Purification method for avibactam sodium intermediate and avibactam sodium intermediate

Abstract

A purification method for an Avibactam sodium intermediate and an Avibactam sodium intermediate. The purification method comprises: dissolving an Avibactam sodium intermediate containing an isomer impurity compound into an acetone solution; then adding an ethyl acetate solution into the obtained mixed solution, and performing stirring to obtain a precipitate; and finally, filtering the precipitate, washing the precipitate with an ethyl acetate solution, and then performing vacuum drying treatment to obtain a purified Avibactam sodium intermediate. According to the method, the content of the isomer impurity compound in the Avibactam sodium intermediate can be effectively reduced; in addition, by removing the isomer impurity compound in the Avibactam sodium intermediate or controlling the content of said isomer impurity compound, finally, isomer impurities in Avibactam sodium can be well controlled.

Description

A purification method for an avibactam sodium intermediate and an avibactam sodium intermediate Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a purification method of an avibactam sodium intermediate and the avibactam sodium intermediate. Background Art

[0002] Avibactam sodium, an intermediate for avibactam sodium, is a novel β-lactamase inhibitor with a non-β-lactam structure developed by Novexel. Avibactam sodium is a diazobicyclooctanone compound that lacks significant antibacterial activity on its own, but instead works by inhibiting β-lactamases. Avibactam is more potent and has a broader range of activity than the three previously marketed β-lactamase inhibitors—clavulanic acid, sulbactam, and tazobactam—with significant inhibition against Class A, Class C, and some Class D β-lactamases. On February 27, 2015, Allergan's Avycaz (avibactam sodium intermediate plus ceftazidime) received FDA approval for the treatment of complicated intra-abdominal infections (cIAI) and complicated urinary tract infections (cUTI). On June 29, 2016, AstraZeneca's Zavicefta (avibactam sodium intermediate plus ceftazidime) received EMA approval. On May 21, 2019, Pfizer's Zavicefta (avibactam sodium intermediate + ceftazidime) was approved for marketing in China.

[0003] Regarding the synthesis of compound (8) (avibactam sodium), there are two main preparation routes:

[0004] 1) Cyclization followed by amidation;

[0005] 2) Amidation followed by cyclization;

[0006] Two synthetic routes are as follows:

[0007]

[0008] In the two aforementioned routes, compound (1) is a key intermediate for the preparation of compound (8) (avibactam sodium). Compound (1) is a chiral compound, and the main impurity of compound (1) is its isomer compound (2). According to the following synthetic route, compound (2) will synthesize the isomer impurity compound (9) of compound (8):

[0009]

[0010] In order to ensure the high purity of compound (8), it is necessary to control the content of compound (2) in the synthesis route of compound (1). Summary of the Invention

[0011] Based on this, the present invention provides a method for purifying an avibactam sodium intermediate and an avibactam sodium intermediate, aiming to solve the problem in the prior art that compound (2) cannot be removed well, resulting in a high level of isomeric impurities in the avibactam sodium intermediate.

[0012] A first aspect of the embodiments of the present invention provides a method for purifying an avibactam sodium intermediate, comprising the following steps:

[0013] Step 1: dissolving an avibactam sodium intermediate containing an isomeric impurity compound in an acetone solution, wherein the chemical formula of the avibactam sodium intermediate is:

[0014]

[0015] The chemical formula of the isomeric impurity compound is:

[0016] ;

[0017] Step 2: adding ethyl acetate solution to the mixed solution obtained in step 1 and stirring to obtain a precipitate;

[0018] Step 3: Filter the precipitate obtained in step 2, wash it with ethyl acetate solution, and then perform vacuum drying to obtain a purified avibactam sodium intermediate.

[0019] Furthermore, in the step of dissolving the avibactam sodium intermediate containing isomeric impurity compounds in an acetone solution, 3.5 ml to 5 ml of acetone solution is required for each 1 g of the avibactam sodium intermediate containing isomeric impurity compounds added.

[0020] Furthermore, in the step of adding the ethyl acetate solution to the mixed solution obtained in step 1 and stirring to obtain a precipitate, 4 ml to 6 ml of ethyl acetate solution is required for every 1 g of the avibactam sodium intermediate containing isomer impurity compounds.

