Chemical synthesis method of avibactam sodium

Abstract

The invention discloses a chemical synthesis method of avibactam sodium, which comprises the following steps: with (2S)-5-[(benzyloxy) imino] piperidine-2-carboxylic acid ethyl ester as a starting material, carrying out selective reduction under the action of a hand-shaped inducer and a reducing agent to construct 5-site chiral carbon, and carrying out oxalic acid resolution to obtain high-purity oxalate, and then carrying out five-step reaction, namely intramolecular ureization, acylase catalytic hydrolysis amidation, debenzylsulfonic acid esterification salification and sodium ion exchange, so as to obtain the avibactam sodium. According to the method, the chiral inducer is adopted to induce selective reduction, and the acylase catalytic ammonolysis process is optimized, so that the content of isomer impurities in the product is remarkably reduced, and the purity and the overall yield of the product are improved. Wherein the acylase catalytic ammonolysis reaction conditions are mild, and the process safety risk is greatly reduced while the energy consumption is reduced.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis pharmaceutical technology, specifically relating to a chemical synthesis method for avibactam sodium. Background Technology

[0002] Avibactan sodium is a new generation of long-acting β-lactamase inhibitors. While it does not possess significant antibacterial activity on its own, it inhibits both type A (including ESBL and KPC) and type C β-lactamases. When used in combination with various cephalosporins and carbapenems, avibactan sodium exhibits broad-spectrum antibacterial activity, particularly against drug-resistant bacteria such as *Escherichia coli* and *Klebsiella pneumoniae* containing extended-spectrum β-lactamases, *E. coli* containing excessive amounts of AmpC enzymes, and *E. coli* containing both AmpC and extended-spectrum β-lactamases. Avibactan sodium can be combined with various drugs to form compound preparations, such as: avibactan sodium + ceftazidime, avibactan sodium + cefuroxime, avibactan sodium + aztreonam, ceftazidime-avibactan sodium-metronidazole, etc.

[0003] Avibactan sodium is a diazabicyclooctane compound. Its chemical name is: [(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-6-yl]sodium sulfate, molecular formula: C 14 H 17 N3O3, molecular weight: 287.23, CAS number: 1192491-61-4, its structural formula is as follows:

[0004] Currently, the main methods for synthesizing avibactam sodium reported both domestically and internationally are as follows: Method 1: The original patent CN1289500C discloses a method for preparing avibactam sodium, and the synthetic route is as follows:

[0005] This synthetic route begins with an L-pyroglutamic acid derivative, followed by triphosgene cyclization and saponification to remove the allyl group, yielding a carboxylic acid intermediate. This intermediate is then activated with isobutyl chloroformate and reacted with ammonia to generate a primary amide intermediate. The benzyl group is removed via hydrogenolysis, followed by acidification and salt formation under the action of a sulfur trioxide-pyridine complex to obtain avibactam tetrabutylammonium salt. Finally, avibactam sodium is obtained via sodium ion exchange resin, with an overall yield of approximately 30%. The L-pyroglutamic acid derivative, containing a piperidine ring with two chiral centers, is a challenging and expensive raw material. Furthermore, the saponification reaction during the allyl group removal process has a low yield and is prone to generating ring-opening impurities, making industrial-scale production difficult.

[0006] Method 2: Another method for synthesizing avibactam sodium is disclosed in patent WO2012172368A1. The synthetic route is as follows:

[0007] This route uses N-Boc-L-pyroglutamic acid ethyl ester (or benzyl ester) as the starting material and proceeds through 13 steps including ring opening, nucleophilic substitution, deBoc, cyclization, reduction, ammonolysis, intramolecular ureation, debenzylation, sulfonation, salt formation, and cation exchange to obtain sodium avibactam. The synthetic route is relatively simple and has a high yield. Although it has more steps than the first route, the cost is significantly lower, making it a promising route for industrialization.

[0008] However, this route still faces the following prominent problems: expensive starting materials; demanding and complex operation of some process conditions; low selectivity of key reduction reactions, affecting yield; and the generation of highly toxic byproducts, which is unsafe and environmentally unfriendly. These factors all hinder its large-scale production.

