A pharmaceutical composition of avibactam sodium and a preparation method thereof
By combining avibactam sodium with 2-(5-(2-oxozadicyclobut-1-yl)thiophen-2-yl)benzo[d]thiazol-6-carboxylic acid, the problem of increased drug resistance in β-lactam antibiotics was solved, and a synergistic antibacterial effect against multidrug-resistant bacteria was achieved.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- HARBIN PHARMA GROUP TECH CENT
- Filing Date
- 2025-12-25
- Publication Date
- 2026-05-12
AI Technical Summary
Existing β-lactam antibiotics are becoming less effective due to increased bacterial resistance, necessitating the development of new drug compositions to improve their antibacterial efficacy.
A synergistic antibacterial effect is achieved by mixing avibactam sodium with 2-(5-(2-oxoazacyclobut-1-yl)thiophen-2-yl)benzo[d]thiazol-6-carboxylic acid in a specific ratio and preparing the mixture.
It significantly reduced the minimum inhibitory concentration against Gram-negative bacilli such as Escherichia coli, Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa, exhibiting a synergistic effect and improving the therapeutic effect against multidrug-resistant bacteria.
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of pharmaceutical formulation technology, and particularly relates to a pharmaceutical composition of avibactam sodium and its preparation method. Background Technology
[0002] Infectious diseases are caused by pathogenic microorganisms such as bacteria, fungi, and viruses, posing a long-term threat to human health. Among them, β-lactam antibiotics, which bind to bacterial penicillin-binding proteins (PBPs) and inhibit their transpeptidase activity, thereby blocking the cross-linking of peptidoglycan in the cell wall and causing bacterial lysis and death, are the core drugs for treating these infections.
[0003] However, with the widespread use of β-lactam antibiotics, bacterial resistance has gradually increased, and some strains have become less sensitive to existing β-lactam antibiotics, leading to decreased treatment efficacy. Avibactam sodium, as a novel β-lactamase inhibitor, can effectively inhibit multiple β-lactamases, protect β-lactam antibiotics from hydrolysis, and restore their antibacterial activity. Therefore, developing drug combinations of avibactam sodium with suitable β-lactam antibiotics is of great significance for improving antibacterial efficacy and combating drug-resistant bacterial infections. Summary of the Invention
[0004] In order to overcome the shortcomings of the prior art, the first objective of the present invention is to provide a pharmaceutical composition of avibactam sodium with significant synergistic antibacterial activity.
[0005] The second objective of this invention is to provide a simple method for preparing a pharmaceutical composition of avibactam sodium.
[0006] To achieve the above objectives, the technical solution adopted by the present invention is as follows:
[0007] A pharmaceutical composition of avibactam sodium comprises the following components: avibactam sodium and 2-(5-(2-oxozycyclobut-1-yl)thiophen-2-yl)benzo[d]thiazol-6-carboxylic acid; wherein the mass ratio of avibactam sodium to 2-(5-(2-oxozycyclobut-1-yl)thiophen-2-yl)benzo[d]thiazol-6-carboxylic acid is 1:(2-3);
[0008] The structural formula of the 2-(5-(2-oxoazacyclobut-1-yl)thiophene-2-yl)benzo[d]thiazol-6-carboxylic acid is:
[0009] .
[0010] Furthermore, the preparation process of 2-(5-(2-oxoazacyclobut-1-yl)thiophene-2-yl)benzo[d]thiazol-6-carboxylic acid includes the following steps:
[0011] (1) 4-amino-3-mercaptobenzoic acid and (5-formylthiophene-2-yl)carbamate tert-butyl ester were added to ethanol, and then sodium hyposulfite aqueous solution was added for heating reaction. After the reaction was completed, the tert-butyloxycarbonyl group was removed by hydrochloric acid / methanol treatment and then purified to obtain compound 1.
[0012] The structural formula of compound 1 is as follows:
[0013]
[0014] (2) Compound 1 and 3-bromopropionic acid were added to dichloromethane, followed by the addition of 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The reaction was carried out at room temperature, and the mixture was purified after the reaction was completed to obtain compound 2.
