Method for synthesizing loxoprofen sodium by using resin catalyst

Abstract

The invention discloses a method for synthesizing loxoprofen sodium by using a resin catalyst, and belongs to the field of medical chemical synthesis. The preparation method comprises the following steps: synthesizing 2-methylene cyclopentanone through methylenation reaction of cyclopentanone, paraformaldehyde and amine; the preparation method comprises the following steps: reacting 4-halogenated phenylacetate with methyl iodide to synthesize 2-(4-halogenated phenyl) propionate; a target intermediate 2-(4-((5-oxocyclopentyl-1-alkenyl) methyl) phenyl) propionate is generated through a Heck coupling reaction; further reducing to 2-(4-((2-oxygen cyclopentyl) methyl) phenyl) propionate through a catalytic hydrogenation reaction; and finally, carrying out a salt forming reaction to obtain loxoprofen sodium. The method adopts the self-made resin catalyst, is efficient and environment-friendly, has good yield and purity, and is suitable for industrial production.

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical chemical synthesis, in particular to a method for synthesizing loxoprofen sodium by using a resin catalyst. Background Art

[0002] Loxoprofen sodium is a nonsteroidal anti-inflammatory drug (NSAIDs) widely used to treat arthritis, muscle pain and postoperative pain. As a prodrug, loxoprofen sodium releases active ingredients after metabolism in the body, has little irritation to the gastrointestinal tract, and has higher safety and tolerance than traditional NSAIDs such as ibuprofen and naproxen, so it has attracted much attention in clinical practice.

[0003] At present, the industrial synthesis of loxoprofen sodium mainly relies on classical multi-step organic synthesis methods. These methods usually involve the following key reaction steps: 1. Methylene reaction, through the reaction of cyclopentanone, paraformaldehyde and amine to produce 2-methylenecyclopentanone; 2. Preparation of halophenyl propionate, using 4-halophenyl acetate to react with iodomethane to generate 2-(4-halophenyl) propionate; 3. Heck coupling reaction, which realizes the coupling of carbon-carbon bonds through transition metal catalysis; 4. Catalyze hydrogenation reduction reaction to reduce conjugated double bonds to saturated structures; 5. Salt-forming reaction to finally obtain the target product loxoprofen sodium.

[0004] Although the existing methods can meet basic production needs, there are still some problems that cannot be ignored: 1. Catalyst problem: In traditional synthesis, strong acid (such as sulfuric acid or hydrochloric acid) is usually used as a catalyst in the methylation reaction. This not only easily leads to equipment corrosion, but also produces a large amount of acidic waste liquid, increasing the cost of waste treatment and environmental pressure.

[0005] 2. Efficiency and selectivity: Some reaction steps in the existing process have low selectivity and are prone to generate by-products, resulting in low yields of target products. Especially in the Heck coupling and catalytic hydrogenation processes, the separation and purification of by-products is time-consuming and labor-intensive.

[0006] 3. Green and sustainable: With increasingly stringent environmental regulations, the synthesis process needs to pay more attention to green. Traditional methods use a lot of strong acids, heavy metal catalysts and organic solvents, which pose a potential threat to the environment and production safety. Summary of the invention

[0007] In order to overcome at least one of the technical problems in the above-mentioned background technology, the present invention proposes a novel synthesis method of loxoprofen sodium based on a resin catalyst, which not only simplifies the process flow, but also effectively improves the synthesis efficiency and environmental performance. Compared with the traditional method, the present invention achieves significant optimization in the catalytic system, process conditions and environmental benefits, and provides a new idea and new method for the industrial green synthesis of loxoprofen sodium.

