Synthetic method of high-purity loxoprofen sodium

Abstract

The invention discloses a synthesis method of high-purity loxoprofen sodium, and relates to the technical field of loxoprofen sodium synthesis. According to the method, dimethyl adipate is adopted as a cheap initiator, processes such as Deckmann condensation, hydrolysis decarboxylation and alkalization salt preparation are adopted for optimizing routes, precise temperature, time and pH control is assisted, and solvent recovery and activated carbon decoloration treatment are combined, so that the impurity content is effectively reduced. The HPLC purity of the final product reaches 99.95% or above, the content of single impurities is smaller than or equal to 0.05%, the content of total impurities is smaller than or equal to 0.5%, and excellent industrial expandability and economic benefits are shown.

Description

Technical Field

[0001] The invention belongs to the technical field of loxoprofen sodium synthesis, and in particular relates to a method for synthesizing high-purity loxoprofen sodium. Background Art

[0002] Loxoprofen sodium is a commonly used nonsteroidal anti-inflammatory drug (NSAID). Its active form is loxoprofen salt with sustained-release properties, which is widely used to relieve inflammation and pain symptoms.

[0003] Patent publication number CN101412670B discloses a method for synthesizing loxoprofen sodium. Using p-methylacetophenone as a starting material, the process proceeds through reduction, acylation or halogenation, cyanation, hydrolysis, bromination, condensation, decarboxylation, and salt formation. This method offers the advantages of readily available starting materials, a comprehensive reaction system, and simplified operation. High yields are achieved in each step, and solvent recovery reduces costs.

[0004] Patent application CN105218351A discloses a method for synthesizing loxoprofen sodium. The method proposes using dimethyl adipate as a raw material, undergoing Dieckmann cyclization to generate a 2-oxocyclopentane intermediate. This intermediate is then condensed with methyl bromophenylpropionate, followed by acidic hydrolysis, decarboxylation, and alkalization to produce a salt. This method significantly shortens the synthetic route and reduces pollution, but there is still room for improvement in the purity control of key intermediates and the reaction process.

[0005] The patent application with publication number CN108440274A discloses a method for synthesizing high-purity non-steroidal anti-inflammatory drug loxoprofen sodium. It clearly defines the completion criteria as the S2 stage reaction to the HPLC intermediate c content ≥98.5%, the S3 stage intermediate c residue ≤0.01%, the S4 stage salification to the reaction system pH 6.5-7.7, the single impurity ≤0.05%, and the total impurity ≤0.50%, and is accompanied by specific washing, decolorization, and recovery operation instructions to ensure the purity and industrial controllability of the final product.

[0006] Overall, although the above method has certain industrial practical value, it still has the following problems: Raw material cost and source: Patent with authorization announcement number CN101412670B uses p-methylacetophenone as the starting material. Although it has good stability, the raw material price is relatively high and it involves multiple steps of cyanidation and reduction, which is not conducive to industrial economic feasibility.

[0007] Lengthy synthetic routes: Many routes include multi-step halogenation, condensation, decarboxylation, etc., which require the use of hazardous reagents or highly corrosive media, are complex to operate, and impose a heavy environmental burden.

[0008] Insufficient control of impurities and purity: Although the patent application with publication number CN108440274A has strict requirements for purity control, it provides few process path details for intermediate purification and impurity cause identification. If the production is scaled up to 100 kilograms, impurities may still exceed the standard or be unevenly distributed.

[0009] Solvent recovery and environmental treatment issues: Some patents do not provide detailed information on the industrial applicability of the solvent recovery process and decolorization and washing facilities, which has a potential impact on the cost and environmental compliance of large-scale production.

[0010] In summary, while currently available synthetic technologies for loxoprofen sodium cover multiple routes, an industrialized method that balances raw material availability, process simplicity, cost-effectiveness, and high purity (HPLC ≥ 99.9%) is still lacking. Therefore, a new technical solution is urgently needed: starting with inexpensive intermediates, reducing contamination steps, enhancing intermediate purification, and incorporating recyclable solvents and decolorization processes to ensure that the final product meets pharmaceutical-grade high-purity standards, is easily scalable, and maintains stable quality control. Summary of the Invention

[0011] Based on the problems raised by the above background technology, the present invention proposes a method for synthesizing high-purity loxoprofen sodium.

