A synthetic process for S-(+)-4-phenyl-2-oxazolidinone

Abstract

This invention relates to the field of organic synthesis technology, specifically to a synthesis process for S-(+)-4-phenyl-2-oxazolidinone. The synthesis process for S-(+)-4-phenyl-2-oxazolidinone provided by this invention not only enables the recovery and utilization of organic solvents such as tetrahydrofuran and toluene, saving resources and reducing production costs, but also reduces environmental pollution. Furthermore, the S-(+)-4-phenyl-2-oxazolidinone synthesized by this invention has advantages such as high purity and high yield, effectively ensuring the grade and quality of S-(+)-4-phenyl-2-oxazolidinone. It appears as a white or off-white crystalline powder, readily soluble in DMSO, acetone, and ethanol.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically to a synthesis process for S-(+)-4-phenyl-2-oxazolidinone. Background Technology

[0002] (S)-4-phenyl-2-oxazolidinone, as a high-purity, photoactive chiral auxiliary compound, can be used as an intermediate in the synthesis of protease inhibitors for human immunodeficiency virus (HIV) infection, in the synthesis of ezetimibe, a selective cholesterol absorption inhibitor, and is widely used in asymmetric synthesis, as well as in corresponding selective synthesis, stereoselective synthesis, and solid-phase synthesis.

[0003] Hyperlipidemia is one of the high-risk factors for coronary heart disease. The main drugs for the clinical treatment of hyperlipidemia include cholesterol synthesis inhibitors (such as statins), phenoxy acids (such as beta-blockers), bile acid sequestrants (such as cholestyramine), and others (such as niacin analogues).

[0004] Ezetimibe is a novel selective cholesterol absorption inhibitor that inhibits the absorption of dietary cholesterol and cholesterol transported to the intestine via bile by binding to the epithelial protein of small brush border vesicles (relative molecular mass 145 × 10³), thereby reducing cholesterol levels in serum and liver. Unlike bile acid sequestrants, ezetimibe does not affect the absorption of cholesterol, other steroids (such as taurine), triglycerides, and fat-soluble vitamins. Its pharmacological action is independent of the inhibition of acetyl-CoA-cholesterol acetyltransferase (ACAT) and the expression of LDL receptors (scavenger receptors). After absorption, ezetimibe binds to glucuronic acid in the liver and circulates through the enterohepatic system, almost specifically targeting small intestinal mucosal cells, thus playing a unique and highly effective role in controlling high cholesterol levels.

[0005] Currently, the S-(+)-4-phenyl-2-oxazolidinone products synthesized in the prior art have disadvantages such as low yield and relatively low purity. In order to address this technical problem, the present invention provides a synthesis process for S-(+)-4-phenyl-2-oxazolidinone to solve this technical problem. Summary of the Invention

[0006] The purpose of this invention is to provide a synthetic process for S-(+)-4-phenyl-2-oxazolidinone. This process not only enables the recovery and reuse of organic solvents such as tetrahydrofuran and toluene, saving resources and reducing production costs, but also yields S-(+)-4-phenyl-2-oxazolidinone with high purity and high yield, effectively ensuring the grade and quality of the synthesized product.

[0007] To achieve the above objectives, the present invention provides the following technical solution:

[0008] A synthetic process for S-(+)-4-phenyl-2-oxazolidinone includes the following steps:

[0009] Step 1: Add L-phenylglycine and tetrahydrofuran together to a reaction vessel at a solid-liquid ratio of 0.1–0.2 g / mL, and add borane reagent at a mass of 0.5–0.6 times that of L-phenylglycine. After stirring for 2–3 hours, lower the temperature of the resulting product to 10–25°C, and slowly add concentrated sulfuric acid at a mass of 1.2–1.4 times that of the borane reagent. After the addition is complete, maintain the reaction temperature at 20–40°C for 50–80 minutes, and then raise the reaction temperature to 70–80°C within 60–90 minutes, and react at this temperature for 100–150 minutes. After the reaction is complete, distill off and recover the tetrahydrofuran from the product.