[0009] Method 3: Patent WO2012086241A1 discloses another method for synthesizing avibactam sodium. The synthetic route is as follows:

[0010] This synthetic method uses (S)-1-(benzyloxycarbonyl)-5-oxopyrrolidine-2-carboxylic acid as the starting material, and proceeds through 15 steps including tert-butylation, thioylide reaction, cyclization, reduction, de-Cbz, acylation protection, nucleophilic substitution, deprotection, intramolecular ureation, acid deprotection, esterification, ammonolysis, debenzylation, sulfonation, and cation exchange to obtain sodium avibactam. This synthetic route suffers from problems such as lengthy procedures, cumbersome operations, and low yield. The starting materials are expensive, the reaction time is long, and each intermediate step requires silica gel column chromatography separation, resulting in high overall production costs and low efficiency, making it difficult to meet the requirements of industrial production. Summary of the Invention

[0011] To overcome the deficiencies in existing technologies, this invention provides a chemical synthesis method for avibactam sodium. The method uses (2S)-5-[(benzyloxy)imino]piperidine-2-carboxylic acid ethyl ester (compound I) as the starting material. Selective reduction is carried out under the action of a chiral inducer and a reducing agent to construct a 5-chiral carbon. High-purity oxalate is obtained by resolution with oxalic acid, followed by a five-step reaction involving intramolecular ureation, acylase-catalyzed hydrolysis and amidation, debenzylate sulfonation to form a salt, and sodium ion exchange to obtain avibactam sodium. This invention significantly reduces the content of isomer impurities in the product and improves product purity and overall yield by employing a chiral inducer to induce selective reduction combined with optimization of the acylase-catalyzed ammonolysis process. Furthermore, the acylase-catalyzed ammonolysis reaction conditions are mild, reducing energy consumption and significantly lowering process safety risks.

[0012] The technical solution adopted to achieve the above objective is: a chemical synthesis method for avibactam sodium, characterized by comprising the following steps:

[0013] S1: Compound I undergoes selective reduction with a reducing agent in an aprotic solvent under the action of a chiral inducing agent and a strong acid, followed by oxalic acid salt formation to obtain compound II; S2: In an organic solvent, under the action of an organic base, compound II reacts with triphosgene to give compound III; S3: Compound III undergoes hydrolysis and amidation with ammonia in a mixed solvent via the catalysis of an acylase to yield compound IV; S4: Compound IV reacts with hydrogen in an organic solvent under palladium on carbon catalysis to debenzylate, and simultaneously undergoes sulfonation with a sulfur trioxide complex, followed by reaction with an ammonium salt to form compound V; S5: Compound V undergoes an ion exchange reaction with a sodium salt in an organic solvent to yield avibactam sodium.

[0014] Further, the aprotic solvent used in step S1 is one of dichloromethane, 1,2-dichloroethane, ethyl acetate, and tetrahydrofuran, preferably ethyl acetate; the strong acid used is one of hydrochloric acid, sulfuric acid, and trifluoroacetic acid, preferably sulfuric acid; the reducing agent used is one of sodium borohydride, sodium triacetoxyborohydride, and sodium tripropionyloxyborohydride, preferably sodium tripropionyloxyborohydride; the chiral inducing agent used is one of L-camphorsulfonic acid, L-threonine, L-glutamic acid, and L-tartaric acid, preferably L-tartaric acid; the molar ratio of compound I, reducing agent, and chiral inducing agent is 1:2.0~2.5:0.1~0.5, preferably 1:2.3:0.3; the reduction reaction time is 8~12 h, and the reaction temperature is -20~0℃, preferably -10~-5℃.

[0015] Furthermore, the organic solvent used in step S2 is one of ethyl acetate, isopropyl acetate, and toluene, preferably ethyl acetate; the organic base used is one of triethylamine, pyridine, and piperazine, preferably triethylamine; the molar ratio of compound II to triphosgene is 1:0.35~1.0, preferably 1:0.45; the reaction time is 0.5~5h, and the reaction temperature is 20~50℃, preferably 40℃.

