Sulbactam acid crystallization method and device

Abstract

The invention provides a sulbactam acid crystallization method and device.According to the method, a sulbactam acid finished product is obtained by conducting alkalization, liquid separation, acidification, extraction, two-stage reduced pressure distillation and centrifugation on decolored reaction liquid. And separating the organic phase from the water phase. A large amount of impurities are remained in the removed organic phase, so that the impurities in the finished sulbactam acid product can be reduced, and the shelf life is prolonged. The residue of the first solvent in the system can be effectively reduced through a two-stage reduced pressure distillation mode, the second solvent is a poor solvent of sulbactam acid, crystallization of sulbactam acid is facilitated, the residual quantity of sulbactam acid in crystallization mother liquor is reduced, and the yield is increased. The discoloring reaction liquid is separated and then directly concentrated and crystallized, so that the content of impurities in the obtained sulbactam acid is high, and the downstream production link is not facilitated.

Description

Technical Field

[0001] The present application relates to pharmaceutical crystallization technology, and in particular to a sulbactam acid crystallization method and device. Background Art

[0002] Sulbactam acid, molecular formula C 8 H 11 NO 5 S, with a relative molecular mass of 233, is an irreversible competitive β-lactamase inhibitor that inhibits most β-lactamases produced by Gram-positive and Gram-negative bacteria. It protects antibiotics from destruction and improves antibacterial activity by inhibiting enzymes. Sulbactam acid has been widely used in medicine in recent years.

[0003] The common synthesis process of sulbactam acid is to use 6-aminopenicillanic acid (also known as 6-APA) as the starting material, undergo a diazotization reaction with sodium nitrite under acidic conditions, then undergo a dibromination reaction with bromine, then undergo potassium permanganate oxidation, and finally undergo reduction and debromination with metal powder such as zinc powder to obtain the desired compound sulbactam acid. At this time, sulbactam acid is dissolved in an organic solvent. The traditional method is to obtain sulbactam acid by decolorizing, separating, concentrating, and crystallizing the reaction solution. However, the impurities in the sulbactam acid obtained in this way are high, which is not conducive to the downstream production process. Summary of the invention

[0004] The present application provides a sulbactam acid crystallization method and device, which are used to solve the problem that the sulbactam acid crystals obtained by treating the sulbactam acid synthesis reaction solution in the existing method have high impurities, which is not conducive to the downstream production links.

[0005] In a first aspect, the present application provides a method for crystallizing sulbactam acid, comprising the following steps: Decolorizing the reaction solution obtained by the reduction reaction in the process of synthesizing sulbactam acid, then adding alkali solution, adjusting the pH to a weak alkaline state, stirring, and separating the aqueous phase; Adding acid to the aqueous phase to adjust the pH to acidic, and then adding the first solvent to perform extraction; The organic phase after extraction is subjected to preliminary vacuum distillation, and then the second solvent is added to perform vacuum distillation again until the residual amount of the first solvent is less than 1%, and the distillation is terminated; After the distillation is completed, the material temperature is lowered to 5-10°C for crystallization, and then centrifugation and drying operations are performed in sequence to obtain the finished product of sulbactam acid.

[0006] The sulbactam acid crystallization method of the present application has the following beneficial effects: 1) The pH value of the material after the reduction reaction is adjusted to a weak alkaline state with alkali solution to separate the organic phase and the aqueous phase. A large amount of impurities remain in the removed organic phase, which can reduce the impurities in the finished product sulbactam acid and extend the shelf life.

[0007] 2) During the reduced pressure distillation, the first solvent can be effectively recovered, the loss of the first solvent can be reduced, and the production cost can be saved. In addition, during the reduced pressure distillation, the first solvent is first distilled and then the second solvent is added to continue distillation. The two-stage distillation method can fully reduce the residue of the first solvent in the system, and the second solvent is a poor solvent for sulbactam acid, which is beneficial to the crystallization of sulbactam acid, reduces the residual amount of sulbactam acid in the crystallization mother liquor, and improves the yield.

[0008] The method of the present application effectively reduces the content of impurities in the finished sulbactam acid by implementing the above steps in combination, and overcomes the disadvantage that the reaction solution is directly concentrated and crystallized after decolorization and separation in the traditional method, resulting in high impurities in the obtained sulbactam acid, which is not conducive to the downstream production links.