[0010] Step 2: Add 0.4–0.5 times the volume of distilled water and 0.5–0.65 times the volume of alkaline solution dropwise to the recovered tetrahydrofuran. After the addition is complete, raise the temperature of the resulting mixture to 100–110°C within 60–100 minutes and reflux at this temperature for 2–3 hours. After the reaction is complete, add 4–5 times the volume of toluene and 0.6–0.7 times the volume of anhydrous ethanol to the resulting product component. Mix and stir thoroughly, then let stand at 65–75°C for 10–15 minutes. Separate the inorganic phase and transfer it to a transfer reactor. Then add toluene with a volume of 2 times the volume of anhydrous ethanol to the transfer reactor, and let stand at 65–75°C for 10–20 minutes. Separate the aqueous layer, which is then transferred to a high-salt wastewater tank, while the toluene is collected in a toluene receiving tank to obtain the organic phase.

[0011] Step 3: Add potassium carbonate at a mass of 0.08–0.1 times that of toluene to the obtained organic phase, mix and stir thoroughly, then slowly add ethyl chloroformate in an equal amount to potassium carbonate at a temperature of 50–80°C, mix and stir thoroughly, and keep the reaction at 65–75°C for 1–2 hours; after the reaction is complete, distill off the ethanol at 79°C; then distill off the azeotrope of toluene and water at 85–90°C; after the recovery is complete, lower the temperature of the remaining product components to 60–70°C;

[0012] Step 4: Add a reaction promoter with a mass 0.06 - 0.1 times that of potassium carbonate to the remaining product components in Step 3. After mixing evenly, heat up to 80 - 90 °C, hold the reaction for 50 - 80 min, sample and analyze the reaction solution. If the residual acyl compound is less than 3%, it is qualified. After sampling and passing the inspection, add distilled water with a mass 25 - 35 times that of the reaction promoter and glacial acetic acid with a mass 1.5 - 2.5 times that of the reaction promoter successively under stirring conditions. After mixing evenly, let it stand at 70 - 80 °C for 10 - 20 min. The obtained toluene layer is to be concentrated and crystallized, and the water layer is separated into a transfer kettle. Under stirring conditions, add toluene with a mass 8 - 10 times that of glacial acetic acid to the water layer in the transfer kettle. After standing at 70 - 80 °C for 10 - 20 min, separate the water layer. The water layer is separated into a high-salt wastewater tank, and the toluene layer is put into a toluene receiving tank;

[0013] Step 5: Dilute and filter the toluene to be concentrated, and then successively carry out concentration crystallization, centrifugal filtration, vacuum drying and granulation processes, and then package and store it in the warehouse. The finally obtained product is the finished product of S-(+)-4-phenyl-2-oxazolidinone.

[0014] Furthermore, the borane reagent is selected from any one of borane tetrahydrofuran, borane dimethyl sulfide, and borane pyridine.

[0015] Furthermore, in Step 1, the tetrahydrofuran is recovered by atmospheric distillation, where the temperature is set at 60 - 80 °C and the recovery time is controlled at 2 - 2.5 h.

[0016] Furthermore, the method for preparing the alkali solution in Step 2 is: Mix a 30% sodium hydroxide solution and distilled water in a mass ratio of 2:1, and mix and stir at 50 - 60 °C for 1 - 2 h until the mixed solution is clear. The obtained product is the finished alkali solution.

[0017] Furthermore, when dropping concentrated sulfuric acid, the temperature is controlled at 10 - 40 °C, the time is controlled at 4.0 - 6.0 h, and the dropping rate is 11 - 13 L / h.

[0018] Furthermore, the reaction promoter in Step 4 is selected from any one of potassium tert-butoxide and sodium tert-butoxide.

[0019] Furthermore, the specific operation of dilution and filtration in Step 5 is: Add absolute ethanol with a mass 8 - 10 times that of glacial acetic acid to the toluene layer to be concentrated for dilution, and then filter it through a basket filter into a crystallization tank.

