A method for refining an avibactam sodium intermediate

Abstract

The present application discloses a method for refining an avibactam sodium intermediate 1, which comprises the step of refining a crude avibactam sodium intermediate 1 in a good solvent dichloromethane and a poor solvent methyl tert-butyl ether system to obtain a high-purity avibactam sodium intermediate 1. The refining method provided in the present application can effectively reduce the content of isomeric impurities A and open-loop impurities B, and improve the purity. The total purity of the refined avibactam sodium intermediate 1 is greater than 99.9%, the isomeric impurities A and the open-loop impurities B are less than 0.05%, and the other individual impurities are less than 0.10%. The reagents are conventionally available, the operation is simple and safe, and it is very suitable for industrial scale-up under conventional production conditions.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug synthesis, and specifically relates to a method for purifying an avibactam sodium intermediate 1(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide, and in particular to a method for reducing the content of isomeric impurity A and / or open-ring impurity B in the avibactam sodium intermediate 1. Background Art

[0002] Avibactam sodium is a new type of non-β-lactam structure β-lactamase inhibitor developed by Novexel. Avibactam sodium belongs to the diazabicyclooctanone compound, which does not have obvious antibacterial activity itself, but works by inhibiting β-lactamase. Avibactam sodium can inhibit type A (including ESBL and KPC), some type C and some type D β-lactamases. Therefore, when used in combination with penicillin, cephalosporin and carbapenem antibiotics, it has broad-spectrum antibacterial activity, especially against Escherichia coli and Klebsiella pneumoniae containing ultra-extended-spectrum β-lactamases, Escherichia coli containing excessive AmpC enzymes, and Escherichia coli containing both AmpC and ultra-extended-spectrum β-lactamases. Avibactam sodium is a reversible enzyme inhibitor, and its own structure can be restored by reverse reaction, so it has a long-term enzyme inhibitory effect. In addition, avibactam sodium itself does not have a β-lactam structure and will not induce the production of β-lactamases. Therefore, avibactam sodium is a highly promising new β-lactamase inhibitor that can effectively alleviate the problem of antibiotic resistance. On February 27, 2015, Allergan's Avycaz (avibactam sodium + ceftazidime) was approved by the FDA for marketing. The dosage form is injection, and the indications are complicated intra-abdominal infections, complicated urinary tract infections (cUTI), kidney infections (pyelonephritis) and Gram-negative bacterial infections in adults. On June 29, 2016, AstraZeneca's Zavicefta (avibactam sodium + ceftazidime) was approved by the EMA. On May 21, 2019, Pfizer's Zavicefta (avibactam sodium + ceftazidime) was approved for marketing in China. The combination of avibactam sodium with ceftaroline and aztreonam is also under clinical research.

[0003] Avibactam sodium has a diazabicyclooctane skeleton, which is different from the structure of classic β-lactamase inhibitors. Its own structure can be restored by reverse reaction and has a long-lasting inhibitory effect on enzymes. In addition, classic β-lactamase inhibitors have no or weak inhibitory effect on class C enzymes, but avibactam sodium has a significant inhibitory effect on class C enzymes and a wider enzyme inhibition spectrum. Avibactam sodium is used clinically in the form of its sodium salt. Its chemical name is mono[(1R,2S,5R)-2-aminocarbonyl-7-oxo-1,6-azabicyclo[3.2.1]octan-6-yl sulfate sodium salt, and its specific structure is as follows:

[0004]

[0005] Regarding the synthesis of avibactam sodium, there are many literature reports, and there are two types of preparation routes according to the cyclization strategy: 1) first cyclic ureidation followed by amidation (CN102834395A, CN103649051A, CN103328476A, CN106279163A, CN106565712A, US9284273, US9567335), 2) first amidation followed by cyclic ureidation (CN103649051A, CN105294690A), see the following routes.

