Synthesis method of phenylglycine derivative

Abstract

The invention provides a synthetic method of phenylglycine derivatives, and particularly provides a synthetic method of halogen para-substituted phenylglycine. The synthesis method comprises the following steps: S1, mixing benzylamine hydrochloride, sodium cyanide and water, adding substituted benzaldehyde, carrying out a reaction at 25-30 DEG C for 16-25 h, and after the reaction is finished, carrying out filtering to obtain a filter cake so as to obtain a product; the substituted benzaldehyde is p-chlorobenzaldehyde, p-bromobenzaldehyde or p-fluorobenzaldehyde; s2, mixing the product obtained in the step S1 with hydrochloric acid, and carrying out reflux reaction for 5-24 hours; after the reaction is finished, adding palladium on carbon at the temperature of 25-50 DEG C, introducing hydrogen, and reacting for 18-30 hours at the pressure of 0.2-1.0 MPa and the temperature of 40-50 DEG C; the synthesis method of halogen para-substituted phenylglycine provided by the invention is mild in reaction condition, and does not use an alcohol solvent while ensuring high yield and high quality of products. The synthesis method provided by the invention is safer and more environment-friendly, and is convenient for industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of synthesis of pharmaceutical and pesticide intermediates, and more specifically, to a method for synthesizing a phenylglycine derivative, and in particular to a method for synthesizing a halogen-substituted para-phenylglycine. Background Art

[0002] Phenylglycine and its derivatives are important pharmaceutical and pesticide intermediates, mainly used in the preparation of β-hydantoin antibiotics, polypeptide hormones and pesticides. Currently, there are several main process routes for the synthesis of phenylglycine derivatives, especially substituted phenylglycine:

[0003] 1) Landini method: substituted benzaldehyde, chloroform and sodium hydroxide are used as raw materials to generate 2,2-dichloro-3-substituted phenyl oxirane, and then ammonia is passed to open the oxirane ring to generate α-amino substituted phenylacetyl chloride, and then hydrochloric acid is used to acidify to obtain substituted phenylglycine. The process route is shown in formula (I). This method easily generates substituted mandelic acid, has a low yield, and has poor product quality.

[0004]

[0005] 2) Bucherer-Bergs method: substituted benzaldehyde, ammonium bicarbonate and sodium cyanide are used as raw materials to first cyclize to obtain p-chlorophenyl hydantoin, then alkaline hydrolysis, and finally acidification to obtain substituted phenylglycine. The process route is shown in formula (II). Due to the characteristics of high synthesis yield, stable product quality and good economic benefits, this process is currently mainly used in China to prepare substituted phenylglycine.

[0006]

[0007] However, since the process requires the use of methanol or ethanol as a solvent, during the recovery of the solvent, the water, carbon dioxide and ammonia carried by the distillation recrystallize in the condenser after cooling to form ammonium bicarbonate, which causes the condenser to be blocked, posing a great safety hazard to production. At present, most of the research focuses on how to optimize and improve the above two methods, but the results are not satisfactory. Summary of the invention

[0008] In order to solve or at least partially solve the problems existing in the prior art, the present invention provides a method for synthesizing phenylglycine derivatives, and in particular provides a method for synthesizing halogen para-substituted phenylglycine. The synthesis method provided by the present invention has mild reaction conditions, high yield, and high product quality. At the same time, no alcohol solvent is used in the synthesis method, and the alcohol solvent does not need to be recovered, which will not cause condenser blockage.

[0009] The synthesis method of halogen para-substituted phenylglycine provided by the present invention comprises the following steps:

[0010] S1, benzylamine hydrochloride, sodium cyanide and water are mixed, and substituted benzaldehyde is slowly added, and the mixture is reacted at 25-30° C. for 16-25 hours. After the reaction is completed, a filter cake is filtered to obtain a product; the substituted benzaldehyde is p-chlorobenzaldehyde, p-bromobenzaldehyde or p-fluorobenzaldehyde;

[0011] S2, mixing the product obtained in step S1 with hydrochloric acid, and reflux reaction for 5-24h; after the reaction, adding palladium carbon at 25-50°C, introducing hydrogen, and reacting at 0.2-1.0MPa, 40-50°C for 18-30h.

[0012] The research team of the present invention found that the synthesis method is more suitable for the synthesis of p-chlorophenylglycine, that is, in a preferred embodiment of the present invention, the substituted benzaldehyde is preferably p-chlorobenzaldehyde.