[0020] Furthermore, atmospheric distillation is used for concentration crystallization, and the temperature of the crystallization kettle is 20 - 40 °C. Drain the cooling water in the jacket of the crystallization kettle, open the freezing brine in the jacket of the crystallization kettle, maintain the temperature of the crystallization kettle at 5 - 15 °C, and carry out crystal cultivation at this temperature for 3 h.

[0021] Furthermore, during centrifugal filtration, the material from the crystallization vessel is pressurized into a bottom-discharge centrifuge using nitrogen gas, rinsed with toluene at 3–8°C, and then dried to obtain S-(+)-4-phenyl-2-oxazolidinone wet product.

[0022] Furthermore, when vacuum drying the wet S-(+)-4-phenyl-2-oxazolidinone product, it is placed in a rotary dryer for vacuum drying, the water temperature of the hot water tank is controlled at 60-80℃, the vacuum degree is ≤-0.085MPa, and the drying time is set to 8-12h.

[0023] Compared with the prior art, the beneficial effects of the present invention are:

[0024] The synthesis process of S-(+)-4-phenyl-2-oxazolidinone provided by this invention not only enables the recovery and utilization of organic solvents such as tetrahydrofuran and toluene, saving resources and reducing production costs, but also reduces environmental pollution. Furthermore, the S-(+)-4-phenyl-2-oxazolidinone synthesized by this invention has advantages such as high purity and high yield, effectively ensuring the grade and quality of S-(+)-4-phenyl-2-oxazolidinone. It appears as a white or off-white crystalline powder, readily soluble in DMSO, acetone, and ethanol. Detailed Implementation

[0025] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0026] Example 1

[0027] A synthetic process for S-(+)-4-phenyl-2-oxazolidinone includes the following steps:

[0028] Step 1: Add L-phenylglycine and tetrahydrofuran together to a reaction vessel at a solid-liquid ratio of 0.1 g / mL. Add borane tetrahydrofuran at a mass of 0.5 times that of L-phenylglycine. After stirring for 2 hours, lower the temperature of the resulting product to 10°C and slowly add concentrated sulfuric acid at a mass of 1.2 times that of borane tetrahydrofuran. After the addition is complete, maintain the reaction temperature at 20°C for 50 minutes, then raise the temperature to 70°C within 60 minutes and react at this temperature for 100 minutes. After the reaction is complete, distill off and recover the tetrahydrofuran from the product. Tetrahydrofuran is recovered by atmospheric distillation at 60°C for 2 hours. When adding concentrated sulfuric acid, maintain the temperature at 10°C for 4.0 hours and the dropping rate at 11 L / h.

[0029] Step 2: Add 0.4 times the volume of distilled water and 0.5 times the volume of alkali solution to the recovered tetrahydrofuran dropwise. After the addition is complete, raise the temperature of the resulting mixture to 100℃ within 60 minutes and reflux at this temperature for 2 hours. After the reaction is complete, add 4 times the volume of toluene and 0.6 times the volume of anhydrous ethanol to the resulting product component. Mix and stir evenly, then let stand at 65℃ for 10 minutes. Separate the inorganic phase and transfer it to a transfer vessel. Then add 2 times the volume of anhydrous ethanol to the transfer vessel, let stand at 65℃ for 10 minutes, and separate the aqueous layer. The aqueous layer is transferred to a high-salt wastewater tank, and the toluene is collected in a toluene receiving tank to obtain the organic phase. The alkali solution is prepared by mixing a 30% sodium hydroxide solution with distilled water at a mass ratio of 2:1 and stirring at 50℃ for 1 hour until the mixture is clear. The resulting product is the alkali solution.

[0030] Step 3: Add potassium carbonate (0.08 times the mass of toluene) to the obtained organic phase, mix and stir evenly, then slowly add ethyl chloroformate (equal in volume to potassium carbonate) dropwise at 50°C, mix and stir evenly, and keep the reaction at 65°C for 1 hour; after the reaction is complete, distill off the ethanol at 79°C; then distill off the azeotrope of toluene and water at 85°C; after the recovery is complete, lower the temperature of the remaining product components to 60°C.

