A kind of synthetic method of oxacillin sodium

Abstract

The present invention belongs to the field of drug synthesis, and in particular to a method for synthesizing oxacillin sodium. The method is based on 6-aminopenicillanic acid (6-APA) and 5-methyl-3-phenyl-4-isoxazolecarbonyl chloride (MPCC) as raw materials, including a synthesis process of a condensation stage, an extraction salt formation stage, and a refined crystallization stage. The method of the present invention adopts a low-temperature phase-splitting process, introduces a phase-transfer catalyst, shortens the reaction time, suppresses the degradation of raw materials, and improves product quality; the refined crystallization stage adopts an inorganic salt-forming agent for refined salt formation, which has lower cost and further reduces the level of impurities. The crystal scale of the product is larger, the product particle size uniformity is better, and the fluidity is better. At the same time, the product does not need to be crushed and can be directly packaged.

Description

Technical Field

[0001] The invention belongs to the field of drug synthesis, and particularly relates to a method for synthesizing oxacillin sodium. Background Art

[0002] Oxacillin sodium is a penicillin antibiotic and a bactericidal agent during the growth phase. It exerts its bactericidal effect by inhibiting bacterial cell wall synthesis. Oxacillin sodium is not destroyed by penicillinase produced by Staphylococcus aureus and is effective against enzyme-producing strains of Staphylococcus aureus. It is used orally or by intramuscular injection for mild infections, and intravenously or by intravenous drip for severe infections. Oxacillin sodium is used to treat various infections caused by penicillin-resistant Staphylococci, such as sepsis, respiratory tract infections, and soft tissue infections, as well as mixed infections caused by Streptococcus pyogenes and penicillin-resistant cocci.

[0003] The sterile API for oxacillin sodium is a white or crystalline powder; it is odorless or slightly odorous. It is readily soluble in water, very slightly soluble in acetone or butanol, and virtually insoluble in ethyl acetate or petroleum ether. Its chemical name is (2S,5R,6R)-3,3-dimethyl-6-(5-methyl-3-phenyl-4-oxazolylcarboxamido)-7-oxo-4-thia-1-azabicyclo[3,2,0]heptane-2-carboxylic acid sodium salt monohydrate. Its molecular weight is 441.43, and its structural formula is:

[0004]

[0005] The drug is enzyme-resistant and acid-resistant, and can be taken orally or injected. The most commonly used one at present is injectable oxacillin sodium. We know that injectable oxacillin sodium is prepared by dividing oxacillin sodium dry powder into penicillin bottles. During the subpackaging process, there are requirements for the amount of oxacillin sodium in each bottle. Generally speaking, the deviation of each bottle cannot be higher than 4%, and the amount of 0.5g / bottle cannot exceed the range of 0.48-0.52g. If it exceeds this range, it will be identified as a substandard product by the manufacturer. In the subpackaging process, the fluidity of oxacillin sodium powder will seriously affect the weighing accuracy during subpackaging.

[0006] Currently, the synthesis of oxacillin sodium mainly uses the acyl chloride method, that is, 6-aminopenicillanic acid (abbreviated as 6-APA) and 5-methyl-3-phenyl-4-isoxazolecarbonyl chloride (abbreviated as MPCC) are condensed as raw materials to form sodium salt.

[0007] Chinese invention patent application CN201110114417.7 discloses a method for preparing oxacillin sodium and oxacillin sodium for injection. The method utilizes 6-APA and benzylisothiazolyl chloride as raw materials, and includes the steps of condensation, acidification, crystallization, crystal washing, crushing, and packaging. However, the condensation stage in this invention has a long reaction time, resulting in a product with a high content of impurities, requiring further crushing and packaging, and exhibiting poor fluidity.

[0008] Penicillin compounds such as 6-APA and oxacillin are unstable at high temperatures and in the presence of strong acids and bases, while MPCC remains solid at low temperatures (below 30°C). This presents a challenge in selecting the right temperature for the reaction. In existing techniques, at temperatures between 5 and 8°C, 6-APA degrades slowly, and MPCC uses ethyl acetate for dissolution and separate phase reactions, resulting in high reaction residues and long reaction times. At temperatures around 25°C, 6-APA degrades rapidly, and MPCC uses a small amount of acetone to promote dissolution (incomplete dissolution), resulting in a fast reaction rate and low residues, but also high impurity content.