[0008] To achieve the above object, the technical solution adopted by the present invention is as follows: A method for synthesizing loxoprofen sodium using a resin catalyst comprises the following steps: Step (1) Methylene reaction: According to the weight ratio, 100 parts of cyclopentanone, 90-120 parts of polyformaldehyde and 10-20 parts of amine are mixed, and reacted at 20-50° C. for 2-6 hours under the catalysis of 2-10 parts of resin catalyst to obtain 2-methylenecyclopentanone; Step (2) Synthesis of 2-(4-halophenyl)propionate: 100 parts of 4-halogenophenylacetic acid ester, 1.5-2 parts of methyl iodide and 20-30 parts of sodium hydroxide or potassium carbonate are reacted in 220-260 parts of methanol or ethanol solvent at 30-80° C. for 1-5 hours to obtain 2-(4-halogenophenyl) propionate; Step (3) Heck coupling reaction: 100 parts of 2-methylenecyclopentanone obtained in step (1) and 100 parts of 2-(4-halophenyl)propionate obtained in step (2), 1 to 2 parts of a transition metal catalyst, 1 to 2 parts of a phosphine ligand triphenylphosphine, 5 to 10 parts of a base and 200 to 300 parts of a solvent are added to a reaction flask, and reacted at 20 to 80° C. for 6 to 24 hours to generate an intermediate 2-(4-((5-oxocyclopent-1-enyl)methyl)phenyl)propionate; Step (4) catalytic hydrogenation reaction: 100 parts of the intermediate obtained in step (3) are mixed with 1 to 3 parts of Raney nickel catalyst, and after replacing hydrogen in 200 parts of an organic solvent, the mixture is reacted at 0 to 50° C. for 1 to 24 hours to generate 2-(4-((2-oxycyclopentyl)methyl)phenyl)propanoate; Step (5) salt formation reaction: 100 parts of 2-(4-((2-oxocyclopentyl)methyl)phenyl)propanoate obtained in step (4) are dissolved in a mixed solution of 450-600 parts of water and acetone, 10-50 parts of an aqueous sodium hydroxide solution are slowly added dropwise until the pH value of the solution reaches 8-10, the mixture is reacted at 0-50° C. for 0.5-5 hours, and loxoprofen sodium is obtained after filtering and drying.

[0009] Furthermore, the preparation method of the resin catalyst in step (1) is: Acylation reaction: 10-20 parts of acryloyl chloride, 2-6 parts of 3-boric acid benzenesulfonyl chloride, 0.02-0.2 parts of (oxapentyl) methanesulfonyl chloride, 100-200 parts of solid resin catalyst, 1000-1500 parts of ethylene dichloride, and 5-10 parts of zinc chloride are added into a reaction vessel, and the acylation reaction is carried out at 40-50° C. for 160-200 minutes; The solid resin catalyst grease is selected from at least one of D006 resin catalyst, A15 resin catalyst, A35 resin catalyst and D005 resin catalyst, and the factory type is sodium-based resin; Amino-acryl addition reaction: add 5-10 parts of ammonium phosphotungstate and 1-3 parts of triethylamine to the above reaction system, and carry out amino-acryl addition reaction at 60-70° C. for 160-200 minutes; Post-treatment: After the reaction is completed, filter and wash with ethanol to obtain a resin catalyst; The solid resin catalyst is placed in an exchange column for transformation treatment before use, and 2-4 volumes of hydrochloric acid with a mass percentage of 15-25% are passed through the exchange column from top to bottom for 100-200 minutes to obtain a hydrogen-type solid resin catalyst.

[0010] Furthermore, in step (1), the amine is a primary amine or a secondary amine selected from methylamine or ethylamine.

[0011] Furthermore, in step (2), the 4-halogenated phenylacetic acid ester is selected from at least one of methyl p-bromophenylacetate, methyl p-iodophenylacetate or methyl p-chlorophenylacetate.

[0012] Furthermore, in step (3), the transition metal catalyst is selected from at least one of palladium trichloride, tetrakis(triphenylphosphine)palladium or bis(diphenylphosphino)ethanepalladium dichloride.

[0013] Furthermore, in step (3), the base is selected from sodium acetate or triethylamine, and the solvent is selected from toluene, DMF or DMSO.

[0014] Furthermore, in step (4), the organic solvent is selected from ethanol, methanol or isopropanol.

[0015] Furthermore, in step (5), the volume ratio of water to acetone is 1:(8-12).

[0016] Furthermore, the drying in step (5) is vacuum drying, the drying temperature is 40 to 60° C., and the drying time is 6 to 12 hours.

[0017] Resin catalyst reaction mechanism: Synergistic activation by electrons and acid-base: The Lewis acidity of the boric acid group can activate reactants, such as coordinating with the carbonyl oxygen of cyclopentanone to enhance electrophilicity; ammonium phosphotungstate provides protons to promote the depolymerization of paraformaldehyde and the protonation of the carbonyl group of cyclopentanone, accelerating the reaction.