[0012] The technical solution is as follows: The synthesis method of high-purity loxoprofen sodium comprises the following steps, calculated by weight: S1 is methylated to produce intermediate b: 100 parts by weight of 2-(4-bromomethylphenyl)propionic acid are reacted with 150-200 parts of methanol and 5-15 parts of concentrated sulfuric acid. The reaction temperature is adjusted for 5-8 hours until the residual 2-(4-bromomethylphenyl)propionic acid is ≤ 0.3 parts (determined by HPLC). After the reaction, the mixture is cooled, washed with aqueous sodium carbonate solution, and neutralized. 0.6-1.2 parts by weight of epoxy turmeric oil-semicarbazide adduct (EGU) is added, and the mixture is stirred for 20-30 minutes. The epoxy turmeric oil-semicarbazide adduct (EGU) is removed by filtration, and then dried to obtain intermediate b. S2 Dieckmann condensation to obtain intermediate c: Add 5-15 parts of solvent to 100-150 parts of dimethyl adipate, cool to 0-5°C, slowly add 105-115 parts of sodium methoxide dropwise, stir and react for 1-2 hours, then add 100-120 parts of intermediate b and heat and react for 3-5 hours. After the reaction, wash with water, extract, concentrate the organic phase, and dry to obtain intermediate c; S3 acidic hydrolysis and decarboxylation to produce loxoprofen acid: Mix 100 parts of intermediate c with 10-12 parts of acetic acid, 20-25 parts of water and 160-180 parts of concentrated sulfuric acid, heat to 100-120°C, react for 1-3 hours, then cool to 50-60°C and maintain for 3-6 hours until the residual intermediate c in HPLC is ≤0.01 parts; after the reaction, cool and dilute, adjust the pH to 5.0-5.5 with dilute HCl or sodium bicarbonate, crystallize, filter and dry to obtain loxoprofen acid; S4 alkalizes salt to produce loxoprofen sodium: 100 parts of loxoprofen acid are dissolved in 150-200 parts of an organic solvent, and 95-105 parts of a 30 wt% NaOH solution are slowly added dropwise to control the pH of the reaction system at 6.5-7.5. After the salt is formed, the temperature is raised to 40-50°C, activated carbon is used for decolorization, impurities and carbon black are removed by hot filtration, and the product is slowly cooled for crystallization, washed with acetone, and vacuum dried to finally obtain high-purity loxoprofen sodium.

[0013] Preferably, the reaction temperature in S1 is 30-40°C.

[0014] Preferably, the preparation method of EGU in S1 comprises: Dissolve 10-15 parts by weight of epoxy turmeric oil in 50-70 parts by weight of ethyl acetate, add 0.2-0.5 parts by weight of pyridine as a catalyst, slowly dropwise add 8-12 parts by weight of an ethanol solution of semicarbazide with a semicarbazide mass fraction of 25%, heat to 55-65°C and stir to react for 3-5 hours, cool to 10-15°C after the reaction to crystallize, filter, wash with ethyl acetate 2-3 times, and dry in vacuo at 50-60°C for 4-5 hours to obtain the product.

[0015] Preferably, the solvent in S2 is selected from one of DMSO, DMF and N-DMAc.

[0016] Preferably, the temperature of the heating reaction in S2 is 50-60°C.

[0017] Preferably, the crystallization temperature in S3 is 20-30°C.

[0018] Preferably, the organic solvent in S4 is selected from acetone or acetonitrile.

[0019] Preferably, the temperature during the dropwise addition of the NaOH solution in S4 is controlled at 10-15°C.

[0020] Preferably, the crystallization temperature in S4 is controlled at 0-5°C.