[0009] The salt-forming agents in the crystallization process are sodium 2-ethylhexanoate and sodium acetate. The crystallization solvents reported include alcohol solvents such as ethanol and n-butanol. However, there is a problem that the product is lumpy and has poor fluidity, which requires the steps of crushing, grinding and screening.

[0010] Based on this, a synthesis method of oxacillin sodium is proposed and applied in the field of drug synthesis. Summary of the Invention

[0011] The present invention addresses the shortcomings of the prior art by providing a method for synthesizing oxacillin sodium. This method utilizes a low-temperature phase separation process, shortens reaction time, reduces costs, improves product quality, and eliminates the need for crushing, allowing for direct packaging.

[0012] In order to achieve the above-mentioned purpose of the present invention, the specific technical solution adopted by the present invention is:

[0013] A method for synthesizing oxacillin sodium comprises the following steps:

[0014] (1) Condensation stage:

[0015] 6-aminopenicillanic acid is mixed with water and then dissolved with alkaline solution. A first organic solvent and a phase transfer catalyst are added to obtain solution A. 5-methyl-3-phenyl-4-isoxazolecarbonyl chloride is dissolved in an ester solvent to obtain an MPCC solution. The MPCC solution reacts with solution A to obtain solution 1. The temperature in the condensation stage is 5-15°C.

[0016] (2) Extraction and salt formation stage:

[0017] Acid is added to adjust the pH of solution 1, and extraction is performed to obtain solution 2 containing oxacillin; a salt-forming agent, water, and a second organic solvent are mixed to obtain a salt-forming agent solution; the salt-forming agent solution is added dropwise to solution 2; separation and washing are performed to obtain a crude oxacillin sodium product;

[0018] (3) Crystallization stage:

[0019] Add the third organic solvent, the fourth organic solvent and water to the crude oxacillin sodium, mix, decolorize, crystallize and dry to obtain oxacillin sodium.

[0020] Preferably, the molar ratio of 6-aminopenicillanic acid to 5-methyl-3-phenyl-4-isoxazolecarbonyl chloride in step (1) is 1:1-2, preferably 1:1.1-1.2.

[0021] Preferably, the temperature of the condensation stage in step (1) is preferably 8-12°C.

[0022] Preferably, the alkali solution in step (1) is selected from one or more of sodium hydroxide solution, sodium carbonate solution, sodium bicarbonate solution, and ammonia water, preferably ammonia water, preferably 9% ammonia water.

[0023] Preferably, the first organic solvent in step (1) is an ester solvent, preferably an ester compound formed by a C1-C3 acid and a C1-C5 alcohol.

[0024] Preferably, the ester solvent is selected from one or more of ethyl acetate, butyl acetate, and isopropyl acetate.

[0025] Preferably, the phase transfer catalyst in step (1) is a quaternary ammonium salt compound, preferably tetrabutylammonium chloride.

[0026] Preferably, the mass ratio of 6-aminopenicillanic acid to the phase transfer catalyst in step (1) is 1:0.1-0.16.

[0027] Preferably, the mass volume ratio of 6-aminopenicillanic acid to the first organic solvent in solution A of step (1) is 1:1-10 g / mL, preferably 3-7 g / mL, and more preferably 3.2-6.4 g / mL; the mass volume ratio of 5-methyl-3-phenyl-4-isoxazolecarbonyl chloride to the first organic solvent in the MPCC solution is 1:1-5 g / mL, and more preferably 1:1.5-3.5 g / mL.

[0028] Preferably, the acid solution in step (2) is selected from one or more of hydrochloric acid solution, sulfuric acid solution, and nitric acid solution, preferably sulfuric acid solution, and more preferably 25% sulfuric acid solution.

