Process for the preparation of tazobactam from tazobactam dibenzyl ester

Abstract

The application discloses a method for preparing tazobactam from tazobactam diphenylmethyl ester, which comprises the following steps: firstly, micronizing tazobactam diphenylmethyl ester, then adding the micronized tazobactam diphenylmethyl ester into water, and then adding enzymes and a phase transfer catalyst; under a proper temperature, the reaction is carried out in batches by adding alkali to control the pH value; tazobactam is obtained by hydrolysis and removal of the diphenylmethyl group; during the reaction, the liquid is filtered through a nanofiltration system to intercept tazobactam sodium, and the permeate returns to the reaction system; the reaction is completely promoted by removing the product, so that the water-phase reaction is obviously realized. The reaction condition of the application is mild, the water is used as the solvent, and the environment is friendly; the post-treatment is simplified; the continuous automatic operation is realized; the yield is improved; the product quality is improved; and the production cost is reduced.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, and more specifically, to a method for preparing tazobactam from tazobactam diphenylmethyl ester. Background Technology

[0002] Tazobactam, chemically known as 3-methyl-7-oxo-3-(1H-1,2,3,-triazol-1-methylene)-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid-4,4-dioxide, is a novel penicillin sulfone β-lactamase inhibitor developed by Taiho Pharmaceutical Co., Ltd. of Japan. Tazobactam is currently recognized as one of the β-lactamase inhibitors with the broadest antibacterial spectrum, best antibacterial activity, best clinical efficacy, and greatest potential. In 1992, the tazobactam / piperacillin (1:8) combination drug was first marketed in France for the treatment of various bacterial infections.

[0003] Currently, tazobactam is mainly prepared by removing the diphenylmethyl protection from tazobactam diphenylmethyl ester, and the reaction route is as follows.

[0004]

[0005] Depending on the raw materials used, there are two main routes for the removal of diphenylmethyl from tazobactam diphenylmethyl ester: one is the process using m-cresol for deprotection (such as CN102643292A, CN113666945A, etc.). This reaction cannot be carried out in an aqueous phase, has a low conversion rate, is difficult to automate continuously, and suffers from complex post-processing and difficulty in solvent recovery (m-cresol has a high boiling point). The other is the catalytic hydrogenation deprotection process, which requires high temperature and pressure, posing significant safety risks for scale-up production. Summary of the Invention

[0006] This invention overcomes the shortcomings of the prior art by providing a method for preparing tazobactam from tazobactam diphenylmethyl ester. The method involves first micronizing tazobactam diphenylmethyl ester and then adding it to water, followed by the addition of an enzyme and a phase transfer catalyst (PTC). The reaction is carried out under appropriate conditions with batch-addition of alkali at a suitable temperature and pH. Tazobactam is obtained by hydrolysis to remove the diphenylmethyl group. During the reaction, the solution is filtered through a nanofiltration system to remove tazobactam sodium, while the permeate is returned to the reaction system. Removing the product promotes complete reaction, thus achieving a clear aqueous phase reaction. The reaction conditions of this invention are mild, and the use of water as a solvent is environmentally friendly. This not only simplifies post-processing but also enables continuous automated operation, improving yield, product quality, and reducing production costs.

[0007] The technical solution of the present invention is: a method for preparing tazobactam from tazobactam diphenyl ester, characterized in that tazobactam diphenyl ester is micronized to below 100 μm, added to water, and then hydrolytic enzyme and phase transfer catalyst are added. The hydrolysis reaction is carried out in batches at 10-30°C with alkali added to control the pH range of 5-7. After the reaction is complete, tazobactam is obtained by post-treatment.

[0008] Furthermore, the supernatant of the reaction system is passed through a filtration system (solids are returned to the reaction system) and then into a nanofiltration system to retain tazobactam sodium. The dialyzed water is returned to the reaction system. By continuously removing the products, the reaction is completely converted, and continuous automated operation can be achieved.

[0009] The post-treatment process is as follows: after the reaction is complete, the temperature is lowered to 0-5℃ and the insoluble matter is removed by vacuum filtration. The pH of the filtrate is adjusted to 1-2 by adding acid to precipitate the product. The product is then washed with water and dried to obtain tazobactam.

[0010] The hydrolase described above is preferably esterase EC3.1.1.1. The mass ratio of the hydrolase to tazobactam diphenyl methyl ester is 0.001 to 0.005:1.

[0011] The aforementioned phase transfer catalyst is a quaternary ammonium salt, such as benzyltriethylammonium chloride (TEBA), tetrabutylammonium bromide (TBAB), tetrabutylammonium chloride, tetrabutylammonium bisulfate, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride, and tetradecyltrimethylammonium chloride, preferably benzyltriethylammonium chloride and tetrabutylammonium bromide. The mass ratio of the phase transfer catalyst to the tazobactam diphenyl ester is 0.01 to 0.1:1.