[0021] Reaction mechanism: The epoxy group (three-membered ring structure) of epoxy turmeric oil undergoes a nucleophilic addition reaction with the amino group (-NH2) of semicarbazide, opening the ring to form an EGU additive containing a urea group (-NH-CO-NH-) and a turmeric oil terpene chain; the urea group selectively adsorbs trace methylation byproducts (such as dimethyl ester impurities) remaining in the S1 stage through hydrogen bonding, and the hydrophobic structure of the terpene chain can enhance the encapsulation of non-polar impurities.

[0022] EGU is a solid particle that does not dissolve in the washing system and can be completely separated by filtration to avoid entering intermediate b, thereby reducing the source of impurities in subsequent reactions from the source.

[0023] Compared with the prior art, the present invention has the following beneficial effects: 1. The present invention optimizes raw material selection, strictly controls reaction monitoring conditions, and standardizes the purification process. EGU has a high adsorption rate for trace ester impurities, effectively improving the purity of intermediate b and reducing subsequent Diekmann condensation side reactions.

[0024] 2. The loxoprofen sodium synthesized by the present invention has not only a high yield, but also an HPLC purity of more than 99.95%, a single impurity ≤ 0.02%, and a total impurity ≤ 0.05%, which is significantly superior to the existing process. In addition, the raw material cost is low, the operation is simple, and the industrial controllability is strong, making it very suitable for the production of pharmaceutical raw materials. DETAILED DESCRIPTION

[0025] 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 embodiments described 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 making creative efforts are within the scope of protection of the present invention.

[0026] The test method is as follows: Main component content and impurity detection method: RP-HPLC method for the determination of the main components and related impurities in loxoprofen sodium tablets. The chromatographic conditions are as follows: Column: C18 (Inspire C18); Mobile phase: acetonitrile-0.01 mol / L, potassium dihydrogen phosphate (containing 0.2% triethylamine, pH adjusted to 3.0±0.1, volume ratio 62:38); Flow rate: 1.0 mL / min; column temperature: 40°C; detection wavelength: 221 nm; injection volume: 20 µL; Under these conditions, the separation between the main peak and adjacent impurity peaks was >1.5; the linear range was 30-90µg / mL, r=0.9998; the detection limit was 0.3µg / mL; the precision RSD was <1%; and the recovery rate was 99.00-99.87%, RSD=0.33% (n=9).

[0027] Example 1: A method for synthesizing high-purity loxoprofen sodium, comprising the following steps: S1 (methyl esterification): Mix 100 g of 2-(4-bromomethylphenyl)propionic acid, 150 g of methanol, and 5 g of concentrated sulfuric acid, control the reaction temperature to 30°C, and react for 5 h (HPLC detection shows that the residual 2-(4-bromomethylphenyl)propionic acid is ≤ 0.3 g). After cooling, wash with aqueous sodium carbonate solution and neutralize (pH = 7). Add 0.6 g of epoxyturmeric oil-semicarbazide adduct (EGU), stir for 20 min, filter, and dry the organic phase to obtain intermediate b.

[0028] S2 (Dickmann condensation): Add 5 g DMSO to 100 g dimethyl adipate, cool to 0°C, slowly add 105 g sodium methoxide dropwise, stir and react for 1 h, add 100 g intermediate b, heat to 50°C and react for 3 h, wash with water after the reaction, extract with ethyl acetate, and concentrate and dry the organic phase to obtain intermediate c.

[0029] S3 (acidic hydrolysis decarboxylation): Mix 100 g of intermediate c with 10 g of acetic acid, 20 g of water, and 160 g of concentrated sulfuric acid, heat to 100 ° C for 1 h, cool to 50 ° C and maintain for 3 h (HPLC detection of intermediate c residue ≤ 0.01 g), cool and dilute with water, adjust the pH to 5.0 with dilute HCl, crystallize at 20 ° C, filter and dry to obtain loxoprofen acid.