[0031] Step 4: Add potassium tert-butoxide with a mass 0.06 times that of potassium carbonate to the remaining product components in Step 3. After mixing evenly, raise the temperature to 80°C, hold the temperature for reaction for 50 min, sample and analyze the reaction solution. If the residual acyl compound is less than 3%, it is qualified. After sampling and passing the test, add distilled water with a mass 25 times that of potassium tert-butoxide and glacial acetic acid with a mass 1.5 times that of potassium tert-butoxide thereto in sequence under stirring conditions. After mixing evenly, let it stand for 10 min at a temperature of 70°C. The obtained toluene layer is to be concentrated and crystallized, and the water layer is separated into a transfer kettle. Under stirring conditions, add toluene with a mass 8 times that of glacial acetic acid to the water layer in the transfer kettle. After letting it stand for 10 min at a temperature of 70°C, separate the water layer. The water layer is separated into a high-salt wastewater tank, and the toluene layer is put into a toluene receiving tank;

[0032] Step 5: Dilute and filter the toluene to be concentrated, and then successively carry out concentration and crystallization, centrifugal filtration, vacuum drying and granulation processes, and then package and store it. The finally obtained product is the finished product of S-(+)-4-phenyl-2-oxazolidinone; wherein,

[0033] The specific operation of dilution and filtration is as follows: Add absolute ethanol with a mass 8 times that of glacial acetic acid to the toluene layer to be concentrated for dilution, and then filter it through a basket filter into a crystallization tank.

[0034] During concentration and crystallization, atmospheric distillation is adopted, and the temperature of the crystallization kettle is 20°C. Drain the cooling water in the jacket of the crystallization kettle, turn on the chilled brine in the jacket of the crystallization kettle, maintain the temperature of the crystallization kettle at 5°C, and carry out crystal cultivation for 3 h at this temperature.

[0035] During centrifugal filtration, the materials in the crystallization kettle are pressed into a bottom-discharge centrifuge by nitrogen gas, and rinsed with toluene at 3°C, and then dried by centrifugation to obtain the wet product of S-(+)-4-phenyl-2-oxazolidinone.

[0036] When carrying out vacuum drying on the wet product of S-(+)-4-phenyl-2-oxazolidinone, put it into a rotary dryer for vacuum drying, control the water temperature of the hot water tank to be 60°C, the vacuum degree ≤ -0.085 MPa, and set the drying time to 8 h.

[0037] Through detection, the actual yield of S-(+)-4-phenyl-2-oxazolidinone in this example is 90.8%, and the purity is 99.6%.

[0038] Example 2

[0039] A synthesis process of S-(+)-4-phenyl-2-oxazolidinone comprises the following steps:

[0040] Step 1: Add L-phenylglycine and tetrahydrofuran to a reaction vessel at a solid-liquid ratio of 0.15 g / mL. Add borane dimethyl sulfide at a mass of 0.55 times that of L-phenylglycine. After stirring for 2.5 h, lower the temperature of the resulting product to 20 °C and slowly add concentrated sulfuric acid at a mass of 1.3 times that of borane dimethyl sulfide. After the addition is complete, maintain the reaction at 30 °C for 60 min, then raise the temperature to 75 °C within 80 min and react at this temperature for 120 min. After the reaction is complete, distill off and recover the tetrahydrofuran from the product. Tetrahydrofuran is recovered by atmospheric distillation at 70 °C for 2 h. When adding concentrated sulfuric acid, maintain the temperature at 30 °C for 5.0 h and the dropping rate at 12 L / h.

[0041] Step 2: Add 0.45 times the volume of distilled water and 0.6 times the volume of alkali solution to the recovered tetrahydrofuran dropwise. After the addition is complete, raise the temperature of the resulting mixture to 105℃ within 80 minutes and reflux at this temperature for 2 hours. After the reaction is complete, add 4 times the volume of toluene and 0.65 times the volume of anhydrous ethanol to the resulting product component. Mix and stir evenly, then let stand at 70℃ for 12 minutes. Separate the inorganic phase and transfer it to a transfer vessel. Then add 2 times the volume of anhydrous ethanol to the transfer vessel and let stand at 70℃ for 15 minutes. Separate the aqueous layer, which is then transferred to a high-salt wastewater tank, while the toluene is collected in a toluene receiving tank to obtain the organic phase. The alkali solution is prepared by mixing a 30% sodium hydroxide solution with distilled water at a mass ratio of 2:1 and stirring at 505℃ for 1.5 hours until the mixture is clear. The resulting product is the alkali solution.