[0012] The preferred temperature for the above hydrolysis reaction is 20–30°C, and the reaction time is 0.5–12 h.

[0013] The volume-to-mass ratio of water to tazobactam diphenyl methyl ester is 1–30 mL: 1 g, preferably 1–10 mL: 1 g.

[0014] The added alkali can be a strong or weak base, such as sodium hydroxide, sodium carbonate, sodium bicarbonate, or ammonia, with sodium bicarbonate being preferred. To facilitate pH control, the added alkali is selected as a dropwise solution, preferably an aqueous solution of sodium bicarbonate.

[0015] The technical effects of this invention are:

[0016] 1. Micronization

[0017] Because tazobactam diphenylmethyl ester has extremely low solubility in water, it is very difficult to react in the aqueous phase under normal conditions. By pulverizing and sieving it, the specific surface area is significantly increased, enhancing contact with water, enzymes, and PTC, thus promoting the reaction. The selected particle size range is below 100 μm, preferably below 75 μm.

[0018] 2. Add phase transfer catalyst

[0019] Compared with the prior art, the present invention uses water as a solvent, and the addition of a phase transfer catalyst can enhance the interaction between tazobactam diphenylmethyl ester and water and hydrolytic enzymes, and promote the hydrolysis reaction.

[0020] 3. Adjust pH

[0021] An appropriate pH ensures that the generated tazobactam acid reacts with the base to form tazobactam sodium, which dissolves in water and promotes the complete reaction. However, the alkalinity cannot be too strong, as this can cause the β-lactam ring of tazobactam to open, affecting the yield and quality of tazobactam. Therefore, it is advisable to add the base in batches to adjust the pH to an appropriate level of 5-7.

[0022] 4. Achieve continuous production

[0023] During the reaction, the product system liquid is filtered, and the solid is returned to the reaction system. The liquid is filtered through a nanofiltration system to retain tazobactam sodium, and the permeate is returned to the reaction system. By removing the product, the reaction is made complete.

[0024] In summary, the above methods achieve aqueous phase reaction under mild and environmentally friendly conditions, enabling continuous and automated operation, simplifying post-processing, increasing yield, improving product quality, and reducing production costs. Detailed Implementation

[0025] The beneficial effects of this application will be explained below with reference to specific embodiments and comparative examples.

[0026] Example 1:

[0027] Tazobactam dibenzoyl ester was pre-micronized to 75–100 μm.

[0028] At room temperature, 100 g of tetrabutylammonium bromide (phase transfer catalyst) was added to 10 kg of purified water, stirred, and then micronized tazobactam diphenyl ester (1000 g, 2.14 mol) was added. The temperature was controlled at 20–25 °C, and 1 g of esterase EC3.1.1.1 was added. Sodium bicarbonate was added dropwise to adjust the pH to 5–7. The supernatant was removed from the reaction flask through a filtration system, and then concentrated through a nanofiltration system. The dialyzed water was returned to the reaction system.

[0029] After confirming the reaction was complete, the nanofiltration concentrate was cooled to 0-5℃ and filtered to remove insoluble matter. 6 mol / L hydrochloric acid was slowly added dropwise to adjust the pH to 1-2, resulting in the precipitation of a white solid. After stirring at 0℃ for 1 hour, the mixture was filtered, the filter cake was washed with water, and the filter cake was dried at 40℃. 629 g of solid tazobactam was obtained, with an HPLC purity of 99.6% and a yield of 97.7%.

[0030] Example 2:

[0031] Tazobactam dibenzoyl ester was pre-micronized to 75–100 μm.

[0032] At room temperature, 10 g (21.4 mmol) of micronized tazobactam dibenzoate was added to 100 mL of purified water, along with 0.1 g of benzyltriethylammonium chloride (phase transfer catalyst), and the mixture was stirred. The temperature was maintained at 20–25 °C, and after stirring for 0.5 hours, 0.01 g of esterase EC3.1.1.1 was added, and the pH was adjusted to 5–7 by dropwise addition of 7% sodium bicarbonate solution. After the addition was complete, the reaction continued for 0.5–1.0 h.

[0033] After confirming the reaction was complete, the temperature was lowered to 0-5℃ and the insoluble matter was removed by filtration. 6 mol / L hydrochloric acid was added dropwise to adjust the pH to 1-2, and a white solid precipitated out. After stirring at 0℃ for 1 hour, the mixture was filtered, the filter cake was washed with water, and the filter cake was dried at 40℃ to obtain 5.96 g of solid tazobactam with an HPLC purity of 99.5% and a yield of 92.6%.

