A purification method of sulbactam derivatives and application thereof

Abstract

The present invention provides a method for purifying a sulbactam derivative, the method comprising: adding an oxidant to a sulbactam derivative containing (2S)2-amino-3-methyl-3-sulfinylbutyric acid as an impurity, wherein the oxidant is selected from one or more of sodium hypochlorite, sodium chlorate, hydrogen peroxide, and perchloric acid. The method for purifying a sulbactam derivative provided by the present invention can make the content of the (2S)2-amino-3-methyl-3-sulfinylbutyric acid impurity in the final sulbactam derivative lower than 0.1%, thereby increasing the storage time and product qualification rate of sulbactam acid and sulbactam salt and reducing its production cost.

Description

Technical Field

[0001] The present application relates to the technical field of drug synthesis, and in particular to a purification method of sulbactam derivatives and applications thereof. Background Art

[0002] Sulbactam acid is currently the most widely used B-lactamase inhibitor, and it is a competitive irreversible β-lactamase inhibitor. 6-aminopenicillanic acid (6-APA) is used as the starting material, and first undergoes a double bromination reaction with sodium nitrite and bromine in the presence of hydrobromic acid, and then is oxidized with potassium permanganate to obtain sulfone, and finally the sulfone is reduced and debrominated at low temperature and normal pressure (3±2°C) in the presence of zinc powder to prepare sulbactam acid.

[0003] Sulbactam sodium is a β-lactamase inhibitor that has a strong irreversible inhibitory effect on β-lactamases produced by Staphylococcus aureus and various Gram-negative bacteria. In particular, it has a strong inhibitory effect on type II, IV and V β-lactamases and is the only β-lactamase inhibitor with in vivo anti-Acinetobacter activity. Currently, sulbactam sodium is often produced by the reaction and crystallization of sulbactam acid and anhydrous sodium acetate.

[0004] During the production and storage of sulbactam acid and sulbactam salt, it was found that the impurity content of (2S)2-amino-3-methyl-3-sulfinylbutyric acid in sulbactam acid and sulbactam sodium products often increased due to improper operation during the production process or because the product was stored for too long. The existing regulations require that the impurity content of (2S)2-amino-3-methyl-3-sulfinylbutyric acid in sulbactam acid and sulbactam salt be less than 0.1%, that is, if the impurity content increases by more than 0.1%, it will eventually cause the product to fail to meet the quality standards, resulting in a decrease in the product qualification rate and an increase in costs.

[0005] However, in the current prior art, there is no specific method for treating the (2S)2-amino-3-methyl-3-sulfinylbutyric acid impurity in sulbactam derivatives. Summary of the invention

[0006] The object of the present invention is to provide a method for purifying sulbactam derivatives, specifically a method for treating (2S)2-amino-3-methyl-3-sulfinylbutyric acid impurities in sulbactam derivatives, thereby increasing the storage time and product qualification rate of sulbactam acid and sulbactam salts and reducing their production costs.

[0007] On the one hand, the present application provides a method for purifying a sulbactam derivative, the method comprising: adding an oxidant to a sulbactam derivative containing (2S)2-amino-3-methyl-3-sulfinylbutyric acid impurities for treatment, wherein the oxidant is selected from one or more of sodium hypochlorite, sodium chlorate, hydrogen peroxide, and perchloric acid.

[0008] Among them, the present application proves that the above method can effectively reduce the content of (2S)2-amino-3-methyl-3-sulfinylbutyric acid impurity in sulbactam derivatives, and the final (2S)2-amino-3-methyl-3-sulfinylbutyric acid impurity content in sulbactam derivatives is less than 0.1%.

[0009] Furthermore, the sulbactam derivatives include sulbactam acid and / or sulbactam salts; preferably, the sulbactam salts include sulbactam sodium.

[0010] Preferably, in terms of mass percentage, the content of (2S)2-amino-3-methyl-3-sulfinylbutyric acid in the sulbactam derivative containing the (2S)2-amino-3-methyl-3-sulfinylbutyric acid impurity is greater than 0.2%.

[0011] Furthermore, the oxidant is sodium hypochlorite.

[0012] Furthermore, the mass ratio of the sulbactam derivative to the oxidant is (23-24): (1-2).