[0030] S4 (alkalinization salt production): Dissolve 100 g of loxoprofen acid in 150 g of acetone, slowly add 95 g of 30 wt% NaOH solution dropwise at 10°C, control the pH to 6.5, raise the temperature to 40°C, add activated carbon for decolorization, filter hot, slowly cool the filtrate to 0°C for crystallization, wash with acetone, and dry in vacuo to obtain loxoprofen sodium.

[0031] EGU preparation: Dissolve 10 g epoxy turmeric oil in 50 g ethyl acetate, add 0.2 g pyridine, add 8 g 25% semicarbazide ethanol solution dropwise, react at 55 ° C for 3 h, cool to 10 ° C for crystallization, filter, wash twice with ethyl acetate, and dry in a vacuum at 50 ° C for 4 h.

[0032] After testing, HPLC in this example showed that the purity of loxoprofen sodium was 99.95%, with a single impurity of 0.02% and a total impurity of 0.05%.

[0033] Example 2: A method for synthesizing high-purity loxoprofen sodium, comprising the following steps: S1 (methyl esterification): Mix 100 g of 2-(4-bromomethylphenyl)propionic acid, 165 g of methanol, and 8 g of concentrated sulfuric acid, control the reaction temperature to 33°C, and react for 6 h (HPLC detection of residual 2-(4-bromomethylphenyl)propionic acid ≤ 0.3 g). After cooling, wash and neutralize with aqueous sodium carbonate solution (pH = 7), add 0.8 g of epoxyturmeric oil-semicarbazide adduct (EGU), stir for 23 min, filter, and dry the organic phase to obtain intermediate b.

[0034] S2 (Dickmann condensation): 8 g of DMF was added to 120 g of dimethyl adipate, cooled to 2°C, 108 g of sodium methoxide was slowly added dropwise, stirred and reacted for 1.3 h, 105 g of intermediate b was added, the temperature was raised to 53°C and reacted for 3.5 h, washed with water after the reaction, extracted with ethyl acetate, and the organic phase was concentrated and dried to obtain intermediate c.

[0035] S3 (acidic hydrolysis decarboxylation): Mix 100 g of intermediate c with 10.5 g of acetic acid, 22 g of water, and 165 g of concentrated sulfuric acid, heat to 105 ° C for 1.5 h, cool to 53 ° C and maintain for 4 h (HPLC detection of intermediate c residue ≤ 0.01 g), cool and dilute with water, adjust the pH to 5.2 with sodium bicarbonate, crystallize at 23 ° C, filter and dry to obtain loxoprofen acid.

[0036] S4 (alkalinization salt production): Dissolve 100 g of loxoprofen acid in 165 g of acetonitrile, slowly add 98 g of 30 wt% NaOH solution dropwise at 12 ° C, control the pH to 6.8, raise the temperature to 43 ° C, add activated carbon for decolorization, filter hot, slowly cool the filtrate to 2 ° C for crystallization, wash with acetone, and vacuum dry to obtain loxoprofen sodium.

[0037] EGU preparation: Dissolve 12g of epoxy turmeric oil in 55g of ethyl acetate, add 0.3g of pyridine, and dropwise add 9g of 25% semicarbazide ethanol solution. React at 58°C for 3.5h. Cool to 12°C to crystallize, filter, wash twice with ethyl acetate, and dry in a vacuum at 53°C for 4.2h.

[0038] After testing, HPLC in this example showed that the purity of loxoprofen sodium was 99.96%, with a single impurity of 0.02% and a total impurity of 0.04%.

[0039] Example 3: A method for synthesizing high-purity loxoprofen sodium, comprising the following steps: S1 (methyl esterification): Mix 100 g of 2-(4-bromomethylphenyl)propionic acid, 185 g of methanol, and 12 g of concentrated sulfuric acid, control the reaction temperature to 37°C, and react for 7 h (HPLC detection shows that the residual 2-(4-bromomethylphenyl)propionic acid is ≤ 0.3 g). After cooling, wash and neutralize with aqueous sodium carbonate solution (pH = 7), add 1.0 g of epoxyturmeric oil-semicarbazide adduct (EGU), stir for 27 min, filter, and dry the organic phase to obtain intermediate b.

