Synthesis method of tazobactam intermediate debrominated sulfoxide ester
The tazobactam intermediate debrominated sulfoxide was synthesized via a three-step one-pot method of bromination-esterification-oxidation-debromination. Sodium hypochlorite and benzophenone hydrazone were used instead of peracetic acid, and light and ascorbic acid were used instead of zinc powder. This method solved the cumbersome operation and safety issues of traditional processes, achieving high yield and high purity, and is suitable for industrial applications.
Patent Information
- Application Number
- CN202511894793.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-12-16
- Publication Date
- 2026-01-13
AI Technical Summary
The existing synthesis process for the tazobactam intermediate debrominated sulfoxide is cumbersome, has low yield, is unsafe due to the use of hazardous chemicals such as peracetic acid, causes severe equipment corrosion, and makes it difficult to separate zinc powder, resulting in high production costs and unstable product quality.
The synthesis was carried out using a three-step one-pot method of bromination-esterification-oxidation-debromination. Sodium hypochlorite and benzophenone hydrazone were used to replace peracetic acid, and light and ascorbic acid were used to replace zinc powder, which simplified the operation process and improved the reaction efficiency and safety.
The production process has been simplified, the molar yield has been increased to 87%, the loss of mother liquor has been reduced, and the purity and safety of the product have been improved, making it suitable for industrial production.
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Figure CN121319005A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of chemical synthesis, specifically relating to a method for synthesizing a tazobactam intermediate, debromosulfoxide ester. Background Technology
[0002] Tazobactam, an important β-lactamase inhibitor, has wide applications in the pharmaceutical field. When tazobactam sodium is used in combination with piperacillin sodium, it produces a significant synergistic effect and is widely used to treat severe systemic and local infections, abdominal infections, lower respiratory tract infections, soft tissue infections, and sepsis. Debromosulfoxide (also known as a 6-debromo-6-sulfonylpenicillinic acid derivative) is a key intermediate in the production of tazobactam, and its efficient preparation is crucial for the large-scale production of tazobactam.
[0003] The traditional synthetic route for debrominated sulfoxides uses 6-aminopenicillanic acid (hereinafter referred to as 6-APA) as the starting material and proceeds through four steps: bromination, oxidation, esterification and debromination to obtain the target product. The synthetic route is shown below.
[0004]
[0005] The above synthetic route consists of four steps, using flammable and explosive organic solvents such as ethanol, acetone, and methanol. Intermediates 2 and 3 need to be separated before proceeding to the next step, making the operation cumbersome. Furthermore, the mother liquor produced during solid separation contains a large amount of material, leading to significant material loss and a low yield; the molar yield of the four-step reaction is only 73%. Before the esterification reaction (i.e., before the addition of the diphenylmethyl ester protecting group), the intermediates have relatively poor stability, and the lactam bond is easily hydrolyzed and ring-opened, affecting product quality and yield. The esterification step uses peracetic acid, a hazardous chemical with poor stability, easy decomposition, and difficult storage. During the reaction, it easily further oxidizes intermediate 3, producing sulfone byproducts. Moreover, the peracetic acid reaction produces glacial acetic acid, which contains carboxylic acid and competes with intermediate 2 for reaction, resulting in a large consumption of diphenylmethyl ketone hydrazone. The debromination step uses a large amount of zinc powder, which is difficult to completely separate from the reaction system, requiring complex filtration and washing operations, and placing high demands on the corrosion resistance of the equipment. Summary of the Invention
[0006] To address the shortcomings of existing technologies, this invention provides a method for synthesizing the tazobactam intermediate debrominated sulfoxide. This method uses 6-APA as a starting material and employs a one-pot synthesis reaction involving bromination-(esterification-oxidation)-debromination. The esterification-oxidation step utilizes an acid-catalyst-sodium hypochlorite-benzophenone hydrazone combination to achieve a one-pot reaction, while simultaneously removing the hazardous chemical peracetic acid. The debromination step uses a light-catalyst-ascorbic acid combination instead of zinc powder. Compared to traditional processes, this invention simplifies the production process, improves safety, and increases the molar yield by more than 13%, making it suitable for industrial production.