[0018] Microenvironment and adsorption regulation: The oxopentyl ring structure changes the microenvironment of the catalyst surface, affects the adsorption and diffusion of the substrate through weak interactions, makes the substrate easier to approach the active center, and improves the reaction efficiency.

[0019] Selectivity and intermediate optimization: The benzene ring structure introduced by boronic acid increases steric hindrance and guides substrate orientation; the various modification groups synergistically regulate the electron cloud density of the active site, optimize the formation and conversion of reaction intermediates, and improve the selectivity of the target product 2-methylenecyclopentanone.

[0020] The present invention significantly improves the synthesis efficiency and environmental performance of loxoprofen sodium by optimizing the catalytic system and reaction conditions. The specific beneficial effects are as follows: 1. Improve reaction selectivity and reduce by-product generation: The use of resin catalyst as a catalyst for the methylene reaction can significantly improve the reaction activity. The abundant proton supply and electron transfer acceleration enable the reaction to reach a higher conversion rate in a shorter time, greatly improving the reaction efficiency. Effect on selectivity: Although the main function is to improve the reaction activity, a suitable acidic environment also helps to guide the reaction in the direction of generating 2-methylenecyclopentanone, maintaining or improving the selectivity of the product to a certain extent.

[0021] 2. Improve the efficiency of catalytic hydrogenation reaction and reduce energy consumption: Highly active palladium carbon or Raney nickel is used as a catalyst, and the reduction reaction is carried out in a low boiling point solvent such as ethanol. The system is highly active and can efficiently complete the catalytic hydrogenation reaction under mild conditions.

[0022] 3. Optimize Heck coupling reaction and improve reaction efficiency: The introduction of a combination of palladium catalyst and phosphine ligand significantly enhanced the activity and selectivity of carbon-carbon bond formation in the Heck coupling reaction; at the same time, the selection of a suitable solvent increased the substrate solubility and promoted the reaction. DETAILED DESCRIPTION

[0023] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0024] The experimental methods in the following examples without specifying specific conditions are generally carried out under conventional conditions, and the raw materials and reagents used are conventional commercially available products unless otherwise specified.

[0025] Test method: 1) Determination of target product yield: The crude product obtained after the reaction is purified by column chromatography, and the mass of the purified target product is weighed. The yield of the target product is calculated based on the theoretical yield.

[0026] Formula: Yield = (actual yield ÷ theoretical yield) × 100%.

[0027] 2) Purity analysis of target product: Use high performance liquid chromatography (HPLC) to detect the purity of the target product. The detection conditions are as follows: Chromatographic column: C18 reverse phase column (250 mm × 4.6 mm, 5 μm); Mobile phase: acetonitrile / water (60:40, volume ratio); Detection wavelength: 254 nm; Flow rate: 1.0 mL / min; Injection volume: 20 μL.

[0028] Embodiment 1: A method for synthesizing loxoprofen sodium using a resin catalyst comprises the following steps: Step (1) Methylene reaction: 100 g of cyclopentanone, 95 g of paraformaldehyde and 15 g of methylamine were mixed, and reacted at 30° C. for 4 hours under the catalysis of 2 g of resin catalyst to obtain 2-methylenecyclopentanone.

[0029] Among them, the preparation method of the resin catalyst is as follows: 15g of acryloyl chloride, 4g of 3-boric acid benzenesulfonyl chloride, 0.1g of (oxopentyl ring-3-yl) methanesulfonyl chloride, 120g of D006 resin catalyst (sodium base), 1200g of dichloroethane and 8g of zinc chloride are added to the reaction vessel, and the acylation reaction is carried out at 45°C for 180 minutes. Subsequently, 8g of ammonium phosphotungstate and 2g of triethylamine are added to the reaction system, and the temperature is raised to 65°C for amino-acrylic addition reaction for 180 minutes. After the reaction is completed, the resin catalyst is filtered and washed with ethanol to obtain a resin catalyst. Before use, the solid resin catalyst is placed in an exchange column, and 3 times the volume of hydrochloric acid with a mass percentage of 20% is used to flow through the exchange column from top to bottom, and the treatment time is 150 minutes to obtain a hydrogen-type solid resin catalyst.

[0030] Step (2) Synthesis of 2-(4-halophenyl)propionate: 100 g of methyl p-bromophenylacetate, 1.8 g of methyl iodide and 25 g of sodium hydroxide were reacted in 240 g of methanol solvent at 50° C. for 3 hours to obtain 2-(4-bromophenyl)propionate.