[0013] Preferably, the sulbactam derivative is sulbactam acid, and the mass ratio of the sulbactam acid to the oxidant is 23.3:1.

[0014] Preferably, the sulbactam derivative is a sulbactam salt, and the mass ratio of the sulbactam salt to the oxidant is 24:1.

[0015] In a preferred embodiment, the sodium hypochlorite can be added dropwise in the form of a 5% sodium hypochlorite aqueous solution calculated by mass percentage.

[0016] Other oxidants, such as sodium chlorate, hydrogen peroxide, perchloric acid, and nitric acid, can also be added in the form of aqueous solution. Those skilled in the art can make an adaptive selection according to actual conditions.

[0017] Furthermore, the processing temperature of the method is -5°C-15°C, and the processing time is 10-30 minutes.

[0018] Preferably, the treatment temperature of the method is -5°C-15°C, and the treatment time is 15 minutes.

[0019] The sulbactam derivative is sulbactam acid, and the solvent is ethyl acetate and / or water; or,

[0020] The sulbactam derivative is sulbactam salt, and the solvent is water.

[0021] Furthermore, the method also includes the step of adding activated carbon.

[0022] Furthermore, the mass ratio of the sulbactam derivative to the activated carbon is 1:(0.01-0.04).

[0023] Preferably, the mass ratio of the sulbactam derivative to the activated carbon is 1:(0.028-0.034).

[0024] Furthermore, the method also includes a separation and purification step.

[0025] The present application also includes separation and purification steps, including but not limited to filtration, distillation, suction filtration, elution, drying, crystallization, etc.

[0026] In a preferred embodiment, a method for purifying sulbactam acid comprises the following steps:

[0027] Step 1: dissolving sulbactam acid containing (2S)2-amino-3-methyl-3-sulfinylbutyric acid impurity in ethyl acetate, adding water and dropping an oxidant, stirring at -5°C-15°C for 10-30 minutes, washing, and standing to separate into layers;

[0028] Step 2: Add activated carbon, stir, filter and purify.

[0029] The oxidant is selected from one or more of sodium hypochlorite, sodium chlorate, hydrogen peroxide, perchloric acid and nitric acid.

[0030] Preferably, anhydrous magnesium sulfate may be added in step 2 to achieve a drying effect.

[0031] In a preferred embodiment, a method for purifying sulbactam sodium comprises the following steps:

[0032] Step 1, dissolving sulbactam salt containing (2S)2-amino-3-methyl-3-sulfinylbutyric acid impurity in water, adding activated carbon, stirring and filtering;

[0033] Step 2: add oxidant dropwise at -5°C-15°C, stir for 10-30 min, add isopropanol, cool and crystallize, and purify.

[0034] The oxidant is selected from one or more of sodium hypochlorite, sodium chlorate, hydrogen peroxide, perchloric acid and nitric acid.

[0035] Furthermore, the present application found that in the crystallization process of sulbactam sodium, using isopropanol solvent resulted in large crystal size and good particle size.

[0036] On the other hand, the present application also provides a high-purity sulbactam derivative prepared by the above method, wherein the content of (2S)2-amino-3-methyl-3-sulfinylbutyric acid in the high-purity sulbactam derivative is less than 0.1% by mass.

[0037] On the other hand, the present application also provides the application of the above method in the preparation process of sulbactam derivatives.

[0038] The present invention has the following beneficial effects:

[0039] 1. This application provides for the first time a method for treating (2S)2-amino-3-methyl-3-sulfinylbutyric acid impurities in sulbactam derivatives. The final (2S)2-amino-3-methyl-3-sulfinylbutyric acid impurity content in sulbactam derivatives is less than 0.1%, which improves the storage time and product qualification rate of sulbactam acid and sulbactam salts and reduces their production costs.