[0029] Preferably, the extraction in step (2) is performed by extracting and separating the two organic phases twice, combining the two organic phases, washing the organic phase with water, and collecting the upper organic phase after separation.

[0030] Specifically, the pH is adjusted based on step (1) and then extraction is performed. After separation, the first organic solvent is added to the aqueous phase for further extraction. The two organic phases are combined, washed with water, and the organic phase is collected.

[0031] Preferably, the pH in step (2) is 1-3, preferably 1.5-2.5.

[0032] Preferably, the salt-forming agent in step (2) is one or more of sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium methoxide, sodium ethoxide, sodium acetate and sodium isooctanoate, preferably sodium hydroxide.

[0033] Preferably, the molar ratio of sodium ions to 6-aminopenicillanic acid in the salt-forming agent in step (2) is 0.9-2:1, preferably 1.0-1.2:1; the mass ratio of the salt-forming agent to water in the salt-forming agent solution is 1:2-8, preferably 1:5.

[0034] Preferably, in step (2), the second organic solvent is selected from one or more of ethanol, n-propanol, isopropanol, acetone, tetrahydrofuran and dioxane, preferably acetone.

[0035] Preferably, the washing reagent in step (2) is a second organic solvent.

[0036] Preferably, step (3) specifically comprises adding a third organic solvent and a fourth organic solvent to the crude oxacillin sodium product, mixing, adding water until dissolved, adding activated carbon for decolorization, washing with the fourth organic solvent, transferring to a crystallization bottle, crystallizing, and drying.

[0037] Preferably, the third organic solvent in step (3) is an alcohol solvent selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, and amyl alcohol, preferably n-butanol; the amount of n-butanol is 0.5-5 times the weight of the crude oxacillin sodium, preferably 1-3 times.

[0038] Preferably, the crystallization in step (3) is carried out in three steps, and the fourth organic solvent is added in the first two steps until crystals are produced, and then crystal growing is started; after the fourth organic solvent is added for the third time, the temperature is lowered to 0-5°C, crystal growing is started, and the crystals are filtered, washed with the fourth organic solvent, and dried to obtain oxacillin sodium.

[0039] Specifically, the first two crystallizations were performed by controlling the temperature, adding the fourth organic solvent until solid precipitated, stopping the addition, starting crystal growth, and continuing to add the fourth organic solvent after crystal growth was completed; after the third addition of the fourth organic solvent, the temperature was lowered, and after crystal growth was completed, filtering was performed.

[0040] Preferably, the fourth organic solvent in step (3) is selected from one or more of acetone, methyl ethyl ketone, methyl isobutyl ketone and tetrahydrofuran, preferably acetone; the total amount of acetone used is 2-10 times the weight of the crude oxacillin sodium, preferably 4-6 times.

[0041] Preferably, the crystallization temperature in step (3) is 10-50°C, preferably 15-25°C.

[0042] Preferably, the reaction equation of the present invention is as follows:

[0043]

[0044] Compared with the prior art, the present invention has the following beneficial effects:

[0045] (1) The present invention adopts a two-phase reaction process in the oxacillin synthesis stage, ensuring sufficient dissolution of the raw materials. The use of a phase transfer catalyst eliminates the adverse effects of the slow two-phase reaction speed and accelerates the reaction speed. The reaction is carried out at a low temperature, which inhibits the degradation of the raw materials and improves the product quality.

[0046] (2) The use of inorganic salt-forming agents for post-salification refining is more cost-effective than the currently commonly used organic salt-forming agents. The re-refining process is also carried out at low temperatures, resulting in a lower impurity generation rate, larger crystal size, better product particle size uniformity, and better fluidity. The obtained product does not need to be crushed and can be directly packaged. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 This is a microscope image of the product of Example 1 magnified 200 times;

[0048] Figure 2 This is a microscope image of the product of Comparative Example 1 magnified 200 times;

[0049] Figure 3 is the product particle size data in Example 1;

[0050] Figure 4 This is the particle size data of the product of Comparative Example 1. DETAILED DESCRIPTION

[0051] The technical solutions in the embodiments of the present invention are further clearly described. The described embodiments are only a part of the present invention and are used to explain the present invention, but not to limit the present invention. Therefore, other embodiments obtained by other technicians in this field without creative work all fall within the scope of protection of the present invention.