[0013] In a preferred embodiment of the present invention, in order to further improve the yield of the reaction, the molar ratio of benzylamine hydrochloride, sodium cyanide and substituted benzaldehyde is (1.0-1.2): (1.05-1.5): 1. Among them, the research team of the present invention found in the experiment 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 inferior to those in the range of (1.0-1.2): (1.05-1.5): 1. When the amount of sodium cyanide is slightly increased, the yield and quality have unexpected gains. 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 obvious, but on the contrary, there is a downward trend. When the molar ratio of benzylamine hydrochloride to substituted benzaldehyde is within the range of (1.0-1.2): 1, the yield and quality of the final product are the best.

[0014] In a preferred embodiment of the present invention, in order to better balance the quality and yield of the product, sodium cyanide is added to the reaction system in the form of sodium cyanide aqueous solution, and the concentration of the sodium cyanide aqueous solution is preferably 10% to 30%. At the same time, surprisingly, when solid sodium cyanide is used for the reaction, when the amount of water is unchanged or the water in the sodium cyanide aqueous solution is supplemented according to the quality of the water, the reaction effect is not as good as the reaction effect of using the sodium cyanide aqueous solution 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 substituted benzaldehyde. It should be noted that if sodium cyanide is added to the reaction system in the form of sodium cyanide aqueous solution, the amount of water used here does not include the amount of water contained in the sodium cyanide aqueous solution.

[0016] In a preferred embodiment of the present invention, in order to better balance the quality and yield of the product, the addition rate of the substituted benzaldehyde in the step of "slowly adding substituted benzaldehyde" in step S1 is based on controlling the temperature of the reaction system not to exceed 30°C. This is also one of the core invention points that the research team of the present invention unexpectedly discovered based on a large number of experiments that the synthesis method provided by the present invention can balance the high yield and high quality of the product without the need to use alcohol solvents. The research team of the present invention found that when the weighed substituted benzaldehyde is directly mixed with benzylamine hydrochloride, sodium cyanide and water at one time for reaction, and the reaction is carried out at 0°C to 90°C for 1 to 36 hours (specifically, the research team conducted the following parallel experiments: 0°C, 10°C, 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, and 90°C for reaction for 1 hour, 5 hours, 10 hours, 20 hours, 30 hours, and 36 hours, respectively, and the other steps remain unchanged), the purity of the obtained product is poor and the yield is low (the maximum is less than 50%). In the continuous experimental process, it was unexpectedly discovered that when benzylamine hydrochloride, sodium cyanide and water are first mixed and then the substituted benzaldehyde is slowly added, wherein the addition speed of the substituted benzaldehyde is controlled to control the temperature of the reaction system not to exceed 30°C, the purity and yield of the obtained product are higher. At the same time, the research team of the present invention also found that when the addition rate of substituted benzaldehyde is controlled to control the temperature of the reaction system above 30°C (for example, 35°C, 40°C, 45°C, 50°C, etc.), the purity and yield of the obtained product cannot meet the requirements.

[0017] In a preferred embodiment of the present invention, in order to better balance the quality and yield of the product, 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 the quality and yield of the product, in step S2, the molar ratio of the hydrochloric acid to the substituted benzaldehyde is (1-3): 1. The hydrochloric acid can be obtained commercially, and the concentration of the hydrochloric acid is not specifically limited, for example, 31%.

[0019] In a preferred embodiment of the present invention, the content of the effective substance in palladium carbon suitable for use in step S2 of the present invention is 5% to 10%. Among them, it is well known to those skilled in the art that the effective substance in palladium carbon refers to palladium. In a preferred embodiment of the present invention, in step S2, the amount of palladium carbon used 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 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 completed, the filtrate is filtered, the filtrate is adjusted to neutrality (pH value is 7.0-8.0), filtered, the filter cake is collected, washed (water washing can be used), and dried to obtain the product. The filtrate can be adjusted to neutrality using an alkaline solution commonly used in the art, such as a sodium hydroxide solution. In a specific embodiment of the present invention, a 10% sodium hydroxide solution is used.