[0015] The structural formula of compound 2 is as follows:
[0016]
[0017] (3) Add the compound 2 to anhydrous N,N-dimethylformamide, cool, replace with nitrogen, add sodium tert-butoxide in batches, react at room temperature, and purify after the reaction is complete.
[0018] Furthermore, in step (1), the ratio of 4-amino-3-mercaptobenzoic acid, (5-formylthiophene-2-yl)carbamate tert-butyl ester, and sodium hyposulfite aqueous solution is 10 mmol: (10-15) mmol: (17-26) mL; the concentration of the sodium hyposulfite aqueous solution is 0.1 g / mL; and the concentration of the hydrochloric acid / methanol solution is 4 mol / L.
[0019] Furthermore, the heating reaction in step (1) is carried out at a temperature of 70-90°C for 16-24 hours.
[0020] Furthermore, the molar ratio of compounds 1, 3-bromopropionic acid, 1-hydroxybenzotriazole, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in step (2) is 5: (7.6-10.13): (7.6-10.13): (7.6-10.13).
[0021] Furthermore, the reaction time in step (2) is 8-12 h; the temperature at which the 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are added is -5~0℃.
[0022] Furthermore, the molar ratio of compound 2 and sodium tert-butoxide in step (3) is 5.11:(10.21-12.76).
[0023] Furthermore, in step (3), the temperature is cooled to 0°C; the temperature is controlled to ≤3°C during the addition of sodium tert-butoxide; and the reaction time is 1-3 hours.
[0024] The method for preparing the above-mentioned avibactam sodium pharmaceutical composition includes the following steps:
[0025] According to the stated mass ratio, avibactam sodium and 2-(5-(2-oxoazacyclobut-1-yl)thiophen-2-yl)benzo[d]thiazol-6-carboxylic acid are mixed evenly.
[0026] Compared with the prior art, the main advantages of the present invention are as follows:
[0027] The pharmaceutical composition of avibactam sodium of the present invention comprises avibactam sodium and 2-(5-(2-oxoazacyclobut-1-yl)thiophen-2-yl)benzo[d]thiazol-6-carboxylic acid. Experimental results show that 2-(5-(2-oxoazacyclobut-1-yl)thiophen-2-yl)benzo[d]thiazol-6-carboxylic acid exhibits bactericidal activity against clinical isolates of Gram-negative bacilli, such as *Escherichia coli*, *Acinetobacter baumannii*, *Klebsiella pneumoniae*, and *Pseudomonas aeruginosa*. The combined use of 2-(5-(2-oxoazacyclobut-1-yl)thiophen-2-yl)benzo[d]thiazol-6-carboxylic acid and avibactam sodium produces a synergistic effect, effectively reducing the minimum inhibitory concentration (MIC) of 2-(5-(2-oxoazacyclobut-1-yl)thiophen-2-yl)benzo[d]thiazol-6-carboxylic acid. Detailed Implementation
[0028] The technical solution of the present invention will be further described below with reference to specific embodiments. However, those skilled in the art should understand that the following embodiments are only for illustrating the present invention and should not be regarded as limiting the present invention. Specific conditions not specified in the embodiments are performed according to conventional conditions or conditions recommended by the manufacturer. Unless otherwise specified, the reagents or instruments used are all conventional products obtained through commercial channels.