[0052] Example 1

[0053] Add 250 mL of purified water to the reaction flask, start stirring, and cool to 10°C. Add 25 g of 6-APA and add 9% aqueous ammonia dropwise until the 6-APA dissolves. Add 100 mL of ethyl acetate and 2.5 g of tetrabutylammonium chloride. Weigh 28 g of 5-methyl-3-phenyl-4-isoxazolecarbonyl chloride and dissolve it in 50 mL of ethyl acetate. Simultaneously, add the 5-methyl-3-phenyl-4-isoxazolecarbonyl chloride solution and 9% aqueous ammonia solution dropwise to the reaction flask, controlling the pH of the aqueous phase to 7.0. After the addition is complete, keep the reaction warm for 30 minutes.

[0054] After the reaction is complete, 25% sulfuric acid solution is added dropwise to a pH of 2.3, and the mixture is extracted and separated. 100 mL of ethyl acetate is added to the aqueous phase again for a second extraction and separation. The two organic phases are combined and washed with 70 mL of water. After separation, the upper organic phase is collected to obtain an ethyl acetate solution of oxacillin. 5 g of sodium hydroxide is dissolved in 25 g of water, and then 200 mL of acetone is added to prepare a sodium hydroxide solution. The above sodium hydroxide solution is slowly added dropwise to the ethyl acetate solution of oxacillin. Solids precipitate in the system, which are filtered and washed with acetone to obtain 60 g of crude oxacillin sodium by wet weight.

[0055] At room temperature, add 250mL of acetone and 100mL of n-butanol to the above crude oxacillin sodium and stir evenly. Add water until the liquid is clear. Add 1g of activated carbon, stir and decolorize for 30 minutes, filter to remove carbon, wash with a small amount of acetone and transfer to a crystallization bottle. Control the temperature of the liquid in the crystallization bottle at 18°C, add acetone until solid precipitates in the liquid, stop adding dropwise and grow the crystal for 60 minutes. After growing the crystal, continue to add 120mL of acetone, stop adding dropwise and grow the crystal for 30 minutes. After growing the crystal, continue to add 300mL of acetone, stop adding dropwise and slowly cool to 4°C. After growing the crystal for 60 minutes, filter. Wash the filter cake with acetone and dry it to obtain 46g of oxacillin sodium with a yield of 90%.

[0056] Example 2

[0057] Add 310 mL of purified water to the reaction flask, start stirring, and cool to 8°C. Add 25 g of 6-APA and dropwise add 18% ammonia solution until the 6-APA dissolves. Add 80 mL of butyl acetate and 3 g of tetrabutylammonium bromide. Weigh 30 g of 5-methyl-3-phenyl-4-isoxazolecarbonyl chloride and dissolve it in 100 mL of ethyl acetate. Simultaneously, add the 5-methyl-3-phenyl-4-isoxazolecarbonyl chloride solution and 18% ammonia solution to the reaction flask, controlling the pH of the aqueous phase to 6.8. After the addition is complete, keep the reaction warm for 30 minutes.

[0058] After the reaction is completed, concentrated hydrochloric acid is added dropwise to a pH of 2.0, and the solution is extracted and separated; 200 mL of butyl acetate is added to the aqueous phase again for a second extraction and separation, the two organic phases are combined, and the organic phase is washed with 70 mL of water. After separation, the upper organic phase is collected to obtain a butyl acetate solution of oxacillin. 5 g of sodium hydroxide is dissolved in 25 g of water, and then 100 mL of tetrahydrofuran is added to prepare a sodium hydroxide solution. The above sodium hydroxide solution is slowly added dropwise to the butyl acetate solution of oxacillin. Solids precipitate in the system, which are filtered and washed with tetrahydrofuran to obtain a crude product of oxacillin sodium with a wet weight of 57 g.

