A method for synthesizing a dextro-benzenesulfonic acid D-p-hydroxyphenylglycine complex salt

Abstract

The application discloses a synthesis method of dextrophenethylsulfonic acid D-p-hydroxyphenylglycine complex salt, which utilizes the inactive enantiomer levorotatory phenethylsulfonic acid to prepare the dextrophenethylsulfonic acid D-p-hydroxyphenylglycine complex salt through racemization, recycles and utilizes the originally discarded inactive enantiomer levorotatory phenethylsulfonic acid in the mother liquor, greatly reduces the cost of the dextrophenethylsulfonic acid D-p-hydroxyphenylglycine complex salt, and greatly reduces COD in the mother liquor, thereby reducing environmental protection treatment pressure.

Description

Technical Field

[0001] This invention relates to a method for the racemic resolution synthesis of chiral enantiomers, and more particularly to a method for the synthesis of D-p-hydroxyphenylglycine complex salt of dextrorotatory phenylethanesulfonic acid. Background Technology

[0002] Dextrophenylethanesulfonic acid is an important resolving agent in the production of D-p-hydroxyphenylglycine from racemic p-hydroxyphenylglycine. Pure dextrophenylethanesulfonic acid is difficult to prepare and generally exists as a D-p-hydroxyphenylglycine complex salt. D-p-hydroxyphenylglycine is an essential pharmaceutical intermediate in the synthesis of broad-spectrum antibiotics such as amoxicillin and cefadroxil.

[0003] D-p-hydroxyphenylglycine complex salt of dextrophenylethanesulfonic acid, also known as resolving agent complex salt, is a complex salt formed by the 1:1 combination of dextrophenylethanesulfonic acid and D-p-hydroxyphenylglycine. Its structural formula is as follows:

[0004]

[0005] Currently, there are five main methods for synthesizing D-p-hydroxyphenylglycine complex salt of dextro-phenylethanesulfonic acid from phenylethanesulfonic acid suspension:

[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 racemic phenylethanesulfonic acid, which uses 1-hydroxyphenylethane or 1-bromophenylethane as raw material, condenses it with thiourea to obtain 2-(1-phenylethyl)isothiourea hydrobromic acid, decomposes it under alkaline catalysis to obtain 1-phenylethanethiol, and finally oxidizes it with peroxide to obtain racemic phenylethylsulfonic acid, and then adds D-p-hydroxyphenylglycine to resolve it to obtain dextro-phenylethanesulfonic acid D-p-hydroxyphenylglycine double salt.

[0008] Route 2: Sulfite (hydrogen sulfite) substitution method

[0009] Zhang Zhixia (Research on the Preparation of Asymmetric Conversion Resolving Agent (+)-α-phenylethanesulfonic acid [D]. Shijiazhuang: Hebei Normal University, 2008) disclosed a method for preparing an asymmetric conversion resolving agent (+)-1-phenylethanesulfonic acid. The method involves a substitution reaction between 1-phenylbromoethane and bisulfite or sulfite in the presence of concentrated ammonia and a phase transfer catalyst. The reaction directly yields a racemic ammonium phenylethyl sulfonate salt, which is then resolved by adding D-p-hydroxyphenylglycine to obtain a dextrorotatory phenylethanesulfonic 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 involves refluxing 1-phenyl haloethane and sodium disulfide in a solvent to generate 1-phenylethyl disulfide. The latter reacts with hydrogen peroxide as an oxidant to obtain cyclophenylethyl sulfonic acid, and then D-p-hydroxyphenylglycine is added to resolve it to obtain dextrophenylethanesulfonic acid D-p-hydroxyphenylglycine double salt.

