Chiral R-styralyl acetate and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to chiral R-styralyl acetate and a preparation method thereof. The chiral R-styralyl acetate is subjected to functional modification through methylsulfonyl chloride, high-selectivity inhibition on COX-2 is realized through dihydrogen bond anchoring, the inhibition rate of a non-steroidal drug on COX-1 is reduced, and adverse reaction on gastrointestinal tracts after the non-steroidal drug is taken for a long time is relieved; a free radical bromination system composed of N-bromo-succinimide and benzylamine peroxide is adopted to replace traditional bromine, meanwhile, a triphenylphosphine ligand is introduced to serve as a steric hindrance modifier, a dynamic space barrier is constructed near alpha-C by reducing specific bromination activation energy at the alpha position, a halogen free radical attack path is limited in the alpha-C direction, and the steric hindrance modification effect is achieved. The conversion rate of the chiral R-styralyl acetate is increased, so that the obtained chiral R-styralyl acetate non-steroidal drug has both high drug effect and low gastrointestinal toxicity.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to chiral R-type styraxyl acetate and a preparation method thereof. Background Art

[0002] Nonsteroidal anti-inflammatory drugs (NSAIDs) are a class of medications with anti-inflammatory, analgesic, and antipyretic effects. They are one of the most prescribed medications worldwide and are widely used in the clinical treatment of various diseases, especially in the clinical treatment of rheumatic diseases. However, due to the inhibition of COX-1 by NSAIDs, patients taking NSAIDs long-term are at risk of severe gastrointestinal damage. With the discovery of COX-2, an isoenzyme of COX-1, NSAIDs with selective COX-2 inhibition were developed in an effort to mitigate the drug's adverse gastrointestinal effects.

[0003] Chiral R-styraxyl acetate is an organic compound with a specific stereoconfiguration. It is an ester derivative and is optically active. Styraxyl ester compounds typically have a floral and fruity aroma and can be used as pharmaceutical intermediates in the synthesis of non-steroidal anti-inflammatory drugs or neuroactive molecules. Chiral R-styraxyl acetate can generally be synthesized by preparing the intermediate α-halogenated ethylbenzene from ethylbenzene. However, in the α-halogenation reaction of ethylbenzene, halogen free radicals easily attack the β-carbon, leading to the formation of side reactions and subsequent halogen residues. Traditional processes usually control the reaction selectivity by lowering the temperature or increasing the polarity of the solvent, but the results are limited, and the conversion rate of chiral R-styraxyl acetate is very low. Summary of the Invention

[0004] The object of the present invention is to provide a chiral R-type styraxyl acetate and a preparation method thereof to solve the above technical problems.

[0005] In order to achieve the above technical objectives, the technical solution of the present invention is: A method for preparing chiral R-type styraxyl acetate is characterized by comprising the following steps.

[0006] S1. Ethylbenzene and a mixed solvent of n-hexane / acetonitrile were added to a reactor in a mass ratio of 1:4. The mixture was stirred at -5°C and 120 rpm for 10 min. Then, a free radical bromination system consisting of N-bromosuccinimide and benzoyl peroxide was added under a nitrogen atmosphere. The mixture was stirred at 400 rpm for 15 min. The mixture was heated to 15°C and the initiator solution was injected to initiate the reaction. S2. When the initiation reaction is carried out for 80 minutes, the temperature is raised to 25°C at a rate of 2°C / min to continue the reaction; when the initiation reaction is carried out for 2 hours, a 0.1-0.3 mol / L 2,6-di-tert-butyl-p-cresol solution with ethanol as the solvent is injected. After the reaction is completed, the mixture is quenched and allowed to stand for decomposition, and the upper organic phase is separated. After extraction and purification, α-bromoethylbenzene is obtained; S3. α-Bromoethylbenzene and vinyl acetate were mixed in a molar ratio of 1:1.2, and the mixture was catalyzed by nano-alumina-supported KF catalyst at 120°C for 6 hours. The resulting product was added to the active complex, followed by addition of p-methanesulfonyl chloride, and the mixture was refluxed at 90°C for 4 hours. After completion of the reaction, the mixture was quenched, extracted, and purified to obtain functionalized chiral R-type styraxyl acetate.

[0007] As a further improvement, in step S1, the preparation method of the initiator solution is as follows: 1.0 mol of 2-aminoanthraquinone and 2.3 mol of triphenyl phosphite are dissolved in 120 mL of N,N-dimethylformamide, and refluxed at 120°C for 2 hours under a nitrogen atmosphere to obtain a phosphinimine intermediate. After the reaction is completed, the temperature is lowered to -10°C, 1.5 mol of 1,3-dimethylimidazole iodide is added, the reaction is stirred at 200 rpm for 3 hours, and then extracted with supercritical CO2 to obtain an initiator solution.

[0008] As a further improvement, in step S1, the preparation method of the n-hexane / acetonitrile mixed solvent is as follows: under a nitrogen atmosphere, weigh 700 mL of n-hexane; measure 300 mL of acetonitrile, preheat it to 30° C., and then add it dropwise to the n-hexane at a rate of 5 mL / min at 800 rpm. After mixing, add triphenylphosphine, and stir at 25° C. for 30 minutes to obtain a n-hexane / acetonitrile mixed solvent; wherein the amount of triphenylphosphine added is 0.5~1.2 mol% of the n-hexane.

[0009] As a further improvement, in step S3, the active complex is prepared by mixing nitrobenzene and dichloromethane in a volume ratio of 1:2, adding anhydrous ferric chloride in an amount of 1.2% of the total mass of nitrobenzene and dichloromethane, heating to 60° C., and stirring at 600 rpm for 30 minutes to obtain the active complex.

[0010] As a further improvement, in step S1, the amount of the free radical bromination system added is 0.8~1.6wt% of ethylbenzene, wherein the molar ratio of N-bromosuccinimide to benzoyl peroxide is 10:1; the amount of the initiator solution added is 12~18wt% of ethylbenzene; in step S2, the amount of the 2,6-di-tert-butyl-p-cresol solution added is 3~5wt% of the free radical bromination system; in step S3, the amount of the nano-alumina-loaded KF catalyst is 3% of the total mass of α-bromoethylbenzene and vinyl acetate, and the KF loading is 30wt% of the nano-alumina. As a further improvement, in step S2, the specific initiation method of the initiation reaction is: using ultraviolet light irradiation to initiate the reaction, the main wavelength of the ultraviolet light is 254nm, and the irradiation intensity is 50mW / cm 2 , the irradiation time is 2h.

[0011] As a further improvement, in step S2, the specific method of extraction and purification is: according to a volume ratio of 1:1, the obtained upper organic phase is mixed with 5wt% Na2S2O3 solution, and centrifuged at 5000rpm for 10min. After centrifugation, according to the column volume: sample volume = 1:2, the flow rate is 2BV / h, the upper organic phase is taken and passed through a 3Å molecular sieve column, and the effluent is distilled under reduced pressure at 60°C and 10kPa to obtain α-bromoethylbenzene.

[0012] The present invention also provides a chiral R-type styraxyl acetate.