[0031] Step (3) Heck coupling reaction: 100 g of 2-methylenecyclopentanone obtained in step (1), 100 g of 2-(4-bromophenyl)propionate obtained in step (2), 1.5 g of palladium trichloride, 1.5 g of phosphine ligand triphenylphosphine, 7 g of sodium acetate and 250 g of toluene were added to a reaction flask and reacted at 50° C. for 12 hours to generate an intermediate 2-(4-((5-oxocyclopent-1-enyl)methyl)phenyl)propionate.

[0032] Step (4) catalytic hydrogenation reaction: 100 g of the intermediate obtained in step (3) was mixed with 2 g of Raney nickel catalyst, and after replacing hydrogen in 200 g of ethanol solvent, the mixture was reacted at 30° C. for 10 hours to generate 2-(4-((2-oxocyclopentyl)methyl)phenyl)propanoate.

[0033] Step (5) Salt-forming reaction: 100 g of 2-(4-((2-oxocyclopentyl)methyl)phenyl)propanoate obtained in step (4) was dissolved in a mixed solution of 500 g of water and acetone (volume ratio of 1:10), 30 g of sodium hydroxide aqueous solution was slowly added dropwise until the pH value of the solution reached 9, the mixture was reacted at 30° C. for 2 hours, filtered and vacuum dried (drying temperature of 50° C., drying time of 8 hours) to obtain loxoprofen sodium.

[0034] The yield of loxoprofen sodium in this example is 84.8%, and the purity (HPLC) is 98.7%.

[0035] Embodiment 2: A method for synthesizing loxoprofen sodium using a resin catalyst comprises the following steps: Step (1) Methylene reaction: 100 g of cyclopentanone, 110 g of paraformaldehyde and 10 g of ethylamine were mixed, and reacted at 40° C. for 6 hours under the catalysis of 5 g of resin catalyst to obtain 2-methylenecyclopentanone.

[0036] Among them, the preparation method of the resin catalyst is as follows: take 10g of acryloyl chloride, 2g of 3-boric acid benzenesulfonyl chloride, 0.05g of (oxopentyl) methanesulfonyl chloride, 100g of A15 resin catalyst (sodium base), 1000g of dichloroethane and 5g of zinc chloride, and react at 40°C for 160 minutes for acylation. After that, add 5g of ammonium phosphotungstate and 1g of triethylamine, adjust the temperature to 60°C, and carry out an amino-acrylic addition reaction for 160 minutes. After the reaction is completed, filter and wash with ethanol to obtain a resin catalyst. Before use, place the solid resin catalyst in an exchange column, flow 2 times the volume of 15% by mass hydrochloric acid from top to bottom, treat for 100 minutes, and obtain a hydrogen-type solid resin catalyst.

[0037] Step (2) Synthesis of 2-(4-halophenyl)propionate: 100 g of methyl p-iodophenylacetate, 2 g of methyl iodide and 20 g of potassium carbonate were reacted in 260 g of ethanol solvent at 70° C. for 2 hours to obtain 2-(4-iodophenyl)propionate.

[0038] Step (3) Heck coupling reaction: 100 g of 2-methylenecyclopentanone obtained in step (1), 100 g of 2-(4-iodophenyl)propionate obtained in step (2), 2 g of tetrakis(triphenylphosphine)palladium, 1 g of phosphine ligand triphenylphosphine, 5 g of triethylamine and 300 g of DMF were added to a reaction bottle and reacted at 60° C. for 18 hours to generate an intermediate 2-(4-((5-oxocyclopent-1-enyl)methyl)phenyl)propionate.

[0039] Step (4) catalytic hydrogenation reaction: 100 g of the intermediate obtained in step (3) was mixed with 1 g of Raney nickel catalyst, and after replacing hydrogen in 200 g of isopropanol solvent, the mixture was reacted at 40° C. for 24 hours to generate 2-(4-((2-oxocyclopentyl)methyl)phenyl)propanoate.

