Synthesis method of dextro-phenylethanesulfonic acid D-p-hydroxyphenylglycine double salt

Abstract

The invention discloses a method for synthesizing D-p-hydroxyphenylglycine double salt of D-phenylethanesulfonic acid, which is characterized in that the D-p-hydroxyphenylglycine double salt of D-phenylethanesulfonic acid is prepared by racemization of invalid enantiomer-L-phenylethanesulfonic acid, and the invalid enantiomer-L-phenylethanesulfonic acid which is abandoned in original mother liquor is subjected to racemization and recycling to obtain the D-p-hydroxyphenylglycine double salt of D-phenylethanesulfonic acid. The cost of the D-phenylethanesulfonic acid D-p-hydroxyphenylglycine double salt is greatly reduced, meanwhile, the COD (Chemical Oxygen Demand) in the mother liquor is greatly reduced, and the environmental protection treatment pressure is relieved.

Description

Technical Field

[0001] The invention relates to a chiral enantiomer racemic resolution synthesis method, in particular to a synthesis method of dextrorotatory benzeneethanesulfonic acid D-p-hydroxyphenylglycine complex salt. Background Art

[0002] Dextrorotatory phenylethanesulfonic acid is an important resolving agent for the production of D-p-hydroxybenzoic acid by the resolution of 4-hydroxyphenylglycine. Pure dextrorotatory phenylethanesulfonic acid is difficult to prepare and generally exists in the form of dextrorotatory phenylethanesulfonic acid D-p-hydroxybenzoic acid complex salt. D-p-hydroxyphenylglycine is an important pharmaceutical intermediate indispensable for the synthesis of broad-spectrum antibiotics such as amoxicillin (amoxicillin) and cefoperazone (Oeyi).

[0003] Dextrorotatory benzene ethanesulfonic acid D-p-hydroxyphenylglycine double salt, referred to as the resolving agent double salt, is a double salt formed by the combination of dextrorotatory benzene ethanesulfonic acid and D-p-hydroxyphenylglycine in a ratio of 1:1, and its structural formula is as follows:

[0004]

[0005] At present, there are five main methods for preparing dextrorotatory phenylethanesulfonic acid D-p-hydroxyphenylglycine double salt from suspended phenylethanesulfonic acid:

[0006] Route 1: Thiol oxidation method

[0007] Wang Wei (Synthesis of 1-aryl-ethanesulfonic acid [D]. Shijiazhuang: Hebei University of Science and Technology, 2010) disclosed a method for synthesizing mixed benzene ethyl sulfonic acid, which is prepared by condensing 1-hydroxyphenylethane or 1-bromophenylethane with thiourea to obtain 2-(1-phenylethyl)isothiourea hydrobromide, decomposing it under alkali catalysis to obtain 1-phenylethanethiol, and finally oxidizing it with peroxide to obtain mixed benzene ethyl sulfonic acid, and then adding D-p-hydroxyphenylglycine to resolve it to obtain dextrorotatory benzene ethyl sulfonic acid D-p-hydroxyphenylglycine complex salt.

[0008] Route 2: Bisulfite substitution method

[0009] Zhang Zhixia (Study on the Preparation of Asymmetric Transformation Resolving Agent (+)-α-Benzeneethylsulfonic Acid [D]. Shijiazhuang: Hebei Normal University, 2008) disclosed a method for preparing an asymmetric transformation resolving agent (+)-1-phenylethylsulfonic acid, which is prepared by a substitution reaction of 1-phenylethyl bromide and bisulfite or sulfite in the presence of concentrated ammonia water and a phase transfer catalyst. The reaction directly obtains a chromatic ammonium salt of phenylethylsulfonic acid, which is then resolved by adding D-p-hydroxyphenylglycine to obtain a dextrorotatory phenylethylsulfonic acid D-p-hydroxyphenylglycine complex salt.

