Method for synthesizing p-hydroxyphenylglycine based on alkalescent environment

Abstract

The invention belongs to the technical field of synthesis of p-hydroxyphenylglycine, and discloses a method for synthesizing p-hydroxyphenylglycine based on a weakly alkaline environment. The method comprises the following steps: slowly dropwise adding ammonia into a glyoxylic acid aqueous solution to enable the solution to be in a weakly alkaline environment, then dropwise adding phenol into the weakly alkaline solution, and carrying out condensation and ammonolysis reaction on reactants in the weakly alkaline environment to selectively generate p-hydroxyphenylglycine. According to the method, the glyoxylic acid aqueous solution is neutralized by ammonia until the glyoxylic acid aqueous solution is weakly alkaline, and reactants react in a weakly alkaline environment to selectively obtain the target product p-hydroxyphenylglycine. The synthesis method provided by the invention has the advantages of fewer byproducts, higher yield of the target product p-hydroxyphenylglycine, no need of byproduct separation, no need of using a catalyst or an organic solvent in the preparation process, and suitableness for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of p-hydroxyphenylglycine synthesis, and particularly relates to a method for synthesizing p-hydroxyphenylglycine based on a weakly alkaline environment. Background Art

[0002] p-Hydroxyphenylglycine (structure as shown in formula I) is used as a pharmaceutical intermediate, mainly used in the synthesis of semi-synthetic penicillin, amoxicillin, cephalosporin and other drugs.

[0003]

[0004] At present, there are mainly the following methods for synthesizing p-hydroxyphenylglycine: ① Strecker amino acid synthesis method, ② hydroxymandelic acid aminolysis method, ③ p-hydroxyphenylhydantoin hydrolysis method, ④ phenol and 2-hydroxyglycine synthesis method, ⑤ direct reaction method of glyoxylic acid, phenol and active amide compounds.

[0005] The strecker amino acid synthesis method is the earliest method used to prepare p-hydroxyphenylglycine. The hydroxymandelic acid ammonolysis method uses glyoxylic acid and phenol to prepare hydroxymandelic acid and then ammonolyzes it to obtain p-hydroxyphenylglycine. The p-hydroxyphenylhydantoin hydrolysis method uses glyoxylic acid and urea and phenol to prepare p-hydroxyphenylhydantoin and then hydrolyzes it to obtain p-hydroxyphenylglycine. The above methods all have many disadvantages such as low yield of p-hydroxyphenylglycine and many operating steps.

[0006] Chinese patent document 1CN102816076B discloses a method for synthesizing p-hydroxyphenylglycine, which adopts a synthesis method of phenol and 2-hydroxyglycine; the yield of p-hydroxyphenylglycine obtained by this method is improved to a certain extent, but a catalyst and an unfriendly organic solvent are used in the reaction process, and wastewater and waste gas in the pollution-producing link are difficult to treat, which puts great pressure on environmental protection.

[0007] Chinese patent document 2CN101362703B discloses a method for synthesizing p-hydroxyphenylglycine. This patent document uses glyoxylic acid, phenol and an active amide compound as raw materials, and performs a pot reaction under the action of a catalyst such as benzenesulfonic acid, p-toluenesulfonic acid, ortho-toluenesulfonic acid, etc.; although this method has a simple process and low cost, its synthesis environment is still a traditional acidic environment. Under acidic conditions, more by-products will inevitably be produced during the synthesis of p-hydroxyphenylglycine, such as ortho-hydroxyphenylglycine and 2,2-bis(4-hydroxyphenyl)acetic acid, etc., thereby reducing the yield of p-hydroxyphenylglycine and making it difficult to separate the by-products. Summary of the invention

[0008] In view of this, in order to solve the technical problems in the prior art of synthesizing p-hydroxyphenylglycine in an acidic environment, resulting in a large number of by-products causing a decrease in product yield, and the use of catalysts and unfriendly organic solvents during the reaction, the present invention provides a method for synthesizing p-hydroxyphenylglycine based on a weakly alkaline environment.