[0040] S2 (Dickmann condensation): Add 12 g of N-DMAc to 140 g of dimethyl adipate, cool to 4 ° C, slowly add 112 g of sodium methoxide dropwise, stir and react for 1.7 h, add 115 g of intermediate b, heat to 58 ° C and react for 4.5 h. After the reaction, wash with water, extract with ethyl acetate, and concentrate and dry the organic phase to obtain intermediate c.

[0041] S3 (acidic hydrolysis decarboxylation): Mix 100 g of intermediate c with 11.5 g of acetic acid, 24 g of water, and 175 g of concentrated sulfuric acid, heat to 115 ° C for reaction for 2.5 h, cool to 58 ° C and maintain for 5 h (HPLC detection of intermediate c residue ≤ 0.01 g), cool and dilute with water, adjust the pH to 5.4 with dilute HCl, crystallize at 28 ° C, filter and dry to obtain loxoprofen acid.

[0042] S4 (alkalinization salt production): Dissolve 100 g of loxoprofen acid in 185 g of acetone, slowly add 102 g of 30 wt% NaOH solution dropwise at 14 °C, control the pH to 7.2, raise the temperature to 48 °C, add activated carbon for decolorization, filter hot, and slowly cool the filtrate to 4 °C for crystallization, wash with acetone, and vacuum dry to obtain loxoprofen sodium.

[0043] EGU preparation: Dissolve 14 g epoxy turmeric oil in 65 g ethyl acetate, add 0.4 g pyridine, add 11 g 25% semicarbazide ethanol solution dropwise, react at 62 ° C for 4.5 h, cool to 14 ° C for crystallization, filter, wash with ethyl acetate three times, and dry in a vacuum at 58 ° C for 4.8 h.

[0044] After testing, HPLC showed that the purity of loxoprofen sodium in this example was 99.96%, with a single impurity of 0.01% and a total impurity of 0.03%.

[0045] Example 4: A method for synthesizing high-purity loxoprofen sodium, comprising the following steps: Raw materials and parameters: S1 (methyl esterification): Mix 100 g of 2-(4-bromomethylphenyl)propionic acid, 200 g of methanol, and 15 g of concentrated sulfuric acid, control the reaction temperature to 40°C, and react for 8 h (HPLC detection shows that the residual 2-(4-bromomethylphenyl)propionic acid is ≤ 0.3 g). After cooling, wash and neutralize with aqueous sodium carbonate solution (pH = 7), add 1.2 g of epoxyturmeric oil-semicarbazide adduct (EGU), stir for 30 min, filter, and dry the organic phase to obtain intermediate b.

[0046] S2 (Dickmann condensation): Add 15 g of DMF to 150 g of dimethyl adipate, cool to 5°C, slowly add 115 g of sodium methoxide dropwise, stir and react for 2 h, add 120 g of intermediate b, heat to 60°C and react for 5 h, wash with water after the reaction, extract with ethyl acetate, and concentrate and dry the organic phase to obtain intermediate c.

[0047] S3 (acidic hydrolysis decarboxylation): Mix 100 g of intermediate c with 12 g of acetic acid, 25 g of water, and 180 g of concentrated sulfuric acid, heat to 120°C for reaction for 3 h, cool to 60°C and maintain for 6 h (HPLC detection shows that the residual intermediate c is ≤ 0.01 g), cool, dilute with water, adjust the pH to 5.5 with sodium bicarbonate, crystallize at 30°C, filter and dry to obtain loxoprofen acid.

[0048] S4 (alkalinization salt production): Dissolve 100 g of loxoprofen acid in 200 g of acetonitrile, slowly add 105 g of 30 wt% NaOH solution dropwise at 15 ° C, control the pH to 7.5, raise the temperature to 50 ° C, add activated carbon for decolorization, filter hot, slowly cool the filtrate to 5 ° C for crystallization, wash with acetone, and vacuum dry to obtain loxoprofen sodium.

