N-acetyl-L-tyrosine in preparation of medicines for treating inflammatory bowel disease |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1594283A (en) * | 2004-06-24 | 2005-03-16 | 武汉武大弘元药业有限公司 | Process for preparing N-acetyl-L-tyrosine |
CN102219706A (en) * | 2011-04-21 | 2011-10-19 | 宁波市镇海海德生化科技有限公司 | Method for preparing acetyl tyrosine ethyl ester monohydrate and product of acetyl tyrosine ethyl ester monohydrate |
CN102827018A (en) * | 2012-09-25 | 2012-12-19 | 新沂市汉菱生物工程有限公司 | Preparation method of N-acetyl-L-tyrosine |
CN106748870A (en) * | 2015-11-20 | 2017-05-31 | 江苏新汉菱生物工程股份有限公司 | A kind of method for producing Acetyl Tyrosine |
-
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- 2019-12-26 CN CN201911365457.1A patent/CN111153829A/en active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1594283A (en) * | 2004-06-24 | 2005-03-16 | 武汉武大弘元药业有限公司 | Process for preparing N-acetyl-L-tyrosine |
CN102219706A (en) * | 2011-04-21 | 2011-10-19 | 宁波市镇海海德生化科技有限公司 | Method for preparing acetyl tyrosine ethyl ester monohydrate and product of acetyl tyrosine ethyl ester monohydrate |
CN102827018A (en) * | 2012-09-25 | 2012-12-19 | 新沂市汉菱生物工程有限公司 | Preparation method of N-acetyl-L-tyrosine |
CN106748870A (en) * | 2015-11-20 | 2017-05-31 | 江苏新汉菱生物工程股份有限公司 | A kind of method for producing Acetyl Tyrosine |
Non-Patent Citations (1)
Title |
---|
王家荣等: "L-酪氨酸的消旋研究", 《高校化学工程学报》 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN116098884A (en) * | 2022-12-12 | 2023-05-12 | 山东大学 | Application of N-acetyl-L-tyrosine in preparation of medicines for treating inflammatory bowel disease |
CN116098884B (en) * | 2022-12-12 | 2024-04-19 | 山东大学 | Application of N-acetyl-L-tyrosine in preparation of medicines for treating inflammatory bowel disease |
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