Process for the preparation of an avibactam intermediate

Abstract

The application relates to the technical field of medicine synthesis, and discloses a preparation method of an avibactam intermediate, which comprises the following steps: taking AVI-SM-0 as a starting material, and sequentially performing esterification reaction, Boc protection, ring-opening addition reaction, imidization reaction, deprotection ring closure reaction, reduction reaction and salt formation to obtain the avibactam intermediate. The process is simple in operation, low in cost, high in stability, and the product quality meets the registration declaration requirements of avibactam.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, and particularly relates to a method for preparing an avibactam intermediate. Background Technology

[0002] Avibactam is a novel non-β-lactamase inhibitor, first developed by Novexel under the code name NXL-104. Its chemical name is (3R,5S)-6-sulfonico-2-(aminocarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane, with the molecular formula C7H. 11 N3O6S has a relative molecular mass of 265.25. In clinical applications, avibactam is often used in its sodium salt form to exert its biological activity. The chemical structure of avibactam sodium is shown below.

[0003]

[0004] Avibactam, a DBO-type compound with two chiral centers, primarily utilizes natural chiral sources to construct its key chiral centers, avoiding issues such as decreased optical purity, redundant steps, and increased costs caused by racemization. However, it can also be synthesized through asymmetric chemical methods. Depending on the starting material, its synthetic routes mainly include: using chiral piperidine ring derivatives as starting materials and using L-pyroglutamic acid or its derivatives as starting materials.

[0005] In 2003, Novexel, the original research company, proposed the first industrial-scale synthetic route for sodium avibactam (patent publication number CN1468242A). This route is lengthy (16 steps in total), has a low overall yield (approximately 9%), low optical purity, and requires chiral starting materials that are difficult to synthesize. The synthetic route is shown in the following formula.

[0006]

[0007]

[0008] Subsequently, AstraZeneca officially acquired Novexel and continued to advance research on the synthetic routes of avibactam sodium. In 2011, a series of synthetic routes for avibactam sodium and its derivatives using L-pyroglutamic acid derivatives as starting materials were reported (Patent No. WO 2012172368A1). The synthetic routes are shown in the following formula.

[0009]

[0010] Subsequently, many scientists conducted related research on the above-mentioned route. For example, in 2021, Wang Shuai proposed an improved strategy based on the AstraZeneca experimental route (Fine Chemicals. 2021, 38(07): 1494-1499). The synthetic route is shown in the following formula.

[0011]

[0012] Based on numerous patents, it has been found that compound 29 and its derivatives, as key intermediates in the synthesis of avibactam sodium, are of great significance for the industrial production of avibactam sodium, whether by optimizing the overall synthetic route or by optimizing specific reaction conditions (such as improving yield, purity, and process stability, or reducing industrial application costs). Summary of the Invention

[0013] This invention provides a method for preparing avibactam intermediates. This method generates less waste liquid, has lower overall cost, more stable process, higher product purity, can be operated continuously, and is simpler to operate.

[0014] The technical solution of the present invention is as follows:

[0015] A method for preparing an avibactam intermediate includes the following steps:

[0016] S1. AVI-SM-0 and acidic additives are added to the reaction solvent and reacted. After the reaction is completed, the mixture is concentrated, diluted, quenched with triethylamine to remove acid, filtered, and concentrated to obtain AVI-SM-1.

[0017] S2. Add AVI-SM-I and an alkaline catalyst or a catalytic amount of DMAP to the reaction solvent, then react with Boc anhydride. After the reaction is completed, AVI-SM is obtained by quenching, washing with water, extraction, drying and concentration.

[0018] S3. Add AVI-SM, alkaline additives and sulfur ylide reagent to the reaction solvent and react. After the reaction is completed, the AVI-1 feed solution is obtained after post-treatment. No extraction or filtration is required, nor is further concentration or drying required. The filtrate can be used directly for the next reaction.

[0019] S4. Add benzyloxyamine hydrochloride to AVI-1 solution. After the reaction is complete, concentrate and extract with EA to obtain AVI-2 solution.

[0020] S5. Add acidic additives to AVI-2 feed solution to complete Boc removal protection, and continue to add alkaline additives to complete catalytic ring closure. After post-treatment, AVI-3 feed solution is obtained.