[0006]

[0007] Both routes involve the preparation of the key avibactam sodium intermediate 1 (2S, 5R) -6-benzyloxy-7-oxo-1,6-diazabicyclo [3.2.1] octane-2-carboxamide. Since the subsequent transformation of the ester functional group of the starting material involves alkaline conditions, isomerization occurs, and the main isomeric impurity A will be produced in the process of preparing intermediate 1. It has similar structural properties to intermediate 1, and is difficult to purify. It is easy for impurities to be transferred to the raw material drug later, affecting drug safety. In addition, since the bridge ring structure is unstable under acidic and alkaline conditions, open-ring impurities with high polarity will also be produced. At present, there are very few reports on the purification of intermediate 1 in public literature. The purification method disclosed in patent CN103649051A requires purification with an unconventional solvent chlorobutane. The removal of impurities with structures similar to avibactam sodium intermediate 1 is limited, and high purity cannot be guaranteed.

[0008] In order to ensure the safety of subsequent preparations and clinical medication, it is necessary to strictly control the individual impurities in the avibactam sodium intermediate 1 to avoid impurities remaining or being transferred to the raw material drug, preferably controlled below 0.10%, which is impossible to achieve with the existing conventional purification process. Therefore, it is necessary to develop a new refining method to reduce the impurity content in the avibactam sodium intermediate 1, especially for the structurally similar isomeric impurities A and open-ring impurities B, to obtain a high-purity avibactam sodium intermediate 1, thereby meeting the quality requirements of drug development. Summary of the invention

[0009] In view of the above problems, the purpose of the present application is to provide a method for refining an avibactam sodium intermediate 1. The refining method provided in the present application can effectively reduce the content of impurities in the avibactam sodium intermediate 1, especially reduce the content of structurally similar isomeric impurities A and open-ring impurities B, and improve the purity of the product.

[0010] Avibactam sodium intermediate 1 produces isomeric impurity A during the preparation process. In addition, there is also a ring-opening impurity B, the structural formula of which is shown below. The chemical name of impurity A is: (2R,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; the chemical name of impurity B is: (2R,5R)-5-((benzyloxy)amino)piperidine-2-carboxamide.

[0011]

[0012] In a first aspect, the present application provides a method for refining an avibactam sodium intermediate 1, comprising the following steps:

[0013] Step (1): Add dichloromethane, a good solvent, to the crude product of avibactam sodium intermediate 1, and stir and heat;

[0014] Step (2): adding poor solvent methyl tert-butyl ether, cooling to crystallize, stirring, filtering, washing with methyl tert-butyl ether, and drying to obtain avibactam sodium intermediate 1.

[0015] The "crude product" of the avibactam sodium intermediate 1 described in this application is relative to the refined product, including but not limited to samples of the avibactam sodium intermediate 1 with a purity lower than 99.5%, or samples with a purity lower than 99.0%, or samples with a purity lower than 98.0%, etc.

[0016] In some embodiments, in the purification method of the above-mentioned avibactam sodium intermediate 1 of the present application, the mass volume ratio of the avibactam sodium intermediate 1 in step (1) as a pure product to dichloromethane, in grams per milliliter, is 1:2 to 1:15; preferably 1:3 to 1:5, and more preferably 1:4 to 1:5.

[0017] In some embodiments, in the purification method of the above-mentioned avibactam sodium intermediate 1 of the present application, the heating temperature in step (1) is in the range of 30 to 55°C, preferably 35 to 45°C.

[0018] In some embodiments, in the method for purifying the above-mentioned avibactam sodium intermediate 1 of the present application, in the step (2), the mass volume ratio of the avibactam sodium intermediate 1, calculated as a pure product, to the added methyl tert-butyl ether, calculated as g / ml, is 1:5 to 1:30; preferably 1:8 to 1:15; more preferably 1:10 to 1:13.

[0019] In some embodiments, in the purification method of the above-mentioned avibactam sodium intermediate 1 of the present application, in the step (2), the cooling and crystallization temperature is -20 to 30°C; preferably -10 to 0°C.

[0020] In some embodiments, in the purification method of the above-mentioned avibactam sodium intermediate 1 of the present application, the mass volume ratio of the avibactam sodium intermediate 1, calculated as a pure product, to the washed methyl tert-butyl ether, calculated as g / ml, is 1:1 to 1:5, preferably 1:1 to 1:2.