[0010] Route 3: Disulfide oxidation method

[0011] Sun Fengxia et al. (CN101792407B) disclosed a method for preparing 1-arylethanesulfonic acid, which comprises subjecting 1-phenylethane halide and sodium disulfide to a reflux reaction in a solvent to generate 1-phenylethyl disulfide, which is then oxidized with an oxidant, hydrogen peroxide, to obtain a d-phenylethylsulfonic acid, which is then separated by adding D-p-hydroxyphenylglycine to obtain a dextrorotatory phenylethylsulfonic acid D-p-hydroxyphenylglycine complex salt.

[0012] Route 4: Grignard method

[0013] Liu Weijun et al. (CN103613518B) disclosed a method for preparing α-phenylethanesulfonic acid. The specific process is to slowly drip 1-chlorophenylethane or 1-bromophenylethane into tetrahydrofuran with magnesium at 5-15°C to prepare a Grignard reagent, introduce a slightly excess amount of sulfur dioxide gas at 15-25°C to generate (±)-α-phenylethanesulfinic acid, dissolve it in acetic acid solution and oxidize it with hydrogen peroxide at 70-75°C, obtain mixed phenylethanesulfonic acid after treatment, and then add D-p-hydroxyphenylglycine to resolve it to obtain dextrorotatory phenylethanesulfonic acid D-p-hydroxyphenylglycine double salt.

[0014] Route 5: Induced crystallization method

[0015] This method uses the difference in physical properties of diastereoisomer resolving agent salts, adds an optical isomer as a seed crystal to the racemic solution, and induces the precipitation of the isomer with the same competition, so as to achieve the purpose of separation. The induced crystallization method generally requires that the racemate can exist in the form of a racemic mixture or a racemic compound, but its solubility is much greater than the solubility of the corresponding enantiomer. Only then can the induced crystallization method be used for separation. Chen Fangfang (Research on the Synthesis Process of (+)-α-Benzene Ethylene Sulfonic Acid [D]. Zhengzhou: Zhengzhou University, 2018.) discloses a method for preparing a resolving agent complex salt, specifically, using high optical purity D-p-hydroxyphenylglycine (i.e., D-HPG) as a resolving agent, adding it to an aqueous solution of 1(±)-phenylethanesulfonic acid or its ammonium salt, and adding hydrochloric acid to make the solution acidic, heating it to 65-75°C to dissolve it for 2 hours, and then stirring it at room temperature. By utilizing the difference in solubility of the salts D-HPG-(+)-PES and D-HPG-(-)-PES formed by the two, D-HPG-(+)-PES with low solubility is crystallized in the supersaturated salt solution. The pH value of the mother liquor is adjusted to 5.4 with NaOH and crystals are grown at room temperature for 8 hours to obtain D-HPG and secondary mother liquor. D-HPG is applied to the first step, and barium hydroxide solution is added to the secondary mother liquor. After filtration, the filtrate is taken and distilled under reduced pressure to obtain the barium salt of (-)PES. The barium salt is dissolved in water, and a slightly excessive amount of dilute sulfuric acid is added to ensure that the barium ions are completely converted into barium sulfate precipitation and removed. At this time, (-)PES exists in the filtrate. After filtration, (-)PES is subjected to base-catalyzed racemization with sodium hydroxide solution for 10 hours to obtain 1(±)-phenylethanesulfonic acid, which can be applied back to the first step.

