Synthetic method of p-hydroxyphenylglycine

Abstract

The invention belongs to the technical field of synthesis of p-hydroxyphenylglycine, and discloses a synthesis method of p-hydroxyphenylglycine. The first-step reaction of the method comprises the following steps: reacting a glyoxylic acid solution and an ammonium ion-containing compound serving as raw materials, and completely reacting the reactant glyoxylic acid to generate an intermediate 1; in the second-step reaction, phenol is added into the reaction system, the phenol and the intermediate 1 continue to react under the action of a catalyst, after the reaction is finished, aftertreatment is conducted, and p-hydroxyphenylglycine is obtained. According to the synthesis method, generation of by-products can be effectively reduced, the yield of the obtained p-hydroxyphenylglycine is high, the preparation method is simple, the reaction time is short, and industrial production is facilitated.

Description

Technical Field

[0001] The present invention belongs to the technical field of p-hydroxyphenylglycine, and particularly relates to a method for synthesizing p-hydroxyphenylglycine. Background Art

[0002] p-Hydroxyphenylglycine (with the structure shown in Formula I) is an important fine chemical synthesis and pharmaceutical intermediate, mainly used for synthesizing drugs such as penicillin, amoxicillin, cephalosporin, etc.

[0003]

[0004] Currently, the existing methods for synthesizing p-hydroxyphenylglycine mainly include the following: strecker amino acid synthesis method; hydroxy mandelic acid ammonolysis method; p-hydroxyhydantoin hydrolysis method; direct reaction method of glyoxylic acid, phenol and active amide compounds, etc.

[0005] Specifically, the strecker amino acid synthesis method is the earliest method used to prepare p-hydroxyphenylglycine. This method uses p-hydroxybenzaldehyde to react with cyanide and then hydrolyzes it under acidic conditions to obtain p-hydroxyphenylglycine. The raw materials used in this method are expensive, toxic, and have a low yield. The hydroxy mandelic acid ammonolysis method uses glyoxylic acid and phenol to react to form hydroxy mandelic acid and then ammonolyzes it to obtain p-hydroxyphenylglycine. This method requires multiple extraction, filtration and other processes, and the operation steps are cumbersome, and the product yield is low. The p-hydroxyhydantoin hydrolysis method uses glyoxylic acid, urea and phenol as raw materials, reacts to obtain p-hydroxyhydantoin and then hydrolyzes it to obtain p-hydroxyphenylglycine. This method also has the disadvantages of many operation steps and low product yield.

[0006] The direct reaction method of glyoxylic acid, phenol and active amide compounds has few steps and mild reaction conditions, and is the method used more currently. Chinese Patent Application CN101362703A discloses a method for synthesizing p-hydroxyphenylglycine. This method uses glyoxylic acid, phenol and aminosulfonic acid as raw materials, and reacts in one pot under the action of strong acid catalysts such as p-toluenesulfonic acid to prepare p-hydroxyphenylglycine; there are the following problems in this one-pot reaction: 1) The Schiff base intermediate formed by glyoxylic acid and aminosulfonic acid is very active and completely miscible in the reaction system, and is prone to self-condensation side reactions in a strong acidic environment, and this intermediate can also attack the adjacent carbon atom of the benzene ring hydroxyl group to form a by-product o-hydroxyphenylglycine; 2) Phenol and glyoxylic acid are prone to phenolic condensation reaction to form a by-product 2,2-bis(4-hydroxyphenyl)acetic acid.

[0007] Chinese Patent Application CN119490425A discloses a method for synthesizing p-hydroxyphenylglycine based on a weakly alkaline environment. In this method, ammonia is slowly added dropwise to glyoxylic acid to make the solution in a weakly alkaline environment, and then phenol is added dropwise to the weakly alkaline solution to carry out the reaction in a weakly alkaline environment. There are the following problems with this reaction: 1) The reaction intermediate is ammonium glyoxylate, and its aldehyde carbonyl group undergoes a nucleophilic addition reaction with the hydrogen on the para position of phenol to form ammonium 2-hydroxyp-hydroxyphenylacetate. However, under weak base conditions, the reaction activity of the aldehyde carbonyl group undergoing a nucleophilic addition reaction with the hydrogen on the para position of phenol is relatively low, resulting in too long reaction time and reduced product selectivity; 2) The formed ammonium 2-hydroxyp-hydroxyphenylacetate will also react further with phenol to form the by-product 2,2-bis(4-hydroxyphenyl)acetic acid.