[0049] EGU preparation: Dissolve 15 g epoxy turmeric oil in 70 g ethyl acetate, add 0.5 g pyridine, add 12 g 25% semicarbazide ethanol solution dropwise, react at 65 ° C for 5 h, cool to 15 ° C for crystallization, filter, wash with ethyl acetate three times, and dry in a vacuum at 60 ° C for 5 h.

[0050] After testing, HPLC in this example showed that the purity of loxoprofen sodium was 99.97%, with a single impurity of 0.01% and a total impurity of 0.03%.

[0051] Comparative Example 1: A method for synthesizing loxoprofen sodium, comprising the following steps: S1 (methyl esterification): Mix 100 g of 2-(4-bromomethylphenyl)propionic acid, 150 g of methanol, and 5 g of concentrated sulfuric acid, control the reaction temperature to 30°C, and react for 5 h (HPLC detection shows that the residual 2-(4-bromomethylphenyl)propionic acid is ≤ 0.3 g). After cooling, wash and neutralize with aqueous sodium carbonate solution (pH = 7), and dry to obtain intermediate b.

[0052] S2 (Dickmann condensation): Add 5 g DMSO to 100 g dimethyl adipate, cool to 0°C, slowly add 105 g sodium methoxide dropwise, stir and react for 1 h, add 100 g intermediate b, heat to 50°C and react for 3 h, wash with water after the reaction, extract with ethyl acetate, and concentrate and dry the organic phase to obtain intermediate c.

[0053] S3 (acidic hydrolysis decarboxylation): Mix 100 g of intermediate c with 10 g of acetic acid, 20 g of water, and 160 g of concentrated sulfuric acid, heat to 100 ° C for 1 h, cool to 50 ° C and maintain for 3 h (HPLC detection of intermediate c residue ≤ 0.01 g), cool and dilute with water, adjust the pH to 5.0 with dilute HCl, crystallize at 20 ° C, filter and dry to obtain loxoprofen acid.

[0054] S4 (alkalinization salt production): Dissolve 100 g of loxoprofen acid in 150 g of acetone, slowly add 95 g of 30 wt% NaOH solution dropwise at 10°C, control the pH to 6.5, raise the temperature to 40°C, add activated carbon for decolorization, filter hot, slowly cool the filtrate to 0°C for crystallization, wash with acetone, and dry in vacuo to obtain loxoprofen sodium.

[0055] After testing, HPLC showed that the purity of loxoprofen sodium in this example was 99.91%, with a single impurity of 0.04% and a total impurity of 0.07%.

[0056] Comparative Example 2: A method for synthesizing loxoprofen sodium, comprising the following steps: S1 (methyl esterification): Mix 100 g of 2-(4-bromomethylphenyl)propionic acid, 150 g of methanol, and 5 g of concentrated sulfuric acid, control the reaction temperature to 30°C, and react for 5 h (HPLC detection shows that the residual 2-(4-bromomethylphenyl)propionic acid is ≤ 0.3 g). After cooling, wash and neutralize with aqueous sodium carbonate solution (pH = 7), add 0.6 g of epoxyturmeric oil-semicarbazide adduct (EGU), stir for 20 min, filter, and dry the organic phase to obtain intermediate b.

[0057] S2 (Dickmann condensation): Add 5 g DMSO to 100 g dimethyl adipate, cool to 0°C, slowly add 105 g sodium methoxide dropwise, stir and react for 1 h, add 100 g intermediate b, heat to 50°C and react for 3 h, wash with water after the reaction, extract with ethyl acetate, and concentrate and dry the organic phase to obtain intermediate c.

[0058] S3 (acidic hydrolysis decarboxylation): Mix 100 g of intermediate c with 10 g of acetic acid, 20 g of water, and 160 g of concentrated sulfuric acid, heat to 100 ° C for 1 h, cool to 50 ° C and maintain for 3 h (HPLC detection of intermediate c residue ≤ 0.01 g), cool and dilute with water, adjust the pH to 5.0 with dilute HCl, crystallize at 20 ° C, filter and dry to obtain loxoprofen acid.

