Green synthesis process of non-steroidal loxoprofen sodium

Abstract

The invention discloses a green synthesis process of non-steroidal loxoprofen sodium, and relates to the field of loxoprofen sodium synthesis. A water / organic two-phase free radical bromination and functionalized Pd-Ru / NH2-ZIF-8 catalysis one-step hydrogenation degreasing-tert-butyl ester removal path is adopted. The catalyst is modified by a thiol ligand and cooperates with a chiral inducer to construct a Pd-Ru bimetallic active site, so that the product purity and the product yield are effectively improved, and the catalyst can be repeatedly used. The method is environment-friendly and efficient in process and suitable for industrial application.

Description

Technical Field

[0001] This invention relates to the field of loxoprofen sodium synthesis, and in particular to a green synthesis process for nonsteroidal loxoprofen sodium. Background Technology

[0002] Loxoprofen sodium is a thiazoline butyrate nonsteroidal anti-inflammatory drug developed by Sankyo Co., Ltd. of Japan. It was approved for use in 1986 and currently ranks among the top-selling NSAIDs in Japan. It is widely used for oral and topical treatment of muscle and joint pain and inflammation.

[0003] CN119822949A discloses a method for synthesizing loxoprofen sodium using a resin catalyst. The method involves synthesizing 2-methylenecyclopentanone via a methyleneization reaction of cyclopentanone, paraformaldehyde, and an amine; synthesizing 2-(4-halophenyl)propionate via a reaction of 4-halophenylacetic acid ester and iodomethane; generating the target intermediate 2-(4-((5-oxocyclopent-1-enyl)methyl)phenyl)propionate via a Heck coupling reaction; further reducing it to 2-(4-((2-oxocyclopentyl)methyl)phenyl)propionate via catalytic hydrogenation; and finally obtaining loxoprofen sodium via a salt formation reaction.

[0004] CN119019242A discloses a method for synthesizing loxoprofen sodium and its intermediate compounds. Cyclopentanone, paraformaldehyde, and an amine undergo a methyleneization reaction at the α-position of the ketone under acidic conditions to generate 2-methylenecyclopentanone (II). 4-Halophenylacetic acid ester (III) reacts with iodomethane under alkaline conditions to generate 2-(4-halophenyl)propionate (IV). Compounds (II) and (IV) undergo a Heck coupling reaction under the action of a transition metal catalyst, a phosphine ligand, and an alkaline environment to give 2-(4-((5-oxocyclopent-1-enyl)methyl)phenyl)propionate (V). Compound (V) is catalytically hydrogenated under palladium on carbon or Raney nickel to give 2-(4-((2-oxocyclopentyl)methyl)phenyl)propionate (VI). Compound (VI) is then salted in NaOH aqueous solution to give loxoprofen sodium (I).

[0005] CN117623904A discloses a production process for high-purity loxoprofen sodium. In this process, loxoprofen sodium is prepared from p-bromomethylisophenylpropionic acid as a starting point through esterification, condensation, and salt formation reactions.

[0006] In its industrial synthesis, the key intermediate is 2-(4-bromomethylphenyl)propionic acid, a compound widely used due to its low cost and high reactivity. However, the traditional synthetic route has significant drawbacks:

[0007] 1. Single-solvent Br2 photo-irradiation method: Br2 is commonly introduced into a cyclohexane or CCl4 system, and free radical bromination is carried out under light or AIBN conditions. This method has a simple apparatus and mild conditions, but Br2 volatilizes and generates a large amount of HBr acid mist, which is severely corrosive to the environment and equipment, requiring long-term waste gas treatment.

[0008] 2. NBS / Wohl–Ziegler radical bromination: N-bromosuccinimide (NBS) is used to replace Br2, avoiding the toxicity of liquid Br2. However, it usually requires the use of toxic solvents such as CCl4 and produces succinimide waste residue, causing problems with solvent recovery and waste disposal.