[0016]

[0017] Taking into account the cost, environmental protection, and process advancement, Route 1 has a low yield and more wastes, Route 2 has many side reactions and is difficult to purify, Route 3 has easy-to-obtain raw materials, a high total yield, and a low overall cost, while Route 4 has a high production cost and is not the best choice; in all the above synthesis methods, the ineffective enantiomer L-phenylethanesulfonic acid in the mother liquor after splitting is not recycled, which not only causes a waste of raw materials, but also brings pressure to environmental protection treatment. The advantage of Route 5 is that L-phenylethanesulfonic acid is recycled and the racemized mother liquor can be continuously applied; however, the first step of the splitting step of this route uses a large amount of D-HPG, and all the phenylethanesulfonic acid needs to be salified, and then the pH is adjusted to precipitate the excess D-HPG, and then the more expensive barium hydroxide is used to precipitate the L-phenylethanesulfonic acid. The operation is cumbersome and the production cost is high. In addition, only a qualitative description of the recovery is given, and the yield of the L-phenylethanesulfonic acid precipitated by barium hydroxide and the splitting results of the phenylethanesulfonic acid after racemization are not given, and it is difficult to effectively evaluate the actual application effect of the mother liquor. Summary of the invention

[0018] The invention solves the problems existing in the prior art and provides a method for synthesizing a dextrorotatory benzeneethanesulfonic acid D-phenylglycine double salt, which is simple to operate, low in cost and high in yield. The method can be used to racemize and recycle the ineffective enantiomer of the dextrorotatory benzeneethanesulfonic acid in the mother liquor, thereby greatly reducing the cost of the dextrorotatory benzeneethanesulfonic acid D-p-hydroxyphenylglycine double salt, simplifying the operation steps and improving the recovery efficiency.

[0019] A method for synthesizing dextrorotatory benzeneethanesulfonic acid D-p-hydroxyphenylglycine double salt comprises the following steps:

[0020] Step a, adding D-p-hydroxyphenylglycine to the d-phenylethanesulfonic acid aqueous solution for splitting, filtering and washing to obtain dextrorotatory phenylethanesulfonic acid D-p-hydroxyphenylglycine double salt and splitting mother liquor;

[0021] Step b. adding L-p-hydroxyphenylglycine to the split mother liquor to form a double salt with the L-phenylethanesulfonic acid in the split mother liquor, and filtering and washing to obtain L-p-hydroxyphenylglycine double salt of L-phenylethanesulfonic acid;

[0022] Step c. adding water to prepare a slurry of L-p-hydroxyphenylethanesulfonic acid double salt, adding alkali to neutralize, filtering and washing to obtain L-p-hydroxyphenylglycine and a filtrate;

[0023] Step d. adding a base to the filtrate and heating the mixture to perform a racemization reaction to obtain a racemic solution;

[0024] Step e. Acid is added to the racemic solution for acidification, D-p-hydroxyphenylglycine is added for resolution, and the solution is filtered and washed to obtain dextrorotatory benzeneethanesulfonic acid D-p-hydroxyphenylglycine double salt and resolution mother liquor.

[0025] In the present invention, D-p-hydroxyphenylglycine is first added to separate the dextrorotatory phenylethanesulfonic acid, and the levorotatory phenylethanesulfonic acid is retained in the separation mother liquor, and then L-p-hydroxyphenylglycine is added. The low solubility of the L-p-hydroxyphenylglycine and L-p-hydroxyphenylglycine double salt is utilized to realize the separation and purification of the levorotatory phenylethanesulfonic acid. On the basis of fully utilizing the invalid enantiomer levorotatory phenylethanesulfonic acid, the operation steps are shortened.

[0026] Preferably, in step a, the molar ratio of D-p-hydroxyphenylglycine to d-phenylethylsulfonic acid is 0.5-0.6:1;

[0027] The mass percentage concentration of the d-phenylethanesulfonic acid aqueous solution is 15-30%. The amount of D-p-hydroxyphenylglycine can make the dextrorotatory phenylethanesulfonic acid form a complex salt and reduce the formation of a complex salt of the levorotatory phenylethanesulfonic acid, so as to facilitate the implementation of subsequent operations.

[0028] Preferably, the splitting temperature is 60-80° C., and the splitting time is 1-5 h.

[0029] In step b, the molar ratio of L-p-hydroxyphenylglycine to L-phenylethanesulfonic acid is 1 to 1.4:1, preferably 1.05 to 1.2:1.