[0009] Optionally, the alkali solution is an aqueous solution of an inorganic base with a concentration of 5wt% to 10wt%, and the inorganic base includes one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium bicarbonate, and potassium carbonate.

[0010] Optionally, after adding alkali solution to the reaction solution, the weak alkalinity is adjusted to pH = 7-8.

[0011] Optionally, the acid added to the aqueous phase is hydrochloric acid with a concentration of 35wt% to 37wt% or sulfuric acid with a concentration of 96wt% to 98wt%.

[0012] Optionally, acid is added to the aqueous phase to adjust the acidity to pH = 1-2.

[0013] Optionally, the first solvent is one or more of ethyl acetate, chloroform or dichloromethane, and the volume ratio of the first solvent added to the aqueous phase is (0.8-1.2):1; The second solvent is a saturated monohydric alcohol having 1 to 4 carbon atoms.

[0014] Optionally, during the reduced pressure distillation process, the negative pressure used is -0.09~-0.095MPa.

[0015] Optionally, during the initial reduced pressure distillation, the amount of the first solvent distilled out is 80-85% of the volume of the organic phase; The amount of the second solvent added is the same as the amount of the first solvent distilled off.

[0016] In a second aspect, the present application provides a sulbactam acid crystallization device, which is applied to any of the sulbactam acid crystallization methods of the first aspect, comprising an alkalization kettle, an acidification kettle, an extraction kettle, a first distillation kettle, a centrifuge, a drying device and a finished product storage tank connected in series in sequence; The alkalization kettle is respectively connected with the alkali metering pump and the second distillation kettle; The acidification kettle is connected to the acid metering pump; The extraction kettle is connected to the first solvent storage tank, and the first solvent storage tank is connected to the second distillation kettle through the first condenser; The first distillation kettle is connected to the first solvent storage tank and the miscible solvent storage tank respectively through the second condenser, the first distillation kettle is also connected to the second solvent storage tank, and the second condenser is also connected to the vacuum pump; The centrifuge is also connected to the mother liquor storage tank.

[0017] Optionally, the extraction kettle is also connected to a wastewater treatment device; The wastewater treatment device comprises a Fenton oxidation tank, a biochemical treatment tank, an ozone oxidation tank and a reuse water tank which are connected in series.

[0018] The beneficial effects of the sulbactam acid crystallization device provided in the present application have been described in the sulbactam acid crystallization method of the first aspect above, and will not be repeated here. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, a brief introduction will be given below to the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are some embodiments of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0020] Figure 1 A schematic diagram of a sulbactam acid crystallization device provided in one embodiment of the present application; Figure 2 This is a schematic diagram of a sulbactam acid crystallization device provided in another embodiment of the present application.

[0021] Description of reference numerals: 1. Alkalization kettle; 2. Acidification kettle; 3. Extraction kettle; 4. First distillation kettle; 5. Centrifuge; 6. Drying device; 7. Finished product storage tank; 8. Wastewater treatment device; 10. Alkali metering pump; 11. Second distillation kettle; 20. Acid metering pump; 30. Vacuum pump; 31. First solvent storage tank; 41. Miscible solvent storage tank; 42. Second solvent storage tank; 51. Mother liquor storage tank; 81. Fenton oxidation tank; 82. Biochemical treatment tank; 83. Ozone oxidation tank; 84. Recycled water tank; 100. First condenser; 200. Second condenser. DETAILED DESCRIPTION

[0022] In order to make the purpose, technical scheme and advantages of the embodiments of the present application clearer, the technical scheme in the embodiments of the present application is clearly and completely described below. Obviously, the described embodiments are part of the embodiments of the present application, not all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field without creative work also fall within the scope of protection of the present application.

[0023] The present application provides a sulbactam acid crystallization method and device, which are used to solve the problem that the sulbactam acid crystals obtained by treating the sulbactam acid synthesis reaction solution in the existing method have high impurities, which is not conducive to the downstream production links.

[0024] In a first aspect, the present application provides a method for crystallizing sulbactam acid, comprising the following steps: Decolorizing the reaction solution obtained by the reduction reaction in the process of synthesizing sulbactam acid, then adding alkali solution, adjusting the pH to a weak alkaline state, stirring, and separating the aqueous phase; Adding acid to the aqueous phase to adjust the pH to acidic, and then adding the first solvent to perform extraction; The organic phase after extraction is subjected to preliminary vacuum distillation, and then the second solvent is added to perform vacuum distillation again until the residual amount of the first solvent is less than 1%, and the distillation is terminated; After the distillation is completed, the material temperature is lowered to 5-10°C for crystallization, and then centrifugation and drying operations are performed in sequence to obtain the finished product of sulbactam acid.