[0016] Furthermore, the mixed solvent used in step S3 is one of isooctanol / water mixed solution and acetone / water mixed solution, wherein the mixing ratio of isooctanol / water mixed solution is 1:5~10, and the mixing ratio of acetone / water mixed solution is 1:4~8; the acylase used is one of immobilized penicillin G acylase and immobilized cephalosporin C acylase, preferably immobilized penicillin G acylase, and the amount used is 10~40% of the mass of compound III; the pH required for the hydrolysis reaction is controlled between 6.0 and 6.8; the pH required for the amidation reaction is controlled between 6.8 and 7.5, preferably 7.0~7.3; the concentration of ammonia water used is preferably 30%, the amidation reaction time is 5~10h, and the reaction temperature is 10~15℃.

[0017] Furthermore, in step S4, the organic solvent used for debenzylation is either methanol or ethanol, preferably methanol; the hydrogen pressure is 0.4~0.6 MPa; the sulfur trioxide complex used is either trimethylamine sulfur trioxide or pyridine sulfur trioxide, preferably trimethylamine sulfur trioxide; the debenzylation reaction temperature is controlled at 15~35°C; the organic solvent used for the salt formation reaction is ethanol, and the ammonium salt is preferably tetrabutylammonium acetate; the salt formation reaction time is 2~3 h, and the reaction temperature is 15~30°C. The molar ratio of compound IV, the sulfur trioxide complex, and the ammonium salt is 1:1.0~1.5:1.0~1.5.

[0018] Furthermore, the organic solvent used in step S5 is ethanol, and the sodium salt is sodium isooctanoate; the reaction time is 4-5 hours, and the reaction temperature is -5 to 5°C. The molar ratio of compound V to sodium isooctanoate is 1:2.0-3.0.

[0019] Furthermore, a preferred embodiment of the present invention is as follows: S1: Add compound I and ethyl acetate to the reaction vessel, and add concentrated sulfuric acid dropwise while controlling the temperature within -10 to -5℃. After the addition is complete, add a chiral inducing agent, and add sodium tripropionyloxyborohydride while controlling the temperature within -10 to -5℃. After the addition is complete, keep the reaction at the specified temperature. After the reaction is complete, quench the reaction with water. Adjust the pH of the system to 7.5 to 8.5 with concentrated ammonia, let it stand to separate the layers, separate the liquid and take the organic phase. Wash the organic phase with salt, stir and heat to 40 to 50℃, add oxalic acid, keep the reaction at the specified temperature, and after the reaction is complete, cool down to precipitate a solid to obtain compound II. S2: Add compound II, ethyl acetate and triethylamine to the reaction vessel, add ethyl acetate solution of triphosgene dropwise at room temperature. After the addition is complete, heat to 20~50℃ and keep the temperature for reaction. After the reaction is complete, add sodium carbonate aqueous solution, extract and separate the liquid, combine the organic phases, evaporate to dryness under reduced pressure to obtain yellow oily compound III, and proceed directly to the next reaction. S3: Compound III was added to an isooctanol / water mixture, the temperature was controlled at 10-15℃, the pH was adjusted to 6.0-6.8, immobilized penicillin G acylase was added and the reaction was incubated; then ammonia was slowly added dropwise, and the pH was controlled at 7.0-7.3. After the ammonia was added, the reaction was incubated. After the reaction was completed, the pH was adjusted to 1-2, filtered, the acylase was washed with purified water and recovered, the aqueous layer was collected, the pH was then adjusted to 7.5-8.0 with ammonia, the temperature was controlled at 10-15℃, crystals were precipitated, filtered, and vacuum dried to obtain compound IV; S4: Compound IV was dissolved in methanol, palladium on carbon, trimethylamine sulfur trioxide, and triethylamine were added, and then hydrogen gas was introduced into the system to pressurize the reaction. The pressure was maintained at 0.4~0.6 MPa and the temperature was maintained at 25~30℃. Then tetrabutylammonium acetate was added, and after the reaction was maintained at the temperature, the temperature was lowered to 5~10℃ to crystallize. The crystals were filtered, and the filter cake was dried under vacuum to obtain compound V. (5) Formation of sodium salt Compound V was dissolved in ethanol, and then an ion exchange reaction was carried out by adding an ethanol solution of sodium isooctanoate dropwise at a controlled temperature of 20-30°C. The reaction temperature was -5-5°C. After the reaction was completed, the mixture was filtered, washed and dried to finally obtain sodium avibactam.