[0040] 2. The impurity removal process of this application also includes an activated carbon treatment step, which can improve the whiteness and color of the product and provide a good foundation for the preparation of subsequent sulbactam-related products;

[0041] 3. The present application found that when isopropanol was used as a solvent during the crystallization of sulbactam sodium, the crystal size was larger and the particle size was better. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] The drawings described herein are used to provide a further understanding of the present application and constitute a part of the present application. The illustrative embodiments of the present application and their descriptions are used to explain the present application and do not constitute an improper limitation on the present application. In the drawings:

[0043] Figure 1 This is a liquid chromatogram of the sulbactam acid product before treatment in Example 1;

[0044] Figure 2 This is the liquid chromatogram of the sulbactam acid product after treatment in Example 1. DETAILED DESCRIPTION

[0045] In order to more clearly explain the overall concept of the present application, the following is described in detail in conjunction with the accompanying drawings of the specification by way of embodiment. In the following description, a large number of specific details are provided to provide a more thorough understanding of the present invention. However, it is obvious to those skilled in the art that the present invention can be implemented without one or more of these details. In other examples, in order to avoid confusion with the present invention, some technical features well known in the art are not described.

[0046] If no specific conditions are specified in the examples, the experiments were carried out according to conventional conditions or conditions recommended by the manufacturer.

[0047] Unless otherwise specified, in the following embodiments, the reagents or instruments used without indicating the manufacturer are all conventional products that can be purchased commercially.

[0048] Those skilled in the art will appreciate that water in the present application can be selected from purified water, deionized water, ultrapure water, etc.

[0049] Among them, the liquid chromatography determination method related to sulbactam derivatives includes the following contents:

[0050] Reagent solution: 6-aminopenicillanic acid reference substance, sulbactam sodium / sulbactam acid reference substance, chromatographic acetonitrile, potassium dihydrogen sulfate (analytical grade), 1 mol / L phosphoric acid solution

[0051] Chromatographic conditions:

[0052] UV detector Detection wavelength: 215nm Flow rate: 1.0ml / min Injection volume: 10uL

[0053] Chromatographic column: C18 4.6×250mm 5um Column temperature: 30℃

[0054] Mobile phase: buffered saline solution: acetonitrile = 98:2

[0055] Buffered saline solution: Weigh 5.44 g potassium dihydrogen phosphate into a beaker and dissolve it in 1000 mL purified water, stirring to mix evenly. Adjust the pH to 4.0 with 1 mol / L phosphoric acid solution.

[0056] Solution preparation:

[0057] (0.015→50) 6-aminopenicillanic acid solution: Accurately weigh 0.015 g of 6-aminopenicillanic acid into a 50 mL volumetric flask, dissolve it to volume with purified water, and shake well.

[0058] System suitability solution: Accurately weigh 20 mg of sulbactam sodium into a 50 mL volumetric flask, add 2 mL of water and 0.5 mL of 0.1 mol / L sodium hydroxide solution to dissolve, let stand at room temperature for 10 min, add 0.5 mL of 0.1 mol / L hydrochloric acid solution and 1 mL of 6-aminopenicillanic acid solution (0.015→50), dilute to volume with mobile phase, and shake well.

[0059] Reference solution: Take about 32 mg of sulbactam acid reference, weigh accurately, place in a 50 mL volumetric flask, add mobile phase to dissolve and dilute to the scale, and shake well.

[0060] Test solution: accurately weigh about 32 mg of sulbactam derivative test sample, place in a 50 mL volumetric flask, add mobile phase to dissolve and dilute to the scale, and shake well.

[0061] System suitability test:

[0062] After the machine is turned on and stabilized for 20 minutes, after the system is balanced, the samples are injected in sequence according to the injection sequence table 1, and the chromatogram is recorded. The separation between the sulbactam peak and the 6-aminopenicillanic acid peak is greater than 4.0; the RSD between the retention times of 5 injections of sulbactam acid is ≤2.0%, and the RSD between the peak areas is ≤2.0%; the number of theoretical plates is calculated based on the sulbactam acid peak ≥3500; the tailing factor of the sulbactam peak is ≤2.0; the recovery rate is 98.0%-102.0%.

[0063] Table 1

[0064] Serial number Solution name Number of injection needles Remark 1 (Blank) 1 blank solution 2 Sy 1 System Suitability Solutions 3 ST1 5 Reference solution 1 4 ST2 2 Reference solution 2 5 SP1 1 Test solution 1 6 SP2 1 Test solution 2

[0065] After the system suitability test is passed, the samples are tested in turn, the chromatograms are recorded, and the detection-related calculation methods are shown in the following formulas (1) and (2).

