A process for the preparation of sulbactam acid

Abstract

A method for preparing sulbactamic acid, applicable to the field of drug synthesis technology, comprises the following steps: 6,6-dibromopelinane sulfonic acid and a weak base undergo a salt-forming reaction in the inorganic solvent water; a reduction reaction is carried out under the conditions of a metal reducing agent and dilute acid; filtration, diversion, dehydration with a dehydrating agent, decolorization, concentration, cooling for crystallization, filtration, and drying to obtain sulbactamic acid. This method is safe, environmentally friendly, and produces a high-yield, high-purity, stable, and aesthetically pleasing product, making it suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical synthesis technology, and in particular to a method for preparing sulbactamic acid. Background Technology

[0002] Sulbactamic acid, chemical name (2S-cis)-3,3-dimethyl-7-oxo-4-thio-1-azabicyclo[3,2,0]heptane-2-carboxylic acid-4,4-dioxide, molecular formula C8H 11 NO5S has a molecular weight of 233.24.

[0003] Structural formula:

[0004]

[0005] Sulbactamic acid is an irreversible competitive β-lactamase inhibitor with weak antibacterial activity. However, when used in combination with penicillins or cephalosporins, it exhibits a significant synergistic effect, enhancing both antibacterial activity and broadening the antibacterial spectrum. Currently, there are two main methods for producing sulbactamic acid in China: Method 1 involves pressurized hydrogenation, as disclosed in CN102503957A, which describes the debromination of 6,6-dibromopenicillin sulfone acid (DBPAS) to prepare sulbactamic acid using Raney nickel as a catalyst under a hydrogen pressure of 0.5–0.8 MPa in a liquid-phase circulating jet manner. The drawback of Method 2 is the significant safety risk associated with pressurized hydrogen debromination. Method 2 involves a reduction reaction using a metal reducing agent in a mixture of organic solvent and water. For example, CN116143802A discloses a method for preparing sulbactamic acid by using 6,6-dibromopelinosinol sulfone acid (DBPAS) as the starting material, ethyl acetate and purified water as solvents, and zinc powder reduction. The shortcomings of this method are: when 6,6-dibromopelinosinol sulfone acid (DBPAS) and zinc powder are in an organic solvent, 6,6-dibromopelinosinol sulfone acid (DBPAS) forms free radicals and undergoes a polymerization reaction, generating large molecular colored impurities, which affect the yield, quality and stability of the product. The sulbactamic acid produced in the organic solvent is not white in appearance, and its color deepens significantly over time.

[0006] Therefore, developing a safer, more environmentally friendly method for preparing sulbactamic acid with high product yield, high purity, good stability, and good appearance, suitable for industrial production, is a new issue that urgently needs to be addressed. Summary of the Invention

[0007] To overcome the shortcomings of the prior art, this invention provides a synthetic method for preparing sulbactamic acid in an aqueous environment, which avoids side reactions such as free radical polymerization and greatly improves the purity, yield and stability of the product. This method is an atmospheric pressure reaction, which improves the safety of the preparation process.

[0008] The technical solution adopted in this invention is: a method for preparing sulbactamic acid, the preparation method comprising the following steps:

[0009] (1) 6,6-Dibromopelinone sulfonic acid and a weak base are reacted in an inorganic solvent to form a salt, followed by the slow addition of a reducing agent and a first dilute acid aqueous solution to control the pH of the system and carry out a reduction reaction. The solution is then filtered to obtain a reduction reaction solution. The inorganic solvent is selected from water.

[0010] (2) After the reduction reaction solution and the first organic solvent are mixed, the second dilute acid aqueous solution is slowly added to adjust the pH value of the solution. After reacting for a period of time, the solution is filtered and the filtrate is separated into layers.

[0011] (3) Extract the aqueous layer by adding a second organic solvent, dehydrate the second organic solvent layer with a dehydrating agent, filter first, concentrate, crystallize, filter second, and dry.