[0025] In the present application, the first solvent is a good solvent for sulbactam acid compared to the second solvent.

[0026] In the present application, the specific decolorization operation is to control the temperature to 0-5°C, add 1%-5% of the weight of the reaction solution of activated carbon and stir for 1-1.5h.

[0027] In the present application, it should be noted that in the reduction reaction of synthesizing sulbactam acid, a solvent immiscible with water (such as ethyl acetate, dichloromethane, chloroform, etc.) and an equal volume of water need to be added to react, and after the reaction is completed, the two phases coexist.

[0028] The sulbactam acid crystallization method of the present application has the following beneficial effects: 1) The pH value of the material after the reduction reaction is adjusted to a weak alkaline state with alkali solution to separate the organic phase and the aqueous phase. A large amount of impurities remain in the removed organic phase, which can reduce the impurities in the finished product sulbactam acid and extend the shelf life.

[0029] 2) During the reduced pressure distillation, the first solvent can be effectively recovered, the loss of the first solvent can be reduced, and the production cost can be saved. In addition, during the reduced pressure distillation, the first solvent is first distilled and then the second solvent is added to continue distillation. The two-stage distillation method can fully reduce the residue of the first solvent in the system, and the second solvent is a poor solvent for sulbactam acid, which is beneficial to the crystallization of sulbactam acid, reduces the residual amount of sulbactam acid in the crystallization mother liquor, and improves the yield.

[0030] The method of the present application effectively reduces the content of impurities in the finished sulbactam acid by implementing the above steps in combination, and overcomes the disadvantage that the reaction solution is directly concentrated and crystallized after decolorization and separation in the traditional method, resulting in high impurities in the obtained sulbactam acid, which is not conducive to the downstream production links.

[0031] Optionally, the alkali solution is an aqueous solution of an inorganic base with a concentration of 5wt% to 10wt%, and the inorganic base includes one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium bicarbonate, and potassium carbonate.

[0032] Optionally, after adding alkali solution to the reaction solution, the weak alkalinity is adjusted to pH = 7-8.

[0033] In the present application, since the sulbactam acid in the reaction solution needs to be converted into the sodium salt (or potassium salt) of sulbactam acid, the stability of sulbactam acid needs to be improved while it is separated from the organic phase. At this time, the reaction solution needs to be adjusted to a weak alkalinity (too strong alkalinity will destroy the structure of sulbactam acid).

[0034] Optionally, the acid added to the aqueous phase is hydrochloric acid with a concentration of 35wt% to 37wt% or sulfuric acid with a concentration of 96wt% to 98wt%.

[0035] Optionally, acid is added to the aqueous phase to adjust the acidity to pH = 1-2.

[0036] In the present application, the use of high-concentration acid to adjust the pH can reduce the volume of the aqueous phase, thereby reducing the amount of wastewater generated, which is beneficial to controlling treatment costs.

[0037] Adjusting the acidity to pH = 1~2 can ensure that the sodium salt (or potassium salt) of sulbactam acid in the system is fully converted into sulbactam acid, thereby reducing material losses.

[0038] Optionally, the first solvent is one or more of ethyl acetate, chloroform or dichloromethane, and the volume ratio of the first solvent added to the aqueous phase is (0.8-1.2):1; In the present application, the first organic solvent with a volume of 0.8 to 1.2 times the volume of the aqueous phase is used for extraction. The amount of organic solvent used here is small, which can reduce the volume of the extraction phase and reduce the use of solvent.

[0039] In the present application, the aqueous phase after reduction and stratification is subjected to first solvent extraction. A small amount of the first solvent is used to extract sulbactam acid from the aqueous phase, which can reduce the volume of the extraction phase, thereby shortening the subsequent distillation time, reducing the loss of the first solvent, and reducing environmental pressure.

[0040] The second solvent is a saturated monohydric alcohol having 1 to 4 carbon atoms.