[0009] 3. Aryl rearrangement or catalytic rearrangement: Using noble metals such as AgBF4 and Ti(NO3)3 to catalyze 1,2-aryl rearrangement or iodine-catalyzed rearrangement can reduce the direct use of Br2 in the bromination process to some extent. However, the cost is high, and the control of catalyst activity and by-products has become a bottleneck, limiting the industrial application.

[0010] 4. Multi-step esterification-halogenation-decarboxylation-salting route: For example, first prepare an ester intermediate, then carry out multiple transformations, and finally salt it to loxoprofen sodium. Although these processes are mature, the reaction routes are lengthy, time-consuming, and energy-intensive, and there are still problems with environmental pollution and solvent recovery in this route.

[0011] In summary, the existing technology has the following main problems:

[0012] Bromine sources are highly toxic (Br2, CCl4), which is detrimental to the environment and workshop operation safety;

[0013] The reaction involves many steps, complex processes, long production cycles, high energy consumption, and high costs.

[0014] Catalysts are expensive or difficult to recycle;

[0015] There is still room for improvement in product purity and yield.

[0016] Therefore, developing an environmentally friendly, efficient, simple, and low-cost green synthesis route is crucial. This route should minimize the use of toxic organic solvents and volatile Br2, reduce waste gas and waste liquid pollution, and achieve process simplification, high atom economy, and ease of industrial scale-up, providing a sustainable development path for the large-scale production of loxoprofen sodium. Summary of the Invention

[0017] Based on the problems raised in the background technology mentioned above, this invention proposes a green synthesis process for non-steroidal loxoprofen sodium. Using 2-(4-methylphenyl)propionic acid as a substrate, Br2 is introduced into an aqueous / organic biphase system, and bromination is carried out under light irradiation or AIBN catalysis. HBr is absorbed by the aqueous phase to form the intermediate 2-(4-bromomethylphenyl)propionic acid. Then, through Pd / C catalysis and acid-assisted hydrogenation, deesterification and para-cyclization are simultaneously completed to directly obtain loxoprofen. Salting treatment yields loxoprofen sodium.

[0018] The technical solution is as follows:

[0019] A green synthesis process for nonsteroidal loxoprofen sodium, characterized by comprising the following steps:

[0020] (a) Bromination (free radical two-phase system)

[0021] Substrate: 100 portions;

[0022] Solvent cyclohexane: 200–500 parts;

[0023] Water: 100–300 servings;

[0024] Bromine (Br2): 102–110 parts;

[0025] AIBN or photoinitiator: AIBN is used at a mass of 0.5–2.0 parts of the substrate, or a light source is used for initiation;

[0026] Reaction conditions: temperature 20–40℃, stirring 300–600 rpm, reaction time 6–12 h;

[0027] After the reaction is complete, the phases are separated naturally or by centrifugation. The cyclohexane organic phase is used as an intermediate. The intermediate is purified for later use.

[0028] (b) Hydrogenation for the removal of ethyl ester and tert-butyl ester is completed in one step.

[0029] Intermediate: in equal quantities according to the theoretical yield of reaction (a);

[0030] Hydrogenation catalyst Pd / C ratio: 10–25 parts;

[0031] Trifluoroacetic acid or concentrated hydrochloric acid: 20–50 parts;

[0032] The solvent is acetic acid or a mixture of water and acetic acid;

[0033] Hydrogen pressure: 1 atm for ordinary hydrogen, or 2–5 atm for boosted kinetics;

[0034] Temperature 25–40℃; stirring 200–500 rpm; time 12–24 h;

[0035] After the reaction, the catalyst was removed by filtration, and the product was washed twice with water, each time with 5 times the amount of substrate. The product was then extracted with ethyl acetate or acetonitrile, concentrated under reduced pressure at 30–40 °C, and recrystallized to give pure loxoprofen.

