A method for synthesizing a phenylglycine derivative

Abstract

The application provides a synthesis method of phenylglycine derivatives, in particular, a synthesis method of halogen para-substituted phenylglycine. The synthesis method comprises the following steps: S1, mixing benzylamine hydrochloride, sodium cyanide and water, adding substituted benzaldehyde, reacting at 25-30 DEG C for 16-25 h, after the reaction is completed, filtering the filter cake to obtain a product; the substituted benzaldehyde is para-chlorobenzaldehyde, para-bromobenzaldehyde or para-fluorobenzaldehyde; S2, mixing the product obtained in step S1 with hydrochloric acid, refluxing for 5-24 h; after the reaction is completed, adding palladium-carbon at 25-50 DEG C, passing hydrogen, reacting at 0.2-1.0 MPa and 40-50 DEG C for 18-30 h. The synthesis method of halogen para-substituted phenylglycine provided by the application has mild reaction conditions, high yield and high quality product, and does not use alcohol solvents. The synthesis method provided by the application is safer, more environmentally friendly and convenient for industrial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical and pesticide intermediate synthesis technology, and more specifically, to a method for synthesizing phenylglycine derivatives, particularly to a method for synthesizing halogen-substituted para-phenylglycine. Background Technology

[0002] Phenylglycine and its derivatives are important pharmaceutical and pesticide intermediates, mainly used in the preparation of β-hydantoin antibiotics, peptide hormones, and pesticides. Currently, the synthesis of phenylglycine derivatives, especially substituted phenylglycines, mainly follows these process routes:

[0003] 1) Landini process: 2,2-Dichloro-3-substituted phenyl ethylene oxide is generated from substituted benzaldehyde, chloroform, and sodium hydroxide. Ammonia is then introduced to open the ring of the ethylene oxide, generating α-amino-substituted phenylacetyl chloride. This is then acidified with hydrochloric acid to obtain substituted phenylglycine. The process route is shown in formula (I). This method readily generates substituted mandelic acid, resulting in low yield and poor product quality.

[0004]

[0005] 2) Bucherer-Bergs method: Using substituted benzaldehyde, ammonium bicarbonate, and sodium cyanide as raw materials, p-chlorobenzylhydantoin is first cyclized, then alkaline hydrolyzed, and finally acidified to obtain substituted phenylglycine. The process route is shown in formula (II). Due to its high synthesis yield, stable product quality, and good economic benefits, this method is currently the main method used in China to prepare substituted phenylglycine.

[0006]

[0007] However, since this process requires methanol or ethanol as a solvent, during solvent recovery, water, carbon dioxide, and ammonia entrained during distillation recrystallize in the condenser after cooling, forming ammonium bicarbonate, which can cause condenser blockage and pose a significant safety hazard to production. Currently, most research focuses on optimizing and improving these two methods, but the results are not entirely satisfactory. Summary of the Invention

[0008] To address, or at least partially address, the problems existing in the prior art, this invention provides a method for synthesizing phenylglycine derivatives, particularly a method for synthesizing halogen-substituted para-phenylglycine. The synthesis method provided by this invention features mild reaction conditions, high yield, and high product quality. Furthermore, this synthesis method does not use alcohol solvents, eliminates the need for alcohol solvent recovery, and avoids condenser blockage.

[0009] The method for synthesizing halogen-substituted para-phenylglycine provided by this invention includes the following steps:

[0010] S1, mix benzylamine hydrochloride, sodium cyanide and water, slowly add substituted benzaldehyde, react at 25-30℃ for 16-25h, after the reaction is completed, filter and take the filter cake to obtain the product; the substituted benzaldehyde is p-chlorobenzaldehyde, p-bromobenzaldehyde or p-fluorobenzaldehyde.

[0011] S2, mix the product obtained in step S1 with hydrochloric acid and reflux for 5-24 h; after the reaction is complete, add palladium on carbon at 25-50 °C, introduce hydrogen gas, and react at 0.2-1.0 MPa and 40-50 °C for 18-30 h.

[0012] The research team of this invention discovered that the synthesis method is more suitable for the synthesis of p-chlorophenylglycine, that is, in a preferred embodiment of this invention, the benzaldehyde substitute is preferably p-chlorophenylglycine.