[0021] Preferably, the purification method of the avibactam sodium intermediate 1 described in the present application is mainly used to reduce the content of the isomeric impurity A and / or the open-ring impurity B in the avibactam sodium intermediate 1.

[0022] The “content” refers to the mass percentage (w / w) of the isomeric impurity A or the open-ring impurity B in the total amount of the avibactam sodium intermediate 1.

[0023] In a second aspect, the present application also provides an avibactam sodium intermediate 1 prepared by the above-mentioned purification method, wherein the total purity of the avibactam sodium intermediate 1 is not less than 99.9%, the content of the isomeric impurity A in the avibactam sodium intermediate 1 is less than 0.05%, and the content of the open-ring impurity B is less than 0.05%.

[0024] Preferably, in the avibactam sodium intermediate 1 prepared by the above purification method provided in the present application, the content of other single impurities is less than 0.10%; preferably less than 0.05%; more preferably less than 0.03%.

[0025] In a third aspect, the present application provides a method for reducing the content of isomeric impurity A and / or impurity B in avibactam sodium intermediate 1, comprising the following steps:

[0026] Step (1): Add dichloromethane, a good solvent, to the crude product of avibactam sodium intermediate 1, and stir and heat;

[0027] Step (2): adding poor solvent methyl tert-butyl ether, cooling to crystallize, stirring, filtering, washing with methyl tert-butyl ether, and drying to obtain avibactam sodium intermediate 1.

[0028] In the method for reducing the content of isomeric impurity A and / or impurity B in the avibactam sodium intermediate 1 of the present application, in the steps (1) to (2), the poor solvent can be added in a conventional manner in the art, preferably in a dropwise manner.

[0029] In some embodiments, in the method for reducing the content of isomeric impurity A and / or impurity B in avibactam sodium intermediate 1 provided in the present application, the mass volume ratio of avibactam sodium intermediate 1 in step (1) as pure product to dichloromethane, in grams per milliliter, is 1:2 to 1:15; preferably 1:3 to 1:5; more preferably 1:4 to 1:5.

[0030] In some embodiments, in the method for reducing the content of isomeric impurity A and / or impurity B in avibactam sodium intermediate 1 provided in the present application, the heating temperature range is 30 to 55°C; preferably 35 to 45°C.

[0031] In some embodiments, in the method for reducing the content of isomeric impurity A and / or impurity B in avibactam sodium intermediate 1 provided in the present application, in the step (2), the mass volume ratio of avibactam sodium intermediate 1, calculated as pure product, to the added methyl tert-butyl ether, calculated as g / ml, is 1:5 to 1:30; preferably 1:8 to 1:15; more preferably 1:10 to 1:13.

[0032] In some embodiments, in the method for reducing the content of isomeric impurity A and / or impurity B in avibactam sodium intermediate 1 provided in the present application, the cooling and crystallization temperature is -20 to 30°C; preferably -10 to 0°C.

[0033] In some embodiments, in the method for reducing the content of isomeric impurity A and open-ring impurity B in avibactam sodium intermediate 1, the mass volume ratio of avibactam sodium intermediate 1, calculated as pure product, to washed methyl tert-butyl ether, in grams per milliliter, is 1:1 to 1:5; preferably 1:1 to 1:2.

[0034] The "good solvent" and "poor solvent" described in this application are relative to the solute to be dissolved. A "good solvent" is a solvent with a strong solubility for the solute and an interaction parameter χ with the solute of less than 0.5; on the contrary, a "poor solvent" is a solvent with a weak solubility for the solute and an interaction parameter χ with the solute of greater than 0.5. For different solutes, the "good solvent" or "poor solvent" is different. A "good solvent" used for one solute may be a "poor solvent" for another solute; a "poor solvent" used for one solute may be a "good solvent" for another solute. For example, in this application, the "poor solvent" methyl tert-butyl ether used for the avibactam sodium intermediate is a "good solvent" for the solute benzene. The "good solvent" and "poor solvent" in this application are both relative to the avibactam sodium intermediate 1 described in this application. DETAILED DESCRIPTION

[0035] The invention of the present application is further explained below through specific examples, but it should not be understood that the scope of the present application is limited to the following examples. According to the inventive ideas and the full content of the present application, the raw materials, solvents, reagents, operating steps, reaction conditions, etc. in the following examples can be appropriately combined / replaced / adjusted / modified, which is obvious to those skilled in the art and still falls within the scope of protection of the present application.