[0030] In step c, the added alkali is one or more of sodium carbonate, potassium carbonate, solid sodium hydroxide, sodium hydroxide aqueous solution, solid potassium hydroxide, and lithium hydroxide, preferably sodium hydroxide aqueous solution.

[0031] The alkali added in step d is one or more of solid sodium hydroxide, sodium hydroxide aqueous solution, solid potassium hydroxide, and lithium hydroxide, preferably sodium hydroxide aqueous solution.

[0032] The molar ratio of the base to the L-phenylethanesulfonic acid is 0.2 to 0.7:1, preferably 0.3 to 0.5:1.

[0033] The racemization reaction temperature in step d is 110 to 160°C, preferably 130 to 150°C.

[0034] The racemization reaction time in step d is 4 to 10 hours, preferably 5 to 7 hours.

[0035] The acid added in step e is one or more of sulfuric acid, hydrochloric acid and nitric acid, preferably sulfuric acid.

[0036] Preferably, the split mother liquor obtained in step e is returned to step b, and is circulated according to the process of steps b to e.

[0037] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0038] The invention adopts L-p-hydroxyphenylglycine and the invalid enantiomer L-phenylethanesulfonic acid in the split mother liquor to form a complex salt precipitation, separates the mother liquor and removes impurities, neutralizes the complex salt with alkali, and then recovers L-p-hydroxyphenylglycine for application, heats the mother liquor under alkaline conditions for racemization to obtain a racemic benzeneethanesulfonic acid solution, adds D-p-hydroxyphenylglycine for splitting, and obtains a dextrorotatory benzeneethanesulfonic acid D-p-hydroxyphenylglycine complex salt, and recycles the split mother liquor through the above process, racemizes and recycles the invalid enantiomer L-phenylethanesulfonic acid originally discarded in the mother liquor, greatly reduces the cost of the dextrorotatory benzeneethanesulfonic acid D-p-hydroxyphenylglycine complex salt, and at the same time greatly reduces the COD in the mother liquor, thereby alleviating the pressure of environmental protection treatment. DETAILED DESCRIPTION

[0039] The present invention is further described in detail below through examples.

[0040] The general preparation method of the present invention is as follows: a, adding D-p-hydroxyphenylglycine to a d-phenylethanesulfonic acid aqueous solution for splitting, filtering and washing to obtain a dextrorotatory phenylethanesulfonic acid D-p-hydroxyphenylglycine double salt and a split mother liquor; b, adding L-p-hydroxyphenylglycine to the split mother liquor to form a double salt with levorotatory phenylethanesulfonic acid, filtering and washing to obtain a levorotatory phenylethanesulfonic acid L-p-hydroxyphenylglycine double salt; c, adding water to the levorotatory phenylethanesulfonic acid L-p-hydroxyphenylglycine double salt to make a slurry, adding alkali to neutralize, filtering and washing to obtain L-p-hydroxyphenylglycine and a filtrate; d, putting the filtrate into a pressure autoclave, adding alkali, heating to carry out a racemization reaction to obtain a racemic solution; e, adding acid to the racemic solution to acidify, adding D-p-hydroxyphenylglycine to split, filtering and washing to obtain a dextrorotatory phenylethanesulfonic acid D-p-hydroxyphenylglycine double salt and a split mother liquor, and recycling the split mother liquor for racemization.

