Preparation method of sulbactam acid

Abstract

The invention discloses a sulbactam acid preparation method, which comprises: S1, bromination reaction: dissolving 6-aminopenicillanic acid in a hydrobromic acid aqueous solution, adding a sodium nitrite aqueous solution, and carrying out a reaction to generate dibromo-penicillin alkanoic acid; s2, oxidation reaction: dissolving the brominated product in water, and adding an oxidation system composed of potassium hydrogen persulfate composite salt, sodium tungstate and a phosphate buffer solution for reaction; s3, reduction purification: adding a sodium hydrogen sulfite aqueous solution to terminate the reaction, extracting with a mixed solvent, and treating an organic phase with a composite adsorbent; s4, filtering and purifying: adding the extracting solution into a filtering and purifying device for filtering and purifying treatment; and S5, crystallization and purification: concentrating the filtered and purified extract liquor, adding a cosolvent and an anti-solvent, introducing carbon dioxide for crystallization, growing crystals, and then filtering, washing and drying to obtain the high-purity sulbactam acid. According to the invention, the preparation of sulbactam acid with high yield and high purity is realized by improving bromination, oxidation and purification processes.

Description

Technical Field

[0001] The present invention relates to the technical field of preparation of sulbactam acid, and particularly to a method for preparing sulbactam acid. Background Art

[0002] Sulbactam acid is a white crystalline solid with the chemical name (2S,5R)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3,2,0]heptane-2-carboxylic acid-4,4-dioxide. Sulbactam acid, used in the synthesis of sulbactam sodium, is a broad-spectrum β-lactamase inhibitor with strong, irreversible inhibition of penicillinases and cephalosporinases. It is often used in combination with other β-lactam antibiotics, exhibiting significant synergistic effects, greatly enhancing antimicrobial activity and broadening the antimicrobial spectrum. It exhibits significantly enhanced antimicrobial activity against Staphylococcus aureus, Catarrhalis, Neisseria gonorrhoeae, Escherichia coli, Klebsiella pneumoniae, Haemophilus influenzae, and Bacteroides spp., making it suitable for the treatment of respiratory infections.

[0003] The existing preparation methods of sulbactam acid mainly have the following problems: 1. The traditional process uses bromine as a brominating agent, which causes environmental pollution and equipment corrosion problems; 2. Potassium permanganate is usually used in the oxidation step, but the reaction selectivity is poor and many by-products are produced; 3. Existing purification methods are difficult to effectively remove process impurities, affecting product purity and yield; 4. A large amount of organic solvents are used in the process, which increases costs and environmental burden. Summary of the Invention

[0004] The problem to be solved by the present invention is to provide a method for preparing sulbactam acid, which realizes the preparation of sulbactam acid with high yield and high purity by improving the bromination, oxidation and purification processes.

[0005] The present invention provides a technical solution to solve the above problems: a method for preparing sulbactam acid, which comprises the following steps: S1. Bromination reaction: dissolve 6-aminopenicillanic acid in aqueous hydrobromic acid at 0-5°C, add aqueous sodium nitrite to react and generate dibromopenicillanic acid; S2. Oxidation reaction: dissolve the brominated product in water, adjust the pH to 7.0-7.5, and add an oxidation system consisting of potassium persulfate complex salt, sodium tungstate and phosphate buffer to react; S3, reduction purification: adding sodium bisulfite aqueous solution to terminate the reaction, adjusting the pH to 1.5-2.0, extracting with a mixed solvent, and treating the organic phase with a composite adsorbent; S4, filtration and purification: adding the extract to a filtration and purification device for filtration and purification; S5. Crystallization purification: The extract after filtration and purification is concentrated, a cosolvent and an antisolvent are added, carbon dioxide is introduced to crystallize, and after crystal growth, the high-purity sulbactam acid is obtained by filtering, washing, and drying.

[0006] Preferably, the molar ratio of 6-aminopenicillanic acid, hydrobromic acid and sodium nitrite in S1 is 1:3-5:1.05-1.2.

[0007] Preferably, the concentration of the hydrobromic acid aqueous solution in S1 is 10-15 wt %.