[0021] S6. Add sulfuric acid and a self-made sodium borohydride derivative EA solution to the above liquid. After the reaction is completed, obtain AVI-4 viscous substance by quenching, washing with water, decolorizing with activated carbon and concentrating.

[0022] S7. Oxalic acid dihydrate is added to the above AVI-4 viscous substance to form a salt, and the salt is precipitated by a mixed solvent, purified by recrystallization twice with a mixed solvent, and dried to obtain product AVI-5; the compound AVI-SM-0 is... Compound AVI-SM-1 is Compound AVI-SM is Compound AVI-1 is Compound AVI-2 is Compound AVI-3 is Compound AVI-4 is Product AVI-5 is .

[0023] Furthermore, the synthetic route for the compound AVI-5 is as follows:

[0024] Furthermore, the acidic additive in S1 can be selected from thionyl chloride, 30 wt% concentrated sulfuric acid, 1.0~4.0 eq concentrated sulfuric acid and 8.84% HCl / ethanol solution, preferably thionyl chloride and the amount used is only 0.7 eq; the reaction solvent can be anhydrous ethanol and anhydrous ethanol / DMF, preferably anhydrous ethanol; the amount of triethylamine used is only 0.7 eq.

[0025] Furthermore, the reaction solvent in S2 can be acetonitrile, acetonitrile / water, toluene, toluene / water, or water, with toluene being preferred; the alkaline catalyst can be triethylamine, sodium carbonate, or sodium hydroxide, with triethylamine being more preferred, and even more preferred to use only a catalytic amount of DMAP without adding an alkaline catalyst.

[0026] Furthermore, the reaction solvent in S3 can be selected from acetonitrile, THF, toluene, acetone, MTBE, DCM, 2-methyltetrahydrofuran, DMSO / toluene, DMSO / acetonitrile, DMSO / THF, DMSO / 2-methyltetrahydrofuran, DMF / THF, or DMF / acetonitrile, with THF being preferred. The alkaline additive can be selected from sodium tert-butoxide, sodium tert-amyloxide, sodium methoxide, sodium ethoxide, potassium tert-amyloxide, potassium ethoxide, and potassium tert-butoxide, with potassium tert-butoxide being preferred. The thioyl ylide reagent can be selected from trimethyl sulfoxide, trimethyl sulfonium bromide, and trimethyl iodide sulfoxide, with trimethyl sulfonium bromide being preferred. Post-treatment can be selected from ammonium chloride / water quenching followed by EA extraction and concentration, or from acetic acid quenching and filtration followed by direct use in the next step, with acetic acid quenching being preferred. Filtration after acetic acid quenching is difficult; activated carbon, silica gel, activated alumina, flocculants, and custom-made PTFE membrane filter paper can be used as filtration aids, with silica gel being preferred. The filtrate does not require further concentration or drying and can be used directly in the next step.

[0027] Furthermore, the amount of reaction solvent in S4 is preferably 5 V to 10 V.

[0028] Furthermore, in the S5 deBoc protection process, the amount of reaction solvent EA is preferably 8.0 V. The acidic additive can be methanesulfonic acid, HCl / EA, concentrated sulfuric acid, formic acid, and acetic acid, with methanesulfonic acid being preferred. In the ring-closing reaction, the basic additive can be an organic base such as aniline, n-propylamine, ethanolamine, isopropanolamine, pyridine, morpholine, diethylamine, DIPEA, 1,4-dimethylpiperazine, and triethylamine, or an inorganic base such as potassium acetate, sodium ethoxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium phosphate, sodium phosphate, and potassium bicarbonate, with sodium bicarbonate and potassium bicarbonate being preferred.

[0029] Furthermore, the reducing agent in S6 can be sodium tripropionyloxyborohydride, sodium tributyryloxyborohydride, or sodium trivalveyloxyborohydride, with sodium tripropionyloxyborohydride being preferred; the reaction temperature can be relaxed to -10 ℃; the activated carbon type can be selected from Egret A, Egret Z, Japanese Egret, WPSM-W, WPSM-1, GBSP type, WPSM-2, WPSM-S, CLR-06, SCP-15, and FSG-A.

[0030] Furthermore, the salt-forming and recrystallization solvents in S7 can be selected from EA / ethanol, EA / THF, EA / acetone, EA / acetonitrile, EA / IPA, THF / water, acetonitrile / water, acetone / water, ethanol / water, and IPA / water, preferably isopropanol / water (v / v, 2:1), acetonitrile / water (4:1), ethanol / water (4:1), and THF / water (2:1), and more preferably IPA / water (2:1).