[0041] In the present application, the first solvent is a good solvent for sulbactam acid compared to the second solvent, and its purpose is to extract sulbactam acid from the aqueous phase as much as possible during the extraction process. Correspondingly, the second solvent is a poor solvent for sulbactam acid and should be miscible with the first solvent, so as to reduce the solubility of sulbactam acid in the second solvent while removing the first solvent during subsequent distillation, which is beneficial to the crystallization of sulbactam acid and reduces the content of sulbactam acid in the mother liquor.

[0042] Optionally, during the reduced pressure distillation process, the negative pressure used is -0.09~-0.095MPa.

[0043] In the present application, the use of a negative pressure of -0.09 to -0.095 MPa can reduce the boiling point of the evaporated solvent, which is beneficial to the evaporation of the solvent.

[0044] Optionally, during the initial reduced pressure distillation, the amount of the first solvent distilled out is 80-85% of the volume of the organic phase; The amount of the second solvent added is the same as the amount of the first solvent distilled off.

[0045] In the present application, during the initial reduced pressure distillation process, the amount of the first solvent evaporated is controlled to 80-85% of the volume of the organic phase. This can avoid the product being locally heated and destroyed due to the evaporation of the solvent, and secondly, a certain amount of solvent is left to make the system flow, which is beneficial to the stirring during the distillation process. The purpose of adding the second solvent is to replace the first solvent, and the solubility of the product sulbactam acid in the second solvent should be less than that in the first solvent, which is convenient for the subsequent crystallization process.

[0046] like Figure 1 As shown, in the second aspect, the present application provides a sulbactam acid crystallization device, which is applied to the sulbactam acid crystallization method of any one of the first aspects above, comprising an alkalization kettle 1, an acidification kettle 2, an extraction kettle 3, a first distillation kettle 4, a centrifuge 5, a drying device 6 and a finished product storage tank 7 connected in series in sequence; The alkalization kettle 1 is connected to the alkali metering pump 10 and the second distillation kettle 11 respectively; The acidification kettle 2 is connected to the acid metering pump 20; The extraction kettle 3 is connected to the first solvent storage tank 31, and the first solvent storage tank 31 is connected to the second distillation kettle 11 through the first condenser 100; The first distillation kettle 4 is connected to the first solvent storage tank 31 and the miscible solvent storage tank 41 respectively through the second condenser 200, the first distillation kettle 4 is also connected to the second solvent storage tank 42, and the second condenser 200 is also connected to the vacuum pump 30; The centrifuge 5 is also connected to the mother liquid storage tank 51 .

[0047] When the device of the present application is used, the decolorized sulbactam acid synthesis reaction liquid is added to the alkalization kettle 1, stirring is started, and alkali solution (a sodium hydroxide aqueous solution with a concentration of 5wt%~10wt% is used in the present application) is added to the alkalization kettle 1 through the alkali metering pump 10, and the pH of the reaction liquid is adjusted to 7~8. At this time, the sulbactam acid in the reaction liquid forms a sodium salt and precipitates in the organic solvent and dissolves in the aqueous phase. After the alkalization is complete, stirring is stopped, the mixture is allowed to stand for stratification, and the upper organic phase is transferred to the second distillation kettle 11 for distillation, and condensed and recovered into the first solvent storage tank 31 through the first condenser 100 (in a feasible manner, the first condenser 100 can also be connected to a vacuum pump to evacuate the second distillation kettle 11 for reduced pressure distillation). The aqueous phase in the alkalization kettle 1 is transferred to the acidification kettle 2, and sulfuric acid with a concentration of 96wt% to 98wt% is added through the acid metering pump 20 to adjust the pH of the aqueous phase to between 1 and 2. After the acidification, sulbactam acid will precipitate in the aqueous phase to form a suspension. At this time, the aqueous phase suspension containing sulbactam acid is transferred to the extraction kettle 3, and the first solvent (the first solvent in this application is ethyl acetate) is added through the first solvent storage tank 31. The amount of the first solvent added is 0.8 to 1.2 times the volume of the aqueous phase. Stirring is turned on for extraction until the aqueous phase is clear, and then the stirring is turned off and the mixture is allowed to stand for stratification, and the lower aqueous phase is transferred to the corresponding wastewater treatment section for treatment.