[0013] Due to the adoption of the above technical solution, the present invention has the following beneficial effects: 1. To inhibit halogen attack on non-target sites, triphenylphosphine ligand was introduced as a steric hindrance modifier. The weak coordination bond formed by the lone pair electrons of the phosphorus atom of triphenylphosphine and N-bromosuccinimide can construct a dynamic spatial barrier near the α-C where the energy barrier is relatively low. The aromatic ring structure of the triphenyl group limits the attack path of the halogen free radical to the α-C direction through the steric hindrance effect, thereby reducing the probability of β-position attack, improving the conversion rate of chiral R-type styraxyl acetate, and reducing the formation of by-products.

[0014] 2. Functionalization of chiral R-styraxyl acetate with methanesulfonyl chloride. The side-chain isopropyl group of COX-1 and the methyl substituent of the sulfonylamino group undergo van der Waals repulsion. The sulfonylamino group, however, can anchor COX-2 through double hydrogen bonds, forming hydrogen bonds with the -SO2-O and -NH2- groups in COX-2. This achieves highly selective inhibition of COX-2, reduces the inhibitory rate of chiral R-styraxyl acetate nonsteroidal drugs on COX-1, and thus mitigates the adverse gastrointestinal reactions of nonsteroidal drugs.

[0015] 3. A free radical bromination system consisting of N-bromosuccinimide and benzylamine peroxide is used instead of traditional bromine. The succinimide group in N-bromosuccinimide can stabilize the free radical transition state of the α-position of ethylbenzene through an electron-withdrawing effect, reduce the activation energy of specific bromination at the α-position, achieve α-position specific bromination under mild conditions, and reduce the formation of by-products. The benzoyloxy radical produced by the decomposition of benzoyl peroxide can selectively capture the α-CH in ethylbenzene, reduce the attack probability of the β-position, and improve the conversion rate of chiral R-type styraxyl acetate. DETAILED DESCRIPTION

[0016] The technical scheme of the present invention will be clearly and completely described below in conjunction with specific embodiments, but it will be understood by those skilled in the art that the following described embodiments are part of embodiments of the present invention, rather than all embodiments, and are only used to illustrate the present invention, and should not be considered as limiting the scope of the present invention. Based on the embodiments in the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative work premise belong to the scope of protection of the present invention. Those who do not specify specific conditions in the embodiments are carried out according to normal conditions or the conditions recommended by the manufacturer. Those whose reagents or instruments are not specified by the manufacturer are conventional products that can be purchased commercially.

[0017] Example 1 A method for preparing chiral R-type styraxyl acetate and its non-steroidal drug preparation comprises the following steps: 1. Optimization of α-bromoethylbenzene preparation process: 1. Preparation of initiator solution: 1.0 mol of 2-aminoanthraquinone and 2.3 mol of triphenyl phosphite were dissolved in 120 mL of N,N-dimethylformamide, and refluxed at 120°C for 2 h under a nitrogen atmosphere to obtain a phosphinimine intermediate. The temperature was lowered to -10°C, 1.5 mol of 1,3-dimethylimidazolium iodide was added, and the mixture was stirred at 200 rpm for 3 h. The crude product was placed in a supercritical CO2 extraction device and extracted at a pressure of 20 MPa and 50°C for 3 h to remove unreacted monomers and residual solvent to obtain an initiator solution. The reaction equation of the phosphinimine intermediate is: .

[0018] 2. n-Hexane / acetonitrile mixed solvent: Under a nitrogen atmosphere, weigh 700 mL of n-hexane; measure 300 mL of acetonitrile, preheat to 30°C, and add it dropwise to the n-hexane at a rate of 5 mL / min at 800 rpm. After mixing, add triphenylphosphine and stir at 25°C for 30 min to obtain a n-hexane / acetonitrile mixed solvent; wherein the added amount of triphenylphosphine is 0.5 mol% of the n-hexane.

[0019] 3. Reaction system construction: Ethylbenzene and a mixed solvent of n-hexane / acetonitrile were added to a reactor in a mass ratio of 1:4. After stirring at -5°C and 120 rpm for 10 min, a free radical bromination system consisting of N-bromosuccinimide and benzoyl peroxide was added at a feeding rate of 1.5 mL / min under a nitrogen atmosphere. After stirring at 400 rpm for 15 min, the temperature was raised to 15°C, the initiator solution was injected, and ultraviolet irradiation was turned on. The main wavelength of ultraviolet light was 254 nm and the irradiation intensity was 50 mW / cm 2, the irradiation time is 2h, and the initiation reaction is carried out; wherein, the addition amount of the free radical bromination system is 0.8wt% of ethylbenzene; the molar ratio of N-bromosuccinimide to benzoyl peroxide is 10:1; the addition amount of the initiator solution is 12wt% of ethylbenzene.

[0020] 4. When the initiation reaction is carried out for 80 minutes, the temperature is raised to 25°C at a rate of 2°C / min and the reaction is continued; when the initiation reaction is carried out for 2 hours, 0.1 mol / L 2,6-di-tert-butyl-p-cresol solution is injected. After the reaction is completed, it is quenched with hydroquinone for 30 seconds. After standing and stratification, the upper organic phase is separated to obtain a crude product of α-bromoethylbenzene; wherein the addition amount of the 2,6-di-tert-butyl-p-cresol solution is 3wt% of the free radical bromination system.

[0021] 2. Purification of brominated products and removal of bromine 1. Extraction and purification: Mix the crude α-bromoethylbenzene with a 5 wt% Na2S2O3 solution in a volume ratio of 1:1 and centrifuge at 5000 rpm for 10 min. After centrifugation, pass the upper organic phase through a 3Å molecular sieve column at a column volume: sample volume ratio of 1:2 and a flow rate of 2 BV / h. Distill the effluent under reduced pressure at 60°C and 10 kPa to obtain α-bromoethylbenzene.

[0022] 3. Preparation of Chiral R-type Styraxyl Acetate: 1. Mix nitrobenzene and dichloromethane in a volume ratio of 1:2, add 1.2% anhydrous ferric chloride based on the total mass of nitrobenzene and dichloromethane, heat to 60°C, and stir at 600 rpm for 30 minutes to obtain an active complex.

[0023] 2. Mix α-bromoethylbenzene and vinyl acetate in a molar ratio of 1:1.2, add nano-alumina-supported KF catalyst, and carry out catalytic reaction at 120°C for 6 hours; after the reaction is completed, add the obtained product to the active complex, then add p-toluenesulfonyl chloride, and reflux at 90°C for 4 hours. After the reaction is completed, quench with ice water for 30 minutes, extract with ether, separate the upper organic phase, and pass through a silica gel column (V 石油醚 :V 乙酸乙酯 =5:1) chromatography purification to obtain functionalized chiral R-type styraxyl acetate; wherein the amount of nano-alumina-supported KF catalyst is 3% of the total mass of α-bromoethylbenzene and vinyl acetate, and the KF loading amount is 30wt% of the nano-alumina.