[0031] Based on the above technical solution, the embodiments of the present invention can produce at least the following technical effects:

[0032] It has lower overall cost, more stable process, can be operated continuously and is easier to operate.

[0033] The obtained AVI-5 has a purity of 99.9%, an isomer content of no more than 0.01%, an Ee value of no less than 99.8%, and a total recrystallization yield of no less than 40%. Attached Figure Description

[0034] To more clearly illustrate the technical solutions in this invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of this invention. For those skilled in the art, other drawings can be obtained based on the structures shown in these drawings without creative effort.

[0035] Figure 1 It is the AVI-4 obtained in Example 1. 1 H NMR spectrum.

[0036] Figure 2 This is an HPLC chromatogram of the AVI-5 product.

[0037] Figure 3 This is an HPLC chiral purity test result for the AVI-5 product. Detailed Implementation

[0038] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0039] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, regarding numerical ranges in this invention, it should be understood that any range between the upper and lower limits is acceptable. Each smaller range within any stated value or stated range is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0040] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0041] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be apparent to those skilled in the art. This specification and embodiments are merely exemplary.

[0042] All reagents used in this article are commercially available.

[0043] THF - Tetrahydrofuran; DMF - N,N-Dimethylformamide; EA - Ethyl acetate; IPA - Isopropanol; DIPEA - N,N-Diisopropylethylamine; Boc - Tert-Butoxycarbonyl; HCl - Hydrochloric acid; MTBE - Methyl tert-butyl ether; DMSO - Dimethyl sulfoxide.

[0044] Unless otherwise specified, all solutions of inorganic salts or bases mentioned in the following examples are aqueous solutions.

[0045] Example 1

[0046] S1. Feeding: Add L-pyroglutamic acid (95.0 g) and anhydrous ethanol (950.0 mL, 10 times the volume of the reactants, i.e., 10 V) sequentially to a 2 L three-necked flask and stir. After cooling to -10 ℃, slowly add 61.3 g (0.7 eq) of SOCl2 dropwise over 1–2 h. After the addition is complete, maintain the temperature at -10 ℃ and stir for 30 min. Then, slowly raise the temperature of the reaction system to 0–10 ℃ and continue the reaction for 8 h, monitoring the residual reactants by HPLC. Post-treatment: After the reaction, concentrate the system under reduced pressure at 40–45 ℃ and -0.1 MPa. Add 950.0 mL (10 V) of toluene to the concentrate, maintaining the temperature at 0–5 ℃, and slowly add 52.2 g (0.7 eq) of triethylamine dropwise. After the addition was complete, stirring was continued for 30 min. The mixture was then filtered, and the filter cake was washed with 190.0 mL (2 V) of toluene. The filtrates were combined and concentrated under reduced pressure at 40–45 °C and -0.1 MPa until solvent-free distillation was obtained to yield L-pyroglutamic acid ethyl ester (AVI-SM-1).

[0047] S2. Feeding: First, prepare the Boc anhydride solution by mixing 160.4 g (1.0 eq) of Boc anhydride with 190 mL (2 V) of toluene. Add all of the AVI-SM-1 obtained in the previous batch to 285 mL (3 V) of toluene and 1.8 g (0.02 eq) of DMAP, stir for 10 minutes, and slowly add the above Boc anhydride / toluene solution (containing 160.4 g of Boc anhydride and 190 mL of toluene) dropwise while controlling the temperature at 0–5 °C. After the addition is complete, raise the temperature of the reaction system to 25–30 °C and stir the reaction for 3–5 h, monitoring the process using HPLC. Post-processing: After the reaction was complete, 950 mL (10 V) of 5% sodium bicarbonate solution was added to the system. After stirring for 10 minutes, the mixture was allowed to stand and separate into layers. The organic phase was collected. The organic phase was then washed twice with 475 mL (5 V) of water, and the aqueous phases were combined. Subsequently, the combined aqueous phases were back-extracted with 285 mL (3 V) of toluene. The aqueous phase was discarded after separation (environmentally friendly treatment). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure at 40-45 °C and -0.1 MPa to obtain 162.0 g of the product Boc-L-pyroglutamic acid ethyl ester (AVI-SM).