[0048] The first solvent phase in the upper layer of the extraction kettle 3 is transferred to the first distillation kettle 4 and sucked by the vacuum pump 30 for preliminary reduced pressure distillation (the negative pressure in the first distillation kettle 4 is controlled to be -0.09~-0.095MPa). The gas phase first organic solvent evaporated during the distillation process is condensed by the second condenser 200 and then transferred to the first solvent storage tank 31. When the volume of the first solvent phase is concentrated to 15~20% of the original volume (that is, the amount of the first solvent evaporated is 80~85% of the volume of the first solvent phase), the second solvent (isopropanol is used in this application) in the second solvent storage tank 42 is added to the first distillation kettle 4, and the amount of the second solvent added is the same as the amount of the first solvent evaporated.

[0049] After the second solvent is added to the first distillation kettle 4, distillation is continued. At this time, the distilled gas phase contains the first solvent and the second solvent, which is condensed by the second condenser 200 and stored in the miscible solvent storage tank 41 for subsequent rectification and separation. During the distillation process, the gas phase distilled from the first distillation kettle 4 is sampled in real time for analysis (such as online gas chromatography analysis). When it is detected that the content of the first solvent in the gas phase is less than 1%, the distillation is stopped, and the vacuum pump 30 is turned off after the vacuum is broken.

[0050] Then, the first distillation kettle 4 is cooled by heat exchange with circulating cooling water to reduce the temperature in the kettle to 5-10°C. During the cooling process, sulbactam acid crystals will be precipitated in the system. After the crystallization is complete, the solvent containing the crystals is transferred to the centrifuge 5 for centrifugation, and the filtrate is collected in the mother liquid storage tank 51 for recycling and crystallization. The collected filter cake is transferred to the drying device 6 (such as a drying cylinder, a drying box, etc.) and dried at 25-35°C to a constant weight to obtain the sulbactam acid product, which is stored in the finished product storage tank 7.

[0051] Optionally, the extraction kettle 3 is also connected to a wastewater treatment device 8; like Figure 2 As shown, the wastewater treatment device 8 includes a Fenton oxidation tank 81, a biochemical treatment tank 82, an ozone oxidation tank 83 and a reuse water tank 84 which are connected in series in sequence.

[0052] In the present application, since the wastewater contains a certain amount of sulbactam acid, if it is directly subjected to biochemical treatment, the bacteria in the biochemical treatment tank 82 will be inhibited. Therefore, it is necessary to pre-treat it and set up a Fenton oxidation tank 81 before sending it to the biochemical treatment tank 82. Fenton oxidation can not only utilize the original acidity of the wastewater, but also Fenton oxidation, as an advanced oxidation method, can fully oxidize the sulbactam acid in the wastewater and the by-products in the synthesis into small fragments of molecules, thereby reducing the antibacterial properties of the wastewater. The biochemical treatment tank 82 can, for example, use one or more of anaerobic fermentation, anoxic fermentation, and aerobic fermentation to treat the wastewater.

[0053] Since the water discharged after the biochemical treatment contains a small amount of products of microbial fermentation or microorganisms, the ozone oxidation tank 83 is set up to use ozone oxidation to deeply oxidize these substances and improve the cleanliness of the recycled water.

[0054] A sulbactam acid crystallization device, the working process of which is as follows: When in use, the decolorized sulbactam acid synthesis reaction liquid is added to the alkalization kettle 1, stirring is started, and alkali solution (a sodium hydroxide aqueous solution with a concentration of 5wt%~10wt% is used in this application) is added to the alkalization kettle 1 through the alkali metering pump 10, and the pH of the reaction liquid is adjusted to 7~8. At this time, the sulbactam acid in the reaction liquid forms a sodium salt and precipitates in the organic solvent and dissolves in the aqueous phase. After the alkalization is complete, stirring is stopped, the mixture is allowed to stand for stratification, and the upper organic phase is transferred to the second distillation kettle 11 for distillation, and condensed and recovered into the first solvent storage tank 31 through the first condenser 100. The aqueous phase in the alkalization kettle 1 is transferred to the acidification kettle 2, and sulfuric acid with a concentration of 96wt% to 98wt% is added through the acid metering pump 20 to adjust the pH of the aqueous phase to between 1 and 2. After the acidification, sulbactam acid will precipitate in the aqueous phase to form a suspension. At this time, the aqueous phase suspension containing sulbactam acid is transferred to the extraction kettle 3, and the first solvent (the first solvent in this application is ethyl acetate) is added through the first solvent storage tank 31. The amount of the first solvent added is 0.8 to 1.2 times the volume of the aqueous phase, and the stirring is turned on. The water phase is extracted by stirring until it becomes clear, and then the stirring is turned off and the mixture is allowed to stand for stratification. The lower water phase is transferred to the Fenton oxidation tank 81 to adjust the pH to between 3 and 5 for Fenton oxidation. After Fenton oxidation, the supernatant is transferred to the biochemical treatment tank 82 for biochemical treatment. After the biochemical treatment, the water phase is transferred to the ozone oxidation tank 83 for further deep treatment. After treatment, the water phase can be transferred to the reuse water tank 84 for use in the factory sections that do not require high water quality (such as floor cleaning, etc.).