[0024] 4. Preparation of functional chiral R-type styroyl acetate-based non-steroidal drugs 1. Under a nitrogen atmosphere, anhydrous tetrahydrofuran was precooled to -78°C; using precooled anhydrous tetrahydrofuran as a solvent, 1.0 mol of functional chiral R-type styraxyl acetate, 1.2 mol of diethyl malonate, and 2.5 mol of lithium diisopropylamide were slowly added dropwise to the functional chiral R-type styraxyl acetate. After stirring at 600 rpm for 30 minutes, diethyl malonate was added dropwise. After reacting for 4 hours, the mixture was cooled to 0°C and saturated NH4Cl was slowly added dropwise. After quenching for 30 minutes, the mixture was extracted with ethyl acetate, separated, and dried with anhydrous Na2SO4 for 2 hours. The mixture was filtered and distilled under reduced pressure at 1.5 mmHg and 65°C for 1 hour to obtain a β-ketoester intermediate. The reaction equation of the β-ketoester intermediate is: .

[0025] 2. Take 1.5 mol of iodomethane, 2.0 mol of potassium carbonate, and 1.0 mol of β-ketoester intermediate, mix the β-ketoester intermediate and potassium carbonate, dissolve in 150 mL of acetone, add iodomethane dropwise, stir at 60°C and 800 rpm for 25 min, filter, and concentrate under reduced pressure at 2.0 kPa, 35°C, and 150 rpm for 45 min to obtain an α-methylated product; take 1.2 mol of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1.5 mol of N-hydroxysuccinimide, mix them evenly, and stir at 40°C and 600 rpm for 20 min to obtain a silane coupling agent; the reaction equation of the α-methylated product is: .

[0026] 3. Using 200 mL of anhydrous N,N-dimethylformamide as solvent, under a nitrogen atmosphere, 1.0 mol of the α-methylated product was mixed with 1.1 mol of cysteine ​​ethyl ester, and the mixture was stirred at 400 rpm for 35 min at room temperature. After the reaction was completed, 200 mL of icy ether was added, and the mixture was centrifuged at 1000 rpm for 10 min. The supernatant was discarded, and the resulting product was washed with acetonitrile and methanol in sequence, and dried at 45°C under a vacuum of 1.0 mmHg for 4 h to obtain a functional chiral R-type styroyl acetate non-steroidal drug; the reaction equation for the functional chiral R-type styroyl acetate non-steroidal drug is as follows: .

[0027] Example 2 A method for preparing chiral R-type styraxyl acetate and its non-steroidal drug preparation comprises the following steps: 1. Optimization of α-bromoethylbenzene preparation process: 1. Preparation of initiator solution: 1.0 mol of 2-aminoanthraquinone and 2.3 mol of triphenyl phosphite were dissolved in 120 mL of N,N-dimethylformamide. Under a nitrogen atmosphere, the mixture was refluxed at 120 ° C for 2 h to obtain a phosphinimine intermediate. The mixture was cooled to -10 ° C, 1.5 mol of 1,3-dimethylimidazole iodide was added, and the mixture was stirred at 200 rpm for 3 h. The crude product was placed in a supercritical CO2 extraction device and extracted at a pressure of 20 MPa and 50 ° C for 3 h to remove unreacted monomers and solvent residues to obtain an initiator solution.

[0028] 2. n-Hexane / acetonitrile mixed solvent: Under a nitrogen atmosphere, weigh 700 mL of n-hexane; measure 300 mL of acetonitrile, preheat to 30°C, and add it dropwise to the n-hexane at a rate of 5 mL / min at 800 rpm. After mixing, add triphenylphosphine and stir at 25°C for 30 min to obtain a n-hexane / acetonitrile mixed solvent; wherein the added amount of triphenylphosphine is 1.0 mol% of the n-hexane.

[0029] 3. Reaction system construction: Ethylbenzene and a mixed solvent of n-hexane / acetonitrile were added to a reactor in a mass ratio of 1:4. After stirring at -5°C and 120 rpm for 10 min, a free radical bromination system consisting of N-bromosuccinimide and benzoyl peroxide was added at a feeding rate of 1.5 mL / min under a nitrogen atmosphere. After stirring at 400 rpm for 15 min, the temperature was raised to 15°C, the initiator solution was injected, and ultraviolet light irradiation was turned on. The main wavelength of ultraviolet light was 254 nm and the irradiation intensity was 50 mW / cm 2 , the irradiation time is 2h, and the initiation reaction is carried out; wherein, the addition amount of the free radical bromination system is 1.2wt% of ethylbenzene; the molar ratio of N-bromosuccinimide to benzoyl peroxide is 10:1; the addition amount of the initiator solution is 14wt% of ethylbenzene.

[0030] 4. When the initiation reaction is carried out for 80 minutes, the temperature is raised to 25°C at a rate of 2°C / min and the reaction is continued; when the initiation reaction is carried out for 2 hours, 0.2 mol / L 2,6-di-tert-butyl-p-cresol solution is injected. After the reaction is completed, it is quenched with hydroquinone for 30 seconds. After standing and stratification, the upper organic phase is separated to obtain a crude product of α-bromoethylbenzene; wherein the addition amount of the 2,6-di-tert-butyl-p-cresol solution is 4wt% of the free radical bromination system.

[0031] 2. Purification of brominated products and removal of bromine 1. Extraction and purification: Mix the crude α-bromoethylbenzene with a 5 wt% Na2S2O3 solution in a volume ratio of 1:1 and centrifuge at 5000 rpm for 10 min. After centrifugation, pass the upper organic phase through a 3Å molecular sieve column at a column volume: sample volume ratio of 1:2 and a flow rate of 2 BV / h. Distill the effluent under reduced pressure at 60°C and 10 kPa to obtain α-bromoethylbenzene.

[0032] 3. Preparation of Chiral R-type Styraxyl Acetate: 1. Mix nitrobenzene and dichloromethane in a volume ratio of 1:2, add 1.2% anhydrous ferric chloride based on the total mass of nitrobenzene and dichloromethane, heat to 60°C, and stir at 600 rpm for 30 minutes to obtain an active complex.

[0033] 2. Mix α-bromoethylbenzene and vinyl acetate in a molar ratio of 1:1.2, add nano-alumina-supported KF catalyst, and carry out catalytic reaction at 120°C for 6 hours; after the reaction is completed, add the obtained product to the active complex, then add p-toluenesulfonyl chloride, and reflux at 90°C for 4 hours. After the reaction is completed, quench with ice water for 30 minutes, extract with ether, separate the upper organic phase, and pass through a silica gel column (V 石油醚 :V 乙酸乙酯 =5:1) chromatography purification to obtain functionalized chiral R-type styraxyl acetate; wherein the amount of nano-alumina-supported KF catalyst is 3% of the total mass of α-bromoethylbenzene and vinyl acetate, and the KF loading amount is 30wt% of the nano-alumina.

[0034] 4. Preparation of functional chiral R-type styroyl acetate-based non-steroidal drugs 1. Under a nitrogen atmosphere, precool anhydrous tetrahydrofuran to -78°C; using precooled anhydrous tetrahydrofuran as a solvent, take 1.0 mol of functional chiral R-type styraxyl acetate, 1.2 mol of diethyl malonate, and 2.5 mol of lithium diisopropylamide, slowly add lithium diisopropylamide to the functional chiral R-type styraxyl acetate, stir at 600 rpm for 30 minutes, then add diethyl malonate dropwise, react for 4 hours, cool to 0°C, slowly add saturated NH4Cl dropwise, quench for 30 minutes, extract with ethyl acetate, separate, add anhydrous Na2SO4, dry for 2 hours, filter, and distill under reduced pressure at 1.5 mmHg and 65°C for 1 hour to obtain a β-ketoester intermediate.