[0036] (c) Salting steps

[0037] Take the loxoprofen obtained in step (b) and neutralize it with water-soluble NaOH powder to pH 7–8;

[0038] Dilute with 70–100 parts of aqueous solution, cool to 5–10°C to precipitate loxoprofen sodium; filter, wash with 5–10 times the amount of water, and dry to obtain loxoprofen sodium.

[0039] As a preferred embodiment of the above technical solution, the substrate in step (a) may be any one of the following:

[0040] 2-(4-Methylphenyl)propionic acid;

[0041] tert-butyl 2-(4-methylphenyl)propionate;

[0042] Potassium 2-(4-methylphenyl)propionate;

[0043] Sodium 2-(4-methylphenyl)propionate.

[0044] As a preferred embodiment of the above technical solution, the light source for triggering the illumination in step (a) is 365nm, 10–20W.

[0045] As a preferred embodiment of the above technical solution, the purification process in step (a) is as follows:

[0046] Wash with water diluted 10–20 times the weight of the substrate;

[0047] Further extraction with degassed cyclohexane or ethyl acetate followed by vacuum concentration.

[0048] As a preferred embodiment of the above technical solution, the preparation method of the hydrogenation catalyst Pd / C in step (b) is as follows:

[0049] Step 1: After activating 100-140 parts by weight of NH2-ZIF-8 (CAS: 2762331-72-4) under vacuum at 100-200℃ for 5-10 hours, mix it with 1-5 parts by weight of 12-mercaptododecyl phosphoric acid, 0.01-0.5 parts by weight of (2R,3S)-2,3-epoxysuccinic acid, and 1-5 parts by weight of catalyst in an organic solvent, and stir the mixture at 60-100℃ for 8-24 hours.

[0050] Step 2: Add 0.5-2 parts by weight of palladium nitrate and 0.5-2 parts by weight of RuCl·3H2O, and stir the reaction under a nitrogen atmosphere at 70-80℃ for 4-7 hours; separate the solid product, wash it with water and alcohol in sequence, and dry it under vacuum at 60-100℃ for 8-16 hours to obtain the catalyst supported on Pd-Ru bimetal.

[0051] As a preferred embodiment of the above technical solution, the organic solvent is one or more of toluene, xylene, ethanol, and isopropanol.

[0052] As a preferred embodiment of the above technical solution, the volume ratio of the water / acetic acid mixture in step (b) is water:acetic acid = 1:1–1:2.

[0053] As a preferred embodiment of the above technical solution, the amount of water-soluble alkali NaOH used in step (c) is consistent with the mass of loxoprofen.

[0054] As a preferred embodiment of the above technical solution, the moisture content of loxoprofen sodium after drying in step (c) is <0.5%.

[0055] Reaction mechanism

[0056] 1. Carrier modification and metal anchoring

[0057] After vacuum activation, the amino groups (-NH2) on the surface of NH2-ZIF-8 combine with the phosphate groups of 12-mercaptododecyl phosphate through acid-base interactions to form a thiol-modified mesoporous structure.

[0058] 2. (2R,3S)-2,3-epoxysuccinic acid, as a chiral inducing agent, has epoxy groups that interact with the Zn group of ZIF-8. 2+ Coordination regulates metal dispersion.

[0059] 3. Bimetallic Cooperative Load

[0060] Palladium nitrate (Pd(NO3)2) and RuCl3·3H2O are stably fixed within the ZIF-8 channels through the coordination of thiol groups (-SH). The addition of Ru optimizes the electron cloud density of Pd and lowers the energy barrier for the hydrogenation reaction.

[0061] Compared with the prior art, the present invention has the following advantages:

[0062] 1. This catalyst significantly improves the efficiency and selectivity of hydrogenation reactions through bimetallic synergy and support functionalization design. Pd-Ru bimetallic nanoparticles are uniformly dispersed on an NH2-ZIF-8 support. The introduction of thiol modification and chiral inducer ((2R,3S)-2,3-epoxysuccinic acid) further optimizes the metal electronic structure and improves product yield.