[0012] In step (1), the weak base is selected from one or more of sodium bicarbonate, potassium bicarbonate, sodium carbonate, and potassium carbonate; the temperature of the salt formation reaction is 0-15℃; the pH value during the salt formation reaction is 2.5-4.5; the reducing agent is selected from one or more of zinc and nickel; the first dilute acid is selected from one or more of dilute hydrochloric acid and dilute sulfuric acid; the concentration of the first dilute acid is 4-12%; the pH of the control system is controlled at 3-5; the addition time of the reducing agent and dilute acid is 0.1-3 hours; the reduction reaction continues for 15-50 minutes after the reducing agent is added.

[0013] In step (2), the first organic solvent is selected from one or more of ethyl acetate, chloroform, methyl acetate, and dichloromethane; the second dilute acid is selected from one or more of dilute hydrochloric acid and dilute sulfuric acid; the concentration of the dilute sulfuric acid is 25-30%; the pH value of the solution is adjusted to be between 0.6 and 1.5; the reaction time is 5-20 minutes; and the reaction temperature is 0-20℃.

[0014] In step (3), the second organic solvent is selected from one or more of ethyl acetate, chloroform, methyl acetate, and dichloromethane; the dehydrating agent is selected from one of a solution dehydrating agent and a solid dehydrating agent; the solution dehydrating agent is selected from one of a saturated calcium chloride aqueous solution and a saturated sodium chloride aqueous solution; the solid dehydrating agent is selected from anhydrous sodium sulfate; the mass ratio of 6,6-dibromopenicillin sulfone acid to the volume ratio of the second organic solvent is 30:100-300, preferably 30:150-250, where the mass is in g and the volume is in ml; the mass ratio of 6,6-dibromopenicillin sulfone acid to the volume ratio of the liquid dehydrating agent is 30:30-90, preferably 30:45-75; after the second filtration and before drying, the step of washing the material with the second organic solvent is also included.

[0015] In step (1), the mass ratio of 6,6-dibromopenicillin sulfone acid to the volume ratio of the inorganic solvent is 30:150-300, preferably 30:175-250, where the mass is in g and the volume is in ml; the mass ratio of 6,6-dibromopenicillin sulfone acid to the reducing agent is 30:11-12.5, preferably 30:11-12; the mass ratio of 6,6-dibromopenicillin sulfone acid to the first organic solvent is 30:125-200, preferably 30:140-170, where the mass is in g and the volume is in ml.

[0016] In step (2), after the reaction has proceeded for a period of time but before filtration, a first activated carbon decolorization step is included; the first activated carbon decolorization time is 0.5-2 hours, preferably 0.7-1.5 hours; the first activated carbon decolorization temperature is 15-30°C, preferably 18-25°C; the mass ratio of 6,6-dibromopelinosyl sulfone acid to the first activated carbon is 30:0.1-2, preferably 30:0.2-1.

[0017] In step (3), after the second organic solvent layer is dehydrated with a dehydrating agent and before the first filtration, a second activated carbon decolorization step is included; the second activated carbon decolorization time is 0.5-2 hours, preferably 0.7-1.5 hours; the second activated carbon decolorization temperature is -2 to 6°C, preferably -1 to 5°C; the mass ratio of 6,6-dibromopelinosyl sulfone acid to the second activated carbon is 30:0.1-2, preferably 30:0.2-1; the concentration is selected from vacuum concentration; the vacuum concentration temperature is 20-35°C, preferably 25-30°C; the vacuum degree of the vacuum concentration is -0.09 to -0.1 MPa; the concentration The solution is concentrated to obtain a concentrate. The mass ratio of the 6,6-dibromopelinosyl sulfone acid to the volume of the concentrate is 30:30-60, preferably 30:35-50. The mass is measured in grams (g), and the volume is measured in milliliters (ml). The crystallization temperature is -10 to 10°C, preferably -5 to 5°C. The crystallization time is 10-30 minutes, preferably 15-25 minutes. The drying process is vacuum drying. The vacuum drying temperature is selected from 10 to 40°C, preferably 25 to 35°C. The vacuum drying time is 0.5-2 hours, preferably 0.8-1.2 hours. The vacuum degree of the vacuum drying process is -0.09 to -0.1 MPa.