[0012] Route 4: Grignard Method

[0013] Liu Weijun et al. (CN103613518B) disclosed a method for preparing α-phenylethanesulfonic acid. The specific process involves slowly adding 1-chlorophenylethane or 1-bromophenylethane dropwise into tetrahydrofuran with added magnesium at 5–15 °C to prepare a Grignard reagent. A slightly excess of sulfur dioxide gas is then introduced at 15–25 °C to generate (±)-α-phenylethanesulfinic acid. This is then dissolved in acetic acid solution and oxidized with hydrogen peroxide at 70–75 °C to obtain a mixed phenylethanesulfonic acid. D-p-hydroxyphenylglycine is then added to resolve the mixture to obtain dextro-phenylethanesulfonic acid D-p-hydroxyphenylglycine double salt.

[0014] Route 5: Induced Crystallization Method

[0015] This method utilizes the difference in physical properties of diastereomer resolving agent salts. An optically active isomer is added as a seed crystal to a racemic solution, inducing the precipitation of the competing isomer, thereby achieving separation. Induced crystallization generally requires the racemic mixture or racemic compound to exist, but its solubility must be much greater than that of the corresponding enantiomer. Only then can induced crystallization be used for separation. Chen Fangfang (Research on the Synthesis Process of (+)-α-phenylethanesulfonic acid [D]. Zhengzhou: Zhengzhou University, 2018.) disclosed a method for preparing a resolving agent complex salt. Specifically, high-optical-purity D-p-hydroxyphenylglycine (i.e., D-HPG) is used as the resolving agent, added to an aqueous solution of 1(±)-phenylethanesulfonic acid or its ammonium salt, and hydrochloric acid is added dropwise to make the solution acidic. The solution is heated to 65-75℃ for 2 hours to dissolve, and then stirred at room temperature. Utilizing the solubility difference between the salts D-HPG-(+)-PES and D-HPG-(-)-PES formed by these two compounds, D-HPG-(+)-PES with lower solubility crystallizes out in a supersaturated salt solution. The pH of the mother liquor is adjusted to 5.4 with NaOH, and crystallization is carried out at room temperature for 8 hours to obtain D-HPG and a secondary mother liquor. D-HPG is reused in the first step. Barium hydroxide solution is added to the secondary mother liquor, and after filtration, the filtrate is distilled under reduced pressure to obtain the barium salt of (-)PES. This barium salt is dissolved in water, and a slightly excess of dilute sulfuric acid is added to ensure that the barium ions are completely converted to barium sulfate precipitate and removed. At this point, (-)PES is present in the filtrate. After filtration, (-)PES is subjected to alkaline-catalyzed racemization with sodium hydroxide solution for 10 hours to obtain 1(±)-phenylethanesulfonic acid, which can be reused in the first step.

[0016]

[0017] Considering factors such as cost, environmental protection, and technological advancement, Route 1 has a low yield and generates a significant amount of waste; Route 2 involves numerous side reactions and is difficult to purify; Route 3 uses readily available raw materials, has a high overall yield, and low overall cost; while Route 4 has high production costs and is not the optimal choice. In all the above synthetic methods, the ineffective enantiomer of levamylenesulfonic acid in the mother liquor after resolution is not recovered, resulting in raw material waste and putting pressure on environmental treatment. Route 5 has the advantage of recovering levamylenesulfonic acid, and the racemic mother liquor can be reused continuously; however, the first step of this route uses a large amount of D-HPG, requiring all phenylethanesulfonic acid to be salted, then pH adjusted to precipitate excess D-HPG, and then using expensive barium hydroxide to precipitate levamylenesulfonic acid. This process is cumbersome and has high production costs. Furthermore, the recovery is only qualitatively described, without providing the yield of barium hydroxide precipitation of levamylenesulfonic acid or the resolution results of racemic phenylethanesulfonic acid, making it difficult to effectively assess the actual reuse effect of the mother liquor. Summary of the Invention

[0018] To address the problems existing in the prior art, this invention provides a simple, low-cost, and high-yield method for synthesizing dextro-phenylethanesulfonic acid D-phenylglycine double salt. This method can racemic and recover ineffective enantiomers of levo-phenylethanesulfonic acid from the mother liquor, significantly reducing the cost of dextro-phenylethanesulfonic acid D-p-hydroxyphenylglycine double salt, simplifying the operation steps, and improving the recovery efficiency.