[0021] Furthermore, in the step of dissolving the avibactam sodium intermediate containing isomer impurity compounds in an acetone solution, stirring is performed at 25° C. to 30° C. to obtain a clear mixed solution.

[0022] Furthermore, in the step of adding the ethyl acetate solution to the mixed solution obtained in step 1 and stirring to obtain a precipitate, the mixture is stirred at 25° C. to 30° C. for 2 h to 10 h to obtain a precipitate.

[0023] Furthermore, in the step of filtering the precipitate obtained in step 2, washing it with ethyl acetate solution, and then performing vacuum drying to obtain the purified avibactam sodium intermediate, the vacuum drying is performed at 40° C. to 45° C.

[0024] Furthermore, in the step of filtering the precipitate obtained in step 2, washing it with ethyl acetate solution, and then performing vacuum drying to obtain the purified avibactam sodium intermediate, the precipitate is filtered at 25° C. to 30° C.

[0025] A second aspect of the embodiments of the present invention provides an avibactam sodium intermediate, which is prepared by the above-mentioned purification method of the avibactam sodium intermediate, and the content of the avibactam sodium intermediate is 99.88%.

[0026] Compared with the prior art, the present invention has the following beneficial effects:

[0027] The method comprises dissolving an avibactam sodium intermediate containing isomeric impurity compounds in an acetone solution, adding an ethyl acetate solution to the obtained mixed solution, and stirring to obtain a precipitate. Finally, the precipitate is filtered, washed with an ethyl acetate solution, and then vacuum-dried to obtain a purified avibactam sodium intermediate. The method can effectively reduce the content of the isomeric impurity compounds in the avibactam sodium intermediate. In addition, by removing or controlling the content of the isomeric impurity compounds in the avibactam sodium intermediate, the isomeric impurities in the avibactam sodium can ultimately be well controlled. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] FIG1 is a flow chart of a method for purifying an avibactam sodium intermediate provided by the present invention;

[0029] FIG2 is a chiral HPLC chromatogram of an unpurified avibactam sodium intermediate in the prior art;

[0030] FIG3 is a chiral HPLC chromatogram of the purified avibactam sodium intermediate prepared in Example 7 of the present invention.

[0031] The following specific implementation manner will be further described in conjunction with the above-mentioned drawings. Implementation Method

[0032] To facilitate understanding of the present invention, the present invention will be described more fully below with reference to the accompanying drawings. The drawings illustrate several embodiments of the present invention. However, the present invention may be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided to provide a more thorough and comprehensive understanding of the present invention.

[0033] It should be noted that when an element is referred to as being "fixed to" another element, it may be directly on the other element or there may be an intermediate element. When an element is referred to as being "connected to" another element, it may be directly connected to the other element or there may be an intermediate element. The terms "vertical," "horizontal," "left," "right," and similar expressions used herein are for illustrative purposes only.

[0034] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one skilled in the art to which this invention pertains. The terms used in this specification of the present invention are for the purpose of describing specific embodiments only and are not intended to limit the present invention. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0035] Please refer to Figure 1, which is a flow chart of a method for purifying an avibactam sodium intermediate provided by the present invention, wherein the preparation method specifically comprises the following steps:

[0036] Step 1: dissolving an avibactam sodium intermediate containing an isomeric impurity compound in an acetone solution.

[0037] Among them, the chemical formula of the avibactam sodium intermediate is:

[0038] The chemical formula of the isomeric impurity compound is:

[0039] ;

[0040] Specifically, the avibactam sodium intermediate containing an isomeric impurity compound is mixed with an acetone solution and stirred at 25° C. to 30° C. to obtain a clear mixed solution, wherein, for every 1 g of the avibactam sodium intermediate containing an isomeric impurity compound, 3.5 ml to 5 ml of acetone solution is provided. Exemplarily, for every 1 g of the avibactam sodium intermediate containing an isomeric impurity compound, 3.5 ml, 3.6 ml, 3.7 ml, 3.8 ml, 3.9 ml, 4 ml, 4.1 ml, 4.2 ml, 4.3 ml, 4.4 ml, 4.5 ml, 4.6 ml, 4.7 ml, 4.8 ml, 4.9 ml or 5 ml of acetone solution is provided, but is not limited thereto.