[0009] In order to solve the above-mentioned technical problems, the present invention adopts the following technical solutions:

[0010] A method for synthesizing p-hydroxyphenylglycine based on a weak alkaline environment, wherein ammonia is slowly added to a glyoxylic acid aqueous solution to make the solution a weak alkaline environment, and then phenol is added to the weak alkaline solution. The reactants undergo condensation and aminolysis reactions in the weak alkaline environment to selectively generate p-hydroxyphenylglycine. The reaction formula is shown below:

[0011]

[0012] The molar ratio of the glyoxylic acid aqueous solution, phenol and ammonia provided by the invention is 0.8-1.2:1:2.4-3.4.

[0013] Furthermore, the mass concentration of the glyoxylic acid aqueous solution is 20-80%.

[0014] Furthermore, the ammonia may be ammonia gas or ammonia water.

[0015] Furthermore, the reaction temperature is controlled at 20-95°C.

[0016] Preferably, the present invention further comprises the steps of adjusting pH value and crystallizing after the reaction is completed.

[0017] Furthermore, hydrochloric acid, sulfuric acid or hydrobromic acid is used to adjust the pH value, and the pH value is controlled at 3.8-5.4; and the crystallization time is controlled at 2-6 hours.

[0018] Finally, the present invention also provides p-hydroxyphenylglycine synthesized by a method for synthesizing p-hydroxyphenylglycine based on a weakly alkaline environment.

[0019] At present, the synthesis environment of p-hydroxyphenylglycine is mostly acidic. In actual production, whether it is a strong acid environment or a strong base environment, glyoxylic acid will attack the ortho- and para-carbon atoms of the hydroxyl group of the benzene ring to generate p-hydroxyphenylglycine and by-product o-hydroxyphenylglycine. In addition, in a strong acid or strong base environment, at the initial stage of the reaction, the phenolic condensation reaction product is easy to continue to react with phenol to generate a by-product 2,2-bis(4-hydroxyphenyl)acetic acid (structure as shown in Formula II), thereby further reducing the yield of the target product p-hydroxyphenylglycine.

[0020]

[0021] In order to solve the above technical problems, the present invention uses inorganic weak ammonia to participate in the reaction. First, ammonia reacts with glyoxylic acid to make the entire reaction environment present a weak alkaline environment. Under the weak alkaline environment, the reactants undergo condensation and aminolysis reactions. Under the above weak alkaline environment, glyoxylic acid mainly attacks the para-carbon atom of the hydroxyl group of the benzene ring, and finally selectively generates the target product p-hydroxyphenylglycine, thereby improving the yield of p-hydroxyphenylglycine. Moreover, under this weak alkaline environment, the phenolic condensation reaction product will not continue to condense with phenol to generate the by-product 2,2-bis(4-hydroxyphenyl)acetic acid, so the yield of the product hydroxyphenylglycine can be further improved.

[0022] Secondly, the addition of ammonia will cause the alkali solution to be too high locally, causing the glyoxylic acid to undergo a local disproportionation reaction to generate glycolic acid and oxalic acid. In order to solve this technical problem, the present invention adopts a slow dripping method for adding ammonia, which can appropriately reduce the local alkali solution concentration of glyoxylic acid, avoid the occurrence of disproportionation reaction as much as possible, and enable the condensation reaction to proceed first, thereby improving the reaction efficiency and product yield.

[0023] It can be seen from the above technical scheme that the present invention uses ammonia to neutralize the glyoxylic acid aqueous solution, so that the reaction environment presents weak alkalinity, and the reactants undergo condensation and aminolysis reactions in a weak alkaline environment to selectively synthesize the target product p-hydroxyphenylglycine. The synthesis method provided by the present invention has fewer by-products and a high product yield. The yield of the target product p-hydroxyphenylglycine can reach more than 80%, and there is no need to separate by-products. The preparation process also does not require the use of catalysts and organic solvents, and the discharge of three wastes is small, which is more suitable for industrial production. DETAILED DESCRIPTION

[0024] The present invention discloses a method for synthesizing p-hydroxyphenylglycine based on a weakly alkaline environment. Those skilled in the art can refer to the content of this article and appropriately improve the process parameters to achieve the method. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention. The method and application of the present invention have been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the method and application described herein without departing from the content, spirit and scope of the present invention to achieve and apply the technology of the present invention.