[0042] Step 3: Add potassium carbonate in an amount equal to 0.09 times the mass of toluene to the obtained organic phase, mix and stir evenly, then slowly add ethyl chloroformate in an equal amount to potassium carbonate at 60°C, mix and stir evenly, and keep the reaction at 70°C for 1.5 hours; after the reaction is complete, distill off the ethanol at 79°C; then distill off the azeotrope of toluene and water at 88°C; after the recovery is complete, lower the temperature of the remaining product components to 65°C;

[0043] Step 4: Add sodium tert-butoxide with a mass 0.08 times that of potassium carbonate to the remaining product components in Step 3. After mixing evenly, heat up to 85°C, hold the temperature for reaction for 60 min, sample and analyze the reaction solution. If the residual acyl compound is less than 3%, it is qualified. After sampling and passing the inspection, add distilled water with a mass 30 times that of sodium tert-butoxide and 2.0 times of glacial acetic acid to it successively under stirring conditions. After mixing evenly, let it stand for 15 min at a temperature of 75°C. The obtained toluene layer is to be concentrated and crystallized, and the water layer is put into the transfer kettle. Under stirring conditions, add toluene with a mass 9 times that of glacial acetic acid to the water layer in the transfer kettle. After standing for 15 min at a temperature of 75°C, separate the water layer. The water layer is put into the high-salt wastewater tank, and the toluene layer is put into the toluene receiving tank;

[0044] Step 5: Dilute and filter the toluene to be concentrated, and then successively go through the processes of concentration and crystallization, centrifugal filtration, vacuum drying and granulation, and then package and store it. The finally obtained product is the finished product of S-(+)-4-phenyl-2-oxazolidinone; among which,

[0045] The specific operation of dilution and filtration is: add absolute ethanol with a mass 8 - 10 times that of glacial acetic acid to the toluene layer to be concentrated for dilution, and then filter it through a basket filter into the crystallization tank.

[0046] During concentration and crystallization, atmospheric distillation is adopted, and the temperature of the crystallization kettle is 30°C. Drain the cooling water in the jacket of the crystallization kettle, turn on the freezing brine in the jacket of the crystallization kettle, maintain the temperature of the crystallization kettle at 10°C, and conduct crystal cultivation for 3 h at this temperature.

[0047] During centrifugal filtration, press the materials in the crystallization kettle into a bottom-discharge centrifuge by nitrogen gas, and rinse it with toluene at 5°C, and then obtain the wet product of S-(+)-4-phenyl-2-oxazolidinone after centrifuging.

[0048] When vacuum drying the wet product of S-(+)-4-phenyl-2-oxazolidinone, put it into a rotary dryer for vacuum drying, control the water temperature in the hot water tank to be 70°C, the vacuum degree ≤ -0.085 MPa, and set the drying time to 10 h.

[0049] After detection, the actual yield of S-(+)-4-phenyl-2-oxazolidinone in this example is 92.3%, and the purity is 99.5%.

[0050] Example 3

[0051] A synthesis process of S-(+)-4-phenyl-2-oxazolidinone, comprising the following steps:

[0052] Step 1: Add L-phenylglycine and tetrahydrofuran to a reaction vessel at a solid-liquid ratio of 0.2 g / mL, and add boranepyridine at a mass of 0.6 times that of L-phenylglycine. After stirring for 3 hours, lower the temperature of the resulting product to 25°C and slowly add concentrated sulfuric acid at a mass of 1.4 times that of boranepyridine. After the addition is complete, maintain the reaction temperature at 20–40°C for 80 minutes, then raise the temperature to 80°C within 90 minutes and react at this temperature for 150 minutes. After the reaction is complete, distill off and recover the tetrahydrofuran from the product. Tetrahydrofuran is recovered by atmospheric distillation at 80°C for 2.5 hours. When adding concentrated sulfuric acid, maintain the temperature at 40°C for 6.0 hours at a dropping rate of 13 L / h.