[0066]

[0067]

[0068] Where: f——content correction factor, mg / mL;

[0069] m st ——Weighing amount of reference substance, mg;

[0070] p——reference substance content, %;

[0071] A st ——Average peak area of ​​reference substance;

[0072] V st ——Dilution volume of reference substance, mL;

[0073] A st ——Peak area of ​​the test product;

[0074] m sp ——Weighing amount of test sample, mg.

[0075] Example 1

[0076] 1. Put 310g of ethyl acetate into a four-necked bottle, start stirring and add 17.5g of sulbactam acid ((2S)2-amino-3-methyl-3-sulfinylbutyric acid impurity content>0.2%, (2S)2-amino-3-methyl-3-sulfinylbutyric acid test results are as follows Figure 1 As shown, the impurity content of (2S) 2-amino-3-methyl-3-sulfinylbutyric acid is 0.22%), and stirred for 30 minutes until it is completely dissolved;

[0077] 2. Add 17.5g purified water, slowly drop 15g 5% sodium hypochlorite solution, -5℃-15℃, stir for 15min, then let stand for 15min to separate layers;

[0078] 3. Wash the organic phase after stratification twice with 17.5 g of purified water, stirring for 15 min each time and standing for 15 min to separate the layers;

[0079] 4. Add 0.5 g activated carbon and 4 g anhydrous magnesium sulfate to the washed organic phase, stir for 60 min and filter;

[0080] 5. The organic phase after decolorization and drying was distilled and concentrated, filtered, rinsed with 5 g of ethyl acetate, and vacuum dried for 2 h to obtain 11.3 g of sulbactam acid with a purity of 99.3%. The impurity content of (2S)2-amino-3-methyl-3-sulfinylbutyric acid was less than 0.04%, meeting the quality standard. The test results of (2S)2-amino-3-methyl-3-sulfinylbutyric acid after treatment were as follows: Figure 2 As shown, the content of (2S)2-amino-3-methyl-3-sulfinylbutyric acid impurity in the treated sample is 0.03%.

[0081] It can be seen that the method described in the present application can effectively reduce the content of (2S) 2-amino-3-methyl-3-sulfinylbutyric acid impurity in sulbactam derivatives.

[0082] Example 2

[0083] 1. Pour 310 g of ethyl acetate into a four-necked bottle, start stirring, add 17.5 g of sulbactam acid ((2S)2-amino-3-methyl-3-sulfinylbutyric acid impurity content>0.2%), and stir for 30 min until it is completely dissolved;

[0084] 2. Add 17.5g purified water, slowly drop 15g 5% sodium chlorate solution, at -5℃-15℃, stir for 10min, then let stand for 15min to separate layers;

[0085] 3. Wash the organic phase after stratification twice with 17.5 g of purified water, stirring for 15 min each time and standing for 15 min to separate the layers;

[0086] 4. Add 0.5 g activated carbon and 4 g anhydrous magnesium sulfate to the washed organic phase, stir for 60 min and filter;

[0087] 5. The decolorized and dried organic phase was concentrated by distillation, filtered, rinsed with 5 g of ethyl acetate, and dried in vacuo for 2 h to obtain 11.2 g of sulbactam acid with a purity of 99.1% and an impurity content of (2S)2-amino-3-methyl-3-sulfinylbutyric acid less than 0.05%, meeting the quality standard.

[0088] Example 3

[0089] 1. Pour 310 g of ethyl acetate into a four-necked bottle, start stirring, add 17.5 g of sulbactam acid ((2S)2-amino-3-methyl-3-sulfinylbutyric acid impurity content>0.2%), and stir for 30 min until it is completely dissolved;

[0090] 2. Add 17.5g purified water, slowly drop 15g 5% hydrogen peroxide solution, at -5℃-15℃, stir for 20min, then let stand for 15min to separate layers;

[0091] 3. Wash the organic phase after stratification twice with 17.5 g of purified water, stirring for 15 min each time and standing for 15 min to separate the layers;

[0092] 4. Add 0.5 g activated carbon and 4 g anhydrous magnesium sulfate to the washed organic phase, stir for 60 min and filter;

[0093] 5. The decolorized and dried organic phase was concentrated by distillation, filtered, rinsed with 5 g of ethyl acetate, and dried in vacuo for 2 h to obtain 11.2 g of sulbactam acid with a purity of 99.1% and an impurity content of (2S)2-amino-3-methyl-3-sulfinylbutyric acid less than 0.05%, meeting the quality standard.