[0035] 2. Take 1.5 mol of iodomethane, 2.0 mol of potassium carbonate, and 1.0 mol of β-ketoester intermediate, mix the β-ketoester intermediate and potassium carbonate, dissolve in 150 mL of acetone, add iodomethane dropwise, stir at 60°C and 800 rpm for 25 min, filter, and concentrate under reduced pressure at 2.0 kPa, 35°C, and 150 rpm for 45 min to obtain an α-methylated product; take 1.2 mol of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1.5 mol of N-hydroxysuccinimide, mix them evenly, and stir at 40°C and 600 rpm for 20 min to obtain a silane coupling agent.

[0036] 3. Using 200 mL of anhydrous N,N-dimethylformamide as solvent, under a nitrogen atmosphere, 1.0 mol of the α-methylated product was mixed with 1.1 mol of cysteine ​​ethyl ester. The mixture was stirred at 400 rpm at room temperature for 35 min. After the reaction was completed, 200 mL of icy ether was added and the mixture was centrifuged at 1000 rpm for 10 min. The supernatant was discarded and the resulting product was washed with acetonitrile and methanol in sequence. It was dried at 45°C under a vacuum of 1.0 mmHg for 4 h to obtain a functional chiral R-type styroyl acetate non-steroidal drug.

[0037] Example 3 A method for preparing chiral R-type styraxyl acetate and its non-steroidal drug preparation comprises the following steps: 1. Optimization of α-bromoethylbenzene preparation process: 1. Preparation of initiator solution: 1.0 mol of 2-aminoanthraquinone and 2.3 mol of triphenyl phosphite were dissolved in 120 mL of N,N-dimethylformamide. Under a nitrogen atmosphere, the mixture was refluxed at 120 ° C for 2 h to obtain a phosphinimine intermediate. The mixture was cooled to -10 ° C, 1.5 mol of 1,3-dimethylimidazole iodide was added, and the mixture was stirred at 200 rpm for 3 h. The crude product was placed in a supercritical CO2 extraction device and extracted at a pressure of 20 MPa and 50 ° C for 3 h to remove unreacted monomers and solvent residues to obtain an initiator solution.

[0038] 2. n-Hexane / acetonitrile mixed solvent: Under a nitrogen atmosphere, weigh 700 mL of n-hexane; measure 300 mL of acetonitrile, preheat to 30°C, and add it dropwise to the n-hexane at a rate of 5 mL / min at 800 rpm. After mixing, add triphenylphosphine and stir at 25°C for 30 min to obtain a n-hexane / acetonitrile mixed solvent; the amount of triphenylphosphine added is 1.2 mol% of the n-hexane.

[0039] 3. Reaction system construction: Ethylbenzene and a mixed solvent of n-hexane / acetonitrile were added to a reactor in a mass ratio of 1:4. After stirring at -5°C and 120 rpm for 10 min, a free radical bromination system consisting of N-bromosuccinimide and benzoyl peroxide was added at a feeding rate of 1.5 mL / min under a nitrogen atmosphere. After stirring at 400 rpm for 15 min, the temperature was raised to 15°C, the initiator solution was injected, and ultraviolet irradiation was turned on. The main wavelength of ultraviolet light was 254 nm and the irradiation intensity was 50 mW / cm 2 , the irradiation time is 2h, and the initiation reaction is carried out; wherein, the addition amount of the free radical bromination system is 1.6wt% of ethylbenzene; the molar ratio of N-bromosuccinimide to benzoyl peroxide is 10:1; the addition amount of the initiator solution is 18wt% of ethylbenzene.

[0040] 4. When the initiation reaction is carried out for 80 minutes, the temperature is raised to 25°C at a rate of 2°C / min and the reaction is continued; when the initiation reaction is carried out for 2 hours, 0.3 mol / L 2,6-di-tert-butyl-p-cresol solution is injected. After the reaction is completed, it is quenched with hydroquinone for 30 seconds. After standing and stratification, the upper organic phase is separated to obtain a crude product of α-bromoethylbenzene; wherein the addition amount of the 2,6-di-tert-butyl-p-cresol solution is 5wt% of the free radical bromination system.

[0041] 2. Purification of brominated products and removal of bromine 1. Extraction and purification: Mix the crude α-bromoethylbenzene with a 5 wt% Na2S2O3 solution in a volume ratio of 1:1 and centrifuge at 5000 rpm for 10 min. After centrifugation, pass the upper organic phase through a 3Å molecular sieve column at a column volume: sample volume ratio of 1:2 and a flow rate of 2 BV / h. Distill the effluent under reduced pressure at 60°C and 10 kPa to obtain α-bromoethylbenzene.

[0042] 3. Preparation of Chiral R-type Styraxyl Acetate: 1. Mix nitrobenzene and dichloromethane in a volume ratio of 1:2, add 1.2% anhydrous ferric chloride based on the total mass of nitrobenzene and dichloromethane, heat to 60°C, and stir at 600 rpm for 30 minutes to obtain an active complex.

[0043] 2. Mix α-bromoethylbenzene and vinyl acetate in a molar ratio of 1:1.2, add nano-alumina-supported KF catalyst, and carry out catalytic reaction at 120°C for 6 hours; after the reaction is completed, add the obtained product to the active complex, then add p-toluenesulfonyl chloride, and reflux at 90°C for 4 hours. After the reaction is completed, quench with ice water for 30 minutes, extract with ether, separate the upper organic phase, and pass through a silica gel column (V 石油醚 :V 乙酸乙酯=5:1) chromatography purification to obtain functionalized chiral R-type styraxyl acetate; wherein the amount of nano-alumina-supported KF catalyst is 3% of the total mass of α-bromoethylbenzene and vinyl acetate, and the KF loading amount is 30wt% of the nano-alumina.

[0044] 4. Preparation of functional chiral R-type styroyl acetate-based non-steroidal drugs 1. Under a nitrogen atmosphere, precool anhydrous tetrahydrofuran to -78°C; using precooled anhydrous tetrahydrofuran as a solvent, take 1.0 mol of functional chiral R-type styraxyl acetate, 1.2 mol of diethyl malonate, and 2.5 mol of lithium diisopropylamide, slowly add lithium diisopropylamide to the functional chiral R-type styraxyl acetate, stir at 600 rpm for 30 minutes, then add diethyl malonate dropwise, react for 4 hours, cool to 0°C, slowly add saturated NH4Cl dropwise, quench for 30 minutes, extract with ethyl acetate, separate, add anhydrous Na2SO4, dry for 2 hours, filter, and distill under reduced pressure at 1.5 mmHg and 65°C for 1 hour to obtain a β-ketoester intermediate.