[0018] In step (1), the specific steps of the salt formation reaction of 6,6-dibromopelinosyl sulfonic acid and weak base in inorganic solvent include adding the weak base to adjust the pH after mixing the inorganic solvent and 6,6-dibromopelinosyl sulfonic acid; the temperature of the mixture after mixing the inorganic solvent and 6,6-dibromopelinosyl sulfonic acid is 0-10℃.

[0019] In step (1), the temperature of the salt formation reaction is 0-10℃; the pH value during the salt formation reaction is 3-4; the concentration of the first dilute acid is 5-10%; the pH of the control system is controlled at 3.5-4.5; the addition time of the reducing agent and dilute acid is 0.5-2 hours; and the reduction reaction continues for 20-40 minutes after the reducing agent is added.

[0020] In step (2), the reaction time is 5-15 minutes; the reaction temperature is 5-15℃.

[0021] The principle of the technical solution adopted in this invention is as follows: (1) Sulbactam acid is prepared and synthesized in an aqueous environment, which avoids the occurrence of side reactions such as free radical polymerization, greatly improves the purity, yield and stability of the product, reduces the impurity content, and improves the absorbance and appearance of the product; (2) By controlling the pH value of the salt formation reaction process to about 3-4, the purity, yield, stability, impurity content and absorbance of the product can be improved; (3) By controlling the amount of inorganic solvent water used in the salt formation reaction process, the appearance of the product can be improved, and within the optional range specified in this application, the greater the amount of water used, the better the appearance of the product. (4) In the reduction reaction step, within the selectable concentration range specified in this application, when the concentration of the first dilute acid used is lower, the product appearance is better, the yield is higher, and the impurity content is smaller; (5) By controlling the pH and the addition time of the reducing agent during the reduction reaction, the reaction yield and product appearance can be improved; (6) By performing the first activated carbon decolorization step within the decolorization temperature range specified in this application, and the second activated carbon decolorization step within the decolorization temperature range specified in this application, the appearance of the product can be improved, especially the first activated carbon decolorization step has a greater effect on improving the appearance of the product.

[0022] Compared with the prior art, the beneficial effects of the present invention are:

[0023] 1. The purpose of this invention is to avoid the shortcomings of the prior art, control the generation of impurities at the source, improve product quality, yield and stability, improve product appearance, and provide a good quality foundation for downstream products.

[0024] 2. The sulbactam acid obtained by the method described in this invention improves product quality, reduces impurity content, and results in a product with a clean and bright white appearance that does not turn yellow when placed at room temperature. Under preferred conditions, the absorbance can reach 0.002. Using the EP method to detect impurities in sulbactam acid, the purity can reach 99.8%, with a maximum non-specific impurity of 0.01% and a total of 0.05% for other impurities.

[0025] 3. The sulbactam acid obtained by the method of the present invention has good stability. Under room temperature conditions, the product quality does not change significantly after 6 months. Under preferred conditions, its product content remains above 99.5%, and the product color does not change significantly, remaining white.

[0026] 4. The method described in this invention greatly improves the yield of sulbactam acid, with a yield of over 91% under preferred conditions, which is 10% higher than that of organic reaction environments.

[0027] 5. This invention improves the safety of the sulbactam acid production process. Attached Figure Description

[0028] The present invention will now be described in detail with reference to the accompanying drawings and embodiments.

[0029] Figure 1 This is a diagram of the reaction equation for this invention.

[0030] Figure 2 This is a flowchart of the preparation method of the present invention. Detailed Implementation

[0031] The following examples will help to understand the present invention, but these examples are only for illustration and the present invention is not limited thereto.