[0036] In the following examples, as well as in the specification and claims of this application, the following abbreviations have the following meanings, and for undefined abbreviations, they have generally recognized meanings.

[0037] HPLC = High Performance Liquid Chromatography

[0038] Experimental conditions:

[0039] The purity of this product was determined by HPLC, and the calculation method was: area normalization method.

[0040] The chromatographic column is C 18 Chromatographic column; detection wavelength 210nm; flow rate 1.0ml / min;

[0041] Mobile phase A: 0.1% phosphoric acid solution (1 ml of phosphoric acid was added to 1000 ml of water and the pH was adjusted to 4.0 with concentrated ammonia)-acetonitrile (90:10);

[0042] Mobile phase B: 0.1% phosphoric acid solution (1 ml of phosphoric acid was added to 1000 ml of water and the pH was adjusted to 4.0 with concentrated ammonia)-acetonitrile (20:80);

[0043] The gradient elution program was:

[0044] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 95 5 15 90 10 50 40 60 55 40 60 56 95 5 60 95 5

[0045] Preparation Example 1: Preparation of crude product of avibactam sodium intermediate 1:

[0046] The crude product of avibactam sodium intermediate 1 was prepared by referring to the method disclosed in Example 3c of patent document CN201280029765.7 (page 30 of the specification).

[0047] The obtained crude avibactam sodium intermediate 1 was subjected to HPLC purity test, and its total purity was 88.37%, the impurity A content was 2.33%, the impurity B content was 0.66%, and the total impurity content was 11.63%, as shown in Table 1. The obtained avibactam sodium intermediate 1 was used as a crude avibactam sodium intermediate 1 in the following examples or test examples.

[0048] Table 1 HPLC test results of crude product of avibactam sodium intermediate 1

[0049]

[0050]

[0051] Example 1: Purification of Avibactam Sodium Intermediate 1

[0052] Step (1): Take 20 g of the crude product of avibactam sodium intermediate 1 (based on the pure product of avibactam sodium intermediate 1), add 60 mL of dichloromethane, and heat to 35-45° C. while stirring;

[0053] Step (2): add 180 mL of methyl tert-butyl ether dropwise for 0.5 to 1 h, solid precipitates, cool to -10 to 0°C, stir for 1 to 2 h, filter, wash with 20 mL of methyl tert-butyl ether, and dry to obtain 19.0 g of avibactam sodium intermediate 1 (yield 95%).

[0054] The refined avibactam sodium obtained in this example was tested by HPLC, and the experimental data are shown in Table 2. The total purity was 99.92%, impurity A was not detected, the impurity B content was 0.011%, and the contents of other individual impurities were all less than 0.03%, meeting the pharmaceutical requirement of less than 0.10%.

[0055] Table 2 HPLC test results of the refined product of Avibactam Sodium Intermediate 1 obtained in Example 1

[0056] Serial number Retention time (min) Peak area (mAU*s) Peak area (%) Impurity No. 1 2.154 1.15566 0.0054 / 2 3.085 2.41909 0.0113 Open ring impurity B 3 3.455 1.34051 0.0063 / 4 5.250 2.24009 0.0105 / 5 10.218 6.01726 0.0281 / 6 10.863 3.04699 0.0142 / 7 16.846 21367.63725 99.9154 Avibactam Sodium Intermediate 1 8 38.521 1.86882 0.0087 /

[0057] Experimental Examples 1-1 to 1-6: Investigation of Purification Conditions of Avibactam Sodium Intermediate 1

[0058] According to the method of Example 1, the amount of dichloromethane used in step (1) of the refining process and the amount of methyl tert-butyl ether used in the crystallization process of step (2) were investigated, the crude product of avibactam sodium intermediate 1 (based on the pure product of avibactam sodium intermediate 1) was 20 g, and the remaining steps and conditions were the same as in Example 1. The investigation conditions and results are shown in Table 3 below.