[0040] Step (5) Salt-forming reaction: 100 g of 2-(4-((2-oxocyclopentyl)methyl)phenyl)propanoate obtained in step (4) was dissolved in a mixed solution of 450 g of water and acetone (volume ratio of 1:8), 10 g of sodium hydroxide aqueous solution was slowly added dropwise until the pH value of the solution reached 8, the mixture was reacted at 0° C. for 5 hours, filtered and vacuum dried (drying temperature of 40° C., drying time of 12 hours) to obtain loxoprofen sodium.

[0041] The yield of loxoprofen sodium in this example is 85.4% and the purity (HPLC) is 99.0%.

[0042] Embodiment 3: A method for synthesizing loxoprofen sodium using a resin catalyst comprises the following steps: Step (1) Methylene reaction: 100 g of cyclopentanone, 120 g of paraformaldehyde and 20 g of methylamine were mixed, and reacted at 20° C. for 2 hours under the catalysis of 8 g of resin catalyst to obtain 2-methylenecyclopentanone.

[0043] Among them, the preparation method of the resin catalyst is as follows: 20g of acryloyl chloride, 6g of 3-boric acid benzenesulfonyl chloride, 0.2g of (oxopentyl) methanesulfonyl chloride, 200g of D005 resin catalyst (sodium base), 1500g of dichloroethane and 10g of zinc chloride are mixed, and the acylation is completed at 50°C for 200 minutes. Then, 10g of ammonium phosphotungstate and 3g of triethylamine are added, the temperature is raised to 70°C, and the reaction is continued for 200 minutes for amino-acrylic addition. After the reaction is completed, the resin catalyst is filtered and washed with ethanol to obtain a resin catalyst. Before use, the solid resin catalyst needs to be placed in an exchange column, and 4 times the volume of 25% hydrochloric acid by mass is passed through the exchange column for 200 minutes to obtain a hydrogen-type solid resin catalyst.

[0044] Step (2) Synthesis of 2-(4-halophenyl)propionate: 100 g of methyl p-chlorophenylacetate, 1.5 g of methyl iodide and 30 g of sodium hydroxide were reacted in 220 g of methanol solvent at 30° C. for 5 hours to obtain 2-(4-chlorophenyl)propionate.

[0045] Step (3) Heck coupling reaction: 100 g of 2-methylenecyclopentanone obtained in step (1), 100 g of 2-(4-chlorophenyl)propionate obtained in step (2), 1 g of di(diphenylphosphino)ethanepalladium dichloride, 2 g of phosphine ligand triphenylphosphine, 10 g of sodium acetate and 200 g of DMSO were added to a reaction bottle and reacted at 20° C. for 24 hours to generate an intermediate 2-(4-((5-oxocyclopent-1-enyl)methyl)phenyl)propionate.

[0046] Step (4) catalytic hydrogenation reaction: 100 g of the intermediate obtained in step (3) was mixed with 3 g of Raney nickel catalyst, and after replacing hydrogen in 200 g of methanol solvent, the mixture was reacted at 0° C. for 1 hour to generate 2-(4-((2-oxocyclopentyl)methyl)phenyl)propanoate.

[0047] Step (5) salt formation reaction: 100 g of 2-(4-((2-oxocyclopentyl)methyl)phenyl)propanoate obtained in step (4) was dissolved in a mixed solution of 600 g of water and acetone (volume ratio of 1:12), 50 g of sodium hydroxide aqueous solution was slowly added dropwise until the pH value of the solution reached 10, the mixture was reacted at 50° C. for 0.5 hour, filtered and vacuum dried (drying temperature of 60° C., drying time of 6 hours) to obtain loxoprofen sodium.

[0048] The yield of loxoprofen sodium in this example is 85.8%, and the purity (HPLC) is 99.2%.

[0049] Embodiment 4: A method for synthesizing loxoprofen sodium using a resin catalyst comprises the following steps: Step (1) Methylene reaction: 100 g of cyclopentanone, 105 g of paraformaldehyde and 12 g of ethylamine were mixed, and reacted at 50° C. for 3 hours under the catalysis of 10 g of resin catalyst to obtain 2-methylenecyclopentanone.