[0008] Preferably, the concentration of the sodium nitrite aqueous solution in S1 is 20-30 wt%.

[0009] Preferably, the molar ratio of the bromination product to the potassium persulfate complex salt in S2 is 1:1.5-2.5.

[0010] Preferably, the amount of sodium tungstate in S2 is 0.5-1.5% of the mass of 6-aminopenicillanic acid; and the pH of the phosphate buffer is 6.5-7.0.

[0011] Preferably, the mixed solvent in S3 is a mixture of ethyl acetate and methyl isobutyl ketone in a volume ratio of 2 to 4:1.

[0012] Preferably, the composite adsorbent in S3 is a mixture of activated carbon and molecular sieve in a mass ratio of 1:1 to 3.

[0013] Preferably, the cosolvent in S5 is cyclohexanone, and the amount added is 0.3 to 0.8 times the theoretical mass of sulbactam acid; the antisolvent is n-heptane, and the amount added is 1 to 2 times the volume of the concentrate.

[0014] Preferably, the filtering and purification device in S4 includes a filter barrel and a filter assembly, and the filter assembly is installed in the filter barrel; The filter assembly includes several filter modules. The filter barrel is provided with an upper chamber and a lower chamber. The upper chamber is provided with several cylindrical filter chambers. The filter modules are detachably installed in the filter chamber. The filter chamber is connected to the lower chamber through a through hole at the bottom of the chamber.

[0015] Compared with the prior art, the advantages of the present invention are: the present invention realizes the preparation of sulbactam acid with high yield and high purity by improving the bromination, oxidation and purification processes. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] The drawings described herein are used to provide further understanding of the present invention and constitute a part of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0017] Figure 1is a flow chart of the preparation method of sulbactam acid of the present invention; Figure 2 It is a schematic diagram of the three-dimensional structure of the filtering and purification device of the present invention; Figure 3 is a cross-sectional view of the filtering and purification device of the present invention; Figure 4 yes Figure 3 A magnified schematic diagram of point A in the middle; Figure 5 yes Figure 3 A magnified schematic diagram of point B in the middle; Figure 6 yes Figure 4 Enlarged schematic diagram of point C in the middle; Figure 7 is a top sectional view of the cylindrical housing of the filtering and purification device of the present invention; Figure 8 It is a bottom sectional view of the cylindrical shell of the filtering and purification device of the present invention.

[0018] The accompanying drawings are marked: 1. Filter barrel, 2. Upper shell, 3. Upper cover, 4. Hollow fiber membrane tube, 5. Filter chamber, 6. Lower chamber, 7. Switch plate, 8. Flexible sleeve, 9. Spring four, 10. Liquid inlet hole, 11. Lower shell, 12. Connecting chamber, 13. Connecting rod, 14. Connecting ring, 15. Positioning column three, 16. Spring three, 17. Mounting block, 18. Spring one, 19. Positioning column one, 20. Fixing hole one, 21. Annular piston, 22. Annular piston chamber, 23. Annular air pipe, 24. Ejecting air bag column, 25. Fixing hole two, 26. Magnet block, 27. Sealing ring, 28. Positioning column two, 29. Spring two. DETAILED DESCRIPTION

[0019] The following will describe the embodiments of the present invention in detail with reference to the accompanying drawings and examples, so that the implementation process of how the present invention applies technical means to solve technical problems and achieve technical effects can be fully understood and implemented accordingly.

[0020] In the description of the present invention, it should be noted that, for directional words, such as the terms "center", "horizontal", "longitudinal", "length", "width", "thickness", "up", "down", "front", "back", "left", "right", "vertical", "horizontal", "top", "bottom", "inside", "outside", "clockwise", "counterclockwise" and so on, indicating directions and positional relationships, are based on the directions or positional relationships shown in the accompanying drawings, and are only for the convenience of describing the present invention and simplifying the description, and do not indicate or imply that the device or element referred to must have a specific direction, be constructed and operated in a specific direction, and cannot be understood as limiting the specific scope of protection of the present invention.

