Synthesis method of novel D-p-hydroxyphenylglycine

Abstract

The invention relates to the field of preparation of p-hydroxyphenylglycine, in particular to a synthetic method of novel D-p-hydroxyphenylglycine. The synthesis method comprises the following steps: S1, adding D-tartaric acid into a methanol solution of D, L-p-hydroxyphenylglycine methyl ester, and reacting to obtain a mixed solution; s2, cooling and filtering the mixed solution obtained in the step S1 to obtain D-p-hydroxyphenylglycine methyl ester tartrate; s3, adding sodium carbonate and deionized water into the filtrate obtained in the step S2, reacting for 1-2 hours to obtain a reaction solution, and filtering to obtain D-sodium p-phenolate phenylglycine methyl ester tartrate; s4, combining the D-p-hydroxyphenylglycine methyl ester tartrate obtained in the step S2 and the D-sodium p-phenolate phenylglycine methyl ester tartrate obtained in the step S3, then adding into deionized water, uniformly stirring, and hydrolyzing; and S5, neutralizing the hydrolyzed solution obtained in the step S4, and slowly separating out a solid to obtain the D-p-hydroxyphenylglycine. The synthesis method disclosed by the invention is simple in preparation process, low in reagent cost, high in resolution rate and easy for industrial production, and can be quickly popularized and applied.

Description

Technical Field

[0001] This invention relates to the field of p-hydroxyphenylglycine preparation, specifically a novel method for synthesizing D-p-hydroxyphenylglycine. Background Technology

[0002] D-p-hydroxyphenylglycine is an important pharmaceutical intermediate widely used in the production of semi-synthetic antibiotics such as penicillins and cephalosporins. Currently, the main methods for synthesizing D-p-hydroxyphenylglycine are biosynthesis and chemical synthesis.

[0003] While biosynthesis offers advantages such as mild reaction conditions and high selectivity, it also suffers from drawbacks including long production cycles, difficulties in strain cultivation, and high production costs. In chemical synthesis, traditional methods often yield racemic DL-p-hydroxyphenylglycine, requiring further resolution to obtain D-p-hydroxyphenylglycine. Existing methods for resolving racemic compounds mainly include chemical resolution, enzymatic resolution, and chromatographic resolution.

[0004] Chemical resolution typically uses chiral resolving agents, but traditional resolving agents suffer from low resolution efficiency, difficult recovery, and environmental pollution. Enzymatic resolution, while exhibiting high stereoselectivity, suffers from high enzyme preparation and preservation costs, and the reaction system significantly impacts enzyme activity. Chromatographic resolution, although capable of achieving efficient resolution, requires substantial equipment investment, is complex to operate, and is unsuitable for large-scale production.

[0005] CN102382000A relates to the fields of chemical and pharmaceutical production, specifically to a method for producing D-p-hydroxyphenylglycine. The method includes the following steps: (1) preparing a solution as a reaction liquid with a weight ratio of water:D-p-hydroxyphenylhydantoin:sodium chloride = 100:20-30:1-3; (2) adding 10-15% ammonium carbonate solution to the above reaction liquid while stirring, the weight of the added ammonium carbonate being 10% of the weight of D-p-hydroxyphenylhydantoin, and stirring at 25-30°C until the content of D-p-hydroxyphenylhydantoin in the solution is below 0.12%, then crystallizing to obtain D-p-hydroxyphenylglycine. This method of producing D-p-hydroxyphenylglycine is convenient to operate, requires no heating at room temperature, has a short reaction time of 5-7 hours, and a yield as high as 75%. However, the preparation method has a low yield, the raw materials are not easy to obtain, and it is difficult to promote its application.