[0008] It can be seen from this that the existing synthesis method of p-hydroxyphenylglycine has more side reactions and difficult separation of by-products, resulting in reduced selectivity of the target product and thus low product yield. In addition, the reaction activity is relatively low and the reaction time is too long. Summary of the Invention

[0009] In order to solve the problems in the prior art that the existing synthesis method of p-hydroxyphenylglycine has more side reactions, difficult separation of by-products, and relatively low reaction activity, resulting in low product yield and too long reaction time. This application provides a synthesis method of p-hydroxyphenylglycine.

[0010] In order to solve the above technical problems, this application adopts the following technical solutions:

[0011] A synthesis method of p-hydroxyphenylglycine, which is prepared by reacting according to the following reaction formula:

[0012]

[0013] Among them, A in the reaction formula ANH4 is or OH — ;

[0014] Specifically, it includes the following reaction steps:

[0015] 1) The first-step reaction uses a glyoxylic acid solution and an ammonium ion-containing compound as raw materials for reaction. The reactant glyoxylic acid reacts completely to form intermediate 1;

[0016] 2) The second-step reaction is to add phenol to the reaction system, and phenol and intermediate 1 continue to react under the action of a catalyst. After the reaction is completed, post-treatment is carried out to obtain p-hydroxyphenylglycine;

[0017] The ammonium ion-containing compound is ammonium formate, ammonium acetate or ammonium hydroxide.

[0018] Furthermore, the temperature of the first-step reaction is 0-20 °C, and the reaction time is 1-3 h.

[0019] Furthermore, the temperature of the second-step reaction is 40 - 80 °C, and the reaction time is 2 - 4 h.

[0020] The catalyst described in this application is benzenesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, phosphoric acid or sulfuric acid.

[0021] Furthermore, the molar ratio of glyoxylic acid, phenol and ammonium ion-containing compound described in this application is 0.8 - 1.2:1:1 - 3.5. Furthermore, the molar ratio of the catalyst to phenol is 0.1 - 2:1.

[0022] The glyoxylic acid solution described in this application is an aqueous solution with a mass concentration of 20 - 80%.

[0023] The post-treatment in the second reaction described in this application includes steps such as cooling, neutralization crystallization, suction filtration, washing and drying.

[0024] Furthermore, in the neutralization crystallization, the pH value is adjusted to 3 - 6 with a base, and the base is selected from inorganic bases such as ammonia water, liquid ammonia, sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide.

[0025] The method for synthesizing p-hydroxyphenylglycine provided in this application is a two-step synthesis method. The first-step reaction uses a glyoxylic acid solution and an ammonium ion-containing compound as raw materials for reaction. The reactant glyoxylic acid reacts completely to generate intermediate 1. The intermediate generated in the first-step reaction has very low solubility in water and is generated under weakly acidic conditions. Under this reaction condition, it is very stable and no side reactions such as self-condensation will occur.

[0026] Secondly, in the second-step reaction of the method for synthesizing p-hydroxyphenylglycine provided in this application, phenol is added to the reaction system, and phenol and intermediate 1 continue to react under the action of a catalyst to generate p-hydroxyphenylglycine. The reaction between intermediate 1 and phenol is carried out under strong acid catalysis. In this reaction system, there is no longer the reactant glyoxylic acid, and no side reactions and by-products between glyoxylic acid and phenol exist. Therefore, the two-step reactions of the synthesis method provided in this application have fewer side reactions that can occur, and p-hydroxyphenylglycine with a higher yield can be obtained.

[0027] Thirdly, the two-step synthesis of the method for synthesizing p-hydroxyphenylglycine provided in this application both have relatively high reaction activities. Especially, the reaction activity of the nucleophilic addition of intermediate 1 and the hydrogen on the para-position of phenol in the second-step reaction is relatively high. The total time of the two-step reactions can basically be controlled to be completed in about 6 h, greatly shortening the reaction time, and the high reaction activity also further improves the yield of the product.

[0028] The synthesis method provided in this application prepares p-hydroxyphenylglycine through a two-step synthesis method. The test results show that the reaction time of the two-step synthesis method provided in this application can be controlled within about 6 hours, and the yield of the target product p-hydroxyphenylglycine can reach over 89%. The preparation method described in this application can effectively reduce the generation of by-products, and the obtained p-hydroxyphenylglycine has a high yield. The preparation method is simple, the reaction time is short, which is conducive to industrial production. Detailed Embodiments

[0029] The present invention discloses a synthesis method of p-hydroxyphenylglycine. Those skilled in the art can draw on the content of this article and appropriately modify the process parameters to achieve it. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art, and they are all regarded as included in the present invention. The method and application of the present invention have been described through preferred embodiments, and those skilled in the art can obviously make changes or appropriate alterations and combinations to the methods and applications described herein without departing from the content, spirit and scope of the present invention to implement and apply the technology of the present invention.