[0021] Furthermore, the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of technical features. Therefore, the terms "first" and "second" may explicitly or implicitly refer to one or more of these features. Throughout the description of the present invention, "several" means two or more, unless otherwise specifically defined.

[0022] In the present invention, unless otherwise specified or limited, the terms "assemble," "connect," and "connect" should be understood in a broad sense. For example, they may refer to fixed connection, detachable connection, or integral connection; mechanical connection; direct connection, connection through an intermediate medium, or internal communication between two components. Those skilled in the art will understand the specific meanings of the above terms in the present invention based on specific circumstances.

[0023] It will be understood that when used in this specification and the appended claims, the terms “comprises” and “comprising” indicate the presence of described features, integers, steps, operations, elements and / or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components and / or groups thereof.

[0024] It should also be understood that the terms used in this description of the embodiments of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the embodiments of the present invention. As used in the description of the embodiments of the present invention and the appended claims, the singular forms "a", "an", and "the" are intended to include the plural forms unless the context clearly indicates otherwise. Example 1

[0025] like Figure 1 As shown, this embodiment discloses a method for preparing sulbactam acid, which comprises the following steps: S1. Bromination reaction: dissolve 6-aminopenicillanic acid in aqueous hydrobromic acid at 0-5°C, add aqueous sodium nitrite to react and generate dibromopenicillanic acid; S2. Oxidation reaction: dissolve the brominated product in water, adjust the pH to 7.0-7.5, and add an oxidation system consisting of potassium persulfate complex salt, sodium tungstate and phosphate buffer to react; S3, reduction purification: adding sodium bisulfite aqueous solution to terminate the reaction, adjusting the pH to 1.5-2.0, extracting with a mixed solvent, and treating the organic phase with a composite adsorbent; S4, filtration and purification: adding the extract to a filtration and purification device for filtration and purification; S5. Crystallization purification: The extract after filtration and purification is concentrated, a cosolvent and an antisolvent are added, carbon dioxide is introduced to crystallize, and after crystal growth, the high-purity sulbactam acid is obtained by filtering, washing, and drying.

[0026] The molar ratio of 6-aminopenicillanic acid, hydrobromic acid and sodium nitrite in S1 is 1:3-5:1.05-1.2.

[0027] The concentration of the hydrobromic acid aqueous solution in S1 is 10-15 wt %.

[0028] The concentration of the sodium nitrite aqueous solution in S1 is 20-30 wt%.

[0029] Wherein, the molar ratio of the bromination product to the potassium persulfate complex salt in S2 is 1:1.5-2.5.

[0030] The amount of sodium tungstate in S2 is 0.5-1.5% of the mass of 6-aminopenicillanic acid; and the pH of the phosphate buffer is 6.5-7.0.

[0031] The mixed solvent in S3 is a mixture of ethyl acetate and methyl isobutyl ketone in a volume ratio of 2 to 4:1.

[0032] The composite adsorbent in S3 is a mixture of activated carbon and molecular sieve in a mass ratio of 1:1 to 3.

[0033] Wherein, the cosolvent in S5 is cyclohexanone, and the added amount is 0.3 to 0.8 times the theoretical mass of sulbactam acid; the antisolvent is n-heptane, and the added amount is 1 to 2 times the volume of the concentrate.

[0034] The above technical solution has the following advantages: 1. Use hydrobromic acid instead of bromine to reduce environmental pollution and equipment corrosion; 2. Innovative use of potassium persulfate complex salt-sodium tungstate catalytic oxidation system, with high reaction selectivity and few by-products; 3. Develop composite adsorbent and mixed solvent purification systems to effectively remove process impurities; 4. Improve crystal purity and yield through carbon dioxide-assisted crystallization; 5. Product purity ≥99.5%, maximum single impurity ≤0.1%, total yield ≥75%; 6. The process conditions are mild and suitable for industrial production. Example 2

[0035] To a 500 mL reaction flask, add 150 g of 15% aqueous hydrobromic acid solution and cool to 0°C. Add 6-APA (30 g, 0.139 mol) in portions and stir to dissolve. Maintaining the temperature at 0-2°C, add 25% aqueous sodium nitrite (42 g, 0.152 mol) dropwise over approximately 1.5 hours. Continue the reaction for 30 minutes. Extract the reaction solution with ethyl acetate (100 mL x 2). Combine the organic phases and set aside.