[0019] A method for synthesizing D-p-hydroxyphenylglycine complex salt of dextrorotatory phenylethanesulfonic acid includes the following steps:

[0020] Step a: Add D-p-hydroxyphenylglycine to the mixed phenylethanesulfonic acid aqueous solution for resolution, filter and wash to obtain dextro-phenylethanesulfonic acid D-p-hydroxyphenylglycine double salt and resolution mother liquor;

[0021] Step b. Add L-p-hydroxyphenylglycine to the resolution mother liquor to form a double salt with L-phenylethanesulfonic acid in the resolution mother liquor. After filtration and washing, L-p-hydroxyphenylglycine double salt of L-phenylethanesulfonic acid is obtained.

[0022] Step c. Add L-p-hydroxyphenylglycine complex salt of L-phenylethanesulfonic acid to water to make a slurry, add alkali to neutralize, filter and wash to obtain L-p-hydroxyphenylglycine and filtrate;

[0023] Step d. Add alkali to the filtrate and heat to carry out a racemic reaction to obtain a racemic liquid;

[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 dextro-phenylethanesulfonic acid D-p-hydroxyphenylglycine double salt and resolution mother liquor.

[0025] In this invention, D-p-hydroxyphenylglycine is first added to separate dextrophenylethanesulfonic acid, while levophenylethanesulfonic acid is retained in the mother liquor. Then, L-p-hydroxyphenylglycine is added. Taking advantage of the low solubility of the L-p-hydroxyphenylglycine complex salt, the separation and purification of levophenylethanesulfonic acid are achieved. This shortens the operation steps while making full use of the ineffective enantiomer of levophenylethanesulfonic acid.

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

[0027] The mass percentage concentration of the mixed ethanesulfonic acid aqueous solution is 15-30%. The amount of D-p-hydroxyphenylglycine used allows for better precipitation of the double salt from dextro-phenylethanesulfonic acid while reducing the formation of the double salt from levo-phenylethanesulfonic acid, thus facilitating subsequent operations.

[0028] Preferably, the splitting temperature is 60–80℃ and the splitting time is 1–5 hours.

[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, aqueous sodium hydroxide solution, solid potassium hydroxide, and lithium hydroxide, preferably aqueous sodium hydroxide 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 alkali to L-phenylethanesulfonic acid is 0.2–0.7:1, preferably 0.3–0.5:1.

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

[0034] The racemic 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, with sulfuric acid being preferred.

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

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

[0038] This invention utilizes L-p-hydroxyphenylglycine to form a complex salt precipitate with the ineffective enantiomer L-phenylethanesulfonic acid in the resolution mother liquor. After separating the mother liquor and removing impurities, the complex salt is neutralized with alkali, and L-p-hydroxyphenylglycine is recovered for reuse. The mother liquor is then racemized under alkaline conditions to obtain a racemic phenylethanesulfonic acid solution. D-p-hydroxyphenylglycine is added for resolution to obtain dextro-phenylethanesulfonic acid D-p-hydroxyphenylglycine complex salt. The resolution mother liquor is recycled through the above process, thus reusing the previously discarded ineffective enantiomer L-phenylethanesulfonic acid in the mother liquor. This significantly reduces the cost of dextro-phenylethanesulfonic acid D-p-hydroxyphenylglycine complex salt and substantially reduces the COD in the mother liquor, alleviating environmental treatment pressure. Detailed Implementation