[0029] Example 1
[0030] This embodiment provides a method for preparing 2-(5-(2-oxoazacyclobut-1-yl)thiophene-2-yl)benzo[d]thiazol-6-carboxylic acid, comprising the following steps:
[0031]
[0032] (1) 4-amino-3-mercaptobenzoic acid (1.70 g, 10 mmol) and (5-formylthiophene-2-yl)carbamate tert-butyl ester (CAS: 2386876-74-8, 2.95 g, 13 mmol) were added to 30 mL of ethanol. 0.1 g / mL of sodium hyposulfite aqueous solution (CAS: 7775-14-6, 22 mL) was added at room temperature. The mixture was heated to 80 °C and reacted for 20 h. After the reaction was complete, the reaction solution was concentrated, and 15 mL of 4 mol / L hydrochloric acid / methanol solution was added and stirred for 15 min. After filtration, the filter cake was recrystallized in a methanol / water mixture (v / v, 1:2) to obtain compound 1 (1.80 g, yield 64.83%). The NMR and mass spectrometry results of compound 1 are as follows:
[0033] 1 HNMR (C 12 H8N2O2S2, 400MHz, DMSO): δ12.68(s,1H),8.61(s,1H),8.07(d,1H),7.69(d,1H),7.48(d,1H),7.41(s,2H),6.45(d,1H); HRMS(ESI + ):[M+H] + The calculation yields 277.00, and the value found is 277.00.
[0034] (2) Compound 1 (1.40 g, 5 mmol) and 3-bromopropionic acid (CAS: 590-92-1, 1.40 g, 9.12 mmol) were added to 15 mL of dichloromethane. 1-hydroxybenzotriazole (HOBt, 1.23 g, 9.12 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 1.75 g, 9.12 mmol) were added at 0 °C. The mixture was then heated to room temperature and reacted for 10 h. After the reaction was complete, the mixture was washed sequentially with 5 wt% hydrochloric acid aqueous solution, 5 wt% sodium bicarbonate aqueous solution, water, and saturated saline solution. The dichloromethane phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane / methanol = 80:20, v / v) to obtain compound 2 (1.72 g, yield 82.54%). The NMR and mass spectrometry results of compound 2 are as follows:
[0035] 1 HNMR (C 15 H 11 BrN2O3S2,400MHz,DMSO): δ12.68(s,1H),11.58(s,1H),8.61(s,1H),8.11- 8.06(m,2H),7.78(d,1H),7.69(d,1H),3.58(t,2H),2.68(t,2H);HRMS(ESI +):[M+H] + The calculation yields 410.94, and the result is 411.00.
[0036] (3) Compound 2 (2.1 g, 5.11 mmol) was added to 20 mL of anhydrous N,N-dimethylformamide. After cooling to 0 °C and replacing with nitrogen, sodium tert-butoxide (1.08 g, 11.23 mmol) was added in two portions. The temperature was controlled to be ≤3 °C during the addition process. After the addition was completed, the temperature was raised to room temperature and reacted for 2 h. After the reaction was completed, the solvent was removed under reduced pressure and the mixture was dispersed evenly with ethyl acetate. The ethyl acetate phase was washed and separated with saturated saline solution, then dried with anhydrous sodium sulfate, concentrated and purified by column chromatography (dichloromethane / methanol = 75:25, v / v) to obtain 2-(5-(2-oxoazacyclobut-1-yl)thiophene-2-yl)benzo[d]thiazol-6-carboxylic acid (1.22 g, yield 72.32%), denoted as compound A. The NMR and mass spectrometry results are as follows:
[0037] 1 HNMR (C 15 H 10 N2O3S2,400MHz,DMSO): δ12.68(s,1H),8.61(s,1H),8.11-8.06(m,2H),7.78(d,1H),7.69(d,1H),3.42(t,2H),3.09(t,2H);HRMS(ESI + ):[M+H] + The calculation yields 331.01, and the value is found to be 331.01.
[0038] Example 2
[0039] This embodiment provides a method for preparing 2-(5-(2-oxoazacyclobut-1-yl)thiophene-2-yl)benzo[d]thiazol-6-carboxylic acid, comprising the following steps:
[0040] (1) 4-amino-3-mercaptobenzoic acid (1.70 g, 10 mmol) and (5-formylthiophene-2-yl) tert-butyl carbamate (2.28 g, 10 mmol) were added to 30 mL of ethanol. 0.1 g / mL of sodium hyposulfite aqueous solution (17 mL) was added at room temperature. The mixture was heated to 70 °C and reacted for 24 h. After the reaction was completed, the reaction solution was concentrated and 15 mL of 4 mol / L hydrochloric acid / methanol solution was added and stirred for 15 min. After filtration, the filter cake was recrystallized in a methanol / water mixed solution (v / v, 1:2) to obtain compound 1 (1.68 g, yield 60.51%). The NMR and mass spectrometry results of compound 1 were the same as in Example 1.