[0036] Transfer the organic phase to an oxidation reactor, add 100 mL of water, and adjust the pH to 7.2 with 10% NaOH. Prepare the oxidant solution: Dissolve Oxone (128 g, 0.208 mol) and sodium tungstate (0.3 g) in 200 mL of phosphate buffer (pH 6.8). Maintain the temperature at 0-5°C and add the oxidant solution dropwise over approximately 2 hours. Keep the mixture warm for 3 hours.

[0037] After the reaction is complete, add 50 mL of 10% aqueous sodium bisulfite solution and adjust the pH to 1.8 with concentrated hydrochloric acid. Extract with a mixed solvent (ethyl acetate:methyl isobutyl ketone = 3:1, 150 mL x 2) and combine the organic phases. Add a composite adsorbent (1 g activated carbon + 2 g molecular sieves), stir for 40 minutes, and filter.

[0038] The filtrate was concentrated under reduced pressure to approximately 100 mL, 15 mL of cyclohexanone was added, and 50 mL of n-heptane was slowly added dropwise while carbon dioxide was introduced at a rate of 6 L / min. The mixture was cooled to -8°C and allowed to crystallize for 1.5 hours. The mixture was filtered, washed with cold n-heptane, and dried under reduced pressure at 40°C to yield 25.8 g of sulbactam acid with a purity of 99.6% and a yield of 76.3%.

[0039] Example 3

[0040] To a 1L reaction flask, add 300g of 12% aqueous hydrobromic acid solution and cool to 2°C. Add 6-APA (60g, 0.278mol) in portions and stir to dissolve. Maintaining the temperature at 2-5°C, add 30% aqueous sodium nitrite (80g, 0.292mol) dropwise over approximately 2 hours. Continue the reaction for 40 minutes. Extract the reaction solution with ethyl acetate (200mL x 2). Combine the organic phases and set aside.

[0041] Transfer the organic phase to an oxidation reactor, add 200 mL of water, and adjust the pH to 7.0 with 10% NaOH. Prepare the oxidant solution: Dissolve Oxone (260 g, 0.422 mol) and sodium tungstate (0.9 g) in 400 mL of phosphate buffer (pH 6.5). Maintain the temperature at 2-5°C and add the oxidant solution dropwise over approximately 3 hours. Keep the reaction warm for 4 hours.

[0042] After the reaction is complete, add 100 mL of 15% aqueous sodium bisulfite solution and adjust the pH to 1.5 with concentrated hydrochloric acid. Extract with a mixed solvent (ethyl acetate:methyl isobutyl ketone = 3:1, 300 mL x 2) and combine the organic phases. Add a composite adsorbent (2 g of activated carbon + 4 g of molecular sieves), stir for 50 minutes, and filter.

[0043] The filtrate was concentrated under reduced pressure to approximately 200 mL, cyclohexanone (30 mL) was added, and n-heptane (100 mL) was slowly added dropwise while carbon dioxide was introduced at a rate of 8 L / min. The mixture was cooled to -5°C and allowed to crystallize for 2 hours. The mixture was filtered, washed with cold n-heptane, and dried under reduced pressure at 45°C to yield 52.1 g of sulbactam acid with a purity of 99.7% and a yield of 77.0%. Example 4

[0044] like Figure 2-8 As shown, this embodiment discloses a filtering and purification device, which is applied in Example 1. Specifically, the filtering and purification device includes a filter barrel 1 and a filter assembly, and the filter assembly is installed in the filter barrel 1; The filter assembly includes several filter modules. The filter barrel 1 is provided with an upper chamber and a lower chamber 6. The upper chamber is provided with several cylindrical filter chambers 5. The filter modules are detachably installed in the filter chamber 5. The filter chamber 5 is connected to the lower chamber 6 through a through hole at the bottom of the chamber.