[0013] In a preferred embodiment of the present invention, to further improve the reaction yield, the molar ratio of benzylamine hydrochloride, sodium cyanide, and substituted benzaldehyde is (1.0–1.2):(1.05–1.5):1. The research team of the present invention found in experiments that when the molar ratio of benzylamine hydrochloride, sodium cyanide, and substituted benzaldehyde is 1:1:1, the yield and quality of the final product are far lower than within the range of (1.0–1.2):(1.05–1.5):1. Slightly increasing the amount of sodium cyanide yields unexpected improvements in both yield and quality. However, if the molar ratio of sodium cyanide to substituted benzaldehyde is greater than 1.5, the increase in the yield and quality of the final product is not significant; on the contrary, it tends to decrease. The optimal yield and quality of the final product are achieved when the molar ratio of benzylamine hydrochloride to substituted benzaldehyde is within the range of (1.0–1.2):1.

[0014] In a preferred embodiment of the present invention, in order to better balance product quality and yield, sodium cyanide is added to the reaction system in the form of an aqueous sodium cyanide solution, the concentration of which is preferably 10% to 30%. Surprisingly, when using solid sodium cyanide for the reaction, even with the same amount of water or when water is added to the aqueous sodium cyanide solution, the reaction effect is not as good as when the aqueous sodium cyanide solution is directly added to the reaction system.

[0015] In a preferred embodiment of the present invention, the amount of water used is 3 to 5 times the mass of the benzaldehyde replaced. It should be noted that if sodium cyanide is added to the reaction system in the form of an aqueous solution, the amount of water used here does not include the water content contained in the aqueous sodium cyanide solution.

[0016] In a preferred embodiment of the present invention, in order to better balance product quality and yield, the addition rate of the substituted benzaldehyde in step S1, specifically the "slow addition of substituted benzaldehyde," is controlled so that the temperature of the reaction system does not exceed 30°C. This is one of the core inventive points of the present invention, which was discovered by the research team through numerous experiments that the synthesis method provided by the present invention can achieve both high product yield and high quality without the need for alcohol solvents. The research team of this invention discovered that when weighed substituted benzaldehyde is directly mixed with benzylamine hydrochloride, sodium cyanide and water in one reaction, the reaction is carried out at 0℃~90℃ for 1~36h (specifically, the research team conducted the following parallel experiments: 0℃, 10℃, 20℃, 30℃, 40℃, 50℃, 60℃, 70℃, 80℃, 90℃ for 1h, 5h, 10h, 20h, 30h, 36h respectively, with other steps unchanged), the purity of the obtained product is poor and the yield is low (less than 50% at most). In the process of continuous experimentation, it was unexpectedly discovered that when benzylamine hydrochloride, sodium cyanide and water are mixed first, and then substituted benzaldehyde is slowly added, wherein the addition rate of substituted benzaldehyde is controlled to keep the temperature of the reaction system below 30℃, the purity and yield of the obtained product are higher. Meanwhile, the research team of this invention also found that when the addition rate of the substituted benzaldehyde was controlled to keep the temperature of the reaction system above 30°C (e.g., 35°C, 40°C, 45°C, 50°C, etc.), the purity and yield of the obtained product could not meet the requirements.

[0017] In a preferred embodiment of the present invention, in order to better balance product quality and yield, the reaction temperature in step S1 needs to be maintained at 25-30°C. Too low or too high a reaction temperature will lead to a decrease in product quality and a reduction in reaction yield.

[0018] In a preferred embodiment of the present invention, in order to better balance product quality and yield, in step S2, the molar ratio of hydrochloric acid to the substituted benzaldehyde is (1-3):1. The hydrochloric acid can be commercially available, and its concentration is not specifically limited, for example, 31%.

[0019] In a preferred embodiment of the present invention, the content of the effective substance in palladium on carbon used in step S2 is suitable to be 5% to 10%. It is well known to those skilled in the art that the effective substance in palladium on carbon refers to palladium. In a preferred embodiment of the present invention, in step S2, the amount of palladium on carbon is 0.8% to 2% of the mass of the substituted benzaldehyde.

[0020] In a preferred embodiment of the present invention, in step S2, the reflux reaction time is 9 to 10 hours.

[0021] In a preferred embodiment of the present invention, in step S2, after hydrogen gas is introduced, the reaction is carried out at 0.5-0.6 MPa and 40-50°C for 20-24 hours.