[0059] At room temperature, add 250mL of tetrahydrofuran and 100mL of isopropanol to the above crude oxacillin sodium, stir evenly, and add water until the liquid is clear. Add 1g of activated carbon, stir and decolorize for 30 minutes, filter to remove carbon, wash with a small amount of tetrahydrofuran, and transfer to a crystallization bottle. Control the temperature of the liquid in the crystallization bottle at 18°C, add tetrahydrofuran until solid precipitates in the liquid, stop adding dropwise and grow the crystal for 60 minutes. After growing the crystal, continue to add 120mL of tetrahydrofuran, stop adding dropwise and grow the crystal for 30 minutes. After growing the crystal, continue to add 300mL of tetrahydrofuran, stop adding dropwise and slowly cool to 4°C. After growing the crystal for 60 minutes, filter. Wash the filter cake with tetrahydrofuran and dry it to obtain 47g of oxacillin sodium with a yield of 92%.

[0060] Example 3

[0061] Add 230mL of purified water to the reaction flask, start stirring, and cool to 12°C. Add 25g of 6-APA, add 6% sodium bicarbonate dropwise until the 6-APA dissolves, add 160mL of isopropyl acetate and 4g of tetrabutylammonium chloride. Weigh 29g of 5-methyl-3-phenyl-4-isoxazolecarbonyl chloride and dissolve it in 100mL of isopropyl acetate. At the same time, add 5-methyl-3-phenyl-4-isoxazolecarbonyl chloride solution and 6% sodium bicarbonate solution dropwise to the reaction flask, control the pH of the aqueous phase to 7.0, and keep warm for 30 minutes after the addition is complete.

[0062] After the reaction is completed, 15% nitric acid is added dropwise to a pH of 1.5, and the solution is extracted and separated; 100 mL of isopropyl acetate is added to the aqueous phase again for a second extraction and separation, the two organic phases are combined, and the organic phase is washed with 80 mL of water. After separation, the upper organic phase is collected to obtain an isopropyl acetate solution of oxacillin. 5 g of sodium hydroxide is dissolved in 25 g of water, and then 100 mL of ethanol is added to prepare a sodium hydroxide solution. The above sodium hydroxide solution is slowly added dropwise to the isopropyl acetate solution of oxacillin. Solids precipitate in the system, which are filtered and washed with ethanol to obtain 59 g of crude oxacillin sodium with a wet weight of 59 g.

[0063] At room temperature, 300 mL of methyl isobutyl ketone and 100 mL of n-butanol were added to the crude oxacillin sodium product and stirred evenly. Water was added until the liquid was clear. 1 g of activated carbon was added, and after stirring and decolorizing for 30 minutes, the carbon was removed by filtration and washed with a small amount of methyl isobutyl ketone before transferring to a crystallization bottle. The temperature of the liquid in the crystallization bottle was controlled at 18°C, and methyl isobutyl ketone was added until solid precipitated in the liquid. The addition was stopped and the crystals were grown for 60 minutes. After the crystals were grown, 120 mL of methyl isobutyl ketone was continued to be added dropwise, and the addition was stopped and the crystals were grown for 30 minutes. After the crystals were grown, 300 mL of methyl isobutyl ketone was continued to be added dropwise, and the addition was stopped and the temperature was slowly lowered to 4°C. After the crystals were grown for 60 minutes, the filter cake was washed with methyl isobutyl ketone and dried to obtain 48 g of oxacillin sodium with a yield of 94%.

[0064] Comparative Example 1

[0065] Add 250 mL of purified water to the reaction flask, start stirring, and cool to 10°C. Add 25 g of 6-APA and add 9% aqueous ammonia dropwise until the 6-APA dissolves. Add 100 mL of ethyl acetate and 2.5 g of tetrabutylammonium chloride. Weigh 28 g of 5-methyl-3-phenyl-4-isoxazolecarbonyl chloride and dissolve it in 50 mL of ethyl acetate. Simultaneously, add the 5-methyl-3-phenyl-4-isoxazolecarbonyl chloride solution and 9% aqueous ammonia solution dropwise to the reaction flask, controlling the pH of the aqueous phase to 6.9. After the addition is complete, keep the reaction warm for 30 minutes.