[0045] The filtration module includes a cylindrical shell, a hollow fiber membrane tube 4, a positioning mechanism 1 and a positioning mechanism 2. The hollow fiber membrane tube 4 is installed inside the cylindrical shell. The cylindrical shell is provided with a plurality of liquid inlet holes 10. The upper part of the filter barrel 1 is provided with an upper cover 3. The upper cover 3 is provided with a mounting hole that cooperates with the cylindrical shell. The positioning mechanism 1 is installed at the mounting hole for positioning the upper end of the cylindrical shell, and the positioning mechanism 2 is installed at the through hole for positioning the lower end of the cylindrical shell.

[0046] The positioning mechanism includes a positioning column 19 and a spring 18. A positioning hole 1 is provided on the hole wall of the mounting hole. One end of the spring 18 is fixedly connected to the bottom of the positioning hole 1, and the other end is fixedly connected to the positioning column 19. One end of the positioning column 19 can extend out of the positioning hole 1. A fixing hole 20 that cooperates with the positioning column 19 is provided on the outer circumferential surface of the upper end of the cylindrical shell. The positioning column 19 can extend into the fixing hole 20 and engage with the fixing hole 20 to form a positioning.

[0047] The second positioning mechanism includes a second positioning column 28 and a second spring 29. A second positioning hole is provided on the wall of the through hole. One end of the second spring 29 is fixedly connected to the bottom of the second positioning hole, and the other end is fixedly connected to the second positioning column 28. One end of the second positioning column 28 can extend out of the second positioning hole. A second fixing hole 25 cooperating with the second positioning column 28 is provided on the outer circumferential surface of the lower end of the cylindrical shell. The second positioning column 28 can extend into the second fixing hole 25 and engage with the second fixing hole 25 to form a positioning.

[0048] The cylindrical shell includes an upper shell 2, a lower shell 11 and a spring four 9, the upper shell 2 and the lower shell 11 are fixedly connected by a spring four 9, and a flexible sleeve 8 is mounted on the spring four 9, one end of the flexible sleeve 8 is sealed with the upper shell 2, and the other end is sealed with the lower shell 11 (after the flexible sleeve is installed, its outer surface is flush with the outer surface of the upper shell and the lower shell, that is, the flexible sleeve can also ensure sealing when in contact with the sealing ring, preventing liquid from leaking out from the fitting point between the sealing ring and the flexible sleeve). When the cylindrical shell is installed, the spring four 9 is in a compressed state; a positioning release mechanism is provided in the cylindrical shell for releasing the positioning of the two pairs of cylindrical shells by the positioning mechanism, and the positioning release mechanism includes an annular air pipe 23, an annular piston cavity 22, an annular piston 21 and a connecting rod 13. The annular piston cavity 22 is provided in the lower shell 11, and the annular movable The plug is installed in the annular piston cavity 22, one end of the connecting rod 13 is connected to the upper shell 2, and the other end is connected to the annular piston; the lower shell 11 is also provided with an annular groove for installing an annular air pipe 23, the annular groove is communicated with the second fixing hole 25, and an ejection air bag column 24 is provided in the second fixing hole 25, and a pleated section is provided on the ejection air bag column 24, which is expanded after the ejection air bag column 24 is inflated, thereby lengthening the ejection air bag column 24, and the ejection air bag column 24 is communicated with the annular air pipe 23, and the annular air pipe 23 is communicated with the lower end of the annular piston cavity 22. During the movement of the upper shell 2 relative to the lower shell 11, the annular piston is driven to squeeze the gas in the annular piston cavity 22 into the ejection air bag column 24 through the annular air pipe 23, and the pleated section of the ejection air bag column 24 expands to eject the positioning column 28 from the second fixing hole 25, thereby releasing the positioning of the positioning mechanism 2 on the cylindrical shell.