[0032] Example 1

[0033] Add 200ml of purified water and 30g of DBPAS to a 500ml four-necked flask. Stir and cool to 0-5℃. Add sodium bicarbonate to adjust the pH to 3-4 to initiate the salt formation reaction. Maintain the material temperature at 0-10℃. Slowly add 11.5g of zinc powder simultaneously, while slowly adding 5% hydrochloric acid, controlling the system pH to 3.5-4.5 to initiate the reduction reaction. The total amount of 5% hydrochloric acid used is 72.2g. The zinc powder is added over approximately 1 hour. Then, maintain the temperature at 0-5℃ for 30 minutes to ensure complete reaction. Filter the solution. Add 150ml of ethyl acetate to the filtrate. Cool to 5-15℃ and add a 28% sulfuric acid solution dropwise to adjust the pH to between 0.6 and 1.5. Stir for 10 minutes to initiate the reaction. Raise the material temperature to 18-25℃ and add 0.5g of activated carbon for decolorization for 1 hour. Filter the solution. Separate the filtrate into layers. Extract the aqueous layer twice with 100ml of ethyl acetate each time. 60 ml of saturated calcium chloride aqueous solution was added to the organic layer for dehydration, followed by the addition of 0.5 g of activated carbon. The mixture was stirred at 0°C for 1 hour to decolorize. After filtration, the solution was concentrated at 27°C in a water bath under a vacuum of -0.09 to -0.1 MPa, yielding 40-45 g of concentrated solution. Crystallization was then carried out at 0°C with stirring for 20 minutes. The solution was filtered, and the material was washed with 10 ml of frozen ethyl acetate. The washings were then dried under vacuum for 1 hour at 20-30°C under a vacuum of -0.09 to -0.1 MPa, yielding 16.4 g of sulbactamic acid.

[0034] The method described above uses the EP method to detect sulbactamic acid, with a content of 99.8%, impurity A 0.005%, maximum nonspecific impurity 0.01%, and total other impurities 0.05%.

[0035] Example 2

[0036] Add 200ml of purified water and 30g of DBPAS to a 500ml four-necked flask. Stir and cool to 0-5℃. Add sodium bicarbonate to adjust the pH to 6-7 to initiate the salt formation reaction. Maintain the material temperature at 0-10℃. Slowly add 11.5g of zinc powder simultaneously with 5% hydrochloric acid, controlling the system pH to 3.5-4.5 for the reduction reaction. The total amount of 5% hydrochloric acid used is 119.4g. The zinc powder addition takes approximately 1 hour. Then, maintain the temperature at 0-5℃ for 30 minutes to ensure complete reaction. Filter the solution. Add 150ml of ethyl acetate to the filtrate. Cool to 5-15℃ and add a 28% sulfuric acid solution dropwise to adjust the pH to between 0.6 and 1.5. Stir for 10 minutes to initiate the reaction. Raise the material temperature to 18-25℃ and add 0.5g of activated carbon for decolorization for 1 hour. Filter the solution. Separate the filtrate into layers. Extract the aqueous layer twice with 100ml of ethyl acetate each time. 60 ml of saturated calcium chloride aqueous solution was added to the organic layer for dehydration, followed by the addition of 0.5 g of activated carbon. The mixture was stirred at 0°C for 1 hour to decolorize. After filtration, the solution was concentrated at 27°C in a water bath under a vacuum of -0.09 to -0.1 MPa, yielding 40-45 g of concentrated solution. Crystallization was then carried out at 0°C with stirring for 20 minutes. The solution was filtered, and the material was washed with 10 ml of frozen ethyl acetate. The washings were then dried under vacuum for 1 hour at 20-30°C under a vacuum of -0.09 to -0.1 MPa, yielding 15.6 g of sulbactamic acid.

[0037] The method described above uses the EP method to detect sulbactamic acid, with a content of 99.4%, impurity A of 0.006%, maximum nonspecific impurity of 0.03%, and total other impurities of 0.14%.