[0041] Step 2: adding ethyl acetate solution to the mixed solution obtained in step 1 and stirring to obtain a precipitate.

[0042] Specifically, the prepared ethyl acetate solution is slowly added to the clarified mixed solution and stirred at 25°C to 30°C for 2h to 10h. For example, the mixture is stirred at 25°C to 30°C for 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h or 10h, but not limited thereto, to obtain a precipitate. Generally, a solid precipitate is precipitated after stirring for 20min to 40min. For every 1g of the avibactam sodium intermediate containing isomer impurity compounds, 4ml to 6ml of the mixture is provided. Ethyl acetate solution, illustratively, for every 1 g of avibactam sodium intermediate containing isomer impurity compounds added, 4 ml, 4.1 ml, 4.2 ml, 4.3 ml, 4.4 ml, 4.5 ml, 4.6 ml, 4.7 ml, 4.8 ml, 4.9 ml, 5 ml, 5.1 ml, 5.2 ml, 5.3 ml, 5.4 ml, 5.5 ml, 5.6 ml, 5.7 ml, 5.8 ml, 5.9 ml or 6 ml of ethyl acetate solution is provided, but is not limited thereto.

[0043] Step 3: Filter the precipitate obtained in step 2, wash it with ethyl acetate solution, and then perform vacuum drying to obtain a purified avibactam sodium intermediate.

[0044] Specifically, the precipitate is filtered at 25° C. to 30° C., and then vacuum-dried at 40° C. to 45° C. to obtain the purified avibactam sodium intermediate.

[0045] In summary, the embodiment of the present invention provides a method for purifying an avibactam sodium intermediate, wherein the avibactam sodium intermediate containing isomeric impurity compounds is dissolved in an acetone solution, and then an ethyl acetate solution is added to the mixed solution obtained above, and stirred to obtain a precipitate. Finally, the precipitate is filtered, washed with an ethyl acetate solution, and then vacuum dried to obtain a purified avibactam sodium intermediate. The method can effectively reduce the content of isomeric impurity compounds in the avibactam sodium intermediate. In addition, by removing or controlling the content of isomeric impurity compounds in the avibactam sodium intermediate, the isomeric impurities in avibactam sodium can ultimately be well controlled.

[0046] On the other hand, the present invention also provides an avibactam sodium intermediate, which is prepared by the above-mentioned purification method of the avibactam sodium intermediate, and the content of the avibactam sodium intermediate is 99.88%.

[0047] To facilitate understanding of the present invention, several embodiments of the present invention are provided below. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided to provide a more thorough and comprehensive disclosure of the present invention. Example

[0048] In Example 1 of the present invention, the purification method of the avibactam sodium intermediate specifically comprises the following steps:

[0049] (1) The avibactam sodium intermediate containing isomeric impurity compounds is dissolved in an acetone solution.

[0050] Among them, the chemical formula of the avibactam sodium intermediate is:

[0051]

[0052] The chemical formula of the isomeric impurity compound is:

[0053] ;

[0054] Specifically, 10 g of the avibactam sodium intermediate containing isomer impurity compounds was mixed with 30 ml of acetone solution, and stirred at 25° C. to 30° C. to obtain a clear mixed solution.

[0055] (2) Adding ethyl acetate solution to the mixed solution obtained in step (1) and stirring to obtain a precipitate.

[0056] Specifically, the prepared ethyl acetate solution is slowly added to the above-mentioned clarified mixed solution, and stirred at 25° C. to 30° C. for 2 hours to obtain a precipitate, wherein the volume of the ethyl acetate solution is 50 ml.

[0057] Step (3), filtering the precipitate obtained in step (2), washing it with ethyl acetate solution, and then vacuum drying it to obtain a purified avibactam sodium intermediate.

[0058] Specifically, the precipitate is filtered at 25° C. to 30° C., and then vacuum-dried at 42.5° C. to obtain the purified avibactam sodium intermediate. Example

[0059] In Example 2 of the present invention, the purification method of the avibactam sodium intermediate specifically comprises the following steps:

[0060] (1) The avibactam sodium intermediate containing isomeric impurity compounds is dissolved in an acetone solution.