[0045] 2. Take 1.5 mol of iodomethane, 2.0 mol of potassium carbonate, and 1.0 mol of β-ketoester intermediate, mix the β-ketoester intermediate and potassium carbonate, dissolve in 150 mL of acetone, add iodomethane dropwise, stir at 60°C and 800 rpm for 25 min, filter, and concentrate under reduced pressure at 2.0 kPa, 35°C, and 150 rpm for 45 min to obtain an α-methylated product; take 1.2 mol of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1.5 mol of N-hydroxysuccinimide, mix them evenly, and stir at 40°C and 600 rpm for 20 min to obtain a silane coupling agent.

[0046] 3. Using 200 mL of anhydrous N,N-dimethylformamide as solvent, under a nitrogen atmosphere, 1.0 mol of the α-methylated product was mixed with 1.1 mol of cysteine ​​ethyl ester. The mixture was stirred at 400 rpm at room temperature for 35 min. After the reaction was completed, 200 mL of icy ether was added and the mixture was centrifuged at 1000 rpm for 10 min. The supernatant was discarded and the resulting product was washed with acetonitrile and methanol in sequence. It was dried at 45°C under a vacuum of 1.0 mmHg for 4 h to obtain a functional chiral R-type styroyl acetate non-steroidal drug.

[0047] Comparative Example 1 A method for preparing chiral R-type styraxyl acetate and the preparation of a non-steroidal drug thereof, which differs from Example 1 in that the chiral R-type styraxyl acetate is not functionalized, specifically comprising the following steps: 1. Optimization of α-bromoethylbenzene preparation process: Preparation of initiator solution: Take 1.0 mol of 2-aminoanthraquinone and 2.3 mol of triphenyl phosphite, dissolve them in 120 mL of N,N-dimethylformamide, and reflux at 120°C for 2 hours under a nitrogen atmosphere to obtain a phosphinimine intermediate. Cool it to -10°C, add 1.5 mol of 1,3-dimethylimidazole iodide, stir and react at 200 rpm for 3 hours, and then place the obtained crude product in a supercritical CO2 extraction device, extract it at a pressure of 20 MPa and 50°C for 3 hours to remove unreacted monomers and solvent residues to obtain an initiator solution.

[0048] 2. n-Hexane / acetonitrile mixed solvent: Under a nitrogen atmosphere, weigh 700 mL of n-hexane; measure 300 mL of acetonitrile, preheat to 30°C, and add it dropwise to the n-hexane at a rate of 5 mL / min at 800 rpm. After mixing, add triphenylphosphine and stir at 25°C for 30 min to obtain a n-hexane / acetonitrile mixed solvent; wherein the added amount of triphenylphosphine is 0.5 mol% of the n-hexane.

[0049] 3. Reaction system construction: Ethylbenzene and a mixed solvent of n-hexane / acetonitrile were added to a reactor in a mass ratio of 1:4. After stirring at -5°C and 120 rpm for 10 min, a free radical bromination system consisting of N-bromosuccinimide and benzoyl peroxide was added at a feeding rate of 1.5 mL / min under a nitrogen atmosphere. After stirring at 400 rpm for 15 min, the temperature was raised to 15°C, the initiator solution was injected, and ultraviolet irradiation was turned on. The main wavelength of ultraviolet light was 254 nm and the irradiation intensity was 50 mW / cm 2 , the irradiation time is 2h, and the initiation reaction is carried out; the addition amount of the free radical bromination system is 0.8wt% of ethylbenzene, wherein the molar ratio of N-bromosuccinimide to benzoyl peroxide is 10:1; the addition amount of the initiator solution is 12wt% of ethylbenzene.

[0050] 4. When the initiation reaction is carried out for 80 minutes, the temperature is raised to 25°C at a rate of 2°C / min and the reaction is continued; when the initiation reaction is carried out for 2 hours, 0.1 mol / L 2,6-di-tert-butyl-p-cresol solution is injected. After the reaction is completed, it is quenched with hydroquinone for 30 seconds. After standing and stratification, the upper organic phase is separated to obtain a crude product of α-bromoethylbenzene; wherein the addition amount of the 2,6-di-tert-butyl-p-cresol solution is 3wt% of the free radical bromination system.

[0051] 2. Purification of brominated products and removal of bromine 1. Extraction and purification: Mix the crude α-bromoethylbenzene with a 5 wt% Na2S2O3 solution in a volume ratio of 1:1 and centrifuge at 5000 rpm for 10 min. After centrifugation, pass the upper organic phase through a 3Å molecular sieve column at a column volume: sample volume ratio of 1:2 and a flow rate of 2 BV / h. Distill the effluent under reduced pressure at 60°C and 10 kPa to obtain α-bromoethylbenzene.

[0052] 3. Preparation of Chiral R-type Styraxyl Acetate: 1. Mix nitrobenzene and dichloromethane in a volume ratio of 1:2, add 1.2% anhydrous ferric chloride based on the total mass of nitrobenzene and dichloromethane, heat to 60°C, and stir at 600 rpm for 30 minutes to obtain an active complex.

[0053] 2. Mix α-bromoethylbenzene and vinyl acetate in a molar ratio of 1:1.2, add nano-alumina-supported KF catalyst, and carry out catalytic reaction at 120°C for 6 hours; after the reaction is completed, quench with ice water for 30 minutes, extract with ether, separate the upper organic phase, and pass through a silica gel column (V 石油醚 :V 乙酸乙酯 =5:1) chromatography purification, chiral R-type styraxyl acetate was obtained; wherein, the amount of nano-alumina-supported KF catalyst was 3% of the total mass of α-bromoethylbenzene and vinyl acetate, and the KF loading amount was 30wt% of the nano-alumina.

[0054] 4. Preparation of Chiral R-Styroyl Acetate-Based Non-steroidal Drugs 1. Under a nitrogen atmosphere, anhydrous tetrahydrofuran was precooled to -78°C; using precooled anhydrous tetrahydrofuran as a solvent, 1.0 mol of chiral R-type styraxyl acetate, 1.2 mol of diethyl malonate, and 2.5 mol of lithium diisopropylamide were slowly added dropwise to the chiral R-type styraxyl acetate. After stirring at 600 rpm for 30 minutes, diethyl malonate was added dropwise. After reacting for 4 hours, the mixture was cooled to 0°C and saturated NH4Cl was slowly added dropwise. After quenching for 30 minutes, the mixture was extracted with ethyl acetate, separated, added with anhydrous Na2SO4, dried for 2 hours, filtered, and distilled under reduced pressure at 1.5 mmHg and 65°C for 1 hour to obtain a β-ketoester intermediate; the reaction equation of the β-ketoester intermediate is: .

[0055] 4. Take 1.5 mol of iodomethane, 2.0 mol of potassium carbonate, and 1.0 mol of β-ketoester intermediate, mix the β-ketoester intermediate and potassium carbonate, dissolve in 150 mL of acetone, add iodomethane dropwise, stir at 60°C and 800 rpm for 25 min, filter, and concentrate under reduced pressure at 2.0 kPa, 35°C, and 150 rpm for 45 min to obtain an α-methylated product; take 1.2 mol of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1.5 mol of N-hydroxysuccinimide, mix them evenly, and stir at 40°C and 600 rpm for 20 min to obtain a silane coupling agent; the reaction equation of the α-methylated product is: .