[0055] The first solvent phase in the upper layer of the extraction kettle 3 is transferred to the first distillation kettle 4 and sucked by the vacuum pump 30 for preliminary reduced pressure distillation (the negative pressure in the first distillation kettle 4 is controlled to be -0.09~-0.095MPa). The gas phase first organic solvent evaporated during the distillation process is condensed by the second condenser 200 and then transferred to the first solvent storage tank 31. When the volume of the first solvent phase is concentrated to 15~20% of the original volume (that is, the amount of the first solvent evaporated is 80~85% of the volume of the first solvent phase), the second solvent (isopropanol is used in this application) in the second solvent storage tank 42 is added to the first distillation kettle 4, and the amount of the second solvent added is the same as the amount of the first solvent evaporated.

[0056] After the second solvent is added to the first distillation kettle 4, distillation is continued. At this time, the distilled gas phase contains the first solvent and the second solvent, which is condensed by the second condenser 200 and stored in the miscible solvent storage tank 41 for subsequent rectification and separation. During the distillation process, the gas phase distilled from the first distillation kettle 4 is sampled in real time for analysis (such as online gas chromatography analysis). When it is detected that the content of the first solvent in the gas phase is less than 1%, the distillation is stopped, and the vacuum pump 30 is turned off after the vacuum is broken.

[0057] Then, the first distillation kettle 4 is cooled by heat exchange with circulating cooling water to reduce the temperature in the kettle to 5-10°C. During the cooling process, sulbactam acid crystals will be precipitated in the system. After the crystallization is complete, the solvent containing the crystals is transferred to the centrifuge 5 for centrifugation, and the filtrate is collected in the mother liquid storage tank 51 for recycling and crystallization. The collected filter cake is transferred to the drying device 6 (such as a drying cylinder, a drying box, etc.) and dried at 25-35°C to a constant weight to obtain the sulbactam acid product, which is stored in the finished product storage tank 7.

[0058] The beneficial effects of the sulbactam acid crystallization device provided in the present application have been described in the sulbactam acid crystallization method of the first aspect above, and will not be repeated here. Specific embodiments

[0059] Example 1 A method for crystallizing sulbactam acid, the operating steps of which are as follows: S101, decolorizing the reaction solution after the reduction reaction, adding 5-10wt% alkali solution, adjusting the pH to 7-8, stirring, and separating the aqueous phase.

[0060] S102, adding sulfuric acid with a concentration of 96wt% to 98wt% to the aqueous phase to adjust the pH to 1, and then adding ethyl acetate for extraction, the volume ratio of the added ethyl acetate to the aqueous phase is 0.8:1.

[0061] S103, the organic phase after extraction is initially subjected to reduced pressure distillation, the amount of ethyl acetate distilled out is 80% of the volume of the organic phase, and then isopropanol of the same volume as the distilled ethyl acetate is added to perform reduced pressure distillation again, and the distillation is terminated when the residual amount of ethyl acetate is less than 1%. During the reduced pressure distillation process, the negative pressure used is -0.09~-0.095MPa.

[0062] S104. After the distillation is completed, the material temperature is lowered to 5-10°C for crystallization, and then centrifugation and drying are performed in sequence to obtain the finished product of sulbactam acid.

[0063] Example 2 A method for crystallizing sulbactam acid, the operating steps of which are as follows: S201, decolorizing the reaction solution after the reduction reaction, adding 5-10wt% alkali solution, adjusting the pH to 7-8, stirring, and separating the aqueous phase.

[0064] S202, adding sulfuric acid with a concentration of 96wt% to 98wt% to the aqueous phase to adjust the pH to 2, and then adding ethyl acetate for extraction, the volume ratio of the added ethyl acetate to the aqueous phase is 1.2:1.