[0049] The upper end of the cylindrical shell is provided with a connecting cavity 12, and the lower end of the cylindrical shell is provided with a connecting ring 14 that matches the shape of the connecting cavity 12. The connecting cavity 12 is communicated with the fixing hole 20, and a mounting block 17 is provided in the connecting ring 14. A positioning hole three is provided on the mounting seat, and a positioning column three 15 and a spring three 16 are provided in the positioning hole three. One end of the spring three 16 is fixedly connected to the bottom of the positioning hole three, and the other end is fixedly connected to the positioning column three 15. One end of the positioning column three 15 can extend out of the positioning hole three; the positioning column one 19 and the positioning column three 15 are both made of magnets, and the positioning column one 19 and the positioning column three 15 are repelled when facing each other, and the rigidity coefficient of the spring three 16 is greater than the rigidity coefficient of the spring one 18; a plurality of magnet blocks 26 are also provided in the mounting hole, and the magnet blocks 26 are repelled when facing the positioning column three 15. It should be noted that a guide ridge is provided in the mounting hole, and a guide groove cooperating with the guide ridge is provided on the columnar shell, so that the magnet block can face the positioning column three after the columnar shell is installed into the mounting hole.

[0050] In the above scheme, when the filter module is replaced, the connecting ring at the lower end of the new cylindrical shell is aligned with the connecting cavity at the upper end of the old cylindrical shell and inserted until the positioning post three at the lower end of the new cylindrical shell is snapped into the fixing hole one at the upper end of the old cylindrical shell, so that the positioning post three is directly opposite to the positioning post one. Since the rigidity coefficient of the spring three is greater than the rigidity coefficient of the spring one, the spring one is compressed, the positioning post one is separated from the fixing hole one and retracted into the positioning hole one, and the positioning of the positioning mechanism one to the old cylindrical shell 3 is released. At the same time, the new cylindrical shell is connected to the old cylindrical shell, and then the new cylindrical shell is inserted downward with force. Under the action of the new cylindrical shell, the upper shell of the old cylindrical shell moves downward, compressing the spring, and the upper shell relative to the old cylindrical shell is pressed. During the downward movement of the lower shell, it drives the annular piston to squeeze the gas in the annular piston cavity into the ejection air bag column through the annular air pipe. The pleated section of the ejection air bag column unfolds to eject the positioning column 28 from the fixing hole 25, thereby releasing the positioning of the positioning mechanism 2 on the cylindrical shell. The old cylindrical shell can move downward as a whole until the lower end of the new cylindrical shell is engaged with the positioning mechanism 2 at the through hole. At the same time, the positioning column 3 on the new cylindrical shell is directly opposite to the magnet block in the through hole. The magnet block generates a repulsive force on the positioning column 3, driving the positioning column 3 to compress the spring 3. The positioning block 3 is separated from the fixing hole 1 and retracted into the positioning hole 3. The old cylindrical shell is separated from the new cylindrical shell under the action of its own gravity and falls into the lower chamber, thereby completing the replacement of the filter module.

[0051] When the filter element is old, it can be replaced quickly by replacing the old filter element through the above-mentioned scheme, without disassembling the filter barrel for replacement, thereby improving the replacement efficiency. A plurality of filter chambers are arranged in the upper chamber, and a filter module is arranged in the filter chamber at the same time. When the filtering performance of the filter module in the filter chamber is reduced, only the filter module in the filter chamber can be replaced, and the filter modules in the other filter chambers can work normally, thereby improving the purification efficiency of the device. At the same time, during the replacement process, since the new columnar shell is in a connected state with the old columnar shell, the purification and filtration work in the filter chamber can also continue, further improving the filtration Efficiency; moreover, the cylindrical shell is composed of an upper shell, a lower shell and a spring four. The spring four is in a compressed state after the cylindrical shell is installed, that is, the spring will exert an upward reaction force on the upper shell, which can eliminate the matching gap between the upper shell and the positioning mechanism one, making the upper shell and the positioning mechanism one cooperate more stably. At the same time, the spring will also exert a downward reaction force on the lower shell, which can eliminate the matching gap between the lower shell and the positioning mechanism two, making the lower shell and the positioning mechanism two cooperate more stably. In addition, the positioning of the lower shell by the positioning mechanism two can be easily released by the movement of the upper shell relative to the lower shell, making the disassembly and assembly of the cylindrical shell more convenient.