[0063] 2. The catalyst's stability is significantly enhanced by anchoring metal particles with thiol groups, maintaining an activity retention rate of over 90% after 10 cycles. TEM characterization shows that Ru atoms preferentially occupy Pd lattice defect sites, forming an electronic synergistic effect, increasing H2 adsorption and reducing byproduct formation. This design combines high activity, high selectivity, and long lifetime, making it suitable for industrial applications in green pharmaceutical processes. Detailed Implementation

[0064] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Furthermore, it should be understood that after reading the teachings of this invention, those skilled in the art can make various alterations or modifications to the invention, and these equivalent forms also fall within the scope defined by the appended claims.

[0065] Example 1: Environmentally friendly synthesis process of loxoprofen sodium

[0066] (a) Bromination (free radical two-phase system)

[0067] Substrate: 2-(4-methylphenyl)propionic acid (100g)

[0068] Solvent: cyclohexane: 200g

[0069] Water: 100g

[0070] Bromine (Br2): 102g

[0071] Initiator: AIBN (0.5 g of substrate)

[0072] Reaction conditions: temperature 20℃, stirring 300 rpm, reaction time 6 h.

[0073] Post-processing: Natural separation, take the cyclohexane organic phase; wash with 10 times the weight of the substrate in water, extract with degassed cyclohexane and concentrate under reduced pressure.

[0074] (b) Hydrogenation deesterification step

[0075] Intermediate: equal amount according to (a) theoretical yield

[0076] Hydrogenation catalyst Pd / C: 10g

[0077] Preparation parameters:

[0078] Step 1: 100g of NH2-ZIF-8 was activated in vacuum at 100℃ for 5 hours, and then mixed with 1g of 12-mercaptododecyl phosphoric acid, 0.01g of (2R,3S)-2,3-epoxysuccinic acid and 1g of catalyst in ethanol. The mixture was stirred at 60℃ for 8 hours.

[0079] Step 2: Add 0.5g palladium nitrate and 0.5g RuCl·3H2O, stir at 70℃ under nitrogen atmosphere for 4 hours, separate the solid, wash with water and ethanol, and dry under vacuum at 60℃ for 8 hours.

[0080] Acid reagent: 20g trifluoroacetic acid

[0081] Solvent: Water / acetic acid mixture (volume ratio 1:1)

[0082] Hydrogen pressure: 1 atm for ordinary hydrogen

[0083] Reaction conditions: temperature 25℃, stirring 200 rpm, time 12 h

[0084] Post-treatment: Filter to remove catalyst, wash twice with water (5 times the amount of substrate each time), extract with ethyl acetate, concentrate under reduced pressure at 30°C, and recrystallize to obtain pure loxoprofen.

[0085] (c) Salting steps

[0086] Neutralizing agent: NaOH powder (with the same mass as loxoprofen)

[0087] Dilution conditions: Dilute with 70g of aqueous solution, cool to 5℃ to precipitate.

[0088] Post-treatment: Filter, wash with 5 times the amount of water, and dry until the moisture content is <0.5%.

[0089] Example 2: Environmentally friendly synthesis process of loxoprofen sodium

[0090] (a) Bromination (free radical two-phase system)

[0091] Substrate: Sodium 2-(4-methylphenyl)propionate (100g)

[0092] Solvent: cyclohexane 300g

[0093] Water: 175g

[0094] Bromine (Br2): 104g

[0095] Initiator: Photoinitiator (365nm, 10W light source)

[0096] Reaction conditions: temperature 27℃, stirring 400 rpm, reaction time 8 h.

[0097] Post-processing: Centrifuge to separate the cyclohexane organic phase; wash with 15 times the weight of the substrate in water, extract with degassed ethyl acetate and concentrate under reduced pressure.

[0098] (b) Hydrogenation deesterification step

[0099] Hydrogenation catalyst Pd / C: 15g

[0100] Preparation parameters:

[0101] Step 1: 120g of NH2-ZIF-8 was activated in vacuum at 130℃ for 6 hours, and then mixed with 2g of 12-mercaptododecyl phosphoric acid, 0.1g of epoxy succinic acid, and 2g of catalyst in toluene and stirred at 70℃ for 12 hours.