[0020] Compared with the prior art, the advantages of the present invention are as follows: 1. This invention uses (2S)-5-[(benzyloxy)imino]piperidine-2-carboxylic acid ethyl ester (compound I) as the starting material, and obtains avibactam sodium through a five-step reaction involving selective reduction, intramolecular ureation, hydrolysis and amidation, debenzylation and salt formation, and sodium ion exchange reaction. Compared with the synthesis method mentioned in patent WO2012172368A1, the steps are shorter, the operation is more continuous and simple, and the overall yield is increased to 65%, making it suitable for industrial production.

[0021] 2. This invention reduces the content of isomer impurities and significantly improves the product yield by using a chiral inducer to induce selective reduction in the selective reduction reaction, while solving the problem of difficult subsequent isomer purification.

[0022] 3. This invention improves the ammonolysis process catalyzed by acylase, reducing the original two-step reaction of ester hydrolysis and amide condensation to a single step, thereby increasing the product yield. Furthermore, the ammonolysis catalyzed by acylase can be carried out at room temperature, thus reducing energy consumption and significantly reducing process safety risks. At the same time, the acylase can be recycled and reused, which also greatly reduces production costs. Attached Figure Description

[0023] Figure 1 The HPLC chromatogram of the avibactam sodium product obtained in Example 1 is shown below. Figure 2 The single-crystal diffraction pattern of the sodium avibactam product obtained in Example 1; Figure 3 The results are HPLC analysis of the reaction solution from the selective reduction reaction in Example 1. Figure 4 The results are obtained by HPLC analysis of compound II obtained from the selective reduction reaction in Example 1. Specific Implementation The technical solution of the present invention is illustrated below with specific embodiments, but the scope of protection of the present invention is not limited thereto: Example 1: (1) Selective reduction reaction Add 1 kg of compound I and 4 L of ethyl acetate to the reaction flask. Stir at room temperature until dissolved, then cool to -10 to -5 °C. While maintaining the temperature within this range, slowly add 1 L of concentrated sulfuric acid dropwise to the reaction flask. After the addition is complete, add 162.96 g of L-tartaric acid. While maintaining the temperature within this range, add 2.11 kg of sodium tripropionyloxyborohydride in batches. After the addition is complete, maintain the reaction temperature for 10 h. After the reaction is complete, the proportion of enantiomeric impurities in the reaction solution (target configuration: see [reference]) should be recorded. Figure 3 The reaction was quenched by slowly adding 10 L of water to the system. After the addition was complete, the pH of the system was adjusted to 8.0 with concentrated ammonia, and the mixture was allowed to stand to separate into layers. The organic phase was separated and collected. The organic phase was washed twice with 2 L of 20% NaCl aqueous solution, transferred to a reaction flask, stirred and heated to 45 °C, and 358.57 g of oxalic acid was added. After stirring at this temperature for 1 hour, the mixture was cooled to room temperature and stirred at this temperature for 2 hours. The mixture was then filtered, and the filter cake was washed with 0.5 L of ethyl acetate. The obtained wet product was dried under vacuum at 40-50 °C to obtain 1147.38 g of compound II (white solid powder) with a total purity of 99.82% and enantiomer impurities accounting for 0.02% (see [reference]). Figure 4 The reaction solution underwent chiral resolution with oxalic acid, which effectively removed the isomers. The yield of this step was 86.10%.