[0061] Among them, the chemical formula of the avibactam sodium intermediate is:

[0062]

[0063] The chemical formula of the isomeric impurity compound is:

[0064] ;

[0065] Specifically, 10 g of the avibactam sodium intermediate containing isomer impurity compounds was mixed with 30 ml of acetone solution, and stirred at 25° C. to 30° C. to obtain a clear mixed solution.

[0066] (2) Adding ethyl acetate solution to the mixed solution obtained in step (1) and stirring to obtain a precipitate.

[0067] Specifically, the prepared ethyl acetate solution was slowly added to the clarified mixed solution, and stirred at 25° C. to 30° C. for 2 h to obtain a precipitate, wherein the volume of the ethyl acetate solution was 75 ml.

[0068] Step (3), filtering the precipitate obtained in step (2), washing it with ethyl acetate solution, and then vacuum drying it to obtain a purified avibactam sodium intermediate.

[0069] Specifically, the precipitate is filtered at 25° C. to 30° C., and then vacuum-dried at 43° C. to obtain the purified avibactam sodium intermediate. Example

[0070] In Example 3 of the present invention, the purification method of the avibactam sodium intermediate specifically comprises the following steps:

[0071] (1) The avibactam sodium intermediate containing isomeric impurity compounds is dissolved in an acetone solution.

[0072] Among them, the chemical formula of the avibactam sodium intermediate is:

[0073]

[0074] The chemical formula of the isomeric impurity compound is:

[0075] ;

[0076] Specifically, 10 g of the avibactam sodium intermediate containing isomer impurity compounds was mixed with 30 ml of acetone solution, and stirred at 25° C. to 30° C. to obtain a clear mixed solution.

[0077] (2) Adding ethyl acetate solution to the mixed solution obtained in step (1) and stirring to obtain a precipitate.

[0078] Specifically, the prepared ethyl acetate solution is slowly added to the above clarified mixed solution, and stirred at 25° C. to 30° C. for 2 hours to obtain a precipitate, wherein the volume of the ethyl acetate solution is 100 ml.

[0079] Step (3), filtering the precipitate obtained in step (2), washing it with ethyl acetate solution, and then vacuum drying it to obtain a purified avibactam sodium intermediate.

[0080] Specifically, the precipitate is filtered at 25° C. to 30° C., and then vacuum-dried at 40° C. to obtain the purified avibactam sodium intermediate. Example

[0081] In Example 4 of the present invention, the purification method of the avibactam sodium intermediate specifically comprises the following steps:

[0082] (1) The avibactam sodium intermediate containing isomeric impurity compounds is dissolved in an acetone solution.

[0083] Among them, the chemical formula of the avibactam sodium intermediate is:

[0084]

[0085] The chemical formula of the isomeric impurity compound is:

[0086] ;

[0087] Specifically, 10 g of the avibactam sodium intermediate containing isomer impurity compounds was mixed with 40 ml of acetone solution, and stirred at 25° C. to 30° C. to obtain a clear mixed solution.

[0088] (2) Adding ethyl acetate solution to the mixed solution obtained in step (1) and stirring to obtain a precipitate.

[0089] Specifically, the prepared ethyl acetate solution is slowly added to the above-mentioned clarified mixed solution, and stirred at 25° C. to 30° C. for 2 hours to obtain a precipitate, wherein the volume of the ethyl acetate solution is 50 ml.

[0090] Step (3), filtering the precipitate obtained in step (2), washing it with ethyl acetate solution, and then vacuum drying it to obtain a purified avibactam sodium intermediate.

[0091] Specifically, the precipitate is filtered at 25° C. to 30° C., and then vacuum-dried at 41° C. to obtain the purified avibactam sodium intermediate. Example

[0092] In Example 5 of the present invention, the purification method of the avibactam sodium intermediate specifically comprises the following steps:

[0093] (1) The avibactam sodium intermediate containing isomeric impurity compounds is dissolved in an acetone solution.

[0094] Among them, the chemical formula of the avibactam sodium intermediate is:

[0095]

[0096] The chemical formula of the isomeric impurity compound is:

[0097] ;

[0098] Specifically, 10 g of the avibactam sodium intermediate containing isomer impurity compounds was mixed with 45 ml of acetone solution, and stirred at 25° C. to 30° C. to obtain a clear mixed solution.

[0099] (2) Adding ethyl acetate solution to the mixed solution obtained in step (1) and stirring to obtain a precipitate.