[0007] The technical solution of this invention is: a method for synthesizing the tazobactam intermediate debromosulfoxide ester, comprising the following steps: (1) Using 6-APA as the starting material, it undergoes a bromination reaction with potassium bromide under the action of sulfuric acid and sodium nitrite to generate intermediate I; (2) Under the action of acid and catalyst, intermediate I undergoes esterification-oxidation reaction with benzophenone hydrazone and sodium hypochlorite to generate intermediate II; (3) The feed solution of intermediate II reacts with ascorbic acid under the action of light and catalyst to generate debrominated sulfoxide ester.
[0008] The reaction equation is as follows:
[0009] Furthermore, in step (2), the acid is one or more of hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, preferably hydrochloric acid.
[0010] Furthermore, in step (2), the catalyst is one or more of tetrabutylammonium chloride, tetrabutylammonium bromide, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride, tetradecyltrimethylammonium chloride, and benzyltriethylammonium chloride, preferably tetrabutylammonium chloride.
[0011] Furthermore, in step (3), the light source is one or more of visible light, ultraviolet light, and sunlight, preferably visible light.
[0012] Furthermore, in step (3), the catalyst is one or more of TiO2, g-C3N4, and metal-organic frameworks (MOFs), preferably TiO2.
[0013] Furthermore, the solvent for all three steps of the above reaction is dichloromethane, and the reaction is carried out in a one-pot process.
[0014] Furthermore, the reaction temperature of step (1) is 5~0℃; the reaction temperature of step (2) is 20~30℃; and the reaction temperature of step (3) is 25~35℃.
[0015] The specific steps are as follows: (1) Bromination reaction (preparation of intermediate I) 6-APA and potassium bromide were added to a mixed solvent of water and dichloromethane (volume ratio of 1:0.8~1.2), sulfuric acid was added at -5~0℃, and sodium nitrite solution was added dropwise. After the addition was completed, the reaction was kept at the temperature for 0.5~2h. The mixture was filtered, and the filtrate was allowed to stand and separate into layers. The organic layer was washed with salt to obtain the dichloromethane solution of intermediate I. (2) Esterification-oxidation reaction (preparation of intermediate II) Benzophenone hydrazone, sodium hypochlorite, catalyst and acid are added to dichloromethane solvent. The temperature is controlled at 20~30℃. Dichloromethane solution of intermediate I is added dropwise. After the addition is completed, the reaction is kept at the temperature for 0.5~2h. After the reaction is completed, the mixture is filtered and the filtrate is washed with water to obtain dichloromethane solution of intermediate II. (3) Debromination reaction (preparation of debromination sulfoxide) Water, catalyst, and ascorbic acid were added to the dichloromethane solution of intermediate II. The reaction was carried out under light and the temperature was controlled at 25-35℃ for 2-5 hours. After the reaction was completed, the debrominated sulfoxide was obtained through post-treatment.
[0016] Preferably, in step (1), the molar ratio of 6-APA, potassium bromide, sulfuric acid and sodium nitrite is 1:(2~3):(1~2):(1~2), and the preferred molar ratio is 1:(2.2~2.7):(1.2~1.7):(1.2~1.7).
[0017] Preferably, in step (2), the molar ratio of acid (hydrogen ion), catalyst, sodium hypochlorite, benzophenone hydrazone, and 6-APA is (0.03~0.15):(0.01~0.10):(2.2~2.6):(1.0~1.2):1, and more preferably the molar ratio is (0.05~0.10):(0.03~0.08):(2.3~2.4):(1.05~1.15):1.
[0018] Preferably, in step (3), the molar ratio of catalyst, ascorbic acid and 6-APA is (0.01~0.1):(1.0~1.3):1, and more preferably the molar ratio is (0.03~0.05):(1.15~1.25):1.
[0019] Preferably, the post-processing of step (3) is as follows: after the reaction is complete, filter, wash the organic layer, evaporate to near dryness, and then add toluene to crystallize and obtain crude product; add toluene to dissolve the crude product, then cool and crystallize to obtain debrominated sulfoxide ester.