[0094] Example 4

[0095] 1. Pour 310 g of ethyl acetate into a four-necked bottle, start stirring, add 17.5 g of sulbactam acid ((2S)2-amino-3-methyl-3-sulfinylbutyric acid impurity content>0.2%), and stir for 30 min until it is completely dissolved;

[0096] 2. Add 17.5g purified water, slowly drop 15g 5% perchloric acid solution, at -5℃-15℃, stir for 30min, then let stand for 15min to separate layers;

[0097] 3. Wash the organic phase after stratification twice with 17.5 g of purified water, stirring for 15 min each time and standing for 15 min to separate the layers;

[0098] 4. Add 0.5 g activated carbon and 4 g anhydrous magnesium sulfate to the washed organic phase, stir for 60 min and filter;

[0099] 5. The decolorized and dried organic phase was concentrated by distillation, filtered, rinsed with 5 g of ethyl acetate, and dried in vacuo for 2 h to obtain 11.5 g of sulbactam acid with a purity of 99.2%. The impurity content of (2S)2-amino-3-methyl-3-sulfinylbutyric acid was less than 0.07%, meeting the quality standard.

[0100] Comparative Example 1

[0101] The only difference between this comparative example and Example 1 is that no 5% sodium chlorate solution was added, and 11.3 g of sulbactam acid was obtained with a purity of 89.8% and an impurity content of (2S)2-amino-3-methyl-3-sulfinylbutyric acid of 0.32%, which did not meet the quality standard.

[0102] Example 5

[0103] 1. Add 25 g of purified water into a four-necked bottle, start stirring, then add 15 g of sulbactam sodium, the (2S) 2-amino-3-methyl-3-sulfinylbutyric acid impurity content of which is 0.15%, and stir for 30 min until it is completely dissolved;

[0104] 2. Add 0.5g activated carbon, stir for 60min and filter;

[0105] 3. After filtering the material, add 12.5 g of 5% sodium hypochlorite solution to the filtrate at -5°C-15°C and stir for 15 minutes;

[0106] 4. Add 375 g of isopropanol to the treated liquid, slowly cool to 0°C-5°C, grow crystals for 1 hour, filter, rinse with 5 g of isopropanol, and vacuum dry for 12 hours to obtain 12.9 g of sulbactam sodium with a purity of 89.8%. The impurity content of (2S)2-amino-3-methyl-3-sulfinylbutyric acid is less than 0.03%, which meets the quality standards.

[0107] Comparative Example 2

[0108] The difference between this comparative example and Example 5 is that no 5% sodium chlorate solution is added dropwise, and 12.6 g of sulbactam sodium is obtained with a purity of 89.2% and an impurity content of (2S)2-amino-3-methyl-3-sulfinylbutyric acid of 0.3%, which does not meet the quality standard.

[0109] The above is only an embodiment of the present application and is not intended to limit the present application. For those skilled in the art, the present application may have various changes and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application should be included in the scope of the claims of the present application.

Claims

1. A method for purifying a sulbactam derivative, characterized in that: The method comprises: adding an oxidant to a sulbactam derivative containing (2S)2-amino-3-methyl-3-sulfinylbutyric acid as an impurity, the treatment temperature is -5°C to 15°C, the treatment time is 10 to 30 min, and the method comprises a separation and purification step; The mass ratio of the sulbactam derivative to the oxidant is (23-24): (1-2); The sulbactam derivative is sulbactam acid and / or sulbactam salt, and the sulbactam salt is sulbactam sodium; The oxidant is selected from one or more of sodium hypochlorite, sodium chlorate, hydrogen peroxide and perchloric acid.

2. The method according to claim 1, characterized in that The oxidant is sodium hypochlorite.

3. The method according to claim 1, characterized in that The method comprises the step of adding activated carbon.

4. The method according to claim 3, characterized in that The mass ratio of the sulbactam derivative to the activated carbon is 1:(0.01-0.04).

5. Use of the method according to any one of claims 1 to 4 in the preparation of sulbactam derivatives, characterized in that: The sulbactam derivative is sulbactam acid and / or sulbactam salt, and the sulbactam salt is sulbactam sodium.

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