[0025] The method for detecting the quality of the reaction in this step is as follows: The determination was performed according to the high performance liquid chromatography method (Chinese Pharmacopoeia 2015 Edition, Part IV, General Chapter 0512), using octadecylsilane-bonded silica gel as the packing material (Waters XBridge C18 column, 4.6 mm × 150 mm, 3.5 μm or equivalent column); the mobile phase A was 0.02 mol / L dipotassium hydrogen phosphate solution (3.48 g of dipotassium hydrogen phosphate was dissolved in 1000 ml of water and the pH was adjusted to 6.0 with phosphoric acid) - acetonitrile (90:10), and the mobile phase B was 0.02 mol / L dipotassium hydrogen phosphate solution - acetonitrile (30:70), with gradient elution according to Table 1; the flow rate was 0.8 ml / min; the column temperature was 35 ℃; the sample chamber temperature was 5 ℃; and the detection wavelength was 210 nm.

[0026] Table 1 Gradient elution program

[0027] (2) Urea formation reaction 500g of compound II was added to a reaction flask, followed by 2L of ethyl acetate and 550g of triethylamine. 322.6g of triphosgene solution (dissolved in 2L of ethyl acetate) was added dropwise at room temperature. After the addition was complete, the temperature was raised to 40℃ and the reaction was maintained for 30min. After the reaction was completed, an aqueous sodium carbonate solution (350g of sodium carbonate dissolved in 1.5L of water) was added. The mixture was extracted and separated. The aqueous layer was back-extracted with 2L of ethyl acetate. The organic phases were combined and evaporated to dryness under reduced pressure at 35℃ to obtain a yellow oily compound III, which was then directly used for the next reaction.

[0028] (3) Hydrolysis and amidation reaction Add 2.5 L of isooctanol / water mixture (1:5) to compound III obtained in the previous step. After stirring evenly, control the temperature at 10-15℃, adjust the pH to 6.5 with 10% dilute hydrochloric acid, add 250 g of washed immobilized penicillin G acylase (50% water content, enzyme activity: 400 U / g), and incubate the reaction for 2 h. During the reaction, control the pH between 6.0 and 6.8 with 10% dilute hydrochloric acid. Then, slowly add 30% ammonia water and add 10% dilute hydrochloric acid dropwise to control the pH. After the addition of the solution was complete, the temperature was controlled at 10-15℃ and the pH at 7.0-7.3, and the reaction was maintained at this temperature for 6 hours. After the reaction was completed, the pH was adjusted to 1-2 with 10% dilute hydrochloric acid, filtered, and the acylase was washed with purified water and recovered. The aqueous layer was collected, and then the pH was adjusted to 7.5-8.0 with ammonia water. The temperature was controlled at 10-15℃, and crystallization was allowed to occur for 2 hours. The mixture was then filtered, and the filter cake was vacuum dried at 40-50℃ to obtain 325.10 g of compound IV (pale yellow solid powder). The two-step yield was 87.13%.

[0029] (4) Reduction and salt formation 50g of compound IV was dissolved in 500mL of methanol, and 5.0g of 10% palladium on carbon, 28.5g of sulfur trioxide trimethylamine, and 6.25mL of triethylamine were added. Hydrogen gas was then introduced into the system to pressurize the reaction, maintaining the pressure at 0.4~0.6MPa and the temperature at 25~30℃ for 4.5h. Then 75g of tetrabutylammonium acetate was added, and the reaction was maintained at this temperature for 2.5h. After that, the temperature was lowered to 5~10℃ for 2h to crystallize. The crystals were filtered, and the filter cake was dried under vacuum at 35~40℃ to obtain 85.15g of compound V, with a yield of 92.60%.

[0030] (5) Formation of sodium salt 50g of compound V was dissolved in 400mL of ethanol. Then, 200mL of an ethanol solution of sodium isooctanoate (4g / 40mL) was added dropwise at 20-30°C to initiate an ion exchange reaction for 4.5h at -5 to 5°C. After the reaction was complete, the solution was filtered, washed, and dried to obtain 26.93g of avibactam sodium, with a yield of 95.02%. The HPLC chromatogram of the avibactam sodium product obtained in Example 1 is shown below. Figure 1 As shown, the single-crystal diffraction pattern of the sodium avibactam product obtained in Example 1 is as follows. Figure 2 As shown.