[0038] Example 3

[0039] (Comparative Example)

[0040] Add 200ml purified water, 280ml ethyl acetate, and 30g DBPAS to a 500ml four-necked flask. Stir and cool to 0-5℃. Add sodium bicarbonate to adjust the pH to 3-4 to initiate the salt formation reaction. Maintain the material temperature at 0-10℃. Slowly add 11.5g of zinc powder continuously, simultaneously adding 5% hydrochloric acid, controlling the system pH to 3.5-4.5 to initiate the reduction reaction. The total amount of 5% hydrochloric acid used is 72.6g. The zinc powder addition takes approximately 1 hour. Then, maintain the temperature at 0-5℃ for 30 minutes to ensure complete reaction. Filter the solution. Add 150ml of ethyl acetate to the filtrate. Cool to 5-15℃ and add a 28% sulfuric acid aqueous solution dropwise to adjust the pH to between 0.6 and 1.5. Stir for 10 minutes to initiate the reaction. Raise the material temperature to 18-25℃ and add 0.5g of activated carbon for decolorization for 1 hour. Filter the solution. Separate the filtrate into layers. Extract the aqueous layer twice with 100ml of ethyl acetate each time. 60 ml of saturated calcium chloride aqueous solution was added to the organic layer for dehydration, followed by the addition of 0.5 g of activated carbon. The mixture was stirred at 0°C for 1 hour to decolorize. After filtration, the solution was concentrated at 27°C in a water bath under a vacuum of -0.09 to -0.1 MPa, yielding 40-45 g of concentrated solution. Crystallization was then carried out at 0°C with stirring for 20 minutes. The solution was filtered, and the material was washed with 10 ml of frozen ethyl acetate. The washings were then dried under vacuum for 1 hour at 20-30°C under a vacuum of -0.09 to -0.1 MPa, yielding 14.5 g of sulbactamic acid.

[0041] The method described above uses the EP method to detect sulbactamic acid, with a content of 99.2%, impurity A of 0.01%, maximum nonspecific impurity of 0.06%, and total other impurities of 0.24%.

[0042] Example 4

[0043] Add 150ml of purified water and 30g of DBPAS to a 500ml four-necked flask. Stir and cool to 0-5℃. Add potassium bicarbonate to adjust the pH to 3-4 to initiate the salt formation reaction. Maintain the material temperature at 0-10℃. Slowly add 11.5g of zinc powder continuously, simultaneously adding 8% sulfuric acid, controlling the system pH to 3.5-4.5 for the reduction reaction. The total amount of 8% sulfuric acid used is 77.6g. The zinc powder addition takes about 1 hour. Then, maintain the temperature at 0-5℃ for 30 minutes to ensure complete reaction. Filter the solution. Add 150ml of chloroform to the filtrate and cool to 5-15℃. Add a 28% sulfuric acid solution dropwise to adjust the pH to between 0.6 and 1.5. Stir for 10 minutes to initiate the reaction. Raise the material temperature to 18-25℃ and add 0.5g of activated carbon for decolorization for 1 hour. Filter the solution. Separate the filtrate into layers. Extract the aqueous layer twice with 100ml of chloroform each time. 60 ml of saturated calcium chloride aqueous solution was added to the organic layer for dehydration, followed by the addition of 0.5 g of activated carbon. The mixture was stirred at 0°C for 1 hour to decolorize. After filtration, the solution was concentrated at 27°C in a water bath under a vacuum of -0.09 to -0.1 MPa, yielding 40-45 g of concentrated liquid. Crystallization was then carried out at 0°C with stirring for 20 minutes. The solution was filtered, and the material was washed with 10 ml of frozen chloroform, and the washing liquid was dried under vacuum. Vacuum drying was performed for 1 hour at 20-30°C under a vacuum of -0.09 to -0.1 MPa, yielding 16.2 g of sulbactamic acid.

[0044] The method described above uses the EP method to detect sulbactamic acid, with a content of 99.6%, impurity A of 0.007%, maximum nonspecific impurity of 0.03%, and total other impurities of 0.08%.