[0059] S4 (alkalinization salt production): Dissolve 100 g of loxoprofen acid in 150 g of acetone, slowly add 95 g of 30 wt% NaOH solution dropwise at 10°C, control the pH to 6.5, raise the temperature to 40°C, add activated carbon for decolorization, filter hot, slowly cool the filtrate to 0°C for crystallization, wash with acetone, and dry in vacuo to obtain loxoprofen sodium.

[0060] EGU preparation: Dissolve 10 g epoxy turmeric oil in 50 g ethyl acetate, add 0.2 g pyridine, react at 55 °C for 3 h, cool to 10 °C for crystallization, filter, wash twice with ethyl acetate, and dry in vacuum at 50 °C for 4 h.

[0061] After testing, HPLC showed that the purity of loxoprofen sodium in this example was 99.93%, with a single impurity of 0.03% and a total impurity of 0.06%.

[0062] Comparative Example 3: A method for synthesizing loxoprofen sodium, comprising the following steps: S1 (methyl esterification): Mix 100 g of 2-(4-bromomethylphenyl)propionic acid, 150 g of methanol, and 5 g of concentrated sulfuric acid, control the reaction temperature to 30°C, and react for 5 h (HPLC detection shows that the residual 2-(4-bromomethylphenyl)propionic acid is ≤ 0.3 g). After cooling, wash and neutralize with aqueous sodium carbonate solution (pH = 7), add 0.6 g of epoxyturmeric oil-semicarbazide adduct (EGU), stir for 20 min, filter, and dry the organic phase to obtain intermediate b.

[0063] S2 (Dickmann condensation): Add 5 g DMSO to 100 g dimethyl adipate, cool to 0°C, slowly add 105 g sodium methoxide dropwise, stir and react for 1 h, add 100 g intermediate b, heat to 50°C and react for 3 h, wash with water after the reaction, extract with ethyl acetate, and concentrate and dry the organic phase to obtain intermediate c.

[0064] S3 (acidic hydrolysis decarboxylation): Mix 100 g of intermediate c with 10 g of acetic acid, 20 g of water, and 160 g of concentrated sulfuric acid, heat to 100 ° C for 1 h, cool to 50 ° C and maintain for 3 h (HPLC detection of intermediate c residue ≤ 0.01 g), cool and dilute with water, adjust the pH to 5.0 with dilute HCl, crystallize at 20 ° C, filter and dry to obtain loxoprofen acid.

[0065] S4 (alkalinization salt production): Dissolve 100 g of loxoprofen acid in 150 g of acetone, slowly add 95 g of 30 wt% NaOH solution dropwise at 10°C, control the pH to 6.5, raise the temperature to 40°C, add activated carbon for decolorization, filter hot, slowly cool the filtrate to 0°C for crystallization, wash with acetone, and dry in vacuo to obtain loxoprofen sodium.

[0066] EGU preparation: Add 0.2 g of pyridine to 50 g of ethyl acetate, add 8 g of 25% semicarbazide ethanol solution dropwise, react at 55 °C for 3 h, cool to 10 °C for crystallization, filter, wash twice with ethyl acetate, and dry in a vacuum at 50 °C for 4 h.

[0067] After testing, HPLC in this example showed that the purity of loxoprofen sodium was 99.92%, with a single impurity of 0.03% and a total impurity of 0.06%.

[0068] Through the above rigorously designed examples and comparative examples, the comprehensive measured results clearly and professionally confirm the outstanding technical effects of the present invention in purity control, impurity removal, reaction optimization and industrial applicability.

[0069] While 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 these embodiments without departing from the principles and spirit of the invention, and that the scope of the invention is defined by the appended claims and their equivalents.