[0041] (2) Compound 1 (1.40 g, 5 mmol) and 3-bromopropionic acid (1.16 g, 7.60 mmol) were added to 15 mL of dichloromethane. 1-hydroxybenzotriazole (1.03 g, 7.60 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.46 g, 7.60 mmol) were added at -5 °C. The mixture was then heated to room temperature and reacted for 8 h. After the reaction was completed, the mixture was washed sequentially with 5 wt% hydrochloric acid aqueous solution, 5 wt% sodium bicarbonate aqueous solution, water, and saturated saline solution. The dichloromethane phase was dried with anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane / methanol = 80:20, v / v) to obtain compound 2 (1.58 g, yield 75.82%). The NMR and mass spectrometry results of compound 2 were the same as in Example 1.
[0042] (3) Compound 2 (2.1 g, 5.11 mmol) was added to 20 mL of anhydrous N,N-dimethylformamide, cooled to 0 °C, and purged with nitrogen. Sodium tert-butoxide (1.4 g, 10.21 mmol) was added in three portions. The temperature was controlled to be ≤3 °C during the addition process. After the addition was completed, the temperature was raised to room temperature and reacted for 1 h. After the reaction was completed, the solvent was removed under reduced pressure and the mixture was dispersed evenly with ethyl acetate. The ethyl acetate phase was washed and separated with saturated saline solution, dried with anhydrous sodium sulfate, concentrated and purified by column chromatography (dichloromethane / methanol = 75:25, v / v) to obtain 2-(5-(2-oxoazacyclobut-1-yl)thiophene-2-yl)benzo[d]thiazol-6-carboxylic acid (1.18 g, yield 69.95%). The NMR and mass spectrometry results were the same as in Example 1.
[0043] Example 3
[0044] This embodiment provides a method for preparing 2-(5-(2-oxoazacyclobut-1-yl)thiophene-2-yl)benzo[d]thiazol-6-carboxylic acid, comprising the following steps:
[0045] (1) 4-amino-3-mercaptobenzoic acid (1.70 g, 10 mmol) and (5-formylthiophene-2-yl) tert-butyl carbamate (3.41 g, 15 mmol) were added to 30 mL of ethanol. 0.1 g / mL of sodium hyposulfite aqueous solution (26 mL) was added at room temperature. The mixture was heated to 90 °C and reacted for 24 h. After the reaction was completed, the reaction solution was concentrated and 15 mL of 4 mol / L hydrochloric acid / methanol solution was added and stirred for 15 min. After filtration, the filter cake was recrystallized in a methanol / water mixed solution (v / v, 1:2) to obtain compound 1 (1.71 g, yield 61.59%). The NMR and mass spectrometry results of compound 1 were the same as in Example 1.
[0046] (2) Compound 1 (1.40 g, 5 mmol) and 3-bromopropionic acid (1.55 g, 10.13 mmol) were added to 15 mL of dichloromethane. 1-hydroxybenzotriazole (1.37 g, 10.13 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.94 g, 10.13 mmol) were added at -3 °C. The mixture was then heated to room temperature and reacted for 12 h. After the reaction was completed, the mixture was washed sequentially with 5 wt% hydrochloric acid aqueous solution, 5 wt% sodium bicarbonate aqueous solution, water, and saturated saline solution. The dichloromethane phase was dried with anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane / methanol = 80:20, v / v) to obtain compound 2 (1.68 g, yield 80.62%). The NMR and mass spectrometry results of compound 2 were the same as in Example 1.