[0100] Specifically, the prepared ethyl acetate solution is slowly added to the above-mentioned clarified mixed solution, and stirred at 25° C. to 30° C. for 2 hours to obtain a precipitate, wherein the volume of the ethyl acetate solution is 50 ml.

[0101] Step (3), filtering the precipitate obtained in step (2), washing it with ethyl acetate solution, and then vacuum drying it to obtain a purified avibactam sodium intermediate.

[0102] Specifically, the precipitate is filtered at 25° C. to 30° C., and then vacuum-dried at 42° C. to obtain the purified avibactam sodium intermediate. Example

[0103] In Example 6 of the present invention, the purification method of the avibactam sodium intermediate specifically comprises the following steps:

[0104] (1) The avibactam sodium intermediate containing isomeric impurity compounds is dissolved in an acetone solution.

[0105] Among them, the chemical formula of the avibactam sodium intermediate is:

[0106]

[0107] The chemical formula of the isomeric impurity compound is:

[0108] ;

[0109] Specifically, 10 g of the avibactam sodium intermediate containing isomer impurity compounds was mixed with 50 ml of acetone solution, and stirred at 25° C. to 30° C. to obtain a clear mixed solution.

[0110] (2) Adding ethyl acetate solution to the mixed solution obtained in step (1) and stirring to obtain a precipitate.

[0111] Specifically, the prepared ethyl acetate solution is slowly added to the above-mentioned clarified mixed solution, and stirred at 25° C. to 30° C. for 2 hours to obtain a precipitate, wherein the volume of the ethyl acetate solution is 50 ml.

[0112] Step (3), filtering the precipitate obtained in step (2), washing it with ethyl acetate solution, and then vacuum drying it to obtain a purified avibactam sodium intermediate.

[0113] Specifically, the precipitate is filtered at 25° C. to 30° C., and then vacuum-dried at 44° C. to obtain the purified avibactam sodium intermediate. Example

[0114] In Example 7 of the present invention, the purification method of the avibactam sodium intermediate specifically comprises the following steps:

[0115] (1) The avibactam sodium intermediate containing isomeric impurity compounds is dissolved in an acetone solution.

[0116] Among them, the chemical formula of the avibactam sodium intermediate is:

[0117]

[0118] The chemical formula of the isomeric impurity compound is:

[0119] ;

[0120] Specifically, 10 g of the avibactam sodium intermediate containing isomer impurity compounds was mixed with 42.5 ml of acetone solution, and stirred at 25° C. to 30° C. to obtain a clear mixed solution.

[0121] (2) Adding ethyl acetate solution to the mixed solution obtained in step (1) and stirring to obtain a precipitate.

[0122] Specifically, the prepared ethyl acetate solution is slowly added to the above-mentioned clarified mixed solution, and stirred at 25° C. to 30° C. for 2 hours to obtain a precipitate, wherein the volume of the ethyl acetate solution is 50 ml.

[0123] Step (3), filtering the precipitate obtained in step (2), washing it with ethyl acetate solution, and then vacuum drying it to obtain a purified avibactam sodium intermediate.

[0124] Specifically, the precipitate is filtered at 25° C. to 30° C., and then vacuum-dried at 45° C. to obtain the purified avibactam sodium intermediate. Example

[0125] In Example 8 of the present invention, the purification method of the avibactam sodium intermediate specifically comprises the following steps:

[0126] (1) The avibactam sodium intermediate containing isomeric impurity compounds is dissolved in an acetone solution.

[0127] Among them, the chemical formula of the avibactam sodium intermediate is:

[0128]

[0129] The chemical formula of the isomeric impurity compound is:

[0130] ;

[0131] Specifically, 10 g of the avibactam sodium intermediate containing isomer impurity compounds was mixed with 35 ml of acetone solution, and stirred at 25° C. to 30° C. to obtain a clear mixed solution.

[0132] (2) Adding ethyl acetate solution to the mixed solution obtained in step (1) and stirring to obtain a precipitate.

[0133] Specifically, the prepared ethyl acetate solution is slowly added to the above-mentioned clarified mixed solution, and stirred at 25° C. to 30° C. for 2 hours to obtain a precipitate, wherein the volume of the ethyl acetate solution is 50 ml.