[0102] Step 2: Add 1g palladium nitrate and 1g RuCl·3H2O, stir at 72℃ under nitrogen atmosphere for 5 hours, wash, and then vacuum dry at 70℃ for 10 hours.

[0103] Acid reagent: 28g concentrated hydrochloric acid

[0104] Solvent: Water / acetic acid mixture (volume ratio 1:1.2)

[0105] Hydrogen pressure: 2 atm

[0106] Reaction conditions: temperature 29℃, stirring 300 rpm, time 16 h

[0107] Post-processing: Same as in Example 1, washed with water and extracted with acetonitrile, then concentrated under reduced pressure at 35°C.

[0108] (c) Salting steps

[0109] Dilution conditions: Add 80g of aqueous solution and cool to 6℃ to precipitate.

[0110] Washing conditions: Wash with 6 times the amount of water and dry until moisture content is <0.5%.

[0111] Example 3: Environmentally friendly synthesis process of loxoprofen sodium

[0112] (a) Bromination (free radical two-phase system)

[0113] Substrate: tert-butyl 2-(4-methylphenyl)propionate (100g)

[0114] Solvent: cyclohexane: 400g

[0115] Water: 250g

[0116] Bromine (Br2): 108g

[0117] Initiator: Photoinitiator (365nm, 18W light source)

[0118] Reaction conditions: temperature 33℃, stirring 500rpm, reaction time 10h

[0119] Post-treatment: Natural separation, washing with 20 times the substrate weight of water, extraction with a mixture of degassed cyclohexane and ethyl acetate (volume ratio 1:1), and concentration under reduced pressure.

[0120] (b) Hydrogenation deesterification step

[0121] Hydrogenation catalyst Pd / C: 20g

[0122] Preparation parameters:

[0123] Step 1: 130g of NH2-ZIF-8 was activated in vacuum at 170℃ for 8 hours, and then stirred at 90℃ for 20 hours with 4g of 12-mercaptododecyl phosphoric acid, 0.3g of epoxy succinic acid, and 4g of catalyst in a mixed solvent of xylene and isopropanol (volume ratio 1:1).

[0124] Step 2: Add 1.5g palladium nitrate and 1.5g RuCl·3H2O, stir at 78℃ under nitrogen atmosphere for 6 hours, wash, and then vacuum dry at 90℃ for 14 hours.

[0125] Acid reagent: 42g trifluoroacetic acid

[0126] Solvent: Water / acetic acid mixture (volume ratio 1:1.6)

[0127] Hydrogen pressure: 3.5 atm

[0128] Reaction conditions: temperature 35℃, stirring 400 rpm, time 20 h

[0129] Post-processing: Filtered and washed with water, extracted with acetonitrile, and concentrated under reduced pressure at 38°C.

[0130] (c) Salting steps

[0131] Dilution conditions: Add 90g of aqueous solution and cool to 8℃ to precipitate.

[0132] Washing conditions: Wash with 8 times the amount of water and dry until moisture content is <0.5%.

[0133] Example 4: Environmentally friendly synthesis process of loxoprofen sodium

[0134] (a) Bromination (free radical two-phase system)

[0135] Substrate: Potassium 2-(4-methylphenyl)propionate (100g)

[0136] Solvent: cyclohexane: 500g

[0137] Water: 300g

[0138] Bromine (Br2): 110g

[0139] Initiator: Photoinitiator (365nm, 20W light source)

[0140] Reaction conditions: temperature 40℃, stirring 600 rpm, reaction time 12 h

[0141] Post-processing: centrifugation, washing with 20 times the weight of the substrate in water, degassed extraction with ethyl acetate and concentration under reduced pressure.