[0023] The beneficial effects of the present invention are:

[0024] The synthesis method of phenylglycine derivatives provided by the present invention has mild reaction conditions, and does not use alcohol solvents while ensuring high yield and high-quality products. Compared with the Bucherer-Bergs method commonly used in the prior art, the Bucherer-Bergs method requires the use of a large amount of excess ammonium carbonate and ammonia water as reactants, and requires methanol or ethanol as a solvent, while the present invention does not require the use of a large amount of excess ammonium carbonate and ammonia water, and does not require the use of alcohol solvents, and the reaction temperature is low. The synthesis method provided by the present invention is safer, more environmentally friendly, and convenient for industrial production. DETAILED DESCRIPTION

[0025] The following examples are used to illustrate the present invention, but are not intended to limit the scope of the present invention.

[0026] If the specific conditions are not specified in the examples, the conventional conditions or the conditions recommended by the manufacturer are followed. The reagents or instruments used without indicating the manufacturer are all conventional products that can be obtained commercially. Unless otherwise specified, "%" in the present invention is a mass percentage. In a specific embodiment of the present invention, the theoretical yield value in the yield formula of the product is calculated by replacing benzaldehyde.

[0027] Example 1

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

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

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

[0031] Example 2

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

[0033] 1) Add 51.7g benzylamine hydrochloride, 63.9g 30% sodium cyanide and 200g water into a 500mL three-necked flask, and stir the system at 25°C for 0.5h. Continue to slowly add 44.7g p-fluorobenzaldehyde to the system, and the dropwise addition speed is based on controlling the temperature of the reaction system not to exceed 30°C. After the dropwise addition, the system continues to react at 30°C for 20h. After the reaction is completed, filter, take 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 about 85°C) for 10h. After the reaction is completed, the system is cooled to 45°C, transferred to a 500mL high-pressure reactor, 0.9g of 5% palladium carbon is added, and hydrogen is charged to the system pressure at 0.5MPa, and the reaction is kept at 50°C for 20h. After the reaction is completed, filter, adjust the pH value of the system to 7.0 with 10% sodium hydroxide solution, filter, and wash the filter cake with water (about 100g of water) to obtain DL-p-fluorophenylglycine, with a yield of 89.5% and a purity of 98.0% detected 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 about 90°C) for 9h. After the reaction is completed, cool the system to 45°C, transfer it to a 500mL high-pressure reactor, add 1.0g of 5% palladium carbon, and simultaneously charge hydrogen until the system pressure is 0.5MPa, and keep the temperature and pressure at 50°C for 20h. After the reaction is completed, filter, adjust the pH value of the filtrate to 7.0 with 10% sodium hydroxide solution, filter, wash the filter cake with water (about 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 of benzylamine hydrochloride, 88.2g of 30% sodium cyanide aqueous solution and 253g of water to a 500mL three-necked flask and stir at 25°C for 0.5h. Continue to slowly add 50.6g of p-chlorobenzaldehyde to the system, and the dropwise addition speed is based on controlling the temperature of the reaction system not to exceed 25°C. After the dropwise addition is completed, continue the reaction at 25°C for 25h. After the reaction is completed, filter, take the filter cake, and wash with water to obtain the product.

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

[0043] Finally, the method of the present invention is only a preferred embodiment and is not intended to limit the protection scope of the present invention. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for synthesizing halogen-substituted para-phenylglycine, It is characterized in that The steps include: S1, benzylamine hydrochloride, sodium cyanide and water are mixed, and substituted benzaldehyde is slowly added, and the mixture is reacted at 25-30° C. for 16-25 hours. After the reaction is completed, a filter cake is filtered to obtain a product; the substituted benzaldehyde is p-chlorobenzaldehyde, p-bromobenzaldehyde or p-fluorobenzaldehyde; S2, mixing the product obtained in step S1 with hydrochloric acid, and reflux reaction for 5-24h; after the reaction, adding palladium carbon at 25-50°C, introducing hydrogen, and reacting at 0.2-1.0MPa, 40-50°C for 18-30h.

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

3. The synthesis method according to claim 1 or 2, It is characterized in that In step S1, the molar ratio of benzylamine hydrochloride, sodium cyanide and substituted benzaldehyde is (1.0-1.2):(1.05-1.5):

1.

4. The synthesis method according to claim 1 or 2, It is characterized in that In step S1, the sodium cyanide is added into the reaction system in the form of a sodium cyanide aqueous solution; the concentration of the sodium cyanide aqueous solution is 10% to 30%.

5. The synthesis method according to claim 1 or 2, It is characterized in that In step S1, the addition rate of the substituted benzaldehyde is such as to control the temperature of the reaction system not to exceed 30°C.

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

1.

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

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

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

10. The synthesis method according to claim 1 or 2, It is characterized in that In step S2, after hydrogen 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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