[0066] After the reaction is completed, 25% sulfuric acid is added dropwise to a pH of 2.3, and the solution is extracted and separated; 100 mL of ethyl acetate is added to the aqueous phase again for a second extraction and separation, the two organic phases are combined, and the organic phase is washed with 70 mL of water. After separation, the upper organic phase is collected to obtain an ethyl acetate solution of oxacillin. 5 g of sodium hydroxide is dissolved in 25 g of water, and then 200 mL of acetone is added to prepare a sodium hydroxide solution. The above sodium hydroxide solution is slowly added dropwise to the ethyl acetate solution of oxacillin. Solids precipitate in the system, and after filtration and washing with acetone, 55 g of crude oxacillin sodium is obtained. Drying gives 40.5 g of oxacillin sodium with a yield of 79%.

[0067] Comparative Example 2

[0068] Add 250 mL of purified water to the reaction flask and stir at 26°C. Add 25 g of 6-APA and dropwise add 9% aqueous ammonia until the 6-APA dissolves. Add 100 mL of ethyl acetate. Weigh 28 g of 5-methyl-3-phenyl-4-isoxazolecarbonyl chloride and dissolve it in 50 mL of ethyl acetate. Simultaneously add the 5-methyl-3-phenyl-4-isoxazolecarbonyl chloride solution and 9% aqueous ammonia solution to the reaction flask, controlling the pH of the aqueous phase to 7.0. After the additions are complete, allow to react for 90 minutes.

[0069] After the reaction is complete, 25% sulfuric acid is added dropwise to a pH of 2.3, and the mixture is extracted and separated; 100 mL of ethyl acetate is added to the aqueous phase again for a second extraction and separation, the two organic phases are combined, and the organic phase is washed with 70 mL of water. After separation, the upper organic phase is collected to obtain an ethyl acetate solution of oxacillin. 5 g of sodium hydroxide is dissolved in 25 g of water, and then 200 mL of acetone is added to prepare a sodium hydroxide solution. The above sodium hydroxide solution is slowly added dropwise to the ethyl acetate solution of oxacillin. Solids precipitate in the system, which are filtered and washed with acetone to obtain 48 g of crude oxacillin sodium with a wet weight.

[0070] At room temperature, add 250mL of acetone and 100mL of n-butanol to the above crude oxacillin sodium and stir evenly. Add water until the liquid is clear. Add 1g of activated carbon, stir and decolorize for 30 minutes, filter to remove carbon, wash with a small amount of acetone and transfer to a crystallization bottle. Control the temperature of the liquid in the crystallization bottle at 18°C, add acetone until solid precipitates in the liquid, stop adding dropwise and grow the crystal for 60 minutes. After growing the crystal, continue to add 120mL of acetone, stop adding dropwise and grow the crystal for 30 minutes. After growing the crystal, continue to add 300mL of acetone, stop adding dropwise and slowly cool to 4°C. After growing the crystal for 60 minutes, filter. Wash the filter cake with acetone and dry it to obtain 40g of oxacillin sodium with a yield of 78%.

[0071] The products of Examples 1-3 and Comparative Examples 1-2 were tested using the Chinese Pharmacopoeia testing method. The product quality results are shown in Table 1.

[0072] Table 1 Product quality comparison table

[0073]

[0074]

[0075] Note: The theoretical content of oxacillin sodium is 91% based on the oxacillin content. A content higher than 91% is considered incomplete salt formation, while a content lower than 91% is considered excessive salt formation.

[0076] By comparing the data in Table 1, it can be seen that the product of Example 1 of the present invention has the best quality, less impurity content, and larger crystal size. Figure 1 As shown, the particle size uniformity is better as Figure 3 As shown; Comparative Example 1 did not undergo the refined crystallization stage, and there was excessive salt formation or residual salt-forming agent. Figure 2 As shown, the impurity content is high and the particle size is uneven. Figure 4 As shown; in the product of Comparative Example 2, impurities A and G are raw materials, and there are more raw materials remaining and the impurity content is high.