[0056] 5. Using 200 mL of anhydrous N,N-dimethylformamide as the solvent, under a nitrogen atmosphere, 1.0 mol of the α-methylated product was mixed with 1.1 mol of cysteine ​​ethyl ester, and the mixture was stirred at 400 rpm for 35 min at room temperature. After the reaction was completed, 200 mL of glacial ether was added, and the mixture was centrifuged at 1000 rpm for 10 min. The supernatant was discarded, and the resulting product was washed with acetonitrile and methanol in sequence, and dried at 45°C under a vacuum of 1.0 mmHg for 4 h to obtain a chiral R-type styroyl acetate non-steroidal drug. The reaction equation for the chiral R-type styroyl acetate non-steroidal drug is: .

[0057] Comparative Example 2 A method for preparing chiral R-type styraxyl acetate and its non-steroidal drug preparation, which differs from Example 1 in that a traditional bromine is used for the halogenation reaction, comprising the following steps: 1. Optimization of α-bromoethylbenzene preparation process: 1. Preparation of initiator solution: 1.0 mol of 2-aminoanthraquinone and 2.3 mol of triphenyl phosphite were dissolved in 120 mL of N,N-dimethylformamide. Under a nitrogen atmosphere, the mixture was refluxed at 120 ° C for 2 h to obtain a phosphinimine intermediate. The mixture was cooled to -10 ° C, 1.5 mol of 1,3-dimethylimidazole iodide was added, and the mixture was stirred at 200 rpm for 3 h. The crude product was placed in a supercritical CO2 extraction device and extracted at a pressure of 20 MPa and 50 ° C for 3 h to remove unreacted monomers and solvent residues to obtain an initiator solution.

[0058] 2. n-Hexane / acetonitrile mixed solvent: Under a nitrogen atmosphere, weigh 700 mL of n-hexane; measure 300 mL of acetonitrile, preheat to 30°C, and add it dropwise to the n-hexane at a rate of 5 mL / min at 800 rpm. After mixing, add triphenylphosphine and stir at 25°C for 30 min to obtain a n-hexane / acetonitrile mixed solvent; wherein the added amount of triphenylphosphine is 0.5 mol% of the n-hexane.

[0059] 3. Reaction system construction: Ethylbenzene and a mixed solvent of n-hexane / acetonitrile were added to a reactor at a mass ratio of 1:4. After stirring at -5°C and 120 rpm for 10 min, liquid bromine was added at a feeding rate of 1.5 mL / min under a nitrogen atmosphere. After stirring at 400 rpm for 15 min, the temperature was raised to 15°C, the initiator solution was injected, and ultraviolet light irradiation was turned on. The main wavelength of ultraviolet light was 254 nm and the irradiation intensity was 50 mW / cm 2 , the irradiation time is 2h, and the initiation reaction is carried out; the addition amount of the liquid bromine is 0.8wt% of ethylbenzene; the addition amount of the initiator solution is 12wt% of ethylbenzene.

[0060] 4. When the initiation reaction is carried out for 80 minutes, the temperature is raised to 25°C at a rate of 2°C / min and the reaction is continued; when the initiation reaction is carried out for 2 hours, 0.1 mol / L 2,6-di-tert-butyl-p-cresol solution is injected. After the reaction is completed, it is quenched with hydroquinone for 30 seconds. After standing and stratification, the upper organic phase is separated to obtain a crude product of α-bromoethylbenzene; wherein the addition amount of the 2,6-di-tert-butyl-p-cresol solution is 3wt% of the free radical bromination system.

[0061] 2. Purification of brominated products and removal of bromine 1. Extraction and purification: Mix the crude α-bromoethylbenzene with a 5 wt% Na2S2O3 solution in a volume ratio of 1:1 and centrifuge at 5000 rpm for 10 min. After centrifugation, pass the upper organic phase through a 3Å molecular sieve column at a column volume: sample volume ratio of 1:2 and a flow rate of 2 BV / h. Distill the effluent under reduced pressure at 60°C and 10 kPa to obtain α-bromoethylbenzene.

[0062] 3. Preparation of Chiral R-type Styraxyl Acetate: 1. Mix nitrobenzene and dichloromethane in a volume ratio of 1:2, add 1.2% anhydrous ferric chloride based on the total mass of nitrobenzene and dichloromethane, heat to 60°C, and stir at 600 rpm for 30 minutes to obtain an active complex.

[0063] 2. Mix α-bromoethylbenzene and vinyl acetate in a molar ratio of 1:1.2, add nano-alumina-supported KF catalyst, and carry out catalytic reaction at 120°C for 6 hours; after the reaction is completed, add the obtained product to the active complex, then add p-toluenesulfonyl chloride, and reflux at 90°C for 4 hours. After the reaction is completed, quench with ice water for 30 minutes, extract with ether, separate the upper organic phase, and pass through a silica gel column (V 石油醚 :V 乙酸乙酯 =5:1) chromatography purification to obtain functionalized chiral R-type styraxyl acetate; wherein the amount of nano-alumina-supported KF catalyst is 3% of the total mass of α-bromoethylbenzene and vinyl acetate, and the KF loading amount is 30wt% of the nano-alumina.

[0064] 4. Preparation of functional chiral R-type styroyl acetate-based non-steroidal drugs 1. Under a nitrogen atmosphere, precool anhydrous tetrahydrofuran to -78°C; using precooled anhydrous tetrahydrofuran as a solvent, take 1.0 mol of functional chiral R-type styraxyl acetate, 1.2 mol of diethyl malonate, and 2.5 mol of lithium diisopropylamide, slowly add lithium diisopropylamide to the functional chiral R-type styraxyl acetate, stir at 600 rpm for 30 minutes, then add diethyl malonate dropwise, react for 4 hours, cool to 0°C, slowly add saturated NH4Cl dropwise, quench for 30 minutes, extract with ethyl acetate, separate, add anhydrous Na2SO4, dry for 2 hours, filter, and distill under reduced pressure at 1.5 mmHg and 65°C for 1 hour to obtain a β-ketoester intermediate.

[0065] 2. Take 1.5 mol of iodomethane, 2.0 mol of potassium carbonate, and 1.0 mol of β-ketoester intermediate, mix the β-ketoester intermediate and potassium carbonate, dissolve in 150 mL of acetone, add iodomethane dropwise, stir at 60°C and 800 rpm for 25 min, filter, and concentrate under reduced pressure at 2.0 kPa, 35°C, and 150 rpm for 45 min to obtain an α-methylated product; take 1.2 mol of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1.5 mol of N-hydroxysuccinimide, mix them evenly, and stir at 40°C and 600 rpm for 20 min to obtain a silane coupling agent.

[0066] 3. Using 200 mL of anhydrous N,N-dimethylformamide as solvent, under a nitrogen atmosphere, 1.0 mol of the α-methylated product was mixed with 1.1 mol of cysteine ​​ethyl ester. The mixture was stirred at 400 rpm at room temperature for 35 min. After the reaction was completed, 200 mL of icy ether was added and the mixture was centrifuged at 1000 rpm for 10 min. The supernatant was discarded and the resulting product was washed with acetonitrile and methanol in sequence. It was dried at 45°C under a vacuum of 1.0 mmHg for 4 h to obtain a functional chiral R-type styroyl acetate non-steroidal drug.