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

[0040] The general preparation method of this invention is as follows: a) D-p-hydroxyphenylglycine is added to a mixed ethanesulfonic acid aqueous solution for resolution, and the mixture is filtered and washed to obtain dextro-phenylethanesulfonic acid D-p-hydroxyphenylglycine complex salt and resolution mother liquor; b) L-p-hydroxyphenylglycine is added to the resolution mother liquor to form a complex salt with levo-phenylethanesulfonic acid, and the mixture is filtered and washed to obtain levo-phenylethanesulfonic acid L-p-hydroxyphenylglycine complex salt; c) L-phenylethanesulfonic acid L-p-hydroxyphenylglycine complex salt is added to water to make a slurry, neutralized with alkali, and filtered and washed to obtain L-p-hydroxyphenylglycine and filtrate; d) The filtrate is put into a pressure vessel, alkali is added, and the mixture is heated to carry out a racemic reaction to obtain a racemic liquid; e) The racemic liquid is acidified with acid, D-p-hydroxyphenylglycine is added for resolution, and the mixture is filtered and washed to obtain dextro-phenylethanesulfonic acid D-p-hydroxyphenylglycine complex salt and resolution mother liquor. The resolution mother liquor is recycled for racemic recovery.

[0041] Example 1

[0042] 1000g of 20% vortex phenylethanesulfonic acid aqueous solution was added to a 2000ml three-necked flask, followed by 100g of D-p-hydroxyphenylglycine. The mixture was heated to 70℃ and held for 2 hours, then cooled to 20℃ and filtered and washed to obtain 225g of wet D-p-hydroxyphenylglycine complex salt of dextro-phenylethanesulfonic acid. After drying, 186g of dry product was obtained, with a yield of 88.0% (based on D-p-hydroxyphenylglycine). The specific rotation was -78.49°. 100g of L-p-hydroxyphenylglycine was added to the mother liquor of the separation process, and the mixture was heated to 70℃ and held for 2 hours. After cooling to 20℃ and filtered and washed, 232g of wet L-p-hydroxyphenylglycine complex salt of levo-phenylethanesulfonic acid was obtained. The wet product was placed in a 1000ml three-necked flask, 500g of water was added, the temperature was raised to 50℃, and liquid alkali was added dropwise to neutralize the pH to 4.5-5. The temperature was lowered to 30℃, and the product was filtered and washed to obtain L-p-hydroxyphenylglycine and the filtrate. The filtrate was placed in a pressure reactor, 40g of 30% liquid alkali was added, and the temperature was raised to 140℃ for a racemic reaction for 6 hours to obtain a racemic liquid. 50g of sulfuric acid was added for acidification, and 48g of D-p-hydroxyphenylglycine was added. The mixture was kept at 70℃ for 2 hours, cooled to 20℃, filtered and washed to obtain 129g of wet D-p-hydroxyphenylglycine double salt of dextro-phenylethanesulfonic acid. After drying, 93g of dry product was obtained, with a yield of 91.7% (based on D-p-hydroxyphenylglycine). The product was off-white in appearance, and the specific rotation was -78.53°. 50g of L-p-hydroxyphenylglycine was added to the mother liquor, the temperature was raised to 70℃ and kept at that temperature for 2 hours, and then cooled to 20℃. After filtration and washing, 127g of wet L-p-hydroxyphenylglycine complex salt of L-phenylethanesulfonic acid was obtained, which was off-white in appearance.

[0043] The results of this embodiment show that adding L-p-hydroxyphenylglycine to the mother liquor after separation can effectively separate the ineffective enantiomer L-phenylethanesulfonic acid. After subsequent racemization and separation, a high yield of D-p-hydroxyphenylglycine complex salt of D-phenylethanesulfonic acid can be obtained. Moreover, the quality of the D-p-hydroxyphenylglycine complex salt of D-phenylethanesulfonic acid is good, and the optical rotation and product appearance meet the requirements.