[0045] Example 5

[0046] Add 150ml of purified water and 30g of DBPAS to a 500ml four-necked flask. Stir and cool to 0-5℃. Add potassium bicarbonate to adjust the pH to 6-7 to initiate the salt formation reaction. Maintain the material temperature at 0-10℃. Slowly add 11.5g of zinc powder simultaneously, while simultaneously adding 8% sulfuric acid, controlling the system pH to 3.5-4.5 to initiate the reduction reaction. The total amount of 8% sulfuric acid used is 130.3g. The zinc powder addition takes approximately 1 hour. Then, maintain the temperature at 0-5℃ for 30 minutes to ensure complete reaction. Filter the solution. Add 150ml of chloroform to the filtrate and cool to 5-15℃. Add a 28% sulfuric acid solution dropwise to adjust the pH to between 0.6 and 1.5. Stir for 10 minutes to initiate the reaction. Raise the material temperature to 18-25℃ and add 0.5g of activated carbon for decolorization for 1 hour. Filter the solution. Separate the filtrate into layers. Extract the aqueous layer twice with 100ml of chloroform each time. 60 ml of saturated calcium chloride aqueous solution was added to the organic layer for dehydration, followed by the addition of 0.5 g of activated carbon. The mixture was stirred at 0°C for 1 hour to decolorize. After filtration, the mixture was concentrated in a water bath at 27°C under a vacuum of -0.09 to -0.1 MPa, yielding 40-45 g of concentrated solution. Crystallization was then carried out at 0°C with stirring for 20 minutes. The mixture was filtered, and the material was washed with 10 ml of frozen chloroform, and the washing liquid was dried under vacuum. Vacuum drying was performed for 1 hour at 20-30°C under a vacuum of -0.09 to -0.1 MPa, yielding 15.5 g of sulbactamic acid.

[0047] The method described above uses the EP method to detect sulbactamic acid, with a content of 99.4%, impurity A of 0.008%, maximum nonspecific impurity of 0.04%, and total other impurities of 0.15%.

[0048] Example 6

[0049] (Comparative Example)

[0050] Add 150ml purified water, 280ml chloroform, and 30g DBPAS to a 500ml four-necked flask. Stir and cool to 0-5℃. Add potassium bicarbonate to adjust the pH to 3-4 to initiate the salt formation reaction. Maintain the material temperature at 0-10℃. Slowly add 11.5g of zinc powder simultaneously, while simultaneously adding 8% sulfuric acid, controlling the system pH to 3.5-4.5 to initiate the reduction reaction. The total amount of 8% sulfuric acid used is 79.1g. The zinc powder is added over approximately 1 hour. Then, maintain the temperature at 0-5℃ for 30 minutes to ensure complete reaction. Filter the solution. Add 150ml of chloroform to the filtrate and cool to 5-15℃. Add a 28% sulfuric acid solution dropwise to adjust the pH to between 0.6 and 1.5. Stir for 10 minutes to initiate the reaction. Raise the material temperature to 18-25℃ and add 0.5g of activated carbon for decolorization for 1 hour. Filter the solution. Separate the filtrate into layers. Extract the aqueous layer twice with 100ml of chloroform each time. 60 ml of saturated calcium chloride aqueous solution was added to the organic layer for dehydration, followed by the addition of 0.5 g of activated carbon. The mixture was stirred at 0°C for 1 hour to decolorize. After filtration, the solution was concentrated at 27°C in a water bath under a vacuum of -0.09 to -0.1 MPa, yielding 40-45 g of concentrated solution. Crystallization was then carried out at 0°C with stirring for 20 minutes. The solution was filtered, and the material was washed with 10 ml of frozen chloroform, and the washing liquid was dried under vacuum. Vacuum drying was performed for 1 hour at 20-30°C under a vacuum of -0.09 to -0.1 MPa, yielding 14.4 g of sulbactamic acid.

[0051] The method described above uses the EP method to detect sulbactamic acid, with a content of 99.1%, impurity A of 0.012%, maximum nonspecific impurity of 0.06%, and total other impurities of 0.25%.

[0052] Example and Comparative Experimental Parameters

[0053]

[0054]

[0055] Stability tests were conducted on samples from the examples and comparative examples. The samples were stored under accelerated stability conditions: temperature 25% ± 2°C and humidity 60% ± 5°C. The changes in sample quality were detected at 0, 3, and 6 months.