[0022] In a specific embodiment of the present invention, after the reaction is complete, the solution is filtered, the filtrate is adjusted to neutral (pH 7.0–8.0), filtered again, the filter cake is collected, washed (using water), and dried to obtain the product. The filtrate can be adjusted to neutral using a commonly used alkaline solution in the art, such as sodium hydroxide solution. In a specific embodiment of the present invention, a 10% sodium hydroxide solution is used.

[0023] The beneficial effects of this invention are as follows:

[0024] The synthesis method for phenylglycine derivatives provided by this invention features mild reaction conditions, ensuring high yield and high-quality products without the use of alcohol solvents. Compared to the commonly used Bucherer-Bergs method in the prior art, which requires a large amount of excess ammonium carbonate and ammonia as reactants and methanol or ethanol as solvents, this invention does not require a large amount of excess ammonium carbonate and ammonia, nor does it require alcohol solvents. Furthermore, the reaction temperature is low, making the synthesis method provided by this invention safer, more environmentally friendly, and easier for industrial production. Detailed Implementation

[0025] The specific embodiments of the present invention will be described in further detail below with reference to the examples. These examples are for illustrative purposes only and are not intended to limit the scope of the invention.

[0026] Unless otherwise specified in the examples, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all commercially available products. Unless otherwise specified, "%" in this invention refers to a percentage by mass. In the specific embodiments of this invention, the theoretical yield value in the product yield formula is calculated using the substitution of benzaldehyde.

[0027] Example 1

[0028] This embodiment provides a method for synthesizing p-chlorophenylglycine, comprising the following steps:

[0029] 1) Add 51.7 g benzylamine hydrochloride, 63.9 g 30% sodium cyanide aqueous solution, and 200 g water to a 500 mL three-necked flask, and stir at 25 °C for 0.5 h. Continue to slowly add 50.6 g p-chlorobenzaldehyde to the system, controlling the reaction temperature to not exceed 25 °C. After the addition is complete, continue the reaction at 25 °C for 24 h. After the reaction is complete, filter, collect the filter cake, and wash with water to obtain the product.

[0030] 2) Add the product obtained in step 1) and 42.4 g of 31% hydrochloric acid to a 500 mL three-necked flask, and reflux (at approximately 90 °C) for 9 h. After the reaction is complete, cool the system to 45 °C, transfer it to a 500 mL high-pressure reactor, add 0.5 g of 10% palladium on carbon, and simultaneously purge with hydrogen until the system pressure reaches 0.6 MPa. Maintain the temperature and pressure at 50 °C for 24 h. After the reaction is complete, filter the solution, adjust the pH of the filtrate to 7.0 with 10% sodium hydroxide solution, filter again, wash the filter cake with water (approximately 100 g of water), and dry to obtain DL-p-chlorophenylglycine with a yield of 90.5% and a purity of 99.1% as determined by HPLC.

[0031] Example 2

[0032] This embodiment provides a method for synthesizing p-fluorophenylglycine, comprising the following steps:

[0033] 1) Add 51.7 g benzylamine hydrochloride, 63.9 g 30% sodium cyanide, and 200 g water to a 500 mL three-necked flask. Stir the system at 25 °C for 0.5 h. Continue to slowly add 44.7 g p-fluorobenzaldehyde to the system, controlling the reaction temperature to not exceed 30 °C. After the addition is complete, continue the reaction at 30 °C for 20 h. After the reaction is complete, filter, collect the filter cake, and wash with water to obtain the product.

[0034] 2) Add the product obtained in step 1) and 47g of 31% hydrochloric acid to a 500mL three-necked flask, and reflux (at approximately 85℃) for 10 hours. After the reaction, cool the system to 45℃, transfer it to a 500mL high-pressure reactor, add 0.9g of 5% palladium on carbon, and simultaneously purge with hydrogen until the system pressure reaches 0.5MPa. Maintain the temperature and pressure at 50℃ for 20 hours. After the reaction, filter the solution, adjust the pH of the filtrate to 7.0 with 10% sodium hydroxide solution, filter again, and wash the filter cake with water (approximately 100g of water) to obtain DL-p-fluorophenylglycine with a yield of 89.5% and a purity of 98.0% as determined by HPLC.