[0020] The technical effects of this invention are: 1. In the esterification-oxidation reaction, the oxidizing property of sodium hypochlorite is adjusted by adding acid, and a phase-inversion catalyst is used to promote the solid-liquid reaction rate, achieving a rapid one-pot esterification-oxidation reaction. Benzophenone hydrazone is oxidized by sodium hypochlorite to diphenyldiazomethane. Diphenyldiazomethane reacts with intermediate I to generate the esterification product, which is then oxidized by sodium hypochlorite to generate intermediate II. This solves the problem of large amounts of hazardous waste when using potassium permanganate or manganese dioxide to prepare diphenyldiazomethane, and avoids the problems of large byproducts and high consumption of benzophenone hydrazone when using peracetic acid. This invention performs the esterification reaction in advance and adds a diphenyl methyl ester protecting group, solving the problem of poor material stability and improving the yield. 2. In the debromination step, photo-catalyst-ascorbic acid is used instead of zinc powder. Ascorbic acid has weak reducing properties, and the reducing properties of ascorbic acid are enhanced by a photosensitive catalyst. 3. This invention realizes a one-pot continuous addition reaction, which simplifies production operations, shortens the production cycle, eliminates the use of ethanol, acetone, and methanol, making it safer and more environmentally friendly, reducing mother liquor loss, and increasing yield. 4. Compared with traditional processes, this invention simplifies the production process, improves safety, and achieves a molar yield of up to 87% (more than 13% higher than traditional processes), making it suitable for industrial production. Attached Figure Description
[0021] Figure 1 The image shows the HPLC chromatogram of the tazobactam intermediate debrominated sulfoxide prepared in Example 1. Detailed Implementation
[0022] The present invention will be further illustrated with reference to the embodiments, wherein the reagents used in the embodiments are analytical grade or chemically pure.
[0023] Example 1 The method for synthesizing the tazobactam intermediate debromosulfoxide ester includes the following steps: (1) Bromination: 21.6g 6-APA, 30g potassium bromide, 108g water and 108g dichloromethane were put into a reaction flask, stirred and the temperature was controlled at -5~0℃. 16g 93% sulfuric acid was added. After the addition was completed, sodium nitrite solution (10.5g sodium nitrite + 30g water) was added dropwise. After the addition was completed, the reaction was kept at the temperature for 1h. After the temperature was completed, the mixture was filtered and the filtrate was allowed to stand and separate into layers. The organic layer was washed with saturated brine to obtain the dichloromethane solution of intermediate I. (2) Esterification-oxidation: Add 100g dichloromethane, 20g benzophenone hydrazone, 17g sodium hypochlorite, 1g tetrabutylammonium chloride, and 0.6g 32% hydrochloric acid to the reaction flask, stir and control the temperature at 28~30℃, add dichloromethane solution of intermediate I dropwise, keep the temperature for 1h after the addition is complete, filter, and wash the filtrate with water to obtain dichloromethane solution of intermediate II; (3) Debromination: Add 100g of water, 0.6g of TiO2 powder and 20g of ascorbic acid to the dichloromethane solution of intermediate II, control the temperature at 30~32℃, and keep the reaction under visible light for 3h; after the reaction is completed, filter, and wash the filtrate with sodium bicarbonate solution and water respectively. Evaporate the organic layer to near dryness, add 65g of toluene, stir at 20~25℃ for 1h, and filter to obtain crude debrominated sulfoxide; add 108g of toluene to the crude product, stir at 60~70℃ for 1h, cool to 20~25℃, keep the temperature for 1h, filter, wash with toluene to obtain debrominated sulfoxide, dry to constant weight, and obtain 33.09g of debrominated sulfoxide; the four-step molar yield is 86.4%, and the purity is 99.8% (see Figure 1 ).
[0024] Example 2 The method for synthesizing the tazobactam intermediate debromosulfoxide ester includes the following steps: (1) Bromination: 21.6g 6-APA, 30g potassium bromide, 108g water and 108g dichloromethane were put into a reaction flask, stirred and the temperature was controlled at -5~0℃. 16g 93% sulfuric acid was added. After the addition was completed, sodium nitrite solution (10.5g sodium nitrite + 30g water) was added dropwise. After the addition was completed, the reaction was kept at the temperature for 1h. After the temperature was completed, the mixture was filtered and the filtrate was allowed to stand and separate into layers. The organic layer was washed with saturated brine to obtain the dichloromethane solution of intermediate I. (2) Esterification-oxidation: Add 100g dichloromethane, 22g benzophenone hydrazone, 17.5g sodium hypochlorite, 1.5g tetrabutylammonium chloride and 0.5g 93% sulfuric acid to the reaction flask, stir and control the temperature at 24~26℃, add dichloromethane solution of intermediate I dropwise, keep the temperature for 1h after the addition is complete, filter, and wash the filtrate with water to obtain dichloromethane solution of intermediate II; (3) Debromination: Add 100g of water, 0.3g of TiO2 powder and 22g of ascorbic acid to the dichloromethane feed solution of intermediate II, control the temperature at 28~30℃, and keep the reaction at this temperature for 3h under visible light irradiation; after the temperature is maintained, filter, and wash the filtrate with sodium bicarbonate solution and water respectively. Evaporate the organic layer to near dryness, add 65g of toluene, stir at 20~25℃ for 1h, and filter to obtain crude debrominated sulfoxide; add 108g of toluene to the obtained crude product, stir at 60~70℃ for 1h, cool to 20~25℃, keep the temperature for 1h, filter, wash with toluene to obtain debrominated sulfoxide, dry to constant weight, and obtain 33.66g of debrominated sulfoxide; the four-step molar yield is 87.9%, and the purity is 99.8%.