[0006] Therefore, developing an efficient, environmentally friendly, and economical method for synthesizing D-p-hydroxyphenylglycine, especially improving the racemic separation technique, is of great practical significance. Summary of the Invention

[0007] The purpose of this invention is to provide a novel method for synthesizing D-p-hydroxyphenylglycine, comprising the following steps: S1. Add D-tartaric acid to a methanol solution of D,L-p-hydroxyphenylglycine methyl ester, heat to 30~50℃, and react for 2~8 hours to obtain a mixed solution; S2. Cool the mixture obtained in step S1 to 5~10℃, precipitate the solid, filter to obtain D-p-hydroxyphenylglycine methyl tartrate, the filtrate contains partially dissolved D-p-hydroxyphenylglycine methyl tartrate and L-p-hydroxyphenylglycine methyl tartrate. S3. Add sodium carbonate and deionized water to the filtrate obtained in step S2 and react for 1-2 hours to obtain a reaction solution. D-p-phenol sodium phenylglycine methyl tartrate, which is insoluble in the reaction solution, and L-p-phenol sodium phenylglycine methyl tartrate, which is soluble in the reaction solution, are generated. After filtration, D-p-phenol sodium phenylglycine methyl tartrate is obtained. By adding sodium carbonate and reacting with hydroxyl groups, it is converted into sodium salt, which makes the solubility of the generated D-p-phenol sodium phenylglycine methyl tartrate even lower and can be precipitated from the solution. At the same time, sodium carbonate is weakly alkaline and the amount added is small, so it will not react with ester groups and tartrate. Adding a small amount of water is beneficial to the reaction. S4. Combine the D-p-hydroxyphenylglycine methyl tartrate obtained by filtration in step S2 and the D-p-phenol sodium phenylglycine methyl tartrate obtained in step S3, then add 0.2 to 2 times their weight of deionized water and stir evenly. Then slowly add 10 to 30 wt% sodium hydroxide solution to carry out the hydrolysis reaction. After the addition is complete, react for 0.5 to 1 hour until the hydrolysis is complete to obtain the hydrolyzed solution. S5. Add acid to the hydrolyzed liquid obtained in step S4 for neutralization, and slowly precipitate the solid. Control the final pH value of the neutralization reaction to be between 5 and 7, and cool it to 3 to 5°C to precipitate the solid. Filter, wash and dry the precipitated solid to obtain D-p-hydroxyphenylglycine. Controlling the final pH value to be between 5 and 7 can prevent the acid from reacting with the amino group in D-p-hydroxyphenylglycine to form a salt, thus effectively improving the purity of the product.

[0008] Furthermore, the methanol solution of D,L-p-hydroxyphenylglycine methyl ester in step S1 is a solution obtained by dissolving D,L-p-hydroxyphenylglycine methyl ester in methanol.

[0009] Furthermore, the methanol solution of D,L-p-hydroxyphenylglycine methyl ester in step S1 is a methanol mixture obtained after the reaction of D,L-p-hydroxyphenylglycine and methanol under concentrated sulfuric acid catalysis. Before adding tartaric acid, the mixture needs to be neutralized with sodium carbonate to a pH between 9 and 11 to neutralize acidic substances such as sulfuric acid in the mixture.

[0010] Furthermore, in step S1, the molar amount of D-tartaric acid added is 1.05 to 1.5 times the molar amount of D,L-p-hydroxyphenylglycine methyl ester, and the mass of methanol is 3 to 8 times the mass of D,L-p-hydroxyphenylglycine methyl ester.

[0011] Furthermore, the number of moles of D-p-hydroxyphenylglycine methyl tartrate obtained by filtration in step S2 is 0.26 to 0.29 times the number of moles of D,L-p-hydroxyphenylglycine methyl ester added in step S1.

[0012] Furthermore, in step S3, the molar amount of sodium carbonate added is 0.5 to 2 times the molar amount of D,L-p-hydroxyphenylglycine methyl ester added in step S1, and the mass of water added is 0 to 50% of the mass of sodium carbonate. The amount of sodium carbonate added needs to ensure that the hydroxyl groups in the D-p-hydroxyphenylglycine methyl ester tartrate dissolved in methanol and the L-p-hydroxyphenylglycine methyl ester tartrate react completely.

[0013] Furthermore, in step S4, the pH value of the hydrolyzed solution is controlled between 9 and 13. An appropriate pH range can ensure complete hydrolysis, while not adding too much alkali to reduce the amount of acid used in the neutralization step.

[0014] Furthermore, in step S5, the acid is 85 wt% phosphoric acid or oxalic acid. If the acid is too strong, it readily reacts with amino groups to form salts; if the acid is too weak, it cannot react with sodium salts of carboxyl groups. Therefore, the acid of this invention has effective neutralizing and displacement functions.