[0031] Example 2 (Step S1: Selective reduction reaction) Add 100g of compound I and 400ml of ethyl acetate to a reaction flask. Stir at room temperature until dissolved, then cool to -10 to -5℃. Slowly add 100ml of concentrated sulfuric acid dropwise while maintaining the temperature at -10 to -5℃. After the addition is complete, add 15.98g of L-glutamic acid. While maintaining the temperature at -10 to -5℃, add 211g of sodium tripropionyloxyborohydride in batches. After the addition is complete, maintain the reaction temperature for 10 hours. After the reaction is complete, quench the reaction by slowly adding 1L of water to the reaction solution (target configuration: enantiomer impurity = 8.5:1). After the addition is complete, adjust the pH of the system to 8.0 with concentrated ammonia, allow it to stand and separate into layers, and separate the organic phase. The organic phase was washed twice with 200 ml of 20% NaCl aqueous solution. The organic phase was then transferred to a reaction flask, stirred, and heated to 45°C. 35.86 g of oxalic acid was added, and the mixture was stirred and maintained at this temperature for 1 hour. After cooling to room temperature, the mixture was stirred and maintained at this temperature for 2 hours. The mixture was then filtered, and the filter cake was washed with 50 ml of ethyl acetate. The resulting wet product was dried under vacuum at 40–50°C to give 108.34 g of compound II (white solid powder) with a total purity of 99.75%, containing 0.05% enantiomers. The yield for this step was 81.30%.

[0032] Example 3 (Step S1: Selective reduction reaction) Add 100g of compound I and 400ml of ethyl acetate to a reaction flask. Stir at room temperature until dissolved, then cool to -10 to -5℃. Slowly add 100ml of concentrated sulfuric acid dropwise while maintaining the temperature at -10 to -5℃. After the addition is complete, add 25.22g of L-camphorsulfonic acid. While maintaining the temperature at -10 to -5℃, add 211g of sodium tripropionyloxyborohydride in batches. After the addition is complete, maintain the reaction temperature for 10 hours. After the reaction is complete, quench the reaction by slowly adding 1L of water to the reaction solution (target configuration: enantiomer impurity = 8:1). After the addition is complete, adjust the pH of the system to 8.0 with concentrated ammonia, allow it to stand to separate the layers, and separate the organic phase. The organic phase was washed twice with 200 ml of 20% NaCl aqueous solution. The organic phase was then transferred to a reaction flask, stirred, and heated to 45°C. 35.86 g of oxalic acid was added, and the mixture was kept at this temperature and stirred for 1 hour. After cooling to room temperature, the mixture was kept at this temperature and stirred for 2 hours. The mixture was then filtered, and the filter cake was washed with 50 ml of ethyl acetate. The resulting wet product was dried under vacuum at 40–50°C to give 100.28 g of compound II (white solid powder) with a total purity of 99.72%, containing 0.06% enantiomers. The yield for this step was 75.25%.

[0033] Example 4 (Step S1: Selective reduction reaction) Add 100g of compound I and 400ml of ethyl acetate to a reaction flask. Stir at room temperature until dissolved, then cool to -10 to -5℃. Slowly add 100ml of concentrated sulfuric acid dropwise while maintaining the temperature within -10 to -5℃. After the addition is complete, add 12.93g of L-threonine. While maintaining the temperature within -10 to -5℃, add 211g of sodium tripropionyloxyborohydride in batches. After the addition is complete, maintain the reaction temperature for 10 hours. After the reaction is complete, quench the reaction by slowly adding 1L of water to the reaction solution (target configuration: enantiomer impurity = 8.3:1). After the addition is complete, adjust the pH of the system to 8.0 with concentrated ammonia, allow it to stand and separate into layers, and separate the organic phase. The organic phase was washed twice with 200 ml of 20% NaCl aqueous solution. The organic phase was then transferred to a reaction flask, stirred, and heated to 45°C. 35.86 g of oxalic acid was added, and the mixture was kept at this temperature and stirred for 1 hour. After cooling to room temperature, the mixture was kept at this temperature and stirred for 2 hours. The mixture was then filtered, and the filter cake was washed with 50 ml of ethyl acetate. The resulting wet product was dried under vacuum at 40–50°C to give 104.65 g of compound II (white solid powder) with a total purity of 99.74%, containing 0.05% enantiomers. The yield for this step was 78.53%.