[0142] (b) Hydrogenation deesterification step

[0143] Hydrogenation catalyst Pd / C: 25g

[0144] Preparation parameters:

[0145] Step 1: 140g of NH2-ZIF-8 was activated in vacuum at 200℃ for 10 hours, and then stirred at 100℃ for 24 hours with 5g of 12-mercaptododecyl phosphoric acid, 0.5g of epoxy succinic acid and 5g of catalyst in a mixed solvent of ethanol and toluene (volume ratio 2:1).

[0146] Step 2: Add 2g palladium nitrate and 2g RuCl·3H2O, stir at 80℃ under nitrogen atmosphere for 7 hours, wash, and then vacuum dry at 100℃ for 16 hours.

[0147] Acid reagent: 50g concentrated hydrochloric acid

[0148] Solvent: Water / acetic acid mixture (volume ratio 1:2)

[0149] Hydrogen pressure: 5 atm

[0150] Reaction conditions: temperature 40℃, stirring 500rpm, time 24h

[0151] Post-processing: Same as in Example 1, after washing with water, extract with ethyl acetate, concentrate under reduced pressure at 40°C, and recrystallize.

[0152] (c) Salting steps

[0153] Dilution conditions: Add 100g of aqueous solution and cool to 10℃ to precipitate.

[0154] Washing conditions: Wash with 10 times the amount of water and dry until moisture content is <0.5%.

[0155] Comparative Example 1: Environmentally Friendly Loxoprofen Sodium Synthesis Process

[0156] (a) Bromination (free radical two-phase system)

[0157] Substrate: 2-(4-methylphenyl)propionic acid (100g)

[0158] Solvent: cyclohexane: 200g

[0159] Water: 100g

[0160] Bromine (Br2): 102g

[0161] Initiator: AIBN (0.5 g of substrate)

[0162] Reaction conditions: temperature 20℃, stirring 300 rpm, reaction time 6 h.

[0163] Post-processing: Natural separation, take the cyclohexane organic phase; wash with 10 times the weight of the substrate in water, extract with degassed cyclohexane and concentrate under reduced pressure.

[0164] (b) Hydrogenation deesterification step

[0165] Intermediate: equal amount according to (a) theoretical yield

[0166] Hydrogenation catalyst Pd / C: 10g

[0167] Preparation parameters:

[0168] Step 1: 100g of NH2-ZIF-8 was activated in vacuum at 100℃ for 5 hours, and then mixed with 1g of 12-mercaptododecyl phosphate and 1g of catalyst in ethanol. The mixture was stirred at 60℃ for 8 hours.

[0169] Step 2: Add 0.5g palladium nitrate and 0.5g RuCl·3H2O, stir at 70℃ under nitrogen atmosphere for 4 hours, separate the solid, wash with water and ethanol, and dry under vacuum at 60℃ for 8 hours.

[0170] Acid reagent: 20g trifluoroacetic acid

[0171] Solvent: Water / acetic acid mixture (volume ratio 1:1)

[0172] Hydrogen pressure: 1 atm for ordinary hydrogen

[0173] Reaction conditions: temperature 25℃, stirring 200 rpm, time 12 h

[0174] Post-treatment: Filter to remove catalyst, wash twice with water (5 times the amount of substrate each time), extract with ethyl acetate, concentrate under reduced pressure at 30°C, and recrystallize to obtain pure loxoprofen.

[0175] (c) Salting steps

[0176] Neutralizing agent: NaOH powder (with the same mass as loxoprofen)

[0177] Dilution conditions: Dilute with 70g of aqueous solution, cool to 5℃ to precipitate.

[0178] Post-treatment: Filter, wash with 5 times the amount of water, and dry until the moisture content is <0.5%.

[0179] Comparative Example 2: Environmentally Friendly Loxoprofen Sodium Synthesis Process

[0180] (a) Bromination (free radical two-phase system)

[0181] Substrate: 2-(4-methylphenyl)propionic acid (100g)

[0182] Solvent: cyclohexane: 200g

[0183] Water: 100g

[0184] Bromine (Br2): 102g

[0185] Initiator: AIBN (0.5 g of substrate)

[0186] Reaction conditions: temperature 20℃, stirring 300 rpm, reaction time 6 h.