[0041] Example 1

[0042] 1000g of 20% d-phenylethanesulfonic acid aqueous solution was added to a 2000ml three-necked flask, 100g of D-p-hydroxyphenylglycine was added, the temperature was raised to 70°C and kept for 2h, the temperature was lowered to 20°C, filtered and washed to obtain 225g of dextrorotatory phenylethanesulfonic acid D-p-hydroxyphenylglycine double salt wet product, and 186g of dry product was obtained after drying, with a yield of 88.0% (based on D-p-hydroxyphenylglycine), and the specific rotation was -78.49°. 100g of L-p-hydroxyphenylglycine was added to the mother liquor of the separation, the temperature was raised to 70°C and kept for 2h, the temperature was lowered to 20°C, filtered and washed to obtain 232g of L-p-hydroxyphenylglycine double salt wet product. The wet product was put into a 1000ml three-necked flask, 500g of water was added, the temperature was raised to 50°C, liquid alkali was added dropwise to neutralize the pH value to 4.5-5, the temperature was lowered to 30°C, filtered and washed to obtain L-p-hydroxyphenylglycine and filtrate. The filtrate was put into a pressure reactor, 40g of 30% liquid alkali was added, the temperature was raised to 140°C for racemization reaction for 6h to obtain a racemic solution, 50g of sulfuric acid was added for acidification, 48g of D-p-hydroxyphenylglycine was added, the temperature was kept at 70°C for 2h, the temperature was lowered to 20°C, filtered and washed to obtain 129g of a wet product of dextrorotatory phenylethanesulfonic acid D-p-hydroxyphenylglycine double salt, and 93g of a dry product was obtained after drying, with a yield of 91.7% (based on D-p-hydroxyphenylglycine), an off-white appearance, and a specific rotation of -78.53°. Add 50 g of L-p-hydroxyphenylglycine to the mother liquor, raise the temperature to 70°C and keep it for 2 h, then cool to 20°C, filter and wash to obtain 127 g of L-p-hydroxyphenylglycine double salt wet product with off-white appearance.

[0043] The results of this example show that the addition of L-p-hydroxyphenylglycine to the mother liquor after resolution can effectively separate the ineffective enantiomer L-phenylethanesulfonic acid, and after subsequent racemization and resolution, a high-yield dextrorotatory phenylethanesulfonic acid D-p-hydroxyphenylglycine double salt can be obtained, and the dextrorotatory phenylethanesulfonic acid D-p-hydroxyphenylglycine double salt has good quality, and the optical rotation and product appearance shape meet the requirements.

[0044] Example 2

[0045] 1000g of 20% d-phenylethanesulfonic acid aqueous solution was added to a 2000ml three-necked flask, 98g of D-p-hydroxyphenylglycine was added, the temperature was raised to 70°C and kept for 2h, the temperature was lowered to 20°C, filtered and washed to obtain 229g of D-p-hydroxyphenylglycine double salt of D-phenylethanesulfonic acid, and 185g of dry product was obtained after drying, with a yield of 89.3% (based on D-p-hydroxyphenylglycine), and the specific rotation was detected to be -78.52°. 105g of L-p-hydroxyphenylglycine was added to the mother liquor of the separation, the temperature was raised to 70°C and kept for 2h, the temperature was lowered to 20°C, filtered and washed to obtain 239g of L-p-hydroxyphenylglycine double salt of L-phenylethanesulfonic acid. The wet product was put into a 1000ml three-necked flask, 500g of water was added, the temperature was raised to 50°C, potassium hydroxide was added to neutralize the pH value to 4.5-5, the temperature was lowered to 30°C, filtered and washed to obtain L-p-hydroxyphenylglycine and filtrate. The filtrate was put into a pressure reactor, 15g of potassium hydroxide was added, the temperature was raised to 150°C for racemization reaction for 5h to obtain a racemic solution, 50g of sulfuric acid was added for acidification, 50g of D-p-hydroxyphenylglycine was added, the temperature was kept at 70°C for 2h, the temperature was lowered to 20°C, filtered and washed to obtain 128g of a wet product of dextrorotatory benzene ethanesulfonic acid D-p-hydroxyphenylglycine double salt, and 94g of a dry product was obtained after drying, with a yield of 88.9% (based on D-p-hydroxyphenylglycine), an off-white appearance, and a specific rotation of -78.46°. Add 50 g of L-p-hydroxyphenylglycine to the mother liquor, raise the temperature to 70°C and keep it for 2 h, then cool to 20°C, filter and wash to obtain 122 g of L-p-hydroxyphenylglycine double salt wet product with off-white appearance.