[0048] S3. Feeding: Add 87.31 g (1.1 eq) of potassium tert-butoxide and 136.21 g (1.25 eq) of trimethyl sulfoxide (TMS) sequentially to a 2 L four-necked flask, followed by 567 ml (3.5 V) of THF. Mix and stir at 20–25 °C for 20 minutes, then cool to 0–5 °C. Slowly add dropwise a solution prepared by dissolving 162.0 g of Boc-L-pyroglutamic acid ethyl ester (AVI-SM) in 406 ml (2.5 V) of THF. After the addition is complete, maintain the reaction at 0–5 °C for 1–2 hours, monitoring the reaction progress via HPLC. Post-treatment: After the reaction is deemed satisfactory, maintain the system temperature at 0–5 °C and quench the reaction by adding dropwise a solution prepared by dissolving 11.5 g (0.3 eq) of acetic acid in 81 ml (0.5 V) of THF, adjusting the pH of the system to 7. After adjustment, control the temperature at 0~10 ℃, add 162 g (1 times the volume) of silica gel (type 70-230) to the system, and mix and stir for 30 minutes. Then filter, and wash the filter cake with 324 ml (2V) of THF. The resulting filtrate is the AVI-1 solution, which is used for the next feeding step; the filter cake is then disposed of in an environmentally friendly manner.

[0049] S4. Feeding: Add the THF solution of AVI-1 to a 3 L reaction flask, followed by 100.65 g (1.0 eq) of benzyloxyamine hydrochloride. Heat the system to 60 °C and react for 2 hours, monitoring the reaction progress via HPLC. Post-treatment: After the reaction is deemed satisfactory, cool the system to room temperature (20-25 °C) and filter to remove insoluble matter. Then, concentrate under reduced pressure to recover THF. After concentration, add 1296 ml (8 V) of EA and 810 g (5 V) of 10% sodium chloride solution to the system, mix and stir for 30 minutes, and let stand for 30-60 minutes. After the liquid separates into layers, treat the lower aqueous phase using environmentally friendly methods; the resulting upper organic phase is the AVI-2 solution, used for the next feeding step.

[0050] S5. Feeding 1 (Amine De-Boc Protection): Maintaining the system temperature within the range of 10–20 °C, slowly add 181.5 g (3.0 eq) of methanesulfonic acid dropwise to the EA solution of AVI-2. After the addition is complete, raise the system temperature to 42 °C and react for 2 hours, taking samples for HPLC analysis during this period. Feeding 2 (Catalytic Cyclation): Maintaining the system temperature within the range of 15–20 °C, add a solution prepared by dissolving 315.2 g (5.0 eq) of potassium bicarbonate in 810 g (5 V) of water dropwise to the above reaction system. A large number of bubbles are generated during the dropwise addition, accompanied by a small amount of exothermic reaction. After the dropwise addition is complete, raise the system temperature to 47–52 °C and stir vigorously at this temperature for 2 hours, taking samples for HPLC analysis during this period. Post-treatment: After the reaction passes the test, cool the system to room temperature (20–25 °C) and allow it to stand for phase separation. The organic phase was separated, and 486 g (3 V) of 20% sodium chloride solution was added. The mixture was stirred for 30 minutes and then allowed to stand for 30-60 minutes to allow for complete separation. After a second separation, the upper aqueous phase was treated using environmentally friendly methods, and the lower organic phase was concentrated under reduced pressure at 35-40°C. The concentration was reduced to approximately 972 ml (approximately 6 V based on the amount of Boc-L-pyroglutamic acid ethyl ester added). The resulting AVI-3 solution was used for the next feeding step; the filter cake was treated using environmentally friendly methods.