[0034] Example 5 (Step S3: Hydrolysis and amidation reaction) Add 250 ml of isooctanol / water mixture (1:5) to compound III (equivalent to 50 g of compound II), stir well, and maintain the temperature at 10-15°C. Adjust the pH to 6.5 with 10% dilute hydrochloric acid. Add 25 g of washed immobilized cephalosporin C acylase (50% water content, enzyme activity: 110 U / g), and incubate for 2 hours. During the reaction, maintain the pH between 6.0 and 6.8 with 10% dilute hydrochloric acid. Then, slowly add 30% ammonia water, followed by 10%... The pH was controlled between 7.0 and 7.3 with dilute hydrochloric acid. After the addition was complete, the pH was maintained at 7.0-7.3 and the reaction was maintained at this temperature for 6 hours. After the reaction was completed, the pH was adjusted to 1-2 with 10% dilute hydrochloric acid. The mixture was filtered, and the acylase was washed with purified water and recovered. The aqueous layer was collected, and then the pH was adjusted to 7.5-8.0 with ammonia. The temperature was controlled at 10-15℃, and crystallization was allowed to occur for 2 hours. The mixture was then filtered, and the filter cake was vacuum dried at 40-50℃ to obtain 31.35 g of compound IV (pale yellow solid powder). The two-step yield was 84.02%.

Claims

1. A chemical synthesis method for avibactam sodium, characterized in that, Includes the following steps: S1: Compound I undergoes selective reduction with a reducing agent in an aprotic solvent under the action of a chiral inducing agent and a strong acid, followed by oxalic acid salt formation to obtain compound II; S2: In an organic solvent, under the action of an organic base, compound II reacts with triphosgene to give compound III; S3: Compound III undergoes hydrolysis and amidation with ammonia in a mixed solvent via the catalysis of an acylase to yield compound IV; S4: Compound IV reacts with hydrogen in an organic solvent under palladium on carbon catalysis to debenzylate, and simultaneously undergoes sulfonation with a sulfur trioxide complex, followed by reaction with an ammonium salt to form compound V; S5: Compound V undergoes an ion exchange reaction with a sodium salt in an organic solvent to yield avibactam sodium.

2. The chemical synthesis method of avibactam sodium as described in claim 1, characterized in that, In step S1 The aprotic solvent used is one of dichloromethane, 1,2-dichloroethane, ethyl acetate, and tetrahydrofuran; The strong acid used is one of hydrochloric acid, sulfuric acid, and trifluoroacetic acid; The reducing agent used is one of sodium borohydride, sodium triacetoxyborohydride, and sodium tripropionyloxyborohydride; The chiral inducer used is one of L-camphorsulfonic acid, L-threonine, L-glutamic acid, and L-tartaric acid.

3. The chemical synthesis method of avibactam sodium as described in claim 1, characterized in that, In step S1, the reduction reaction time is 8~12h and the reaction temperature is -20~0℃.

4. The chemical synthesis method of avibactam sodium as described in claim 1, characterized in that, In step S2, the organic solvent used is one of ethyl acetate, isopropyl acetate, and toluene; the organic base used is one of triethylamine, pyridine, and piperazine.

5. The chemical synthesis method of avibactam sodium as described in claim 1, characterized in that, In step S2, the reaction time is 0.5~5h and the reaction temperature is 20~50℃.