[0065] S203, the organic phase after extraction is initially subjected to reduced pressure distillation, the amount of ethyl acetate distilled out is 85% of the volume of the organic phase, and then isopropanol of the same volume as the distilled ethyl acetate is added to carry out reduced pressure distillation again, and the distillation is terminated when the residual amount of ethyl acetate is less than 1%. During the reduced pressure distillation process, the negative pressure used is -0.09~-0.095MPa.

[0066] S204. After the distillation is completed, the material temperature is lowered to 5-10°C for crystallization, and then centrifugation and drying are performed in sequence to obtain the finished product of sulbactam acid.

[0067] Example 3 A method for crystallizing sulbactam acid, the operating steps of which are as follows: S301, decolorizing the reaction solution after the reduction reaction, adding 5-10wt% alkali solution, adjusting the pH to 7-8, stirring, and separating the aqueous phase.

[0068] S302, adding sulfuric acid with a concentration of 96wt% to 98wt% to the aqueous phase to adjust the pH to 1.5, and then adding ethyl acetate for extraction, wherein the volume ratio of the added ethyl acetate to the aqueous phase is 1:1.

[0069] S303, the organic phase after extraction is initially subjected to reduced pressure distillation, the amount of ethyl acetate distilled out is 82.5% of the volume of the organic phase, and then isopropanol of the same volume as the distilled ethyl acetate is added to carry out reduced pressure distillation again, and the distillation is terminated when the residual amount of ethyl acetate is less than 1%. During the reduced pressure distillation process, the negative pressure used is -0.09~-0.095MPa.

[0070] S304. After the distillation is completed, the material temperature is lowered to 5-10°C for crystallization, and then centrifugation and drying are performed in sequence to obtain the finished product of sulbactam acid.

[0071] Example 4 A method for crystallizing sulbactam acid, the operating steps of which are as follows: S401, decolorizing the reaction solution after the reduction reaction, adding 5-10wt% alkali solution, adjusting the pH to 7-8, stirring, and separating the aqueous phase.

[0072] S402, adding sulfuric acid with a concentration of 96wt% to 98wt% to the aqueous phase to adjust the pH to 1.5, and then adding ethyl acetate for extraction, the volume ratio of the added ethyl acetate to the aqueous phase is 1.2:1.

[0073] S403, the organic phase after extraction is initially subjected to reduced pressure distillation, the amount of ethyl acetate distilled out is 80% of the volume of the organic phase, and then isopropanol of the same volume as the distilled ethyl acetate is added to perform reduced pressure distillation again, and the distillation is terminated when the residual amount of ethyl acetate is less than 1%. During the reduced pressure distillation process, the negative pressure used is -0.09~-0.095MPa.

[0074] S404. After the distillation is completed, the material temperature is lowered to 5-10°C for crystallization, and then centrifugation and drying are performed in sequence to obtain the finished product of sulbactam acid.

[0075] Comparative Example 1 D101. Decolorize the reaction solution after the reduction reaction (the reaction solution is an ethyl acetate phase and an aqueous phase), separate the liquids, collect the ethyl acetate phase and dry it with anhydrous sodium sulfate.

[0076] D102. Concentrate the dried ethyl acetate phase at 28°C and negative pressure of -0.09 to -0.095 MPa. Stop concentrating when solid appears in the system.

[0077] D103. Cool the concentrated solution to 0-5°C and stir until the crystals are completely precipitated, filter, and dry at 25°C to constant weight to obtain sulbactam acid solid.

[0078] The purity of the finished sulbactam acid products obtained in Examples 1 to 4 and Comparative Example 1 was measured. The results are shown in Table 1.

[0079] The detection method and instruments are as follows: 1. Instruments and equipment: electronic balance, liquid chromatography Ultimate 3000, chromatographic column, filter, ultrasonic, pH meter.

[0080] 2. Reagents and drugs: acetonitrile (chromatographic grade), phosphoric acid (AR), potassium dihydrogen phosphate (AR), purified water, hydrochloric acid, sodium hydroxide.

[0081] 3. Chromatographic conditions: Chromatographic column: Thermo Hypersil GOLD C18 5um; 150*4.6mm or equivalent column.

[0082] Mobile phase A: Weigh 5.44 g of potassium dihydrogen phosphate, dissolve it in water and dilute it to 1000 ml, and adjust the pH value to 4.0 with 1 mol / L phosphoric acid solution.