[0034] Comparative Example 1: Deprotection of conventional m-cresol

[0035] At room temperature, 10 g (21.4 mmol) of tazobactam diphenyl ester was added to 40 mL of m-cresol. The mixture was heated to 45 °C, and after complete dissolution of the substrate, the reaction continued for 1 h until the reactants were fully reacted. The system was rapidly cooled to below 15 °C, and 30 mL of 7% sodium bicarbonate aqueous solution was added. Stirring continued for 30–45 min. Then, 100 mL of ethyl acetate was added and stirred for 5–15 min. The system was allowed to stand at 0–10 °C, and the mixture was separated. The organic phase was extracted once more with 15 mL of 7–8% sodium bicarbonate aqueous solution. The aqueous phases were combined, cooled to 0–5 °C, and the pH was adjusted to 1–2 by slow addition of 6 mol / L hydrochloric acid. A white solid precipitated. After stirring at 0 °C for 1 hour, the mixture was filtered, the filter cake was washed with water, and dried at 40 °C to obtain 5.33 g of solid tazobactam with an HPLC purity of 98.5% and a yield of 82.8%.

[0036] The reaction cannot be carried out in the aqueous phase, has a low conversion rate, is difficult to achieve continuous automation, and has problems such as complex post-processing and difficulty in solvent recovery.

[0037] Comparative Example 2: Ultrafine grinding only

[0038] Tazobactam dibenzoyl ester was pre-micronized to 75–100 μm.

[0039] At room temperature, 10 g (21.4 mmol) of micronized tazobactam dibenzoate was added to 100 ml of purified water and stirred. The mixture was kept at 20–25 °C and stirred for 0.5 hours. Then, 0.01 g of esterase EC3.1.1.1 was added, and 7% sodium bicarbonate solution was added dropwise to control the pH to 5–7 for the reaction. After the addition was complete, the reaction continued for 0.5–1.0 h.

[0040] After confirming the reaction was complete, the temperature was lowered to 0-5℃ and the insoluble matter was removed by filtration. 6 mol / L hydrochloric acid was added dropwise to adjust the pH to 1-2, and a white solid precipitated out. After stirring at 0℃ for 1 hour, the mixture was filtered, the filter cake was washed with water, and the filter cake was dried at 40℃ to obtain 5.60 g of solid tazobactam with an HPLC purity of 99.3% and a yield of 87.0%.

Claims

1. A method for preparing tazobactam from tazobactam diphenylmethyl ester, characterized in that, Tazobactam diphenyl ester was micronized to below 100 μm and added to water, followed by the addition of hydrolytic enzymes and phase transfer catalysts. The hydrolysis reaction was carried out in batches at 10–30 °C with alkali added to control the pH range of 5–7. The supernatant of the reaction system was filtered, with the solids returned to the reaction system and the supernatant entering a nanofiltration system to retain tazobactam sodium. Dialysis water was returned to the reaction system. Complete conversion of the reactants was achieved through continuous product removal, enabling continuous automated operation. After complete reaction, tazobactam was obtained through post-processing. The hydrolase is esterase EC3.1.1.1; the phase transfer catalyst is tetrabutylammonium bromide or benzyltriethylammonium chloride.

2. The method for preparing tazobactam according to claim 1, characterized in that, The post-treatment is as follows: after the reaction is complete, the temperature is lowered to 0-5℃ and the insoluble matter is removed by vacuum filtration. The pH of the filtrate is adjusted to 1-2 by adding acid to precipitate the product. The product is then washed with water and dried to obtain tazobactam.

3. The method for preparing tazobactam according to claim 1, characterized in that, The mass ratio of the hydrolase to tazobactam diphenyl methyl ester is 0.001 to 0.005:

1.

4. The method for preparing tazobactam according to claim 1, characterized in that, The phase transfer catalyst is in a mass ratio of 0.01 to 0.1:1 with tazobactam diphenylmethyl ester.

5. The method for preparing tazobactam according to claim 1, characterized in that, The hydrolysis reaction is carried out at a temperature of 20–30°C for a time of 0.5–12 h.

6. The method for preparing tazobactam according to claim 1, characterized in that, The volume-to-mass ratio of water to tazobactam diphenylmethyl ester is 1–30 mL: 1 g.

7. The method for preparing tazobactam according to any one of claims 1-6, characterized in that, The alkali is sodium hydroxide, sodium carbonate, sodium bicarbonate, or ammonia.

8. The method for preparing tazobactam according to claim 7, characterized in that, The alkali is sodium bicarbonate, and the pH is controlled at 5-7 by adding sodium bicarbonate solution dropwise.

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