[0059] Table 3 Results of investigation on the dosage of good solvent and poor solvent

[0060]

[0061] From the results of the above table, it can be seen that when the good solvent dichloromethane is not used in the refining process and only the poor solvent methyl tert-butyl ether is used (Test Example 1-1), the substrate cannot be dissolved, the purpose of reducing impurities cannot be achieved, and the product contains a large number of single impurities with a content greater than 0.1%, and the content of impurity A is as high as 1.82%, which cannot meet the requirements of pharmaceutical research;

[0062] When the mass volume ratio (g / ml) of the crude intermediate 1 of avibactam sodium to dichloromethane was 1:1, and the mass volume ratio (g / ml) of the crude intermediate 1 to methyl tert-butyl ether was 1:4 (Test Example 1-2), the impurity control was improved, but there were still two single impurities with a content greater than 0.1%;

[0063] When the mass volume ratio (g / ml) of the crude intermediate 1 of avibactam sodium to dichloromethane is 1:20, and the mass volume ratio (g / ml) of the crude intermediate 1 to methyl tert-butyl ether is 1:40 (Test Examples 1-3), the impurities are effectively controlled, but the product yield is low, only 75%, and the amount of solvent used is large, which is not conducive to cost control.

[0064] According to the method and material dosage of Example 1, the heating dissolution temperature of step (1) and the cooling crystallization temperature of step (2) in the refining process were investigated. The investigation conditions and results are shown in Table 4 below:

[0065] Table 4 Temperature investigation results

[0066]

[0067] As can be seen from the above table, the temperature of the heated dissolution material in Test Example 1-4 is relatively low, which affects the purity of the product, the content of impurity A reaches 0.52%, and there are 3 individual impurities with a content greater than 0.1% in the product; Test Example 1-5 and Example 1-6 both achieve effective control of impurities, but the crystallization temperature of Example 1-6 is relatively high and the yield is slightly low.

[0068] Example 2: Purification of Avibactam Sodium Intermediate 1

[0069] Step (1): Take 20 g of the crude product of avibactam sodium intermediate 1 (based on the pure product of avibactam sodium intermediate 1), add 80 mL of dichloromethane, and heat to 35-45° C. while stirring;

[0070] Step (2): add 200 mL of methyl tert-butyl ether dropwise for 1 to 1.5 h, solid precipitates, cool to -10 to 0°C, stir for 1 to 2 h, filter, wash with 40 mL of methyl tert-butyl ether, and dry to obtain 18.6 g of avibactam sodium intermediate 1 (yield 93%).

[0071] The refined avibactam sodium obtained in this example was tested by HPLC, and the experimental data are shown in Table 5. The total purity was 99.97%, the content of impurity A was 0.017%, the content of impurity B was 0.0095%, and other single impurities were not detected.

[0072] Table 5 HPLC test results of the refined product of Avibactam Sodium Intermediate 1 obtained in Example 2

[0073] Serial number Retention time (min) Peak area (mAU*s) Peak area (%) Impurity No. 1 3.565 2.05008 0.0095 Open ring impurity B 2 17.406 3.65267 0.0169 Isomer Impurity A 3 18.316 21651.22337 99.9737 Avibactam Sodium Intermediate 1

[0074] Example 3: Purification of Avibactam Sodium Intermediate 1

[0075] Step (1): Take 20 g of the crude product of avibactam sodium intermediate 1 (based on the pure product of avibactam sodium intermediate 1), add 100 mL of dichloromethane, and heat to 35-45° C. while stirring;

[0076] Step (2): add 260 mL of methyl tert-butyl ether dropwise for 1 to 1.5 h, solid precipitates, cool to -10 to 0°C, stir for 1 to 2 h, filter, wash with 20 mL of methyl tert-butyl ether, and dry to obtain 18.4 g of avibactam sodium intermediate 1 (yield 92%).