[0053] Step 2: Add 0.5 times the volume of distilled water and 0.65 times the volume of alkali solution to the recovered tetrahydrofuran dropwise. After the addition is complete, raise the temperature of the resulting mixture to 110°C within 100 minutes and reflux at this temperature for 3 hours. After the reaction is complete, add 5 times the volume of toluene and 0.7 times the volume of anhydrous ethanol to the resulting product component. Mix and stir thoroughly, then let stand at 75°C for 15 minutes. Separate the inorganic phase and transfer it to a transfer vessel. Then add 2 times the volume of anhydrous ethanol to the transfer vessel and let stand at 75°C for 20 minutes. Separate the aqueous layer, which is then transferred to a high-salt wastewater tank, while the toluene is collected in a toluene receiving tank to obtain the organic phase. The alkali solution is prepared by mixing a 30% sodium hydroxide solution with distilled water at a mass ratio of 2:1 and stirring at 60°C for 2 hours until the mixture becomes clear. The resulting product is the alkali solution.

[0054] Step 3: Add potassium carbonate (0.1 times the mass of toluene) to the obtained organic phase, mix and stir evenly, then slowly add ethyl chloroformate (equal in mass to potassium carbonate) dropwise at 80°C, mix and stir evenly, and keep the reaction at 75°C for 2 hours; after the reaction is complete, distill off the ethanol at 79°C; then distill off the azeotrope of toluene and water at 90°C; after the recovery is complete, lower the temperature of the remaining product components to 70°C.

[0055] Step 4: Add potassium tert-butoxide with a mass 0.1 times that of potassium carbonate to the remaining product components in Step 3. After mixing evenly, heat up to 90°C, keep the temperature for reaction for 80 min, sample and analyze the reaction solution. It is qualified when the residual acyl compound is less than 3%. After sampling and passing the inspection, add distilled water with a mass 35 times that of potassium tert-butoxide and glacial acetic acid with a mass 2.5 times that of potassium tert-butoxide to it in sequence under stirring conditions. After mixing evenly, let it stand for 20 min at a temperature of 80°C. The obtained toluene layer is to be concentrated and crystallized, and the water layer is put into the transfer kettle. Under stirring conditions, add toluene with a mass 10 times that of glacial acetic acid to the water layer in the transfer kettle. After standing for 20 min at a temperature of 80°C, separate the water layer. The water layer is put into the high-salt wastewater tank, and the toluene layer is put into the toluene receiving tank;

[0056] Step 5: Dilute and filter the toluene to be concentrated, and then successively carry out concentration crystallization, centrifugal filtration, vacuum drying and granulation processes, and then package and store it. The finally obtained product is the finished product of S-(+)-4-phenyl-2-oxazolidinone; among which,

[0057] The specific operation of dilution filtration is: add absolute ethanol with a mass 0 times that of glacial acetic acid to the toluene layer to be concentrated for dilution, and then filter it through a basket filter into the crystallization tank.

[0058] During concentration crystallization, atmospheric distillation is adopted, and the temperature of the crystallization kettle is 40°C. Drain the cooling water in the jacket of the crystallization kettle, turn on the chilled brine in the jacket of the crystallization kettle, maintain the temperature of the crystallization kettle at 15°C, and keep the crystals growing at this temperature for 3 h.

[0059] During centrifugal filtration, the materials in the crystallization kettle are pressed into a bottom-discharge centrifuge by nitrogen gas, and rinsed with toluene at 8°C, and then dried by centrifugation to obtain the wet product of S-(+)-4-phenyl-2-oxazolidinone.

[0060] When carrying out vacuum drying on the wet product of S-(+)-4-phenyl-2-oxazolidinone, put it into a rotary dryer for vacuum drying. Control the water temperature of the hot water tank to be 80°C, the vacuum degree ≤ -0.085 MPa, and set the drying time to 12 h.