[0025] Example 3 The method for synthesizing the tazobactam intermediate debromosulfoxide ester includes the following steps: (1) Bromination: 21.6g of 6-APA, 30g of potassium bromide, 108g of water and 108g of dichloromethane were put into a reaction flask, stirred and the temperature was controlled at -5~0℃. 16g of 93% sulfuric acid was added. After the addition was completed, sodium nitrite solution (10.5g sodium nitrite + 30g water) was added dropwise. After the addition was completed, the reaction was kept at the temperature for 1h. After the temperature was completed, the mixture was filtered and the filtrate was allowed to stand and separate into layers. The organic layer was washed with saturated brine to obtain the dichloromethane solution of intermediate I. (2) Esterification-oxidation: Add 100g dichloromethane, 25g benzophenone hydrazone, 18g sodium hypochlorite, 2g trioctylmethylammonium chloride and 0.6g 93% sulfuric acid to the reaction flask, stir and control the temperature at 20~22℃, add dichloromethane solution of intermediate I dropwise, keep the temperature for 1h after the addition is complete, filter, and wash the filtrate with water to obtain dichloromethane solution of intermediate II; (3) Debromination: Add 100g of water, 0.3g of g-C3N4 powder and 21g of ascorbic acid to the dichloromethane solution of intermediate II, control the temperature at 25~30℃, and keep the reaction under ultraviolet light for 3h; after the reaction is completed, filter, and wash the filtrate with sodium bicarbonate solution and water respectively. Evaporate the organic layer to near dryness, add 65g of toluene, stir at 20~25℃ for 1h, and filter to obtain crude debrominated sulfoxide; add 108g of toluene to the crude product, stir at 60~70℃ for 1h, cool to 20~25℃, keep the temperature for 1h, filter, wash with toluene to obtain debrominated sulfoxide, dry to constant weight, and obtain 33.40g of debrominated sulfoxide; the four-step molar yield is 87.2%, and the purity is 99.8%.
[0026] Comparative example: (1) Bromination: 21.6g of 6-APA, 30g of potassium bromide, 108g of water and 108g of dichloromethane were put into a reaction flask, stirred and the temperature was controlled at -5~0℃. 16g of 93% sulfuric acid was added. After the addition was completed, sodium nitrite solution (10.5g sodium nitrite + 30g water) was added dropwise. After the addition was completed, the reaction was kept at the temperature for 1h. After the temperature was completed, the mixture was filtered and the filtrate was allowed to stand and separate into layers. The organic layer was washed with saturated brine to obtain the brominated dichloromethane solution. (2) Oxidation: Add 10g of ethanol to the brominated dichloromethane solution, control the temperature at 0~5℃, add 19g of 27.5% hydrogen peroxide dropwise, keep the temperature for 2h after the addition is complete, filter, and wash the obtained solid with water to obtain the oxidation product; (3) Esterification: The oxidation product obtained in the previous step, 30g benzophenone hydrazone, 50g methanol, 50g acetone and 100g dichloromethane were added to the reaction flask. The temperature was controlled at 0~5℃. 90g peracetic acid solution (concentration 15%) was added dropwise. After the addition was completed, the temperature was maintained for 0.5h. After the temperature was maintained, the layers were separated. The organic layer was washed with sodium bicarbonate solution and water respectively. The organic layer was evaporated to near dryness. 65g toluene was added. The mixture was stirred at 20~25℃ for 1h. The product was obtained by filtration and washing with water. (4) Debromination: The esterification product obtained in the previous step, 100g of dichloromethane, 10g of water and 9g of zinc powder were added to the reaction flask. The temperature was controlled at 5~10℃, and 13g of 93% sulfuric acid was added dropwise. After the addition was completed, the mixture was kept at the temperature for 1h. After the temperature was completed, the layers were separated. The organic layer was washed with sodium bicarbonate solution and purified water, respectively. The organic layer was evaporated to near dryness, and 65g of toluene was added. The mixture was stirred at 20~25℃ for 1h and filtered to obtain crude debrominated sulfoxide. The crude product was added to 108g of toluene and stirred at 60~70℃ for 1h. The temperature was lowered to 20~25℃ and kept at the temperature for 1h. The mixture was filtered and washed with toluene to obtain debrominated sulfoxide. The mixture was dried to constant weight to obtain 27.46g of debrominated sulfoxide. The four-step molar yield was 72.7% and the purity was 99.7%.