[0083] Mobile phase B: acetonitrile Injection volume: 20ul Column temperature: 40℃ Flow rate: 1.0ml / min Detector: 215nm Run time: 13min Elution gradient:

[0084] Table 1

[0085] It can be seen from the data in Table 1 above that the purity of the sulbactam acid product prepared by the method of the present application is higher than that of the sulbactam acid in Comparative Example 1, and no oxide impurities are detected in the product.

[0086] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present application, rather than to limit it. Although the present application has been described in detail with reference to the aforementioned embodiments, ordinary technicians in the field should understand that they can still modify the technical solutions recorded in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present application.

Claims

1. A method for crystallizing sulbactam acid, characterized in that: The steps include: Decolorizing the reaction solution obtained by the reduction reaction in the process of synthesizing sulbactam acid, then adding alkali solution, adjusting the pH to a weak alkaline state, stirring, and separating the aqueous phase; Adding acid to the aqueous phase to adjust the pH to acidic, and then adding the first solvent to perform extraction; The organic phase after extraction is subjected to preliminary vacuum distillation, and then the second solvent is added to perform vacuum distillation again until the residual amount of the first solvent is less than 1%, and the distillation is terminated; After the distillation is completed, the material temperature is lowered to 5-10°C for crystallization, and then centrifugation and drying operations are performed in sequence to obtain the finished product of sulbactam acid.

2. The method for crystallizing sulbactam acid according to claim 1, characterized in that: The alkali solution is an aqueous solution of an inorganic base with a concentration of 5wt% to 10wt%, and the inorganic base includes one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium bicarbonate, and potassium carbonate.

3. The method for crystallizing sulbactam acid according to claim 1, characterized in that: After adding alkali solution to the reaction solution, the weak alkalinity is adjusted to pH = 7~8.

4. The method for crystallizing sulbactam acid according to claim 1, characterized in that: The acid added to the aqueous phase is hydrochloric acid with a concentration of 35wt% to 37wt% or sulfuric acid with a concentration of 96wt% to 98wt%.

5. The method for crystallizing sulbactam acid according to claim 1, characterized in that: Acid is added to the aqueous phase to adjust the acidity to pH = 1~2.

6. The method for crystallizing sulbactam acid according to claim 1, characterized in that: The first solvent is one or more of ethyl acetate, chloroform or dichloromethane, and the volume ratio of the first solvent added to the aqueous phase is (0.8-1.2):1; The second solvent is a saturated monohydric alcohol having 1 to 4 carbon atoms.

7. The method for crystallizing sulbactam acid according to claim 1, characterized in that: During the reduced pressure distillation process, the negative pressure used is -0.09~-0.095MPa.

8. The method for crystallizing sulbactam acid according to claim 1, characterized in that: During the preliminary reduced pressure distillation, the amount of the first solvent distilled out is 80-85% of the volume of the organic phase; The amount of the second solvent added is the same as the amount of the first solvent distilled off.

9. A sulbactam acid crystallization device, used in the sulbactam acid crystallization method according to any one of claims 1 to 8, characterized in that: It comprises an alkalization kettle (1), an acidification kettle (2), an extraction kettle (3), a first distillation kettle (4), a centrifuge (5), a drying device (6) and a finished product storage tank (7) which are connected in series in sequence; The alkalization kettle (1) is connected to the alkali metering pump (10) and the second distillation kettle (11) respectively; The acidification kettle (2) is connected to an acid metering pump (20); The extraction kettle (3) is connected to a first solvent storage tank (31), and the first solvent storage tank (31) is connected to a second distillation kettle (11) via a first condenser (100); The first distillation kettle (4) is connected to the first solvent storage tank (31) and the miscible solvent storage tank (41) respectively through the second condenser (200), the first distillation kettle (4) is also connected to the second solvent storage tank (42), and the second condenser (200) is also connected to the vacuum pump (30); The centrifuge (5) is also connected to a mother liquid storage tank (51).

10. The sulbactam acid crystallization device according to claim 9, characterized in that: The extraction kettle (3) is connected to a wastewater treatment device (8); The wastewater treatment device (8) comprises a Fenton oxidation tank (81), a biochemical treatment tank (82), an ozone oxidation tank (83) and a reuse water tank (84) which are connected in series.

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