Claims

1. A method for synthesizing high-purity loxoprofen sodium, characterized in that: The method comprises the following steps, calculated by weight: S1 is methylated to produce intermediate b: 100 parts by weight of 2-(4-bromomethylphenyl)propionic acid are reacted with 150-200 parts of methanol and 5-15 parts of concentrated sulfuric acid, the reaction temperature is adjusted, and the reaction time is 5-8 hours, until the residual 2-(4-bromomethylphenyl)propionic acid is ≤0.3 parts. After the reaction is completed, the mixture is cooled, washed with sodium carbonate aqueous solution, and neutralized. 0.6-1.2 parts by weight of epoxy turmeric oil-semicarbazide adduct is added, and the epoxy turmeric oil-semicarbazide adduct is removed by filtration after stirring for 20-30 minutes, and then dried to obtain intermediate b; S2 Dieckmann condensation to obtain intermediate c: Add 5-15 parts of solvent to 100-150 parts of dimethyl adipate, cool to 0-5°C, slowly add 105-115 parts of sodium methoxide dropwise, stir and react for 1-2 hours, then add 100-120 parts of intermediate b and heat and react for 3-5 hours. After the reaction, wash with water, extract, concentrate the organic phase, and dry to obtain intermediate c; S3 acidic hydrolysis and decarboxylation to produce loxoprofen acid: Mix 100 parts of intermediate c with 10-12 parts of acetic acid, 20-25 parts of water and 160-180 parts of concentrated sulfuric acid, heat to 100-120°C, react for 1-3 hours, then cool to 50-60°C and maintain for 3-6 hours until the residual intermediate c in HPLC is ≤0.01 parts; after the reaction, cool and dilute, adjust the pH to 5.0-5.5 with dilute HCl or sodium bicarbonate, crystallize, filter and dry to obtain loxoprofen acid; S4 alkalizes salt to produce loxoprofen sodium: 100 parts of loxoprofen acid are dissolved in 150-200 parts of an organic solvent, and 95-105 parts of a 30 wt% NaOH solution are slowly added dropwise to control the pH of the reaction system to 6.5-7.

5. After the salt is formed, the temperature is raised to 40-50° C., activated carbon is used for decolorization, impurities and carbon black are removed by hot filtration, and the mixture is slowly cooled for crystallization, washed with acetone, and vacuum dried to finally obtain high-purity loxoprofen sodium; The epoxy turmeric oil-semicarbazide adduct is prepared by reacting epoxy turmeric oil, pyridine as a catalyst and an ethanol solution of semicarbazide.

2. the synthetic method of high-purity loxoprofen sodium according to claim 1, is characterized in that: The reaction temperature in S1 is 30-40°C.

3. the synthetic method of high-purity loxoprofen sodium according to claim 1, is characterized in that: The preparation method of the epoxy turmeric oil-semicarbazide adduct in S1 comprises: According to the weight parts, 10-15 parts by weight of epoxy turmeric oil are dissolved in 50-70 parts by weight of ethyl acetate, 0.2-0.5 parts by weight of pyridine is added as a catalyst, 8-12 parts by weight of an ethanol solution of semicarbazide is slowly added dropwise, and the mass fraction of semicarbazide is 25%. The temperature is raised to 55-65°C and stirred for reaction for 3-5 hours. After the reaction, the mixture is cooled to 10-15°C for crystallization, filtered, washed with ethyl acetate 2-3 times, and vacuum dried at 50-60°C for 4-5 hours to obtain the product.

4. the synthetic method of high-purity loxoprofen sodium according to claim 1, is characterized in that: The solvent in S2 is selected from one of DMSO, DMF and N-DMAc.

5. The synthetic method of high-purity loxoprofen sodium according to claim 1, wherein: The temperature of the heating reaction in S2 is 50-60°C.

6. The synthetic method of high-purity loxoprofen sodium according to claim 1, wherein: The crystallization temperature in S3 is 20-30°C.

7. The synthetic method of high-purity loxoprofen sodium according to claim 1, wherein: The organic solvent in S4 is selected from acetone or acetonitrile.

8. The synthetic method of high-purity loxoprofen sodium according to claim 1, wherein: The temperature of the NaOH solution in S4 is controlled at 10-15°C during the dropwise addition process.

9. The synthetic method of high-purity loxoprofen sodium according to claim 1, wherein: The crystallization temperature in S4 is controlled at 0-5°C.