[0061] After detection, the actual yield of S-(+)-4-phenyl-2-oxazolidinone in this example is 90.5%, and the purity is 91.1%.

[0062] The synthesis process of S-(+)-4-phenyl-2-oxazolidinone provided by this invention not only enables the recovery and utilization of organic solvents such as tetrahydrofuran and toluene, saving resources and reducing production costs, but also reduces environmental pollution. Furthermore, the S-(+)-4-phenyl-2-oxazolidinone synthesized by this invention has advantages such as high purity and high yield, effectively ensuring the grade and quality of S-(+)-4-phenyl-2-oxazolidinone. Therefore, the synthesis process of S-(+)-4-phenyl-2-oxazolidinone provided by this invention has a broader market prospect and is more suitable for widespread application.

[0063] In the description of this specification, references to terms such as "an embodiment," "example," "specific example," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the invention. In this specification, illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples.

[0064] The preferred embodiments of the present invention disclosed above are merely illustrative of the invention. These preferred embodiments do not exhaustively describe all details, nor do they limit the invention to the specific implementations described. Clearly, many modifications and variations can be made based on the content of this specification. This specification selects and specifically describes these embodiments to better explain the principles and practical applications of the invention, thereby enabling those skilled in the art to better understand and utilize the invention. The invention is limited only by the claims and their full scope and equivalents.

Claims

1. A process for synthesizing S-(+)-4-phenyl-2-oxazolidinone, characterized in that, It includes the following steps: Step 1: Put L-phenylglycinol and tetrahydrofuran into a reaction tank at a solid-liquid ratio of 0.1 - 0.2 g / mL, and add a borane reagent with a mass 0.5 - 0.6 times that of L-phenylglycinol thereto. After stirring and reacting for 2 - 3 h, lower the temperature of the resulting product components to 10 - 25 °C, and slowly dropwise add concentrated sulfuric acid with a mass 1.2 - 1.4 times that of the borane reagent. After the dropwise addition is completed, keep the temperature at 20 - 40 °C for heat preservation reaction for 50 - 80 min, then raise the reaction temperature to 70 - 80 °C within 60 - 90 min, and react at this temperature for 100 - 150 min. After the reaction is completed, distill and recover the tetrahydrofuran in the product components; Step 2: Sequentially dropwise add distilled water with a volume 0.4 - 0.5 times that of the recovered tetrahydrofuran and an alkali solution with a volume 0.5 - 0.65 times that of the recovered tetrahydrofuran thereto. After the dropwise addition is completed, raise the temperature of the resulting mixed components to 100 - 110 °C within 60 - 100 min, and carry out a reflux reaction at this temperature for 2 - 3 h. After the reaction is completed, sequentially add toluene with a volume 4 - 5 times that of the distilled water and absolute ethanol with a volume 0.6 - 0.7 times that of the distilled water to the resulting product components. After mixing and stirring evenly, let it stand for 10 - 15 min under the condition of 65 - 75 °C. Separate the inorganic phase and transport it to a transfer kettle. Then add toluene with a volume 2 times that of the absolute ethanol to the transfer kettle, and let it stand for 10 - 20 min at a temperature of 65 - 75 °C, and then separate the water layer. The water layer is separated into a high-salt wastewater tank, and the toluene flows into a toluene receiving tank to obtain an organic phase; Step 3: Add potassium carbonate with a mass 0.08 - 0.1 times that of the toluene to the obtained organic phase. After mixing and stirring evenly, slowly dropwise add ethyl chloroformate equal in amount to the potassium carbonate at a temperature of 50 - 80 °C. After mixing and stirring evenly, keep the temperature at 65 - 75 °C for heat preservation reaction for 1 - 2 h. After the reaction is completed, distill out ethanol under the condition of 79 °C. Then distill out the azeotrope of toluene and water at a temperature of 85 - 9 °C. After the recovery is completed, lower the temperature of the remaining product components to 60 - 70 °C; Step 4: Add a reaction promoter with a mass 0.06 - 0.1 times that of the potassium carbonate to the remaining product components in Step 3. After mixing evenly, raise the temperature to 80 - 90 °C, and keep the temperature for reaction for 50 - 80 min. Take a sample of the reaction solution for analysis, and it is qualified when the residual acyl compound is less than 3%. After the sampling test is qualified, sequentially add distilled water with a mass 25 - 35 times that of the reaction promoter and glacial acetic acid with a mass 1.5 - 2.5 times that of the reaction promoter thereto under stirring conditions. After mixing evenly, let it stand for 10 - 20 min at a temperature of 70 - 80 °C. The obtained toluene layer is to be concentrated and crystallized, and the water layer is separated into a transfer kettle. Under stirring conditions, add toluene with a mass 8 - 10 times that of the glacial acetic acid to the water layer in the transfer kettle, and let it stand for 10 - 20 min at a temperature of 70 - 80 °C, and then separate the water layer. The water layer is separated into a high-salt wastewater tank, and the toluene layer is put into a toluene receiving tank; Step 5: Dilute and filter the concentrated toluene, then proceed with concentration and crystallization, centrifugal filtration, vacuum drying and granulation processes, and finally package and store it in the warehouse. The final product is S-(+)-4-phenyl-2-oxazolidinone.