[0077] The present invention adopts a two-phase reaction process in the oxacillin synthesis stage, thereby ensuring sufficient dissolution of raw materials. The use of a phase transfer catalyst eliminates the adverse effect of a slow two-phase reaction speed, accelerates the reaction speed, and carries out the reaction at a low temperature, thereby inhibiting degradation of the raw materials, improving product quality, and reducing impurities. The refined crystallization process is also carried out at a low temperature, resulting in a lower impurity generation rate, a larger crystal size, and better product particle size uniformity.

[0078] The above detailed description is a specific description of one feasible embodiment of the present invention. This embodiment is not intended to limit the patent scope of the present invention. Any equivalent implementation or modification that does not depart from the present invention should be included in the scope of the technical solution of the present invention.

Claims

1. A method for synthesizing oxacillin sodium, characterized in that: The steps include: (1) Condensation stage: 6-aminopenicillanic acid is mixed with water and then dissolved with alkaline solution. A first organic solvent and a phase transfer catalyst are added to obtain solution A. 5-methyl-3-phenyl-4-isoxazolecarbonyl chloride is dissolved in the first organic solvent to obtain an MPCC solution. The MPCC solution reacts with solution A to obtain solution 1. The temperature in the condensation stage is 5-15°C. (2) Extraction and salt formation stage: Acid is added to adjust the pH of solution 1, and extraction is performed to obtain solution 2 containing oxacillin; a salt-forming agent, water, and a second organic solvent are mixed to obtain a salt-forming agent solution; the salt-forming agent solution is added dropwise to solution 2, separated, and washed to obtain a crude oxacillin sodium product; (3) Crystallization stage: adding a third organic solvent, a fourth organic solvent, and water to the crude oxacillin sodium, mixing, decolorizing, crystallizing, and drying to obtain oxacillin sodium; In step (1), the first organic solvent is an ester solvent, and the ester solvent is selected from one or more of ethyl acetate, butyl acetate, and isopropyl acetate; the phase transfer catalyst in step (1) is tetrabutylammonium chloride or tetrabutylammonium bromide; The salt-forming agent in step (2) is selected from one or more of sodium hydroxide, sodium carbonate and sodium bicarbonate; The crystallization in step (3) is carried out in three steps, and the fourth organic solvent is added in the first two steps until crystals are produced, and then crystal growth is started; after the fourth organic solvent is added for the third time, the temperature is lowered to 0-5°C, crystal growth is started, and the crystals are filtered, washed with the fourth organic solvent, and dried to obtain oxacillin sodium; the third organic solvent in step (3) is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol and amyl alcohol; the fourth organic solvent is selected from one or more of acetone, methyl ethyl ketone, methyl isobutyl ketone and tetrahydrofuran.

2. The method according to claim 1, characterized in that The molar ratio of 6-aminopenicillanic acid to 5-methyl-3-phenyl-4-isoxazolecarbonyl chloride in step (1) is 1:1-2.

3. The method according to claim 1, characterized in that The alkali solution in step (1) is selected from one or more of sodium hydroxide solution, sodium carbonate solution, sodium bicarbonate solution and ammonia water.

4. The method according to claim 1, wherein The acid solution in step (2) is selected from one or more of hydrochloric acid solution, sulfuric acid solution and nitric acid solution.

5. The method according to claim 1, wherein The pH in step (2) is 1-3.

6. The method according to claim 1, wherein The molar ratio of sodium ion to 6-aminopenicillanic acid in the salt-forming agent in step (2) is 0.9-2:

1.

7. The method according to claim 1, characterized in that In step (2), the second organic solvent is selected from one or more of ethanol, n-propanol, isopropanol, acetone, tetrahydrofuran and dioxane.

8. The method according to claim 1, characterized in that The amount of the third organic solvent used in step (3) is 0.5-5 times the weight of the crude oxacillin sodium product.

9. The method according to claim 1, characterized in that The total amount of the fourth organic solvent is 2-10 times the weight of the crude oxacillin sodium product.

10. The method according to claim 1, characterized in that The crystallization temperature in step (3) is 10-50°C.

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