[0056] Stability parameters of the examples and comparative samples

[0057]

[0058]

Claims

1. A method for preparing sulbactamic acid, characterized in that: The preparation method includes the following steps: (1) 6,6-Dibromopelinone sulfonic acid and a weak base undergo a salt formation reaction in an inorganic solvent, followed by the slow addition of a reducing agent and an aqueous solution of a first dilute acid, controlling the pH of the system, and carrying out a reduction reaction. The solution is then filtered to obtain a reduced reaction solution. The inorganic solvent is selected from water; the weak base is selected from one or more of sodium bicarbonate, potassium bicarbonate, sodium carbonate, and potassium carbonate; the reducing agent is selected from one or more of zinc and nickel; the first dilute acid is selected from one or more of dilute hydrochloric acid and dilute sulfuric acid; the pH of the system is controlled to be between 3 and 5. (2) After the reduction reaction solution and the first organic solvent are mixed, a second dilute acid aqueous solution is slowly added to it to adjust the pH value of the solution. After reacting for a period of time, the solution is filtered and the filtrate is separated into layers. The second dilute acid is selected from one or more of dilute hydrochloric acid and dilute sulfuric acid. The pH value of the solution is adjusted to be between 0.6 and 1.

5. (3) Extract the aqueous layer by adding a second organic solvent, dehydrate the second organic solvent layer with a dehydrating agent, filter first, concentrate, crystallize, filter second, and dry.

2. The method for preparing sulbactamic acid according to claim 1, characterized in that, In step (1), the temperature of the salt formation reaction is 0-15°C; the pH value during the salt formation reaction is 2.5-4.5; the concentration of the first dilute acid is 4-12%; the addition time of the reducing agent and dilute acid is 0.1-3 hours; and the time for continuing the reduction reaction after the reducing agent is added is 15-50 minutes.

3. The method for preparing sulbactamic acid according to claim 1, characterized in that, In step (2), the first organic solvent is selected from one or more of ethyl acetate, chloroform, methyl acetate, and dichloromethane; the concentration of the dilute sulfuric acid is 25-30%; the reaction time is 5-20 minutes; and the reaction temperature is 0-20°C.

4. The method for preparing sulbactamic acid according to claim 1, characterized in that, In step (3), the second organic solvent is selected from one or more of ethyl acetate, chloroform, methyl acetate, and dichloromethane; the dehydrating agent is selected from one of a solution dehydrating agent and a solid dehydrating agent; the solution dehydrating agent is selected from one of a saturated calcium chloride aqueous solution and a saturated sodium chloride aqueous solution; the solid dehydrating agent is selected from anhydrous sodium sulfate; the mass ratio of 6,6-dibromopenicillin sulfone acid to the volume ratio of the second organic solvent is 30:100 to 300, where the mass unit is g and the volume unit is ml; the mass ratio of 6,6-dibromopenicillin sulfone acid to the volume ratio of the liquid dehydrating agent is 30:30 to 90; after the second filtration and before drying, the step of washing the material with the second organic solvent is also included.

5. The method for preparing sulbactamic acid according to claim 4, characterized in that, In step (3), the mass ratio of 6,6-dibromopelinosyl sulfone acid to the volume ratio of the second organic solvent is 30:150-250, where the mass is in g and the volume is in ml; the mass ratio of 6,6-dibromopelinosyl sulfone acid to the volume ratio of the liquid dehydrating agent is 30:45-75.

6. The method for preparing sulbactamic acid according to claim 1, characterized in that, In step (1), the mass ratio of 6,6-dibromopelinosyl sulfone acid to the volume ratio of the inorganic solvent is 30:150-300, where the mass is in g and the volume is in ml; the mass ratio of 6,6-dibromopelinosyl sulfone acid to the reducing agent is 30:11-12.5; and the mass ratio of 6,6-dibromopelinosyl sulfone acid to the volume ratio of the first organic solvent is 30:125-200, where the mass is in g and the volume is in ml.