2. The synthetic process for S-(+)-4-phenyl-2-oxazolidinone according to claim 1, characterized in that: The borane reagent is selected from any one of borane tetrahydrofuran, borane dimethyl sulfide, and borane pyridine.

3. The synthetic process for S-(+)-4-phenyl-2-oxazolidinone according to claim 1, characterized in that: In step one, tetrahydrofuran is recovered by atmospheric distillation, with the temperature set at 60–80°C and the recovery time controlled at 2–2.5 h.

4. The synthetic process for S-(+)-4-phenyl-2-oxazolidinone according to claim 1, characterized in that, The method for preparing the alkali solution in step two is as follows: mix a 30% sodium hydroxide solution with distilled water at a mass ratio of 2:1, and stir at a temperature of 50-60°C for 1-2 hours until the mixture becomes clear. The resulting product is the alkali solution.

5. The synthesis process of S-(+)-4-phenyl-2-oxazolidinone according to claim 1, characterized in that: When adding concentrated sulfuric acid, the temperature should be controlled between 10 and 40°C, the time between 4.0 and 6.0 h, and the dropping rate between 11 and 13 L / h.

6. The synthetic process for S-(+)-4-phenyl-2-oxazolidinone according to claim 1, characterized in that, The reaction promoter in step four can be either potassium tert-butoxide or sodium tert-butoxide.

7. The synthesis process of S-(+)-4-phenyl-2-oxazolidinone according to claim 1, characterized in that, The specific operation of dilution and filtration in step five is as follows: add anhydrous ethanol with a mass of 8 to 10 times that of glacial acetic acid to the toluene layer to be concentrated for dilution, and then filter it through a basket filter into a crystallization tank.

8. The synthetic process for S-(+)-4-phenyl-2-oxazolidinone according to claim 1, characterized in that, During concentration and crystallization, atmospheric distillation is used, and the temperature of the crystallizer is 20-40℃. The cooling water in the jacket of the crystallizer is depressurized, and the chilled brine in the jacket of the crystallizer is turned on to maintain the temperature of the crystallizer at 5-15℃. Crystals are grown at this temperature for 3 hours.

9. The synthetic process for S-(+)-4-phenyl-2-oxazolidinone according to claim 1, characterized in that, During centrifugal filtration, the material from the crystallization vessel is pressurized into a bottom-discharge centrifuge with nitrogen gas, rinsed with toluene at 3-8°C, and then dried to obtain S-(+)-4-phenyl-2-oxazolidinone wet product.

10. The synthesis process of S-(+)-4-phenyl-2-oxazolidinone according to claim 1, characterized in that: When vacuum drying S-(+)-4-phenyl-2-oxazolidinone, it is placed in a rotary dryer for vacuum drying, the water temperature of the hot water tank is controlled at 60-80℃, the vacuum degree is ≤-0.085MPa, and the drying time is set to 8-12h.