[0050] Among them, the preparation method of the resin catalyst is as follows: 12g of acryloyl chloride, 3g of 3-boric acid benzenesulfonyl chloride, 0.15g of (oxopentyl) methanesulfonyl chloride, 160g of A35 resin catalyst (sodium base), 1300g of ethylene dichloride and 7g of zinc chloride are reacted at 48°C for 190 minutes for acylation. Then, 7g of ammonium phosphotungstate and 2.5g of triethylamine are added to the system, and an amino-acrylic addition reaction is carried out at 68°C for 190 minutes. After the reaction is completed, the resin catalyst is filtered and washed with ethanol to obtain a resin catalyst. Before use, the solid resin catalyst needs to be placed in an exchange column, and 3.5 times the volume of 22% hydrochloric acid is passed from top to bottom for 170 minutes to obtain a hydrogen-type solid resin catalyst.

[0051] Step (2) Synthesis of 2-(4-halophenyl)propionate: 100 g of a mixture of equimolar amounts of methyl p-bromophenylacetate and methyl p-iodophenylacetate, 1.7 g of methyl iodide and 28 g of potassium carbonate were reacted in 250 g of ethanol solvent at 60° C. for 4 hours to obtain a mixed 2-(4-halophenyl)propionic acid ester.

[0052] Step (3) Heck coupling reaction: 100 g of 2-methylenecyclopentanone obtained in step (1) and 100 g of mixed 2-(4-halophenyl)propionate obtained in step (2), 1.8 g of palladium trichloride, 1.2 g of phosphine ligand triphenylphosphine, 8 g of triethylamine and 280 g of toluene were added to a reaction bottle and reacted at 80° C. for 6 hours to generate an intermediate 2-(4-((5-oxocyclopent-1-enyl)methyl)phenyl)propionate.

[0053] Step (4) Catalytic hydrogenation reaction: 100 g of the intermediate obtained in step (3) was mixed with 1.5 g of Raney nickel catalyst, and after replacing hydrogen in 200 g of isopropanol solvent, the mixture was reacted at 50° C. for 12 hours to generate 2-(4-((2-oxocyclopentyl)methyl)phenyl)propanoate.

[0054] Step (5) Salt-forming reaction: 100 g of 2-(4-((2-oxocyclopentyl)methyl)phenyl)propanoate obtained in step (4) was dissolved in a mixed solution of 550 g of water and acetone (volume ratio of 1:11), 20 g of sodium hydroxide aqueous solution was slowly added dropwise until the pH value of the solution reached 8.5, and the mixture was reacted at 25° C. for 3 hours. After filtration, the mixture was vacuum dried (drying temperature of 55° C. and drying time of 9 hours) to obtain loxoprofen sodium.

[0055] The yield of loxoprofen sodium in this example is 86.1% and the purity (HPLC) is 99.3%.

[0056] Comparative Example 1: In this example, the resin catalyst in step (1) is directly selected from D006 resin catalyst (sodium-based) without modification, and the remaining steps are the same as those in Example 1.

[0057] The yield of loxoprofen sodium in this comparative example was 82.2%, and the purity (HPLC) was 97.8%.

[0058] Comparative Example 2: In this example, 3-boric acid benzenesulfonyl chloride was not added during the preparation of the resin catalyst, and the remaining steps were consistent with Example 1.

[0059] The yield of loxoprofen sodium in this comparative example was 84.3%, and the purity (HPLC) was 98.4%.

[0060] Comparative Example 3: In this example, ammonium phosphotungstate was not added during the preparation of the resin catalyst, and the remaining steps were the same as those in Example 1.

[0061] The yield of loxoprofen sodium in this comparative example was 84.0%, and the purity (HPLC) was 98.2%.

[0062] Compared with the comparative example, the present invention achieves effective improvement in the yield and purity of the target product by catalyzing with a self-made resin catalyst, while significantly reducing the amount of by-products generated and waste liquid pollution.