[0077] The refined product of avibactam sodium intermediate 1 obtained in this example was tested by HPLC, and the experimental data are shown in Table 6. The total purity was 99.94%, impurity A was not detected, the content of impurity B was 0.015%, and the other single impurities were less than 0.03%, which met the pharmaceutical requirement of less than 0.10%.

[0078] Table 6 HPLC test results of the refined product of Avibactam Sodium Intermediate 1 obtained in Example 3

[0079] Serial number Retention time (min) Peak area (mAU*s) Peak area (%) Impurity No. 1 3.443 3.01199 0.0150 Open ring impurity B 2 17.933 20021.28143 99.9425 Avibactam Sodium Intermediate 1 3 31.785 4.01236 0.0200 / 4 37.306 4.50376 0.0225 /

[0080] Comparative Example 1: Refining of Avibactam Sodium Intermediate 1

[0081] 20 g of crude avibactam sodium intermediate 1 (based on pure avibactam sodium intermediate 1) was dissolved in 200 ml of dichloromethane solution and concentrated at an external bath temperature of 40°C until no obvious fraction was found. Then 30 ml of chlorobutane was added and the solution was concentrated at an external bath temperature of 40°C until about 25 ml remained. Solid precipitated and the solution was cooled to 0°C for crystallization. 14.0 g of avibactam sodium was obtained by suction filtration with a yield of 70%.

[0082] The refined product of the intermediate 1 of avibactam sodium of Comparative Example 1 was tested by HPLC, and the experimental data are shown in Table 7. The total purity was 97.19%, the content of impurity A was 1.00%, and the content of impurity B was 0.36%.

[0083] Table 7 HPLC test results of refined product of Avibactam Sodium Intermediate 1 obtained in Comparative Example 1

[0084] Serial number Retention time (min) Peak area (mAU*s) Peak area (%) Impurity No. 1 0.990 22.59331 0.0952 / 2 3.162 85.79259 0.3613 Open ring impurity B 3 3.425 116.68029 0.4914 / 4 5.155 8.95934 0.0377 / 5 10.002 10.33919 0.0435 / 6 15.284 237.77730 1.0015 Isomer Impurity A 7 16.184 23075.64815 97.1906 Avibactam Sodium Intermediate 1 8 17.061 15.84640 0.0667 / 9 25.757 15.6683 0.0660 / 10 26.376 32.29909 0.1360 / 11 36.798 3.50170 0.0147 / 12 37.269 10.61468 0.0447 / 13 38.859 96.30332 0.4056 / 14 40.242 6.66670 0.0281 / 15 41.751 3.97886 0.0168 /

[0085] The HPLC test results of the crude product of Avibactam Sodium Intermediate 1, the sample of Example 1 and the sample of Comparative Example 1 are summarized in Table 8.

[0086] Table 8 HPLC determination of examples and comparative examples

[0087]

[0088]

[0089] As can be seen from Table 8, the technical solution provided by the present application can effectively reduce the content of isomeric impurity A and open-ring impurity B in the intermediate 1 of avibactam sodium, both of which can be controlled below 0.05%, further improving the purity of the product, with a total purity of not less than 99.9%, providing a guarantee for the safety of subsequent preparations and clinical medication. In addition, the refining system is simple, overcomes the use of unconventional purification reagents, has mild conditions, and is low in cost, making it very suitable for large-scale socialized production.

Claims

1. A method for refining an avibactam sodium intermediate 1, characterized in that: The following steps are involved: Step (1): Add dichloromethane, a good solvent, to the crude product of avibactam sodium intermediate 1, and stir and heat; Step (2): adding poor solvent methyl tert-butyl ether, cooling and crystallizing, stirring, filtering, washing with methyl tert-butyl ether, and drying to obtain avibactam sodium intermediate 1; The structure of the avibactam sodium intermediate 1 is as follows: In the step (1), the mass volume ratio of the avibactam sodium intermediate 1, calculated as pure product, to dichloromethane is calculated in grams per milliliter: 1:2~1:15; The heating temperature range in step (1) is 30 to 55° C. In the step (2), the mass volume ratio of the avibactam sodium intermediate 1 as pure product to the added methyl tert-butyl ether is: In g / ml, it is 1:5 to 1:30; The cooling and crystallization temperature in step (2) is -20 to 0°C.