[0046] Embodiment 3:

[0047] 249g of L-hydroxyphenylglycine double salt of 1-hydroxyphenylethanesulfonic acid and 500g of water were added to a 2000ml three-necked flask, the temperature was raised to 50°C, solid sodium hydroxide was added to neutralize the pH value to 4.5-5, the temperature was lowered to 30°C, filtered and washed to obtain L-hydroxyphenylglycine and filtrate. The filtrate was put into a pressure reactor, 15g of solid sodium hydroxide was added, the temperature was raised to 160°C for racemization reaction for 4h to obtain a racemic solution, 45g of sulfuric acid was added for acidification, 48g of D-hydroxyphenylglycine was added, the temperature was kept at 70°C for 2h, the temperature was lowered to 20°C, filtered and washed to obtain 125g of D-hydroxyphenylglycine double salt of 1-hydroxyphenylethanesulfonic acid, and 92g of dry product was obtained after drying, the yield was 90.7% (based on D-hydroxyphenylglycine), the appearance was off-white, and the specific rotation was -78.73°. Add 50 g of L-p-hydroxyphenylglycine to the mother liquor, raise the temperature to 70°C and keep it for 2 h, then cool to 20°C, filter and wash to obtain 123 g of L-p-hydroxyphenylglycine double salt of L-phenylethanesulfonic acid, which has an off-white appearance.

[0048] Comparative Example 1:

[0049] Into a 2000ml three-necked flask, 1000g of 20% d-phenylethanesulfonic acid aqueous solution was added, 100g of D-p-hydroxyphenylglycine was added, the temperature was raised to 70°C and kept for 2h, the temperature was lowered to 20°C, filtered and washed to obtain 225g of dextrorotatory phenylethanesulfonic acid D-p-hydroxyphenylglycine double salt wet product, and 186g of dry product was obtained after drying, with a yield of 88.0% (based on D-p-hydroxyphenylglycine), and the specific rotation was detected to be -78.49°. The split mother liquor was put into a pressure reactor, and liquid alkali was added to adjust the pH to 13-13.5, and the temperature was raised to 140°C for racemization reaction for 6 hours to obtain a racemic solution, sulfuric acid was added to adjust the pH to 1-1.5, 50g of D-p-hydroxyphenylglycine was added, and the mixture was kept at 70°C for 2 hours, and the mixture was cooled to 20°C for filtration and washing to obtain 135g of a wet product of D-p-hydroxyphenylglycine double salt of dextrorotatory phenylethanesulfonic acid, and 94g of a dry product was obtained after drying, with a yield of 88.94% (based on D-p-hydroxyphenylglycine), a reddish brown appearance, and a specific rotation of -75.48°. 50g of L-p-hydroxyphenylglycine was added to the mother liquor, and the mixture was heated to 70°C for 2 hours, and the mixture was cooled to 20°C for filtration and washing to obtain 127g of a wet product of L-p-hydroxyphenylglycine double salt of dextrorotatory phenylethanesulfonic acid, and a reddish brown appearance.

[0050] According to the results of Example 1 and Comparative Example 1, directly performing racemization after the first step of splitting and then performing subsequent splitting will result in a significant decrease in the specific rotation of the dextrorotatory benzeneethanesulfonic acid D-p-hydroxyphenylglycine double salt, a decrease in purity, and a deterioration in the product appearance; and at this time, even if L-p-hydroxyphenylglycine is added to the subsequent mother liquor again, the product appearance of the obtained L-p-hydroxyphenylglycine double salt is also poor.

[0051] The above contents are only basic descriptions of the concept of the present invention, and any equivalent changes made according to the technical solution of the present invention shall fall within the protection scope of the present invention.