[0015] Furthermore, the number of moles of D-p-hydroxyphenylglycine obtained in step S5 is 0.42 to 0.47 times the number of moles of D,L-p-hydroxyphenylglycine methyl ester in step S1.

[0016] Furthermore, the solvent used for washing in step S5 is deionized water at 35~50℃.

[0017] The synthesis method of the present invention has a simple preparation process, low reagent cost, high resolution rate, is easy to industrialize, and can be quickly promoted and applied. Attached Figure Description

[0018] Figure 1 A flowchart illustrating the synthesis method of this invention. Detailed Implementation

[0019] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0020] Example 1 A novel method for synthesizing D-p-hydroxyphenylglycine includes the following steps: S1. Add 181g of D,L-p-hydroxyphenylglycine methyl ester (1mol) to 720g of methanol to obtain a methanol solution. Then add 165g of D-tartaric acid (1.1mol) to the methanol solution, heat to 35~40℃, and react for 4h to obtain a mixed solution. S2. Cool the mixture obtained in step S1 to 8°C, precipitate the solid, filter to obtain 92.68g of D-p-hydroxyphenylglycine methyl tartrate, the filtrate contains partially dissolved D-p-hydroxyphenylglycine methyl tartrate and L-p-hydroxyphenylglycine methyl tartrate. S3. Add 128g of sodium carbonate and 60g of deionized water to the filtrate obtained in step S2, react for 2 hours to obtain a reaction solution, and generate D-p-phenol sodium phenylglycine methyl tartrate, which is insoluble in the reaction solution and L-p-phenol sodium phenylglycine methyl tartrate, which is soluble in the reaction solution. Filter to obtain D-p-phenol sodium phenylglycine methyl tartrate. S4. Combine the D-p-hydroxyphenylglycine methyl tartrate obtained by filtration in step S2 and the D-p-phenol sodium phenylglycine methyl tartrate obtained in step S3, then add 120g of deionized water and stir well. Then slowly add 15wt% sodium hydroxide solution to carry out the hydrolysis reaction. After the addition is complete, react for 1 hour until the hydrolysis is complete to obtain the hydrolyzed solution. The pH value of the hydrolyzed solution is 12.1. S5. The hydrolyzed solution obtained in step S4 was neutralized with 85wt% phosphoric acid, and a solid was slowly precipitated. The final pH value of the neutralization reaction was controlled at 5.2, and the temperature was lowered to 4℃ to precipitate the solid. The precipitated solid was filtered, washed, and dried to obtain 71.81g of D-p-hydroxyphenylglycine (0.43mol), with a total resolution of 86% and a purity of 99.94%. The solvent used for washing was deionized water at 40℃.

[0021] Example 2 A novel method for synthesizing D-p-hydroxyphenylglycine includes the following steps: S1. Add 181g of D,L-p-hydroxyphenylglycine methyl ester (1mol) to 720g of methanol to obtain a methanol solution. Then add 165g of D-tartaric acid (1.1mol) to the methanol solution, heat to 35~40℃, and react for 4h to obtain a mixed solution. S2. Cool the mixture obtained in step S1 to 8°C, precipitate the solid, filter to obtain 92.73g of D-p-hydroxyphenylglycine methyl tartrate, the filtrate contains partially dissolved D-p-hydroxyphenylglycine methyl tartrate and L-p-hydroxyphenylglycine methyl tartrate. S3. Add 128g of sodium carbonate and 60g of deionized water to the filtrate obtained in step S2, react for 2 hours to obtain a reaction solution, and generate D-p-phenol sodium phenylglycine methyl tartrate, which is insoluble in the reaction solution and L-p-phenol sodium phenylglycine methyl tartrate, which is soluble in the reaction solution. Filter to obtain D-p-phenol sodium phenylglycine methyl tartrate. S4. Combine the D-p-hydroxyphenylglycine methyl tartrate obtained by filtration in step S2 and the D-p-phenylsodium phenylglycine methyl tartrate obtained in step S3, then add 120g of deionized water and stir well. Then slowly add 15wt% sodium hydroxide solution to carry out the hydrolysis reaction. After the addition is complete, react for 1 hour until the hydrolysis is complete to obtain the hydrolyzed solution. The pH value of the hydrolyzed solution is 12.2. S5. The hydrolyzed solution obtained in step S4 was neutralized with oxalic acid, and a solid was slowly precipitated. The final pH value of the neutralization reaction was controlled at 5.2, and the temperature was lowered to 4℃ to precipitate the solid. The precipitated solid was filtered, washed, and dried to obtain 72.99 g of D-p-hydroxyphenylglycine (0.437 mol), with a total resolution of 87.7% and a purity of 99.94%. The solvent used for washing was deionized water at 40℃.