[0035] Example 3

[0036] This embodiment provides a method for synthesizing p-chlorophenylglycine, comprising the following steps:

[0037] 1): Step 1) is the same as step 1) in Example 1;

[0038] 2) Add the product obtained in step 1) and 47g of 31% hydrochloric acid to a 500mL three-necked flask, and reflux (at approximately 90℃) for 9 hours. After the reaction is complete, cool the system to 45℃, transfer it to a 500mL high-pressure reactor, add 1.0g of 5% palladium on carbon, and simultaneously purge with hydrogen until the system pressure reaches 0.5MPa. Maintain the temperature and pressure at 50℃ for 20 hours. After the reaction is complete, filter the solution, adjust the pH of the filtrate to 7.0 with 10% sodium hydroxide solution, filter again, wash the filter cake with water (approximately 100g of water), and dry to obtain DL-p-chlorophenylglycine with a yield of 89.5% and a purity of 99.0% as determined by HPLC.

[0039] Example 4

[0040] This embodiment provides a method for synthesizing p-chlorophenylglycine, comprising the following steps:

[0041] 1) Add 62g benzylamine hydrochloride, 88.2g 30% sodium cyanide aqueous solution, and 253g water to a 500mL three-necked flask, and stir at 25℃ for 0.5h. Continue to slowly add 50.6g p-chlorobenzaldehyde to the system, controlling the reaction temperature to not exceed 25℃. After the addition is complete, continue the reaction at 25℃ for 25h. After the reaction is complete, filter, collect the filter cake, and wash with water to obtain the product.

[0042] 2) Add the product obtained in step 1) and 42.4 g of 31% hydrochloric acid to a 500 mL three-necked flask, and reflux (at approximately 90 °C) for 9 h. After the reaction is complete, cool the system to 45 °C, transfer it to a 500 mL high-pressure reactor, add 0.5 g of 10% palladium on carbon, and simultaneously purge with hydrogen until the system pressure reaches 0.6 MPa. Maintain the temperature and pressure at 50 °C for 24 h. After the reaction is complete, filter the solution, adjust the pH of the filtrate to 7.0 with 10% sodium hydroxide solution, filter again, wash the filter cake with water (approximately 100 g of water), and dry to obtain DL-p-chlorophenylglycine with a yield of 90.0% and a purity of 99.2% as determined by HPLC.

[0043] Finally, the method of this invention is merely a preferred embodiment and is not intended to limit the scope of protection of this invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this invention should be included within the scope of protection of this invention.

Claims

1. A method for synthesizing halogen-substituted para-phenylglycine, characterized in that, Includes the following steps: S1, benzylamine hydrochloride, sodium cyanide, and water are mixed, and substituted benzaldehyde is slowly added. The mixture is reacted at 25-30℃ for 16-25 hours. After the reaction is complete, the filter cake is collected to obtain the product. The substituted benzaldehyde is p-chlorobenzaldehyde, p-bromobenzaldehyde, or p-fluorobenzaldehyde. The molar ratio of benzylamine hydrochloride, sodium cyanide, and substituted benzaldehyde is (1.0~1.2):(1.05~1.5):

1. Sodium cyanide is added to the reaction system in the form of an aqueous solution of sodium cyanide. The concentration of the aqueous solution of sodium cyanide is 10%~30%. The addition rate of the substituted benzaldehyde is controlled to ensure that the temperature of the reaction system does not exceed 30℃. S2, mix the product obtained in step S1 with hydrochloric acid and reflux for 5-24 h; after the reaction is complete, add palladium on carbon at 25-50 °C, introduce hydrogen gas, and react at 0.2-1.0 MPa and 40-50 °C for 18-30 h.

2. The synthesis method according to claim 1, characterized in that, In step S1, the substituted benzaldehyde is p-chlorobenzaldehyde.

3. The synthesis method according to claim 1 or 2, characterized in that, In step S2, the molar ratio of hydrochloric acid to the substituted benzaldehyde is (1~3):

1.

4. The synthesis method according to claim 1 or 2, characterized in that, In step S2, the amount of effective material in the palladium on carbon is 5% to 10%.

5. The synthesis method according to claim 1 or 2, characterized in that, In step S2, the amount of palladium on carbon is 0.8% to 2% of the mass of the substituted benzaldehyde.

6. The synthesis method according to claim 1 or 2, characterized in that, In step S2, the reflux reaction takes 9 to 10 hours.

7. The synthesis method according to claim 1 or 2, characterized in that, In step S2, after hydrogen gas is introduced, the reaction is carried out at 0.5-0.6 MPa and 40-50 °C for 20-24 hours.

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