[0030] In order to enable those skilled in the art to better understand the present invention, the following further detailed description of the present invention is provided in conjunction with the specific embodiments.

[0031] Example 1

[0032] Add 185 g of 40% glyoxylic acid (74 g in terms of pure substance, 1 mol) and 94.5 g of ammonium formate (1.5 mol) into the reaction kettle. After reacting at 10 °C for 2 hours, the glyoxylic acid reacts completely; add 94 g of phenol (1 mol) and 49 g of sulfuric acid (0.5 mol) into the reaction system, and continue to react at 50 °C for 4 hours. Then cool down to 30 °C, neutralize with ammonia water to a pH value of about 5. After neutralization, filter, wash, and dry to obtain 148.6 g of product with a purity of 98.3% and a yield of 89%.

[0033] Example 2

[0034] Add 148 g of 60% glyoxylic acid (1.2 mol in terms of pure substance) and 231 g of ammonium acetate (3 mol) into the reaction kettle. After reacting at 5 °C for 2 hours, the glyoxylic acid reacts completely; add 94 g of phenol (1 mol) and 98 g of sulfuric acid (1 mol) into the reaction system, and continue to react at 60 °C for 3 hours. Then cool down to 30 °C, neutralize with ammonia water to a pH value of about 5.4. After neutralization, filter, wash, and dry to obtain 149.5 g of product with a purity of 98.2% and a yield of 89.5%.

[0035] Example 3

[0036] Add 271.3 g of 30% glyoxylic acid (1.1 mol in terms of pure substance) and 45.5 g of ammonium hydroxide (1.3 mol) into the reaction kettle. After reacting at 20 °C for 3 hours, the glyoxylic acid reacts completely. Then add 94 g of phenol (1 mol) and 49 g of sulfuric acid (0.5 mol) into the reaction system. After continuing to react at 60 °C for 3 hours, cool down to 30 °C, neutralize with ammonia water to a pH value of about 5. After neutralization, perform suction filtration, washing, and drying to obtain 148.8 g of product with a purity of 98.1% and a yield of 89.1%.

[0037] The above are only the preferred embodiments of the present application. It should be noted that for those of ordinary skill in the art in this technical field, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. A method for synthesizing hydroxyphenylglycine, characterized in that, It is prepared by carrying out reactions including the following reaction formulas: Among them, A in the reaction formula ANH4 is or OH — ; Specifically, it includes the following reaction steps: 1) In the first-step reaction, glyoxylic acid solution and an ammonium ion-containing compound are used as raw materials for reaction. The glyoxylic acid as the reactant reacts completely to generate intermediate 1; 2) In the second-step reaction, phenol is added to the reaction system. Phenol and intermediate 1 continue to react under the action of a catalyst. After the reaction ends, post-treatment is carried out to obtain p-hydroxyphenylglycine; The ammonium ion-containing compound is ammonium formate, ammonium acetate or ammonium hydroxide.

2. The synthesis method according to claim 1, wherein The temperature of the first-step reaction is 0 - 20 °C, and the reaction time is 1 - 3 h.

3. The synthesis method according to claim 2 or 3, characterized in that, The temperature of the second-step reaction is 40 - 80 °C, and the reaction time is 2 - 4 h.

4. The synthesis method according to claim 1, wherein The catalyst is benzenesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, phosphoric acid or sulfuric acid.

5. The synthesis method according to claim 1, wherein, The molar ratio of the glyoxylic acid, phenol and the ammonium ion-containing compound is 0.8 - 1.2:1:1 - 3.

5.

6. The synthesis method according to claim 1 or 5, characterized in that, The molar ratio of the catalyst to phenol is 0.1 - 2:

1.

7. The synthesis method according to claim 1 or 5, characterized in that, The glyoxylic acid solution is an aqueous solution with a mass concentration of 20 - 80%.

8. The synthesis method according to claim 1, characterized in that, The post-treatment includes steps of cooling, neutralization crystallization, suction filtration, washing and drying.

9. The synthesis method according to claim 8, wherein For neutralization crystallization, the pH value is adjusted to 3 - 6 with a base; the base selected is an inorganic base such as ammonia water, liquid ammonia, sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide.

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