[0187] Post-processing: Natural separation, take the cyclohexane organic phase; wash with 10 times the weight of the substrate in water, extract with degassed cyclohexane and concentrate under reduced pressure.

[0188] (b) Hydrogenation deesterification step

[0189] Intermediate: equal amount according to (a) theoretical yield

[0190] Hydrogenation catalyst Pd / C: 10g

[0191] Preparation parameters:

[0192] Step 1: 100g of NH2-ZIF-8 was activated in vacuum at 100℃ for 5 hours, and then mixed with 0.01g of (2R,3S)-2,3-epoxysuccinic acid and 1g of catalyst in ethanol. The mixture was stirred at 60℃ for 8 hours.

[0193] Step 2: Add 0.5g palladium nitrate and 0.5g RuCl·3H2O, stir at 70℃ under nitrogen atmosphere for 4 hours, separate the solid, wash with water and ethanol, and dry under vacuum at 60℃ for 8 hours.

[0194] Acid reagent: 20g trifluoroacetic acid

[0195] Solvent: Water / acetic acid mixture (volume ratio 1:1)

[0196] Hydrogen pressure: 1 atm for ordinary hydrogen

[0197] Reaction conditions: temperature 25℃, stirring 200 rpm, time 12 h

[0198] Post-treatment: Filter to remove catalyst, wash twice with water (5 times the amount of substrate each time), extract with ethyl acetate, concentrate under reduced pressure at 30°C, and recrystallize to obtain pure loxoprofen.

[0199] (c) Salting steps

[0200] Neutralizing agent: NaOH powder (with the same mass as loxoprofen)

[0201] Dilution conditions: Dilute with 70g of aqueous solution, cool to 5℃ to precipitate.

[0202] Post-treatment: Filter, wash with 5 times the amount of water, and dry until the moisture content is <0.5%.

[0203] Test method:

[0204] 1. Product yield calculation formula = (Actual weight of crude product / Theoretical weight of product) * 100%

[0205] 2. The method used to determine the purity of the product is HPLC:

[0206] Chromatographic column: Inertsil ODS-3C18 (4.6mm*150mm*5μm)

[0207] Detection wavelength: 222nm

[0208] Flow rate: 1 mL / min

[0209] Injection volume: 10 μL

[0210] Column temperature: 40℃

[0211] Mobile phase: A: 0.1% H3PO4 (water); B: acetonitrile

[0212] The gradient elution procedure is as follows:

[0213] Time (min) <![CDATA[A: 0.1% H3PO4 water (%)]]> B: Acetonitrile (%) 0 80 20 5 80 20 35 20 80 50 20 80

[0214] 3. Catalyst recyclability: After the catalyst is filtered and recovered, it is washed and activated with water and reused for repeated experiments. After repeating 10 times, the product yield is calculated.

[0215] Table 1: Test Results of Examples and Comparative Examples

[0216]

[0217] The embodiments implemented by the above design scheme effectively improve the purity and overall yield of the product. After ten cycles of use, the yield of the catalyst decreases by no more than 10%, demonstrating its long lifespan and reusability.

[0218] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.