[0067] Comparative Example 3 A method for preparing chiral R-type styraxyl acetate and its non-steroidal drug preparation, which differs from Example 1 in that the triphenylphosphine ligand in the n-hexane / acetonitrile solvent is removed, comprising the following steps: 1. Optimization of α-bromoethylbenzene preparation process: 1. Preparation of initiator solution: 1.0 mol of 2-aminoanthraquinone and 2.3 mol of triphenyl phosphite were dissolved in 120 mL of N,N-dimethylformamide. Under a nitrogen atmosphere, the mixture was refluxed at 120 ° C for 2 h to obtain a phosphinimine intermediate. The mixture was cooled to -10 ° C, 1.5 mol of 1,3-dimethylimidazole iodide was added, and the mixture was stirred at 200 rpm for 3 h. The crude product was placed in a supercritical CO2 extraction device and extracted at a pressure of 20 MPa and 50 ° C for 3 h to remove unreacted monomers and solvent residues to obtain an initiator solution.

[0068] 2. n-Hexane / acetonitrile mixed solvent: Under nitrogen atmosphere, weigh 700 mL of n-hexane; weigh 300 mL of acetonitrile, preheat to 30°C, and then add them dropwise to the n-hexane at a rate of 5 mL / min at 800 rpm. After mixing, the n-hexane / acetonitrile mixed solvent was obtained.

[0069] 3. Reaction system construction: Ethylbenzene and a mixed solvent of n-hexane / acetonitrile were added to a reactor in a mass ratio of 1:4. After stirring at -5°C and 120 rpm for 10 min, a free radical bromination system consisting of N-bromosuccinimide and benzoyl peroxide was added at a feeding rate of 1.5 mL / min under a nitrogen atmosphere. After stirring at 400 rpm for 15 min, the temperature was raised to 15°C, the initiator solution was injected, and ultraviolet irradiation was turned on. The main wavelength of ultraviolet light was 254 nm and the irradiation intensity was 50 mW / cm 2 , the irradiation time is 2h, and the initiation reaction is carried out; the addition amount of the free radical bromination system is 0.8wt% of ethylbenzene, wherein the molar ratio of N-bromosuccinimide to benzoyl peroxide is 10:1; the addition amount of the initiator solution is 12wt% of ethylbenzene.

[0070] 4. When the initiation reaction is carried out for 80 minutes, the temperature is raised to 25°C at a rate of 2°C / min and the reaction is continued; when the initiation reaction is carried out for 2 hours, 0.1 mol / L 2,6-di-tert-butyl-p-cresol solution is injected. After the reaction is completed, it is quenched with hydroquinone for 30 seconds. After standing and stratification, the upper organic phase is separated to obtain a crude product of α-bromoethylbenzene; wherein the addition amount of the 2,6-di-tert-butyl-p-cresol solution is 3wt% of the free radical bromination system.

[0071] 2. Purification of brominated products and removal of bromine 1. Extraction and purification: Mix the crude α-bromoethylbenzene with a 5 wt% Na2S2O3 solution in a volume ratio of 1:1 and centrifuge at 5000 rpm for 10 min. After centrifugation, pass the upper organic phase through a 3Å molecular sieve column at a column volume: sample volume ratio of 1:2 and a flow rate of 2 BV / h. Distill the effluent under reduced pressure at 60°C and 10 kPa to obtain α-bromoethylbenzene.

[0072] 3. Preparation of Chiral R-type Styraxyl Acetate: 1. Mix nitrobenzene and dichloromethane in a volume ratio of 1:2, add 1.2% anhydrous ferric chloride based on the total mass of nitrobenzene and dichloromethane, heat to 60°C, and stir at 600 rpm for 30 minutes to obtain an active complex.

[0073] 2. Mix α-bromoethylbenzene and vinyl acetate in a molar ratio of 1:1.2, add nano-alumina-supported KF catalyst, and carry out catalytic reaction at 120°C for 6 hours; after the reaction is completed, add the obtained product to the active complex, then add p-toluenesulfonyl chloride, and reflux at 90°C for 4 hours. After the reaction is completed, quench with ice water for 30 minutes, extract with ether, separate the upper organic phase, and pass through a silica gel column (V 石油醚 :V 乙酸乙酯 =5:1) chromatography purification to obtain functionalized chiral R-type styraxyl acetate; wherein the amount of nano-alumina-supported KF catalyst is 3% of the total mass of α-bromoethylbenzene and vinyl acetate, and the KF loading amount is 30wt% of the nano-alumina.

[0074] 4. Preparation of functional chiral R-type styroyl acetate-based non-steroidal drugs 1. Under a nitrogen atmosphere, precool anhydrous tetrahydrofuran to -78°C; using precooled anhydrous tetrahydrofuran as a solvent, take 1.0 mol of functional chiral R-type styraxyl acetate, 1.2 mol of diethyl malonate, and 2.5 mol of lithium diisopropylamide, slowly add lithium diisopropylamide to the functional chiral R-type styraxyl acetate, stir at 600 rpm for 30 minutes, then add diethyl malonate dropwise, react for 4 hours, cool to 0°C, slowly add saturated NH4Cl dropwise, quench for 30 minutes, extract with ethyl acetate, separate, add anhydrous Na2SO4, dry for 2 hours, filter, and distill under reduced pressure at 1.5 mmHg and 65°C for 1 hour to obtain a β-ketoester intermediate.

[0075] 2. Take 1.5 mol of iodomethane, 2.0 mol of potassium carbonate, and 1.0 mol of β-ketoester intermediate, mix the β-ketoester intermediate and potassium carbonate, dissolve in 150 mL of acetone, add iodomethane dropwise, stir at 60°C and 800 rpm for 25 min, filter, and concentrate under reduced pressure at 2.0 kPa, 35°C, and 150 rpm for 45 min to obtain an α-methylated product; take 1.2 mol of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1.5 mol of N-hydroxysuccinimide, mix them evenly, and stir at 40°C and 600 rpm for 20 min to obtain a silane coupling agent.

[0076] 3. Using 200 mL of anhydrous N,N-dimethylformamide as solvent, under a nitrogen atmosphere, 1.0 mol of the α-methylated product was mixed with 1.1 mol of cysteine ​​ethyl ester. The mixture was stirred at 400 rpm at room temperature for 35 min. After the reaction was completed, 200 mL of icy ether was added and the mixture was centrifuged at 1000 rpm for 10 min. The supernatant was discarded and the resulting product was washed with acetonitrile and methanol in sequence. It was dried at 45°C under a vacuum of 1.0 mmHg for 4 h to obtain a functional chiral R-type styroyl acetate non-steroidal drug.