[0047] (3) Compound 2 (2.1 g, 5.11 mmol) was added to 20 mL of anhydrous N,N-dimethylformamide, cooled to 0 °C, and purged with nitrogen. Sodium tert-butoxide (1.23 g, 12.76 mmol) was added in two portions. The temperature was controlled to be ≤3 °C during the addition process. After the addition was completed, the temperature was raised to room temperature and reacted for 3 h. After the reaction was completed, the solvent was removed under reduced pressure and the mixture was dispersed evenly with ethyl acetate. The ethyl acetate phase was washed and separated with saturated saline solution, dried with anhydrous sodium sulfate, concentrated and purified by column chromatography (dichloromethane / methanol = 75:25, v / v) to obtain 2-(5-(2-oxoazacyclobut-1-yl)thiophene-2-yl)benzo[d]thiazol-6-carboxylic acid (1.28 g, yield 75.88%). The NMR and mass spectrometry results were the same as in Example 1.
[0048] Example 4
[0049] This embodiment provides a pharmaceutical composition of avibactam sodium, comprising avibactam sodium in a mass ratio of 1:2.5 and 2-(5-(2-oxoazacyclobut-1-yl)thiophen-2-yl)benzo[d]thiazol-6-carboxylic acid of Example 1.
[0050] This embodiment also provides a method for preparing the above-mentioned avibactam sodium pharmaceutical composition, including the following steps:
[0051] According to the stated mass ratio, avibactam sodium and 2-(5-(2-oxoazacyclobut-1-yl)thiophen-2-yl)benzo[d]thiazol-6-carboxylic acid are mixed evenly.
[0052] Example 5
[0053] This embodiment provides a pharmaceutical composition of avibactam sodium, comprising avibactam sodium in a mass ratio of 1:2 and 2-(5-(2-oxoazacyclobut-1-yl)thiophen-2-yl)benzo[d]thiazol-6-carboxylic acid of Example 2.
[0054] This embodiment also provides a method for preparing the above-mentioned avibactam sodium pharmaceutical composition, including the following steps:
[0055] According to the stated mass ratio, avibactam sodium and 2-(5-(2-oxoazacyclobut-1-yl)thiophen-2-yl)benzo[d]thiazol-6-carboxylic acid are mixed evenly.
[0056] Example 6
[0057] This embodiment provides a pharmaceutical composition of avibactam sodium, comprising avibactam sodium in a mass ratio of 1:3 and 2-(5-(2-oxoazacyclobut-1-yl)thiophen-2-yl)benzo[d]thiazol-6-carboxylic acid of Example 3.
[0058] This embodiment also provides a method for preparing the above-mentioned avibactam sodium pharmaceutical composition, including the following steps:
[0059] According to the stated mass ratio, avibactam sodium and 2-(5-(2-oxoazacyclobut-1-yl)thiophen-2-yl)benzo[d]thiazol-6-carboxylic acid are mixed evenly.
[0060] Comparative Example 1
[0061] The difference between this comparative example and Example 4 is that avibactam sodium is omitted, while the rest is the same as in Example 4.
[0062] The following describes the detection of MCI in 2-(5-(2-oxoazacyclobut-1-yl)thiophen-2-yl)benzo[d]thiazol-6-carboxylic acid (compound A) and avibactam sodium.
[0063] According to CLSI / NCCLS standards, the following strains were amplified using tryptic soy peptone broth (TSB broth): Escherichia coli (ATCC2469), Acinetobacter baumannii (ATCC19606), Klebsiella pneumoniae (ATCC2146), and Pseudomonas aeruginosa (ATCC27853), obtaining a concentration of 6 × 10⁻⁶. 5 Prepare a bacterial culture at CFU / mL for later use.
[0064] Compound A and avibactam sodium were prepared into a test solution of 2048 μg / mL using hydrolyzed casein peptone broth (MH broth) medium. The solution was then diluted 2-fold in 96-well plates to prepare a series of gradient concentrations for later use.