[0022] Example 3 A novel method for synthesizing D-p-hydroxyphenylglycine includes the following steps: S1. After the reaction of D,L-p-hydroxyphenylglycine containing 181g of D,L-p-hydroxyphenylglycine methyl ester (1mol) and methanol under concentrated sulfuric acid catalysis, 1000g of the resulting methanol mixture was neutralized to pH 10 with sodium carbonate. Then, 180g (1.2mol) of D-tartaric acid was added to the methanol solution, the temperature was raised to 35~40℃, and the reaction was carried out for 4h to obtain the mixture. S2. Cool the mixture obtained in step S1 to 8°C, precipitate the solid, filter to obtain 91.23g of D-p-hydroxyphenylglycine methyl tartrate, the filtrate contains partially dissolved D-p-hydroxyphenylglycine methyl tartrate and L-p-hydroxyphenylglycine methyl tartrate. S3. Add 148g sodium carbonate and 0g deionized water to the filtrate obtained in step S2, react for 2h to obtain a reaction solution, and generate D-p-phenol sodium phenylglycine methyl tartrate, which is insoluble in the reaction solution and L-p-phenol sodium phenylglycine methyl tartrate, which is soluble in the reaction solution. Filter to obtain D-p-phenol sodium phenylglycine methyl tartrate. S4. Combine the D-p-hydroxyphenylglycine methyl tartrate obtained by filtration in step S2 and the D-p-phenylsodium phenylglycine methyl tartrate obtained in step S3, then add 120g of deionized water and stir well. Then slowly add 15wt% sodium hydroxide solution to carry out the hydrolysis reaction. After the addition is complete, react for 1 hour until the hydrolysis is complete to obtain the hydrolyzed solution. The pH value of the hydrolyzed solution is 12.0. S5. The hydrolyzed solution obtained in step S4 was neutralized with oxalic acid, and a solid was slowly precipitated. The final pH value of the neutralization reaction was controlled at 5.1, and the temperature was lowered to 4℃ to precipitate the solid. The precipitated solid was filtered, washed, and dried to obtain 70.14 g of D-p-hydroxyphenylglycine (0.42 mol), with a total resolution of 84.0% and a purity of 99.92%. The solvent used for washing was deionized water at 45℃.

[0023] Comparative Example 1 The sodium carbonate component in step S3 of Example 1 was removed; otherwise, the process remained the same as in Example 1 and will not be repeated. In the final step S5, 57.11 g (0.342 mol) of D-p-hydroxyphenylglycine was obtained, with a total resolution of 68.40% and a purity of 98.5%. Comparative Example 2 In Example 1, sodium carbonate in step S3 was replaced with sodium hydroxide, and the rest was the same as in Example 1, so it will not be repeated here. In the final step S3, D-p-phenol sodium phenylglycine methyl tartrate was hydrolyzed prematurely, and could not be precipitated in step S3, resulting in a low final resolution rate.

[0024] Comparative Example 3 In Example 1, step S5, phosphoric acid was replaced with sulfuric acid; all other steps were the same as in Example 1 and will not be repeated here. The final D-p-hydroxyphenylglycine obtained in step S5 contained a high amount of D-p-hydroxyphenylglycine ammonium sulfate, with a purity of only 88.6%.