[0051] S6. Feeding 1 (Preparation of sodium triacetoxyborohydride): At 0–5 °C, 280 g of propionic acid (6.0 eq) was slowly added dropwise to 972 mL of EA (6 V) solution containing 47.5 g of sodium borohydride (2.0 eq). After the addition was complete, the solution was kept at this temperature and stirred for 6 hours. The resulting solution was then set aside. Feeding 2 (Selective Reduction of Oxime): The system temperature was controlled between -10 and 0 °C. 315 g of sulfuric acid (5.0 eq) was slowly added dropwise to the AVI-3 solution. After the addition was complete, the solution was stirred for 15–30 minutes, and the EA solution of sodium triacetoxyborohydride prepared above was slowly added dropwise while maintaining the temperature at -10 °C. After the addition was complete, the solution was kept at this temperature and stirred for 1–2 hours. Post-treatment: After the reaction was deemed satisfactory, 1620 mL of water (10 V) was added dropwise to the system at a temperature below 0 °C. The pH of the system was then adjusted to 8-9 by adding ammonia solution dropwise at a temperature <0 °C, consuming approximately 1412 g (16.0 eq) of 25% ammonia solution. After adjustment, the mixture was stirred for 30 minutes, allowed to stand for 30-60 minutes to separate into layers, and the lower aqueous phase was discarded. 810 g of water (5 V) was added to the upper organic phase, stirred for 30 minutes, allowed to stand for 30-60 minutes to separate into layers, and the aqueous phase was discarded again. The resulting organic phase was heated to 40-45 °C, and 6.48 g of activated carbon (4 wt%) was added for decolorization. After filtration, the filter cake was washed with 162 mL of EA (1 V). The filtrate was concentrated under reduced pressure, and the resulting AVI-4 viscous liquid was used for the next step (a small amount was purified for structural confirmation, and the chromatogram is shown below). Figure 1 (As shown); the filter cake is treated in an environmentally friendly manner.

[0052] S7. Feeding 1 (Oxalate Crystallization Experiment): Mix the viscous AVI-4 solution obtained in the previous step with 324 g of isopropanol (2 V) and heat to 40-45 °C. Slowly add a solution prepared by dissolving 79.37 g of oxalate dihydrate (1.0 eq) in 324 g of isopropanol (2 V). After the addition is complete, continue to add 162 g of water (1.0 V). After the addition is complete, maintain the temperature at 40-45 °C and stir for 30-60 minutes. Then, cool the system to 10-15 °C at a rate of 10 °C / 0.5 hours and continue stirring at this temperature for 1 hour. After the reaction is complete, filter the mixture. Wash the filter cake with 324 g of isopropanol (2 V) to obtain a white, crude AVI-5 product (wet product). Feeding 2 (Oxalate Purification): Add the above crude AVI-5 to 1036.8 g of isopropanol (6.4 V), heat to 70-75 °C, and stir until the solid is completely dissolved to form a clear solution. Then add 389 g of water (2.4 V) dropwise and continue stirring for 10-15 minutes. Afterward, cool the system to 10-15 °C at a rate of 10 °C / 0.5 hours and stir at this temperature for 1 hour. After the reaction is complete, filter the mixture, and wash the filter cake with 324 g of isopropanol (2 V) to obtain 115.5 g of off-white solid AVI-5 wet product. Drying: Place the above wet AVI-5 product in a vacuum drying oven and dry it at 50-52 °C and -0.1 MPa for 10-15 hours. During the drying process, the moisture content of the material needs to be monitored. If the moisture content is ≤0.5%, it is considered qualified; if it is not qualified, samples should be taken every 3 hours for testing until the moisture content meets the standard. The final product obtained was 97.4 g of dried oxalate AVI-5. Figure 2 This is the HPLC chromatogram of the product. Figure 3 The HPLC chiral purity test result for the product shows a purity of 99.88%, an ee value of 99.86%, and a total yield of 42%.

[0053] Example 2

[0054] Under the same conditions, DMAP (0.02 eq) in S2 was replaced with triethylamine (1.00 eq). HPLC monitoring showed that a small amount of raw material remained, which was not treated.

[0055] Example 3

[0056] Under the same conditions, the crystallization solvent in S7 was acetonitrile / water (4:1), and the resulting product had a purity of 99.93% and an overall yield of 41%.