Claims

1. A method for synthesizing a dextrorotatory benzeneethanesulfonic acid D-p-hydroxyphenylglycine double salt, characterized in that: The following steps are involved: Step a. Add D-p-hydroxyphenylglycine to the d-phenylethanesulfonic acid aqueous solution for splitting, filtering and washing to obtain dextrorotatory phenylethanesulfonic acid D-p-hydroxyphenylglycine double salt and split mother liquor; Step b. adding L-p-hydroxyphenylglycine to the split mother liquor to form a double salt with the L-phenylethanesulfonic acid in the split mother liquor, and filtering and washing to obtain L-p-hydroxyphenylglycine double salt of L-phenylethanesulfonic acid; Step c. adding water to prepare a slurry of L-p-hydroxyphenylethanesulfonic acid double salt, adding alkali to neutralize, filtering and washing to obtain L-p-hydroxyphenylglycine and a filtrate; Step d. adding a base to the filtrate and heating the mixture to perform a racemization reaction to obtain a racemic solution; Step e. Acid is added to the racemic solution for acidification, D-p-hydroxyphenylglycine is added for resolution, and the solution is filtered and washed to obtain dextrorotatory benzeneethanesulfonic acid D-p-hydroxyphenylglycine double salt and resolution mother liquor.

2. The method for synthesizing the dextrorotatory benzeneethanesulfonic acid D-p-hydroxyphenylglycine double salt according to claim 1, characterized in that: In step a, the molar ratio of D-p-hydroxyphenylglycine to d-phenylethylsulfonic acid is 0.5-0.6:1; The mass percentage concentration of the chromatic benzeneethylsulfonic acid aqueous solution is 15-30%.

3. The method for synthesizing the dextrorotatory benzeneethanesulfonic acid D-p-hydroxyphenylglycine double salt according to claim 1, characterized in that: The splitting temperature is 60-80°C and the splitting time is 1-5h.

4. The method for synthesizing the dextrorotatory benzeneethanesulfonic acid D-p-hydroxyphenylglycine double salt according to claim 1, characterized in that: In step b, the molar ratio of L-p-hydroxyphenylglycine to L-phenylethanesulfonic acid is 1 to 1.4:

1.

5. The method for synthesizing the dextrorotatory benzeneethanesulfonic acid D-p-hydroxyphenylglycine double salt according to claim 1, characterized in that: In step c, the added base is one or more of sodium carbonate, potassium carbonate, solid sodium hydroxide, sodium hydroxide aqueous solution, solid potassium hydroxide, and lithium hydroxide.

6. The method for synthesizing the dextrorotatory benzeneethanesulfonic acid D-p-hydroxyphenylglycine double salt according to claim 1, characterized in that: The base added in step d is one or more of solid sodium hydroxide, sodium hydroxide aqueous solution, solid potassium hydroxide, and lithium hydroxide, and the molar ratio of the base to the L-phenylethanesulfonic acid is 0.2 to 0.7:

1.

7. The method for synthesizing the dextrorotatory benzeneethanesulfonic acid D-p-hydroxyphenylglycine double salt according to claim 1, characterized in that: In step d, the racemization reaction temperature is 110-160° C., and the racemization reaction time is 4-10 hours.

8. The method for synthesizing the dextrorotatory benzeneethanesulfonic acid D-p-hydroxyphenylglycine double salt according to claim 1, characterized in that: The acid added in step e is one or more of sulfuric acid, hydrochloric acid and nitric acid.

9. The method for synthesizing the dextrorotatory benzeneethanesulfonic acid D-p-hydroxyphenylglycine double salt according to claim 1, characterized in that: In step c, the obtained L-p-hydroxyphenylglycine is applied to step b.

10. The method for synthesizing dextrorotatory benzeneethanesulfonic acid D-p-hydroxyphenylglycine double salt according to claim 1, characterized in that: The split mother liquor obtained in step e is returned to step b and is circulated according to the process of steps b to e.

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