[0044] Example 2

[0045] 1000g of 20% vortex phenylethanesulfonic acid aqueous solution was added to a 2000ml three-necked flask, followed by 98g of D-p-hydroxyphenylglycine. The mixture was heated to 70℃ and held for 2 hours, then cooled to 20℃ and filtered and washed to obtain 229g of wet D-p-hydroxyphenylglycine complex salt of dextro-phenylethanesulfonic acid. After drying, 185g of dry product was obtained, with a yield of 89.3% (based on D-p-hydroxyphenylglycine). The specific rotation was -78.52°. 105g of L-p-hydroxyphenylglycine was added to the mother liquor of the separation process. The mixture was heated to 70℃ and held for 2 hours, then cooled to 20℃ and filtered and washed to obtain 239g of wet L-p-hydroxyphenylglycine complex salt of levo-phenylethanesulfonic acid. The wet product was placed in a 1000ml three-necked flask, 500g of water was added, the temperature was raised to 50℃, potassium hydroxide was added to neutralize the pH to 4.5-5, the temperature was lowered to 30℃, and the mixture was filtered and washed to obtain L-p-hydroxyphenylglycine and the filtrate. The filtrate was placed in a pressure reactor, 15g of potassium hydroxide was added, the temperature was raised to 150℃ and racemic reaction was carried out for 5h to obtain a racemic liquid, 50g of sulfuric acid was added for acidification, 50g of D-p-hydroxyphenylglycine was added, the temperature was raised to 70℃ and kept for 2h, the temperature was lowered to 20℃, and the mixture was filtered and washed to obtain 128g of wet product of D-p-hydroxyphenylglycine double salt of dextro-phenylethanesulfonic acid. After drying, 94g of dry product was obtained, with a yield of 88.9% (based on D-p-hydroxyphenylglycine), an off-white appearance, and a specific rotation of -78.46°. 50g of L-p-hydroxyphenylglycine was added to the mother liquor, the temperature was raised to 70℃ and kept at that temperature for 2 hours, and then cooled to 20℃. After filtration and washing, 122g of wet L-p-hydroxyphenylglycine complex salt of levonorgestrel was obtained, which was off-white in appearance.

[0046] Example 3:

[0047] 249g of wet L-p-hydroxyphenylglycine complex salt of levonorgestrel was added to a 2000ml three-necked flask along with 500g of water. The mixture was heated to 50℃, and sodium hydroxide was added to neutralize the pH to 4.5-5. The mixture was then cooled to 30℃ and filtered to obtain L-p-hydroxyphenylglycine and the filtrate. The filtrate was transferred to a pressure reactor, and 15g of sodium hydroxide was added. The mixture was heated to 160℃ for a racemic reaction for 4 hours to obtain a racemic liquid. 45g of sulfuric acid was added for acidification, followed by the addition of 48g of D-p-hydroxyphenylglycine. The mixture was kept at 70℃ for 2 hours, cooled to 20℃, and filtered to obtain 125g of wet D-p-hydroxyphenylglycine complex salt of dextro-phenylethanesulfonate. After drying, 92g of the dry product was obtained, with a yield of 90.7% (based on D-p-hydroxyphenylglycine). The product was off-white in appearance, and the specific rotation was -78.73°. 50g of L-p-hydroxyphenylglycine was added to the mother liquor, the temperature was raised to 70℃ and kept at that temperature for 2 hours, and then cooled to 20℃. After filtration and washing, 123g of wet L-p-hydroxyphenylglycine complex salt of levonorgestrel was obtained, which was off-white in appearance.

[0048] Comparative Example 1:

[0049] 1000g of 20% vortex phenylethanesulfonic acid aqueous solution was added to a 2000ml three-necked flask, followed by 100g of D-p-hydroxyphenylglycine. The mixture was heated to 70℃ and kept at that temperature for 2 hours. After cooling to 20℃, the mixture was filtered and washed to obtain 225g of wet D-p-hydroxyphenylglycine double salt of dextrorotatory phenylethanesulfonic acid. After drying, 186g of dry product was obtained, with a yield of 88.0% (based on D-p-hydroxyphenylglycine). The specific rotation was -78.49°. The mother liquor was added to a pressurized reactor, and liquid alkali was added to adjust the pH to 13-13.5. The mixture was then heated to 140℃ for a racemic reaction for 6 hours to obtain a racemic solution. Sulfuric acid was added to adjust the pH to 1-1.5, and 50g of D-p-hydroxyphenylglycine was added. The mixture was heated to 70℃ and held for 2 hours. After cooling to 20℃, it was filtered and washed to obtain 135g of wet D-p-hydroxyphenylglycine double salt of dextrophenylethanesulfonic acid. After drying, 94g of dry product was obtained, with a yield of 88.94% (based on D-p-hydroxyphenylglycine). The product was reddish-brown in appearance, and its specific rotation was -75.48°. 50g of L-p-hydroxyphenylglycine was added to the mother liquor, and the mixture was heated to 70℃ and held for 2 hours. After cooling to 20℃, it was filtered and washed to obtain 127g of wet L-p-hydroxyphenylglycine double salt of levo-phenylethanesulfonic acid, which was also reddish-brown in appearance.

[0050] According to the results of Example 1 and Comparative Example 1, if racemization is performed directly after the first step of separation, and then subsequent separation is performed, the specific rotation of the dextrorotatory ethanesulfonic acid D-p-hydroxyphenylglycine complex salt will decrease significantly, the purity will decrease, and the product appearance will deteriorate. Moreover, even if L-p-hydroxyphenylglycine is added again to the mother liquor at this time, the appearance of the obtained L-phenylethanesulfonic acid L-p-hydroxyphenylglycine complex salt product is also poor.

[0051] The above description is merely a basic explanation of the concept of this invention, and any equivalent modifications made based on the technical solution of this invention shall fall within the protection scope of this invention.

Claims

1. A method for synthesizing D-p-hydroxyphenylglycine complex salt of dextrorotatory phenylethanesulfonic acid, characterized in that, Includes the following steps: Step a. Add D-p-hydroxyphenylglycine to the mixed phenylethanesulfonic acid aqueous solution for resolution, filter and wash to obtain dextro-phenylethanesulfonic acid D-p-hydroxyphenylglycine double salt and resolution mother liquor; Step b. Add L-p-hydroxyphenylglycine to the resolution mother liquor to form a double salt with L-phenylethanesulfonic acid in the resolution mother liquor. After filtration and washing, L-p-hydroxyphenylglycine double salt of L-phenylethanesulfonic acid is obtained. Step c. Add L-p-hydroxyphenylglycine complex salt of L-phenylethanesulfonic acid to water to make a slurry, add alkali to neutralize, filter and wash to obtain L-p-hydroxyphenylglycine and filtrate; Step d. Add alkali to the filtrate and heat to carry out a racemic reaction to obtain a racemic liquid; 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 dextro-phenylethanesulfonic acid D-p-hydroxyphenylglycine double salt and resolution mother liquor; The splitting temperature is 60~80℃, and the splitting time is 1~5h; The alkali 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 alkali to L-phenylethanesulfonic acid is 0.2 to 0.7:1; In step d, the racemic reaction temperature is 110–160℃, and the racemic reaction time is 4–10 h; The L-p-hydroxyphenylglycine obtained in step c is reused in step b; The mother liquor obtained in step e is returned to step b and used cyclically according to the process of steps b to e.

2. The method for synthesizing D-p-hydroxyphenylglycine complex salt of dextrorotatory phenylethanesulfonic acid according to claim 1, characterized in that: In step a, the molar ratio of D-p-hydroxyphenylglycine to cyclohexanesulfonic acid is 0.5–0.6:1; The mass percentage concentration of the vortex phenylethanesulfonic acid aqueous solution is 15-30%.

3. The method for synthesizing the dextrorotatory ethanesulfonic acid D-p-hydroxyphenylglycine complex 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.

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

5. The method for synthesizing the dextrorotatory ethanesulfonic acid D-p-hydroxyphenylglycine complex 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.

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