7. The method for preparing sulbactamic acid according to claim 6, characterized in that, In step (1), the mass ratio of 6,6-dibromopelinosinol sulfone acid to the volume ratio of the inorganic solvent is 30:175-250, where the mass is in g and the volume is in ml; the mass ratio of 6,6-dibromopelinosinol sulfone acid to the reducing agent is 30:11-12; and the mass ratio of 6,6-dibromopelinosinol sulfone acid to the volume ratio of the first organic solvent is 30:140-170.

8. The method for preparing sulbactamic acid according to claim 1, characterized in that, In step (2), after the reaction has proceeded for a period of time but before filtration, a first activated carbon decolorization step is included; the first activated carbon decolorization time is 0.5 to 2 hours; the first activated carbon decolorization temperature is 15 to 30°C; and the mass ratio of 6,6-dibromopelinone sulfonic acid to the first activated carbon is 30:0.1 to 2.

9. The method for preparing sulbactamic acid according to claim 8, characterized in that, In step (2), the decolorization time of the first activated carbon is 0.7 to 1.5 hours; the decolorization temperature of the first activated carbon is 18 to 25°C; and the mass ratio of 6,6-dibromopelinone sulfonic acid to the first activated carbon is 30:0.2 to 1.

10. The method for preparing sulbactamic acid according to claim 1, characterized in that, In step (3), after the second organic solvent layer is dehydrated with a dehydrating agent and before the first filtration, a second activated carbon decolorization step is included; the second activated carbon decolorization time is 0.5 to 2 hours; the second activated carbon decolorization temperature is -2 to 6°C; the mass ratio of 6,6-dibromopelinane sulfonic acid to the second activated carbon is 30:0.1 to 2; the concentration is selected from vacuum concentration; the vacuum concentration temperature is 20 to 35°C; the vacuum degree of the vacuum concentration is -0.09 to -0. 1 MPa; the concentration yields a concentrated solution, wherein the mass ratio of 6,6-dibromopelinane sulfonic acid to the volume of the concentrated solution is 30:30-60, where mass is in g and volume is in ml; the crystallization temperature is -10 to 10°C; the crystallization time is 10 to 30 minutes; the drying is selected from vacuum drying; the vacuum drying temperature is selected from 10 to 40°C; the vacuum drying time is 0.5 to 2 hours; the vacuum degree of the vacuum drying is -0.09 to -0.1 MPa.

11. The method for preparing sulbactamic acid according to claim 10, characterized in that, In step (3), the decolorization time of the second activated carbon is 0.7 to 1.5 hours; the decolorization temperature of the second activated carbon is -1 to 5°C; the mass ratio of 6,6-dibromopelinosyl sulfone acid to the second activated carbon is 30:0.2 to 1; the vacuum concentration temperature is 25 to 30°C; the mass ratio of 6,6-dibromopelinosyl sulfone acid to the volume ratio of the concentrate is 30:35 to 50, where the mass unit is g and the volume unit is ml; the crystallization temperature is -5 to 5°C; the crystallization time is 15 to 25 minutes; the vacuum drying temperature is selected from 25 to 35°C; and the vacuum drying time is 0.8 to 1.2 hours.

12. The method for preparing sulbactamic acid according to claim 1, characterized in that, In step (1), the specific steps of the salt formation reaction of 6,6-dibromopelinosyl sulfone acid and the weak base in the inorganic solvent include adding the weak base to adjust the pH after mixing the inorganic solvent and 6,6-dibromopelinosyl sulfone acid; the temperature of the mixture after mixing the inorganic solvent and 6,6-dibromopelinosyl sulfone acid is 0-10℃.

13. The method for preparing sulbactamic acid according to claim 2, characterized in that, In step (1), the temperature of the salt formation reaction is 0-10℃; the pH value during the salt formation reaction is 3-4; the concentration of the first dilute acid is 5-10%; the pH of the control system is controlled at 3.5-4.5; the addition time of the reducing agent and dilute acid is 0.5-2 hours; and the time for continuing the reduction reaction after the reducing agent is added is 20-40 minutes.

14. The method for preparing sulbactamic acid according to claim 3, characterized in that, In step (2), the reaction time is 5 to 15 minutes; the reaction temperature is 5 to 15°C.

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