[0134] Step (3), filtering the precipitate obtained in step (2), washing it with ethyl acetate solution, and then vacuum drying it to obtain a purified avibactam sodium intermediate.

[0135] Specifically, the precipitate is filtered at 25° C. to 30° C., and then vacuum-dried at 42.5° C. to obtain the purified avibactam sodium intermediate. Example

[0136] In Example 9 of the present invention, the purification method of the avibactam sodium intermediate specifically comprises the following steps:

[0137] (1) The avibactam sodium intermediate containing isomeric impurity compounds is dissolved in an acetone solution.

[0138] Among them, the chemical formula of the avibactam sodium intermediate is:

[0139]

[0140] The chemical formula of the isomeric impurity compound is:

[0141] ;

[0142] Specifically, 10 g of the avibactam sodium intermediate containing isomer impurity compounds was mixed with 42.5 ml of acetone solution, and stirred at 25° C. to 30° C. to obtain a clear mixed solution.

[0143] (2) Adding ethyl acetate solution to the mixed solution obtained in step (1) and stirring to obtain a precipitate.

[0144] Specifically, the prepared ethyl acetate solution was slowly added to the clarified mixed solution, and stirred at 25° C. to 30° C. for 2 h to obtain a precipitate, wherein the volume of the ethyl acetate solution was 60 ml.

[0145] Step (3), filtering the precipitate obtained in step (2), washing it with ethyl acetate solution, and then vacuum drying it to obtain a purified avibactam sodium intermediate.

[0146] Specifically, the precipitate is filtered at 25° C. to 30° C., and then vacuum-dried at 42.5° C. to obtain the purified avibactam sodium intermediate. Example

[0147] In Example 10 of the present invention, the purification method of the avibactam sodium intermediate specifically comprises the following steps:

[0148] (1) The avibactam sodium intermediate containing isomeric impurity compounds is dissolved in an acetone solution.

[0149] Among them, the chemical formula of the avibactam sodium intermediate is:

[0150]

[0151] The chemical formula of the isomeric impurity compound is:

[0152] ;

[0153] Specifically, 10 g of the avibactam sodium intermediate containing isomer impurity compounds was mixed with 45 ml of acetone solution, and stirred at 25° C. to 30° C. to obtain a clear mixed solution.

[0154] (2) Adding ethyl acetate solution to the mixed solution obtained in step (1) and stirring to obtain a precipitate.

[0155] Specifically, the prepared ethyl acetate solution was slowly added to the clarified mixed solution, and stirred at 25° C. to 30° C. for 2 h to obtain a precipitate, wherein the volume of the ethyl acetate solution was 40 ml.

[0156] Step (3), filtering the precipitate obtained in step (2), washing it with ethyl acetate solution, and then vacuum drying it to obtain a purified avibactam sodium intermediate.

[0157] Specifically, the precipitate is filtered at 25° C. to 30° C., and then vacuum-dried at 42.5° C. to obtain the purified avibactam sodium intermediate. Example

[0158] In Example 11 of the present invention, the purification method of the avibactam sodium intermediate specifically comprises the following steps:

[0159] (1) The avibactam sodium intermediate containing isomeric impurity compounds is dissolved in an acetone solution.

[0160] Among them, the chemical formula of the avibactam sodium intermediate is:

[0161]

[0162] The chemical formula of the isomeric impurity compound is:

[0163] ;

[0164] Specifically, 10 g of the avibactam sodium intermediate containing isomer impurity compounds was mixed with 45 ml of acetone solution, and stirred at 25° C. to 30° C. to obtain a clear mixed solution.

[0165] (2) Adding ethyl acetate solution to the mixed solution obtained in step (1) and stirring to obtain a precipitate.

[0166] Specifically, the prepared ethyl acetate solution was slowly added to the clarified mixed solution, and stirred at 25° C. to 30° C. for 2 h to obtain a precipitate, wherein the volume of the ethyl acetate solution was 60 ml.

[0167] Step (3), filtering the precipitate obtained in step (2), washing it with ethyl acetate solution, and then vacuum drying it to obtain a purified avibactam sodium intermediate.

[0168] Specifically, the precipitate is filtered at 25° C. to 30° C., and then vacuum-dried at 42.5° C. to obtain the purified avibactam sodium intermediate.