[0025] In order to enable those skilled in the art to better understand the present invention, the present invention is further described in detail below in conjunction with specific implementation methods.

[0026] Example 1

[0027] 185 g (74 g, 1 mol) of 40% glyoxylic acid was added, 240 g (48 g, 2.84 mol) of 20% aqueous ammonia was slowly added dropwise, 94 g (1 mol) of phenol was added dropwise, the temperature was controlled at 25-85° C., the dropping time was controlled at 12 hours, after the dropping was completed, the temperature was lowered and the pH was adjusted to 5 with hydrochloric acid, after the neutralization was completed, the temperature was lowered to 30° C., crystallized for 6 hours, filtered, washed, and dried to obtain 141.95 g of product with a purity of 98.5% and a yield of 85%.

[0028] Example 2

[0029] 444 g of 20% glyoxylic acid (88.8 g, 1.2 mol) was added, 57.8 g (3.4 mol) of ammonia was introduced, and 94 g (1 mol) of phenol was added dropwise for 24 hours at a temperature of 20-95° C. After the addition was completed, sulfuric acid was added dropwise to adjust the pH to 4. After the pH adjustment was completed, the temperature was lowered to 36° C. for crystallization for 4 hours, filtered, washed, and dried to obtain 136.94 g of product with a purity of 99.1% and a yield of 82%.

[0030] Example 3

[0031] 185 g (74 g, 1 mol) of 80% glyoxylic acid was added, 500 g (50 g, 2.94 mol) of 10% ammonia water was added dropwise, and 94 g (1 mol) of phenol was slowly added dropwise. The addition time was controlled at 8 hours and the addition temperature was controlled at 40-75° C. After the addition of ammonia water was completed, hydrochloric acid was added dropwise to adjust the pH to 4.5. After neutralization, the temperature was lowered to 20° C. for crystallization for 2 hours, filtered, washed, and dried to obtain 130.26 g of product with a purity of 98.6% and a yield of 81%.

[0032] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for synthesizing p-hydroxyphenylglycine based on a weakly alkaline environment, characterized in that: Ammonia is slowly added dropwise to the aqueous solution of glyoxylic acid to make the solution weakly alkaline, and then phenol is added dropwise to the weakly alkaline solution. The reactants undergo condensation and aminolysis reactions in the weakly alkaline environment to selectively generate p-hydroxyphenylglycine.

2. The method for synthesizing p-hydroxyphenylglycine based on a weakly alkaline environment as claimed in claim 1, characterized in that: The molar ratio of the glyoxylic acid aqueous solution, phenol and ammonia is 0.8-1.2:1:2.4-3.

4.

3. The method for synthesizing p-hydroxyphenylglycine based on a weakly alkaline environment as claimed in claim 1 or 2, characterized in that: The mass concentration of the glyoxylic acid aqueous solution is 20-80%.

4. The method for synthesizing p-hydroxyphenylglycine based on a weakly alkaline environment as claimed in claim 1 or 2, characterized in that: The ammonia is ammonia gas or ammonia water.

5. The method for synthesizing p-hydroxyphenylglycine based on a weakly alkaline environment as claimed in claim 1, characterized in that: The reaction temperature was controlled at 20-95°C.

6. The method for synthesizing p-hydroxyphenylglycine based on a weakly alkaline environment as claimed in claim 1 or 5, characterized in that: After the reaction is completed, the steps of adjusting pH value and crystallization are also included.

7. The method for synthesizing p-hydroxyphenylglycine based on a weakly alkaline environment as claimed in claim 7, characterized in that: Use hydrochloric acid, sulfuric acid or hydrobromic acid to adjust the pH value, and control the pH value at 3.8-5.

4.

8. The method for synthesizing p-hydroxyphenylglycine based on a weakly alkaline environment as claimed in claim 7, characterized in that: The crystallization time is controlled at 2-6h.

9. p-Hydroxyphenylglycine synthesized by the method for synthesizing p-Hydroxyphenylglycine in a weakly alkaline environment as claimed in claim 1.

Images