6. The chemical synthesis method of avibactam sodium as described in claim 1, characterized in that, The mixed solvent used in step S3 is one of isooctanol / water mixed solution and acetone / water mixed solution; the acylase used is one of immobilized penicillin G acylase and immobilized cephalosporin C acylase.

7. The chemical synthesis method of avibactam sodium as described in claim 1, characterized in that, In step S3, the pH required for the hydrolysis reaction is controlled at 6.0~6.8; the pH required for the amidation reaction is controlled at 6.8~7.5; the amidation reaction time is 5~10h, and the reaction temperature is 10~15℃.

8. The chemical synthesis method of avibactam sodium as described in claim 1, characterized in that, In step S4, the organic solvent used for debenzylation is either methanol or ethanol; the hydrogen pressure is 0.4~0.6 MPa; the sulfur trioxide complex used is either trimethylamine sulfur trioxide or pyridine sulfur trioxide; the debenzylation reaction temperature is controlled at 15~35°C; the organic solvent used for the salt formation reaction is ethanol; the salt formation reaction time is 2~3 hours, and the reaction temperature is 15~30°C.

9. The chemical synthesis method of avibactam sodium as described in claim 1, characterized in that, The organic solvent used in step S5 is ethanol, and the sodium salt is sodium isooctanoate; the reaction time is 4-5 hours, and the reaction temperature is -5-5°C.

10. A method for the chemical synthesis of avibactam sodium according to any one of claims 1-9, characterized in that, S1: Add compound I and ethyl acetate to the reaction vessel, and add concentrated sulfuric acid dropwise while controlling the temperature within -10 to -5℃. After the addition is complete, add a chiral inducing agent, and add sodium tripropionyloxyborohydride while controlling the temperature within -10 to -5℃. After the addition is complete, keep the reaction at the specified temperature. After the reaction is complete, quench the reaction with water. Adjust the pH of the system to 7.5 to 8.5 with concentrated ammonia, let it stand to separate the layers, separate the liquid and take the organic phase. Wash the organic phase with salt, stir and heat to 40 to 50℃, add oxalic acid, keep the reaction at the specified temperature, and after the reaction is complete, cool down to precipitate a solid to obtain compound II. S2: Add compound II, ethyl acetate and triethylamine to the reaction vessel, add ethyl acetate solution of triphosgene dropwise at room temperature. After the addition is complete, heat to 20~50℃ and keep the temperature for reaction. After the reaction is complete, add sodium carbonate aqueous solution, extract and separate the liquid, combine the organic phases, evaporate to dryness under reduced pressure to obtain yellow oily compound III, and proceed directly to the next reaction. S3: Compound III was added to an isooctanol / water mixture, the temperature was controlled at 10-15℃, the pH was adjusted to 6.0-6.8, and immobilized penicillin G acylase was added and the reaction was incubated. Then, ammonia was slowly added dropwise, and the pH was controlled at 7.0-7.

3. After the ammonia was added, the reaction was incubated. After the reaction was completed, the pH was adjusted to 1-2, the mixture was filtered, and the acylase was washed with purified water and recovered. The aqueous layer was collected, and the pH was adjusted to 7.5-8.0 with ammonia. The temperature was controlled at 10-15℃, crystals were precipitated, filtered, and dried under vacuum to obtain compound IV. S4: Compound IV was dissolved in methanol, palladium on carbon, trimethylamine sulfur trioxide, and triethylamine were added, and then hydrogen gas was introduced into the system to pressurize the reaction. The pressure was maintained at 0.4~0.6 MPa and the temperature was maintained at 25~30℃. Then tetrabutylammonium acetate was added, and after the reaction was maintained at the temperature, the temperature was lowered to 5~10℃ to crystallize. The crystals were filtered, and the filter cake was dried under vacuum to obtain compound V. (5) Formation of sodium salt Compound V was dissolved in ethanol, and then an ion exchange reaction was carried out by adding an ethanol solution of sodium isooctanoate dropwise at a controlled temperature of 20-30°C. The reaction temperature was -5-5°C. After the reaction was completed, the mixture was filtered, washed and dried to finally obtain sodium avibactam.

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