[0169] The purified avibactam sodium intermediates in Examples 1 to 11 and the unpurified avibactam sodium intermediates in the prior art were tested using chiral high performance liquid chromatography, and the test results are as follows:

[0170] The data show that the isomeric impurities of the avibactam sodium intermediate in the purified avibactam sodium intermediate prepared in the embodiment of the present invention are significantly improved compared with the prior art. In Example 5 of the present invention, when the isomeric impurities of the avibactam sodium intermediate were only 0.12%, the yield of the avibactam sodium intermediate was 52.1%. In addition, please refer to Figures 2 and 3. Figure 2 is a chiral HPLC chromatogram of the unpurified avibactam sodium intermediate in the prior art, and Figure 3 is a chiral HPLC chromatogram of the purified avibactam sodium intermediate prepared in Example 7 of the present invention. Specifically, when avibactam sodium is prepared from the purified avibactam sodium intermediate prepared in the embodiment of the present invention, the content of the corresponding isomeric impurity compound (9) is less than 0.1%, that is, qualified avibactam sodium that complies with the ICH guidelines is finally prepared.

[0171] Throughout this specification, reference to terms such as "one embodiment," "some embodiments," "examples," "specific examples," or "some examples" means that a specific feature, structure, material, or characteristic described in conjunction with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.

[0172] The above-described embodiments merely illustrate several implementations of the present invention, and while their descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that a person skilled in the art would be able to make numerous variations and improvements without departing from the spirit of the present invention, all of which fall within the scope of protection of the present invention. Therefore, the scope of protection of the present invention shall be determined by the appended claims.

Claims

1. A method for purifying an avibactam sodium intermediate, characterized in that: The following steps are involved: Step 1, dissolving the avibactam sodium intermediate containing isomeric impurity compounds in an acetone solution, wherein the chemical formula of the avibactam sodium intermediate is: ； The chemical formula of the isomeric impurity compound is: ； Step 2, adding ethyl acetate solution to the mixed solution obtained in step 1, and stirring to obtain a precipitate; Step 3: Filter the precipitate obtained in step 2, wash it with ethyl acetate solution, and then perform vacuum drying to obtain a purified avibactam sodium intermediate.

2. The method for purifying an avibactam sodium intermediate according to claim 1, wherein In the step of dissolving the avibactam sodium intermediate containing isomeric impurity compounds in an acetone solution, 3.5 ml to 5 ml of acetone solution is required for each 1 g of the avibactam sodium intermediate containing isomeric impurity compounds added.

3. The method for purifying an avibactam sodium intermediate according to claim 1, characterized in that: In the step of adding the ethyl acetate solution to the mixed solution obtained in step 1 and stirring to obtain a precipitate, 4 ml to 6 ml of the ethyl acetate solution is required for every 1 g of the avibactam sodium intermediate containing isomer impurity compounds added.

4. The method for purifying an avibactam sodium intermediate according to claim 1, characterized in that: In the step of dissolving the avibactam sodium intermediate containing isomer impurity compounds in the acetone solution, stirring is performed at 25° C. to 30° C. to obtain a clear mixed solution.

5. The method for purifying an avibactam sodium intermediate according to claim 1, characterized in that: In the step of adding the ethyl acetate solution to the mixed solution obtained in step 1 and stirring to obtain a precipitate, stirring is performed at 25° C. to 30° C. for 2 h to 10 h to obtain a precipitate.

6. The method for purifying an avibactam sodium intermediate according to claim 1, characterized in that: In the step of filtering the precipitate obtained in step 2, washing it with ethyl acetate solution, and then performing vacuum drying to obtain the purified avibactam sodium intermediate, the vacuum drying is performed at 40° C. to 45° C.

7. The method for purifying an avibactam sodium intermediate according to claim 1, characterized in that: In the step of filtering the precipitate obtained in step 2, washing it with an ethyl acetate solution, and then performing a vacuum drying treatment to obtain the purified avibactam sodium intermediate, the precipitate is filtered at 25° C. to 30° C.

8. An avibactam sodium intermediate, characterized in that: The product is prepared by the purification method of the avibactam sodium intermediate according to any one of claims 1 to 7, and the content of the avibactam sodium intermediate is 99.88%.

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