[0077] The conversion of chiral R-styroyl acetate was calculated by HPLC analysis. The HPLC conditions were: Astec CHIROBIOTIC T2 analytical column (5 μm, 25 cm × 4.6 mm); flow rate: 0.8 mL / min; injection: 10 μL; UV detection wavelength: 254 nm; detection at room temperature; mobile phase: methanol: triethylamine: glacial acetic acid = 100:0.1:0.1 (v / v / v); chiral R-styroyl acetate was prepared at a concentration of 1 mg / mL (dissolved in methanol). The calculated results are shown in Table 1: Table 1. Conversion rate of chiral R-type styraxyl acetate

[0078] 2. The half-maximal inhibition concentration of chiral R-type styraxyl acetate non-steroidal drugs on COX-2 and COX-1 was tested and calculated using human COX-2 enzyme ELISA kit and human COX-1 enzyme ELISA kit. The test results are shown in Table 2: Half-maximal inhibitory concentration: refers to the concentration of compound required to inhibit 50% of COX-2 enzyme activity. The lower the value, the stronger the inhibitory effect.

[0079] Selectivity ratio: The higher the selectivity ratio, the stronger the targeting of COX-2.

[0080] Table 2. Selectivity test of chiral R-type styraxyl acetate non-steroidal drugs for COX-2 and COX-1

[0081] As shown in Table 1, the conversion of chiral R-styroyl acetate was significantly reduced in Comparative Example 2 using traditional bromine for the halogenation reaction, and in Comparative Example 3 after removing the triphenylphosphine ligand from the n-hexane / acetonitrile solvent. Compared to the examples employing this technique, the conversion rate decreased by up to 31.9%. This demonstrates that triphenylphosphine can create a steric barrier that limits the attack path of halogen free radicals to the α-C direction to the greatest extent, thereby increasing the conversion rate of chiral R-styroyl acetate. Traditional bromine free radicals attack in an undirected manner, resulting in low conversion rates. The use of a free radical bromination system composed of N-bromosuccinimide (NBS) and benzylamine peroxide (BPO) in place of traditional bromine also played a crucial role in improving the conversion rate of chiral R-styroyl acetate.

[0082] As shown in Table 2, the chiral R-styraxyl acetate in the comparative example was not functionalized with methanesulfonyl chloride, resulting in a significant reduction in the targeting of the synthesized nonsteroidal drug for COX-2, with selectivity significantly reduced by 85%. Chiral R-styraxyl acetate functionalized with sulfonyl groups achieves selective inhibition of COX-2, reduces inhibition of COX-1, and alleviates the adverse reactions associated with long-term nonsteroidal drug use.

[0083] The specific embodiments of the present invention described above do not limit the scope of protection of the present invention. Any other corresponding changes and modifications made based on the technical concept of the present invention should be included in the scope of protection of the claims of the present invention.

Claims

1. A method for preparing chiral R-type styraxyl acetate, characterized in that: The following steps are involved: S1. Ethylbenzene and a mixed solvent of n-hexane / acetonitrile were added to a reactor in a mass ratio of 1:

4. The mixture was stirred at -5°C and 120 rpm for 10 min. Then, a free radical bromination system consisting of N-bromosuccinimide and benzoyl peroxide was added under a nitrogen atmosphere. The mixture was stirred at 400 rpm for 15 min. The mixture was heated to 15°C and the initiator solution was injected to initiate the reaction. S2. When the initiation reaction is carried out for 80 minutes, the temperature is raised to 25°C at a rate of 2°C / min to continue the reaction; when the initiation reaction is carried out for 2 hours, a 0.1-0.3 mol / L 2,6-di-tert-butyl-p-cresol solution with ethanol as the solvent is injected. After the reaction is completed, the mixture is quenched and allowed to stand for decomposition, and the upper organic phase is separated. After extraction and purification, α-bromoethylbenzene is obtained; S3. α-Bromoethylbenzene and vinyl acetate were mixed in a molar ratio of 1:1.2, and the mixture was catalyzed by nano-alumina-supported KF catalyst at 120°C for 6 hours. The resulting product was added to the active complex, followed by addition of p-methanesulfonyl chloride, and the mixture was refluxed at 90°C for 4 hours. After completion of the reaction, the mixture was quenched, extracted, and purified to obtain functionalized chiral R-type styraxyl acetate.

2. The method for preparing chiral R-type styraxyl acetate according to claim 1, wherein In step S1, the preparation method of the initiator solution is as follows: 1.0 mol of 2-aminoanthraquinone and 2.3 mol of triphenyl phosphite are dissolved in 120 mL of N,N-dimethylformamide, and refluxed at 120°C for 2 hours under a nitrogen atmosphere to obtain a phosphinimine intermediate. After the reaction is completed, the temperature is lowered to -10°C, 1.5 mol of 1,3-dimethylimidazole iodide is added, and the reaction is stirred at 200 rpm for 3 hours. After supercritical CO2 extraction, the initiator solution is obtained.

3. The method for preparing chiral R-type styraxyl acetate according to claim 1, wherein In step S1, the preparation method of the n-hexane / acetonitrile mixed solvent is as follows: under a nitrogen atmosphere, weigh 700 mL of n-hexane; measure 300 mL of acetonitrile, preheat it to 30° C., and then add it dropwise to the n-hexane at a rate of 5 mL / min at 800 rpm. After mixing, add triphenylphosphine and stir at 25° C. for 30 minutes to obtain a n-hexane / acetonitrile mixed solvent; wherein the amount of triphenylphosphine added is 0.5~1.2 mol% of the n-hexane.

4. The method for preparing chiral R-type styraxyl acetate according to claim 1, wherein In step S3, the active complex is prepared by mixing nitrobenzene and dichloromethane in a volume ratio of 1:2, adding anhydrous ferric chloride in an amount of 1.2% of the total mass of nitrobenzene and dichloromethane, heating to 60° C., and stirring at 600 rpm for 30 minutes to obtain the active complex.

5. The method for preparing chiral R-type styraxyl acetate according to claim 1, wherein In step S1, the amount of the free radical bromination system added is 0.8-1.6 wt % of ethylbenzene, wherein the molar ratio of N-bromosuccinimide to benzoyl peroxide is 10:1; the amount of the initiator solution added is 12-18 wt % of ethylbenzene; in step S2, the amount of the 2,6-di-tert-butyl-p-cresol solution added is 3-5 wt % of the free radical bromination system; in step S3, the amount of the nano-alumina-loaded KF catalyst is 3% of the total mass of α-bromoethylbenzene and vinyl acetate, and the KF loading is 30 wt % of the nano-alumina.

6. The method for preparing chiral R-type styraxyl acetate according to claim 1, wherein In step S1, the initiation reaction is specifically initiated by: using ultraviolet light irradiation to initiate the reaction, the main wavelength of the ultraviolet light is 254nm, and the irradiation intensity is 50mW / cm 2 , the irradiation time is 2h.

7. The method for preparing chiral R-type styraxyl acetate according to claim 1, wherein: In step S2, the specific method of extraction and purification is: according to a volume ratio of 1:1, the obtained upper organic phase is mixed with 5wt% Na2S2O3 solution, centrifuged at 5000rpm for 10min, and after centrifugation, according to the column volume: sample volume = 1:2, the flow rate of 2BV / h, the upper organic phase is taken and passed through a 3Å molecular sieve column, and the effluent is distilled under reduced pressure at 60°C and 10kPa to obtain α-bromoethylbenzene.

8. Chiral R-styraxyl acetate prepared by the method for preparing chiral R-styraxyl acetate according to claim 1.

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