Claims

1. A novel method for the synthesis of D-p-hydroxyphenylglycine, characterized by, The method comprises the following steps: S1. A methanol solution of D, L-p-hydroxyphenylglycine methyl ester is added with D-tartaric acid, and the temperature is raised to 30-50 DEG C, and the reaction is carried out for 2-8 hours to obtain a mixed solution; S2. The mixed solution obtained in step S1 is cooled to 5-10 DEG C, and solid is precipitated, and D-p-hydroxyphenylglycine methyl ester tartrate is obtained by filtration, and the filtrate contains part of dissolved D-p-hydroxyphenylglycine methyl ester tartrate and L-p-hydroxyphenylglycine methyl ester tartrate; S3. Sodium carbonate and deionized water are added to the filtrate obtained in step S2, and the reaction is carried out for 1-2 hours to obtain a reaction solution, and D-p-phenylsodium glycine methyl ester tartrate which is insoluble in the reaction solution and L-p-phenylsodium glycine methyl ester tartrate which is soluble in the reaction solution are generated, and D-p-phenylsodium glycine methyl ester tartrate is obtained by filtration; S4. D-p-hydroxyphenylglycine methyl ester tartrate obtained by filtration in step S2 and D-p-phenylsodium glycine methyl ester tartrate obtained in step S3 are combined, then deionized water with a mass of 0.2-2 times that of D-p-hydroxyphenylglycine methyl ester tartrate is added and stirred uniformly, and then 10-30 wt% sodium hydroxide solution is slowly added for hydrolysis reaction, and after the addition is completed, the reaction is carried out for 0.5-1 hour until the hydrolysis is completed to obtain a hydrolyzed solution; S5. The hydrolyzed solution obtained in step S4 is added with an acid for neutralization, and solid is slowly precipitated, the final neutralization reaction end point pH value is controlled to be between 5-7, and the temperature is cooled to 3-5 DEG C, and the precipitated solid is filtered, washed and dried to obtain D-p-hydroxyphenylglycine.

2. The novel process for synthesis of D-p-hydroxyphenylglycine as claimed in claim 1, wherein, The methanol solution of D, L-p-hydroxyphenylglycine methyl ester in step S1 is a solution of D, L-p-hydroxyphenylglycine methyl ester dissolved in methanol.

3. The novel process for synthesis of D-p-hydroxyphenylglycine as claimed in claim 1, wherein, The methanol solution of D, L-p-hydroxyphenylglycine methyl ester in step S1 is a methanol mixed solution obtained after D, L-p-hydroxyphenylglycine and methanol are reacted under the catalysis of concentrated sulfuric acid.

4. The novel process for synthesis of D-p-hydroxyphenylglycine as claimed in claim 1, wherein, The added amount of D-tartaric acid in step S1 is 1.05-1.5 times the molar amount of D, L-p-hydroxyphenylglycine methyl ester, and the mass of methanol is 3-8 times the mass of D, L-p-hydroxyphenylglycine methyl ester.

5. The novel process for synthesis of D-p-hydroxyphenylglycine as claimed in claim 1, wherein, The molar amount of D-p-hydroxyphenylglycine methyl ester tartrate obtained by filtration in step S2 is 0.26-0.29 times the molar amount of D, L-p-hydroxyphenylglycine methyl ester added in step S1.

6. The novel process for synthesis of D-p-hydroxyphenylglycine as claimed in claim 1, wherein, The added amount of sodium carbonate in step S3 is 0.5-2 times the molar amount of D, L-p-hydroxyphenylglycine methyl ester added in step S1, and the added mass of water is 0-50% of the mass of sodium carbonate.

7. The novel process for synthesis of D-p-hydroxyphenylglycine as claimed in claim 1, wherein, The pH value of the hydrolyzed solution in step S4 is controlled to be between 9-13.

8. The novel process for synthesis of D-p-hydroxyphenylglycine as claimed in claim 1, wherein, The acid in step S5 is 85 wt% phosphoric acid or oxalic acid.

9. The novel process for synthesis of D-p-hydroxyphenylglycine as claimed in claim 1, wherein, The molar amount of D-p-hydroxyphenylglycine obtained in step S5 is 0.42-0.47 times the molar amount of D, L-p-hydroxyphenylglycine methyl ester in step S1.

10. The novel process for synthesis of D-p-hydroxyphenylglycine as claimed in claim 1, wherein, The solvent used for washing in step S5 is 35-50 DEG C deionized water.

Images