[0063] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for synthesizing loxoprofen sodium using a resin catalyst, characterized in that, The following steps are involved: Step (1) Methylene reaction: According to the weight ratio, 100 parts of cyclopentanone, 90-120 parts of polyformaldehyde and 10-20 parts of amine are mixed, and reacted at 20-50° C. for 2-6 hours under the catalysis of 2-10 parts of resin catalyst to obtain 2-methylenecyclopentanone; Step (2) Synthesis of 2-(4-halophenyl)propionate: 100 parts of 4-halogenophenylacetic acid ester, 1.5-2 parts of methyl iodide and 20-30 parts of sodium hydroxide or potassium carbonate are reacted in 220-260 parts of methanol or ethanol solvent at 30-80° C. for 1-5 hours to obtain 2-(4-halogenophenyl) propionate; Step (3) Heck coupling reaction: 100 parts of 2-methylenecyclopentanone obtained in step (1) and 100 parts of 2-(4-halophenyl)propionate obtained in step (2), 1 to 2 parts of a transition metal catalyst, 1 to 2 parts of a phosphine ligand triphenylphosphine, 5 to 10 parts of a base and 200 to 300 parts of a solvent are added to a reaction flask, and reacted at 20 to 80° C. for 6 to 24 hours to generate an intermediate 2-(4-((5-oxocyclopent-1-enyl)methyl)phenyl)propionate; Step (4) catalytic hydrogenation reaction: 100 parts of the intermediate obtained in step (3) are mixed with 1 to 3 parts of Raney nickel catalyst, and after replacing hydrogen in 200 parts of an organic solvent, the mixture is reacted at 0 to 50° C. for 1 to 24 hours to generate 2-(4-((2-oxycyclopentyl)methyl)phenyl)propanoate; Step (5) salt formation reaction: 100 parts of 2-(4-((2-oxocyclopentyl)methyl)phenyl)propanoate obtained in step (4) are dissolved in a mixed solution of 450-600 parts of water and acetone, 10-50 parts of an aqueous sodium hydroxide solution are slowly added dropwise until the pH value of the solution reaches 8-10, the mixture is reacted at 0-50° C. for 0.5-5 hours, and loxoprofen sodium is obtained after filtering and drying.

2. A method for synthesizing loxoprofen sodium using a resin catalyst according to claim 1, characterized in that: The preparation method of the resin catalyst in step (1) is: Acylation reaction: 10-20 parts of acryloyl chloride, 2-6 parts of 3-boric acid benzenesulfonyl chloride, 0.02-0.2 parts of (oxapentyl) methanesulfonyl chloride, 100-200 parts of solid resin catalyst, 1000-1500 parts of ethylene dichloride, and 5-10 parts of zinc chloride are added into a reaction vessel, and the acylation reaction is carried out at 40-50° C. for 160-200 minutes; The solid resin catalyst is selected from at least one of D006 resin catalyst, A15 resin catalyst, A35 resin catalyst and D005 resin catalyst, and the factory type is sodium-based resin; Amino-acryl addition reaction: add 5-10 parts of ammonium phosphotungstate and 1-3 parts of triethylamine to the above reaction system, and carry out amino-acryl addition reaction at 60-70° C. for 160-200 minutes; Post-treatment: After the reaction is completed, filter and wash with ethanol to obtain a resin catalyst; The solid resin catalyst is placed in an exchange column for transformation treatment before use, and 2-4 volumes of hydrochloric acid with a mass percentage of 15-25% are passed through the exchange column from top to bottom for 100-200 minutes to obtain a hydrogen-type solid resin catalyst.

3. A method for synthesizing loxoprofen sodium using a resin catalyst according to claim 1, characterized in that: The amine in step (1) is a primary amine or a secondary amine, selected from methylamine or ethylamine.

4. A method for synthesizing loxoprofen sodium using a resin catalyst according to claim 1, characterized in that: In the step (2), the 4-halogenated phenylacetic acid ester is selected from at least one of methyl p-bromophenylacetate, methyl p-iodophenylacetate or methyl p-chlorophenylacetate.

5. A method for synthesizing loxoprofen sodium using a resin catalyst according to claim 1, characterized in that: The transition metal catalyst in step (3) is selected from at least one of palladium trichloride, tetrakis(triphenylphosphine)palladium or bis(diphenylphosphino)ethanepalladium dichloride.

6. A method for synthesizing loxoprofen sodium using a resin catalyst according to claim 1, characterized in that: In the step (3), the base is selected from sodium acetate or triethylamine, and the solvent is selected from toluene, DMF or DMSO.

7. A method for synthesizing loxoprofen sodium using a resin catalyst according to claim 1, characterized in that: In step (4), the organic solvent is selected from ethanol, methanol or isopropanol.

8. A method for synthesizing loxoprofen sodium using a resin catalyst according to claim 1, characterized in that: In step (5), the volume ratio of water to acetone is 1:(8-12).

9. A method for synthesizing loxoprofen sodium using a resin catalyst according to claim 1, characterized in that: The drying in step (5) is vacuum drying, the drying temperature is 40 to 60° C., and the drying time is 6 to 12 hours.