[0027] As can be seen from the comparison of the examples and comparative examples, the present invention simplifies the production process and achieves a molar yield of up to 87% (more than 13% higher than the traditional process), making it suitable for industrial production.
Claims
1. A method for synthesizing the tazobactam intermediate debromosulfoxide ester, characterized in that, Includes the following steps: (1) Using 6-APA as the starting material, it undergoes a bromination reaction with potassium bromide under the action of sulfuric acid and sodium nitrite to generate intermediate I; (2) Under the action of acid and catalyst, intermediate I undergoes esterification-oxidation reaction with benzophenone hydrazone and sodium hypochlorite to generate intermediate II; (3) The feed solution of intermediate II reacts with ascorbic acid under the action of light and catalyst to generate debrominated sulfoxide ester.
2. The synthesis method as described in claim 1, characterized in that, In step (2), the acid is one or more of hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid.
3. The synthesis method as described in claim 1, characterized in that, In step (2), the catalyst is one or a combination of tetrabutylammonium chloride, tetrabutylammonium bromide, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride, tetradecyltrimethylammonium chloride, and benzyltriethylammonium chloride.
4. The synthesis method as described in claim 1, characterized in that, In step (3), the light source is one or more of the following: visible light, ultraviolet light, and sunlight.
5. The synthesis method as described in claim 1, characterized in that, In step (3), the catalyst is one or more of TiO2, g-C3N4, and metal-organic frameworks (MOFs) in combination.
6. The synthesis method as described in claim 1, characterized in that, The solvent for all three steps of the reaction is dichloromethane, and the reaction is carried out in a one-pot process.
7. The synthesis method as described in claim 1, characterized in that, The reaction temperature in step (1) is 5~0℃; the reaction temperature in step (2) is 20~30℃; and the reaction temperature in step (3) is 25~35℃.
8. The synthesis method according to any one of claims 1-7, characterized in that, Includes the following steps: (1) Bromination reaction 6-APA and potassium bromide were added to a mixed solvent of water and dichloromethane. Sulfuric acid was added at a controlled temperature of -5 to 0°C, and sodium nitrite solution was added dropwise. After the addition was completed, the reaction was kept at the temperature for 0.5 to 2 hours. The mixture was filtered, and the filtrate was allowed to stand and separate into layers. The organic layer was washed with salt to obtain the dichloromethane solution of intermediate I. (2) Esterification-oxidation reaction Benzophenone hydrazone, sodium hypochlorite, catalyst and acid are added to dichloromethane solvent. The temperature is controlled at 20~30℃. Dichloromethane solution of intermediate I is added dropwise. After the addition is completed, the reaction is kept at the temperature for 0.5~2h. After the reaction is completed, the mixture is filtered and the filtrate is washed with water to obtain dichloromethane solution of intermediate II. (3) Debromination reaction Water, catalyst, and ascorbic acid were added to the dichloromethane solution of intermediate II. The reaction was carried out under light and the temperature was controlled at 25-35℃ for 2-5 hours. After the reaction was completed, the debrominated sulfoxide was obtained through post-treatment.
9. The synthesis method as described in claim 8, characterized in that, In step (2), the molar ratio of acid, catalyst, sodium hypochlorite, benzophenone hydrazone and 6-APA is (0.03~0.15):(0.01~0.10):(2.2~2.6):(1.0~1.2):
1.
10. The synthesis method as described in claim 8, characterized in that, In step (3), the molar ratio of catalyst, ascorbic acid and 6-APA is (0.01~0.1):(1.0~1.3):1.