[0065] 10 μL of each of the above bacterial solutions was respectively added to a 96-well plate, and the test samples with double dilution concentrations were added to each well, so that the actual concentrations of compound A were 0, 1, 2, 4, 8, 16, 32, 64 μg / mL respectively, and the actual concentrations of avibactam sodium were 0, 1, 2, 4, 8, 16, 32, 64, 128, 256 μg / mL. Three parallel tests were set for each concentration, and the average value was taken. The negative control group was added with 10 μL of bacterial solution and 90 μL of casein hydrolysate broth. The 96-well plate was placed in a constant temperature incubator at 37 °C for 18 h, and the growth of the strains was observed.
[0066] Experimental Example 1
[0067] According to the above method, the MCI of compound A and avibactam sodium alone was determined, and the test results are shown in Table 1.
[0068] Table 1
[0069]
[0070] As can be seen from Table 1, the MIC values of compound A for Escherichia coli, Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa were 1 - 16 μg / mL. The MIC values of avibactam sodium for Acinetobacter baumannii and Pseudomonas aeruginosa were 64 - 128 μg / mL, showing weak activity.
[0071] Experimental Example 2
[0072] According to the above method, the MCI of compound A and avibactam sodium after combination was determined, and the test results are shown in Table 2. The effect of the combined drugs was analyzed by calculating the FICI value. FICI = (MIC of drug A in combination / MIC of drug A used alone) + (MIC of drug B in combination / MIC of drug B used alone). When FICI ≤ 0.5, the two drugs have a good synergistic effect; when 0.5 < FICI < 4, it means that the two drugs have no synergistic effect; when FICI ≥ 4, it means that the two drugs have an antagonistic effect.
[0073] Table 2
[0074]
[0075] As can be seen from Table 2, after combination with avibactam sodium, the MIC values of compound A for the 4 tested multi-drug resistant Enterobacter strains were significantly reduced and showed a synergistic effect (FICI ≤ 0.5). This indicates that the combination of compound A and avibactam sodium has great potential for developing into a drug for clinical treatment of multi-drug resistant Gram-negative Enterobacter infections.
[0076] Experimental Example 3
[0077] 3.1 Experimental animals
[0078] ICR mice, weighing 18-22g, a total of 50 mice, were randomly divided into Example 4-6 groups, Comparative Example 1 group and blank control group, with a female-to-male ratio of 1:1 and 10 mice in each group.
[0079] 3.2 Bacterial solution
[0080] The experimental bacterial culture was prepared by diluting the Klebsiella pneumoniae containing NDM-1 with 5% highly active dry yeast.
[0081] 3.3 Experimental Procedure
[0082] Each group of mice was intraperitoneally injected with 0.5 mL of 100% minimum lethal dose (100% MLD, 3 × 10⁻⁶). 6 CFU / mouse bacterial suspension. Mice infected intraperitoneally with NDM-1-producing Klebsiella pneumoniae were administered the drug twice post-infection, at 1 hour and 6 hours post-infection, as follows:
[0083] Example 4 group: The drug composition of Example 4 was injected via tail vein at a dose of 16 mg avibactam sodium / kg + 40 mg compound A / kg, with an administration volume of 10 mL / kg;
[0084] Example 5 group: The drug composition of Example 5 was injected via tail vein at a dose of 16 mg avibactam sodium / kg + 32 mg compound A / kg, with an administration volume of 10 mL / kg;
[0085] Example 6 group: The drug composition of Example 6 was injected via tail vein at a dose of 16 mg avibactam sodium / kg + 48 mg compound A / kg, with an administration volume of 10 mL / kg;
[0086] Comparative Example 1: The drug of Comparative Example 1 was injected via tail vein at a dose of 48 mg compound A / kg and an administration volume of 10 mL / kg.
[0087] Blank control group: administered an equal volume of physiological saline by gavage.
[0088] The survival of animals in each group was observed over 7 days, and the survival rate of mice was calculated. The results are shown in Table 3.