[0057] Finally, it should be noted that:

[0058] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing an avibactam intermediate, characterized in that, Includes the following steps: S1. Under the action of acidic additives, AVI-SM-0 and ethanol undergo esterification reaction. After the reaction is completed, AVI-SM-1 is obtained by concentration, dilution, triethylamine quenching to remove acid, filtration, and concentration. S2. Add AVI-SM-I and an alkaline catalyst to the reaction solvent, then react with Boc anhydride. After the reaction is completed, AVI-SM is obtained by quenching, washing with water, extraction, drying and concentration. S3. AVI-SM, basic additives and sulfur ylide reagent are added to the reaction solvent to carry out an addition ring-opening reaction. After the reaction is completed, AVI-1 feed solution is obtained after post-treatment. The filtrate is then used directly for the next reaction. S4. Add benzyloxyamine hydrochloride to AVI-1 solution to carry out iminoization reaction. After the reaction is completed, concentrate and extract to obtain AVI-2 solution. S5. Add acidic additives to AVI-2 feed solution to complete Boc removal protection, and then add alkaline additives to complete catalytic ring closure. After post-treatment, AVI-3 feed solution is obtained. S6. Add sulfuric acid and sodium borohydride derivative to the above liquid to carry out a reduction reaction. After the reaction is completed, AVI-4 viscous substance is obtained by quenching, washing with water, decolorizing with activated carbon and concentrating. S7. Oxalic acid dihydrate is added to the above AVI-4 viscous substance to form a salt, and the salt is precipitated by a mixed solvent, purified by recrystallization in a mixed solvent, and dried to obtain compound AVI-5, which is the avibactam intermediate mentioned above. The synthetic route for the compound AVI-5 is as follows: .

2. The method for preparing the avibactam intermediate according to claim 1, characterized in that, The acidic additive in S1 is selected from one of thionyl chloride, concentrated sulfuric acid, or HCl. The solvent used in the reaction is selected from anhydrous ethanol or DMF.

3. The method for preparing the avibactam intermediate according to claim 1, characterized in that, The reaction solvent in S2 is one of acetonitrile, acetonitrile / water, toluene, toluene / water, or water; The alkaline catalyst is one of triethylamine, sodium carbonate, or sodium hydroxide.

4. The method for preparing the avibactam intermediate according to claim 1, characterized in that, The reaction solvent in S3 is selected from one of acetonitrile, THF, toluene, acetone, MTBE, DCM, 2-methyltetrahydrofuran, DMSO / toluene, DMSO / acetonitrile, DMSO / THF, DMSO / 2-methyltetrahydrofuran, DMF / THF, and DMF / acetonitrile. The alkaline additive is selected from one of sodium tert-butoxide, sodium tert-amyloxide, sodium methoxide, sodium ethoxide, potassium tert-amyloxide, potassium ethoxide, and potassium tert-butoxide. The thioyl ylide reagent is selected from trimethyl thionyl chloride, trimethyl thionyl bromide, and trimethyl thionyl iodide; Post-processing includes: ammonium chloride / water quenching followed by EA extraction and concentration, or acetic acid quenching and filtration followed by direct use in the next step.

5. The method for preparing the avibactam intermediate according to claim 1, characterized in that, The acidic additive in S5 is selected from one of methanesulfonic acid, HCl / EA, concentrated sulfuric acid, formic acid, and acetic acid; the basic additive in the ring-closing reaction is an organic base or an inorganic base. The organic base is selected from one of aniline, n-propylamine, ethanolamine, isopropanolamine, pyridine, morpholine, diethylamine, DIPEA, 1,4-dimethylpiperazine, and triethylamine, and the inorganic base is selected from one of potassium acetate, sodium ethoxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium phosphate, sodium phosphate, and potassium bicarbonate.

6. The method for preparing the avibactam intermediate according to claim 5, characterized in that, The acidic additive in S5 is selected from methanesulfonic acid; The basic additive in the ring-closing reaction is sodium bicarbonate or potassium bicarbonate.

7. The method for preparing the avibactam intermediate according to claim 1, characterized in that, The reducing agent in S6 is selected from one of sodium tripropionyloxyborohydride, sodium tributyryloxyborohydride, and sodium trivalveyloxyborohydride; the reaction temperature is -10~0 ℃.

8. The method for preparing the avibactam intermediate according to claim 7, characterized in that, The reducing agent in S6 is selected from sodium tripropionyloxyborohydride.

9. The method for preparing the avibactam intermediate according to claim 1, characterized in that, The salt-forming and recrystallization solvent in S7 is selected from one of EA / ethanol, EA / THF, EA / acetone, EA / acetonitrile, EA / IPA, THF / water, acetonitrile / water, acetone / water, ethanol / water, and IPA / water.

10. The method for preparing the avibactam intermediate according to claim 9, characterized in that, The salt-forming and recrystallization solvents in S7 are selected from a mixed solvent of IPA / water with a volume ratio of 2:1.

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