[0052] In this embodiment, it should be noted that the filter barrel of this device is made of transparent material. When the filtering effect of the filter module in a certain filter cavity is reduced, the liquid passing through the hollow fiber membrane tube becomes less. Therefore, the staff can observe through the transparent filter barrel that the liquid level in the filter cavity is significantly higher than the liquid level in the other filter cavities, and can replace the filter module in the corresponding filter cavity.

[0053] In order to improve the sealing performance between the columnar housing and the through hole, a sealing groove is provided in the through hole, and a sealing ring 27 is provided in the sealing groove.

[0054] Furthermore, in order to facilitate the staff in taking out the filter module in the lower chamber 6, a take-out port communicating with the lower chamber 6 is provided on the filter barrel 1, and a switch plate 7 that can be opened and closed is provided on the take-out port.

[0055] The above description is merely a description of the preferred embodiment of the present invention and is not to be construed as limiting the scope of the claims. The present invention is not limited to the above embodiment, and variations in the specific structure are permitted. Any variations within the scope of the independent claims of the present invention are also within the scope of protection of the present invention.

Claims

1. A method for preparing sulbactam acid, characterized in that: The preparation method comprises the following steps: S1. Bromination reaction: dissolve 6-aminopenicillanic acid in aqueous hydrobromic acid at 0-5°C, add aqueous sodium nitrite to react and generate dibromopenicillanic acid; S2. Oxidation reaction: dissolve the brominated product in water, adjust the pH to 7.0-7.5, and add an oxidation system consisting of potassium persulfate complex salt, sodium tungstate and phosphate buffer to react; S3, reduction purification: adding sodium bisulfite aqueous solution to terminate the reaction, adjusting the pH to 1.5-2.0, extracting with a mixed solvent, and treating the organic phase with a composite adsorbent; S4, filtration and purification: adding the extract to a filtration and purification device for filtration and purification; S5. Crystallization purification: The extract after filtration and purification is concentrated, a cosolvent and an antisolvent are added, carbon dioxide is introduced to crystallize, and after crystal growth, the high-purity sulbactam acid is obtained by filtering, washing, and drying.

2. The method for preparing sulbactam acid according to claim 1, wherein: The molar ratio of 6-aminopenicillanic acid, hydrobromic acid and sodium nitrite in S1 is 1:3-5:1.05-1.

2.

3. The method for preparing sulbactam acid according to claim 1, wherein: The concentration of the hydrobromic acid aqueous solution in S1 is 10-15 wt %.

4. The method for preparing sulbactam acid according to claim 1, wherein: The concentration of the sodium nitrite aqueous solution in S1 is 20-30 wt %.

5. The method for preparing sulbactam acid according to claim 1, wherein: The molar ratio of the bromination product to the potassium persulfate complex salt in S2 is 1:1.5-2.

5.

6. The method for preparing sulbactam acid according to claim 1, wherein: The amount of sodium tungstate in S2 is 0.5-1.5% of the mass of 6-aminopenicillanic acid; and the pH of the phosphate buffer is 6.5-7.

0.

7. The method for preparing sulbactam acid according to claim 1, wherein: The mixed solvent in S3 is a mixture of ethyl acetate and methyl isobutyl ketone in a volume ratio of 2 to 4:

1.

8. The method for preparing sulbactam acid according to claim 1, wherein: The composite adsorbent in S3 is a mixture of activated carbon and molecular sieve in a mass ratio of 1:1 to 3.

9. The method for preparing sulbactam acid according to claim 1, wherein: The cosolvent in S5 is cyclohexanone, and the amount added is 0.3 to 0.8 times the theoretical mass of sulbactam acid; the antisolvent is n-heptane, and the amount added is 1 to 2 times the volume of the concentrate.

10. The method for preparing sulbactam acid according to claim 1, wherein: The filtering and purification device in S4 includes a filter barrel and a filter assembly, and the filter assembly is installed in the filter barrel; The filter assembly includes several filter modules. The filter barrel is provided with an upper chamber and a lower chamber. The upper chamber is provided with several cylindrical filter chambers. The filter modules are detachably installed in the filter chamber. The filter chamber is connected to the lower chamber through a through hole at the bottom of the chamber.

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