2. The method for refining the avibactam sodium intermediate 1 according to claim 1, characterized in that: In the step (1), the mass volume ratio of the avibactam sodium intermediate 1, calculated as pure product, to dichloromethane, calculated as g / ml, is 1:3 to 1:

5.

3. The method for refining the avibactam sodium intermediate 1 according to claim 1 or 2, characterized in that: The heating temperature range in step (1) is 35 to 45°C.

4. The method for refining the avibactam sodium intermediate 1 according to claim 1, characterized in that: In the step (2), the mass volume ratio of the pure avibactam sodium intermediate 1 to the added methyl tert-butyl ether is 1:8 to 1:15 in g / ml.

5. The method for refining the avibactam sodium intermediate 1 according to claim 1, characterized in that: The cooling and crystallization temperature in step (2) is -10 to 0°C.

6. The method for refining the avibactam sodium intermediate 1 according to claim 1 or 5, characterized in that: The mass volume ratio of the avibactam sodium intermediate 1 in step (2) as pure product to the washed methyl tert-butyl ether is 1:1 to 1:5 in g / ml.

7. The method for refining the avibactam sodium intermediate 1 according to claim 6, characterized in that: The mass volume ratio of the avibactam sodium intermediate 1 in step (2) as pure product to the washed methyl tert-butyl ether is 1:1 to 1:2 in g / ml.

8. The method for purifying the avibactam sodium intermediate 1 according to any one of claims 1 to 2, 4 to 5 and 7, characterized in that: The method is used to reduce the content of isomeric impurity A and / or impurity B in an avibactam sodium intermediate 1.

9. A method for reducing the content of isomeric impurity A and / or impurity B in an avibactam sodium intermediate 1, characterized in that: The following steps are involved: Step (1): Add dichloromethane, a good solvent, to the crude product of avibactam sodium intermediate 1, and stir and heat; Step (2): adding poor solvent methyl tert-butyl ether, cooling and crystallizing, stirring, filtering, washing with methyl tert-butyl ether, and drying to obtain avibactam sodium intermediate 1; The structure of the avibactam sodium intermediate 1 is as follows: In the step (1), the mass volume ratio of the avibactam sodium intermediate 1, calculated as pure product, to dichloromethane, calculated as g / ml, is 1:2 to 1:15; The heating temperature range in step (1) is 30 to 55° C. In the step (2), the mass volume ratio of the avibactam sodium intermediate 1, calculated as pure product, to the added methyl tert-butyl ether, calculated as g / ml, is 1:5 to 1:30; The cooling and crystallization temperature in step (2) is -20 to 0°C.

10. The method for reducing the content of isomeric impurity A or impurity B in the avibactam sodium intermediate 1 according to claim 9, characterized in that: In the step (1), the mass volume ratio of the avibactam sodium intermediate 1, calculated as pure product, to dichloromethane, calculated in g / ml, is 1:3 to 1:5; the heating temperature range is 35 to 45°C; or, In the step (2), the mass volume ratio of the avibactam sodium intermediate 1, calculated as pure product, to the added methyl tert-butyl ether, calculated as g / ml, is 1:8 to 1:15; the cooling and crystallization temperature is -10 to 0°C; or, The mass volume ratio of the avibactam sodium intermediate 1 to the washed methyl tert-butyl ether is 1:1 to 1:5 in g / ml.

11. The method for reducing the content of isomeric impurity A or impurity B in the avibactam sodium intermediate 1 according to claim 9 or 10, characterized in that: The mass volume ratio of the avibactam sodium intermediate 1 to the washed methyl tert-butyl ether is 1:1 to 1:2 in g / ml.

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