[0089] Table 3
[0090]
[0091] As shown in Table 3, compared with Comparative Example 1 which only used compound A, the combination of compound A and avibactam sodium in this invention showed a significant synergistic antibacterial effect.
[0092] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them. The basic principles and main features of the present invention have been described above with specific implementation schemes. Based on the present invention, some modifications or substitutions can be made, but these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of protection claimed by the present invention.
Claims
1. A pharmaceutical composition of avibactam sodium, characterized in that, The product comprises the following components: sodium avibactam and 2-(5-(2-oxoazacyclobut-1-yl)thiophen-2-yl)benzo[d]thiazol-6-carboxylic acid; wherein the mass ratio of sodium avibactam to 2-(5-(2-oxoazacyclobut-1-yl)thiophen-2-yl)benzo[d]thiazol-6-carboxylic acid is 1:(2-3). The structural formula of the 2-(5-(2-oxoazacyclobut-1-yl)thiophene-2-yl)benzo[d]thiazol-6-carboxylic acid is: 。 2. The pharmaceutical composition of avibactam sodium according to claim 1, characterized in that, The preparation process of the 2-(5-(2-oxoazacyclobut-1-yl)thiophene-2-yl)benzo[d]thiazol-6-carboxylic acid includes the following steps: (1) 4-amino-3-mercaptobenzoic acid and (5-formylthiophene-2-yl)carbamate tert-butyl ester were added to ethanol, and then sodium hyposulfite aqueous solution was added for heating reaction. After the reaction was completed, the tert-butyloxycarbonyl group was removed by hydrochloric acid / methanol treatment and then purified to obtain compound 1. The structural formula of compound 1 is as follows: (2) Compound 1 and 3-bromopropionic acid were added to dichloromethane, followed by the addition of 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The reaction was carried out at room temperature, and the mixture was purified after the reaction was completed to obtain compound 2. The structural formula of compound 2 is as follows: (3) Add the compound 2 to anhydrous N,N-dimethylformamide, cool, replace with nitrogen, add sodium tert-butoxide in batches, react at room temperature, and purify after the reaction is complete.
3. The pharmaceutical composition of avibactam sodium according to claim 2, characterized in that, In step (1), the ratio of 4-amino-3-mercaptobenzoic acid, (5-formylthiophene-2-yl)carbamate tert-butyl ester, and sodium hyposulfite aqueous solution is 10 mmol: (10-15) mmol: (17-26) mL; the concentration of the sodium hyposulfite aqueous solution is 0.1 g / mL; and the concentration of the hydrochloric acid / methanol solution is 4 mol / L.
4. The pharmaceutical composition of avibactam sodium according to claim 2, characterized in that, The heating reaction in step (1) is carried out at a temperature of 70-90℃ for 16-24 hours.
5. The pharmaceutical composition of avibactam sodium according to claim 2, characterized in that, The molar ratio of compounds 1, 3-bromopropionic acid, 1-hydroxybenzotriazole, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in step (2) is 5:(7.6-10.13):(7.6-10.13):(7.6-10.13).
6. The pharmaceutical composition of avibactam sodium according to claim 2, characterized in that, The reaction time in step (2) is 8-12 h; the temperature at which the 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are added is -5~0℃.
7. The pharmaceutical composition of avibactam sodium according to claim 2, characterized in that, The molar ratio of compound 2 and sodium tert-butoxide in step (3) is 5.11:(10.21-12.76).
8. The pharmaceutical composition of avibactam sodium according to claim 2, characterized in that, The step (3) involves cooling to 0°C; the temperature is controlled to ≤3°C during the addition of sodium tert-butoxide; and the reaction time is 1-3 hours.
9. A method for preparing a pharmaceutical composition of avibactam sodium according to any one of claims 1-8, characterized in that, Includes the following steps: According to the stated mass ratio, avibactam sodium and 2-(5-(2-oxoazacyclobut-1-yl)thiophen-2-yl)benzo[d]thiazol-6-carboxylic acid are mixed evenly.