Claims

1. A green synthesis process for nonsteroidal loxoprofen sodium, characterized in that, Includes the following steps: (a) Bromination Substrate: 100 portions; Solvent cyclohexane: 200–500 parts; Water: 100–300 servings; Bromine: 102–110 parts; AIBN or photoinitiator: AIBN is used at a mass of 0.5–2.0 parts of the substrate, or a light source is used for initiation; Reaction conditions: temperature 20–40℃, stirring 300–600 rpm, reaction time 6–12 h; After the reaction is complete, the phases are separated naturally or by centrifugation. The cyclohexane organic phase is used as an intermediate. The intermediate is purified for later use. (b) Hydrogenation for the removal of ethyl ester and tert-butyl ester is completed in one step. Intermediate: in equal quantities according to the theoretical yield of reaction (a); Hydrogenation catalyst Pd / C ratio: 10–25 parts; Trifluoroacetic acid or concentrated hydrochloric acid: 20–50 parts; The solvent is acetic acid or a mixture of water and acetic acid; Hydrogen pressure: 1 atm for ordinary hydrogen, or 2–5 atm for boosted kinetics; Temperature 25–40℃; stirring 200–500 rpm; time 12–24 h; After the reaction, the catalyst was removed by filtration, and the product was washed twice with water, each time with 5 times the amount of substrate. The product was then extracted with ethyl acetate or acetonitrile, concentrated under reduced pressure at 30–40 °C, and recrystallized to give pure loxoprofen. (c) Salting steps Take the loxoprofen obtained in step (b) and neutralize it with water-soluble NaOH powder to pH 7–8; Dilute with 70–100 parts of aqueous solution, cool to 5–10°C to precipitate loxoprofen sodium; filter, wash with 5–10 times the amount of water, and dry to obtain loxoprofen sodium; In step (b), the hydrogenation catalyst Pd / C is composed of NH4+. 2- It was prepared by reacting ZIF-, 12-mercaptododecyl phosphate, (2R,3S)-2,3-epoxysuccinic acid, palladium nitrate, and RuCl·3H2O.

2. The green synthesis process for non-steroidal loxoprofen sodium according to claim 1, characterized in that: In step (a), the substrate is one of 2-(4-methylphenyl)propionic acid, tert-butyl 2-(4-methylphenyl)propionate, potassium 2-(4-methylphenyl)propionate, or sodium 2-(4-methylphenyl)propionate.

3. The green synthesis process for nonsteroidal loxoprofen sodium according to claim 1, characterized in that: The light source for illumination in step (a) is 365nm, 10–20W.

4. The green synthesis process for nonsteroidal loxoprofen sodium according to claim 1, characterized in that: The purification process in step (a): Wash with water diluted 10–20 times the weight of the substrate; Further extraction with degassed cyclohexane or ethyl acetate followed by vacuum concentration.

5. The green synthesis process for nonsteroidal loxoprofen sodium according to claim 1, characterized in that: The preparation method of the hydrogenation catalyst Pd / C in step (b) is as follows: Step 1: After activating 100-140 parts by weight of NH2-ZIF-8 (CAS: 2762331-72-4) under vacuum at 100-200℃ for 5-10 hours, mix it with 1-5 parts by weight of 12-mercaptododecyl phosphoric acid, 0.01-0.5 parts by weight of (2R,3S)-2,3-epoxysuccinic acid, and 1-5 parts by weight of catalyst in an organic solvent, and stir the mixture at 60-100℃ for 8-24 hours. Step 2: Add 0.5-2 parts by weight of palladium nitrate and 0.5-2 parts by weight of RuCl·3H2O, and stir the reaction under a nitrogen atmosphere at 70-80℃ for 4-7 hours; separate the solid product, wash it with water and alcohol in sequence, and dry it under vacuum at 60-100℃ for 8-16 hours to obtain the catalyst supported on Pd-Ru bimetal.

6. The preparation method according to claim 5, characterized in that: The organic solvent is one or more of toluene, xylene, ethanol, and isopropanol.

7. The green synthesis process for nonsteroidal loxoprofen sodium according to claim 1, characterized in that: The volume ratio of the water / acetic acid mixture in the solvent of step (b) is water:acetic acid = 1:1–1:

2.

8. The green synthesis process for nonsteroidal loxoprofen sodium according to claim 1, characterized in that: In step (c), the amount of water-soluble alkali NaOH used is the same as the mass of loxoprofen.

9. The green synthesis process for nonsteroidal loxoprofen sodium according to claim 1, characterized in that: In step (c), the moisture content of loxoprofen sodium after drying is <0.5%.

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