Method for synthesizing tazobactam diphenylmethyl ester by microchannel reactor

Abstract

The invention discloses a method for synthesizing tazobactam diphenylmethyl ester as an intermediate product of tazobactam in a micro-channel reactor, which comprises the following steps: (1) respectively pumping a prepared solution 1 and a prepared solution 2 into the micro-channel reactor, and reacting in the micro-channel reactor in sequence; and (2) quenching, extracting, distilling, pulping, growing crystals, carrying out suction filtration and drying the material at the outlet of the microchannel reactor. And the purity is more than 99.5%. The micro-channel reactor is used in the tazobactam preparation process for the first time, the reaction time can be shortened, two phases are efficiently mixed, and the reaction rate is increased. And the whole reactor can realize continuous feeding, is simple in process operation, and has simple synthesis amplification.

Description

Technical Field

[0001] This invention relates to a method for synthesizing tazobactam diphenylmethyl ester using a microchannel reactor, belonging to the field of chemical synthesis and process. Background Technology

[0002] Tazobactam, also 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, has the following structure: Piperacillin is a β-lactamase inhibitor developed by Daiho Pharmaceutical Co., Ltd. of Japan. It is often used in combination with penicillin antibiotics (such as piperacillin) to inhibit the β-lactamase produced by bacteria, thereby protecting the antibiotic from degradation and enhancing its antibacterial activity. It is characterized by high stability, low intrinsic antibacterial activity, low toxicity, and strong enzyme-inhibiting activity.

[0003] Currently, the synthetic routes for tazobactam can be broadly categorized into two types based on the starting materials: those using penicillin derivatives and those using non-penicillin compounds. The penicillin derivative starting route primarily uses penicillin compounds such as penicillin G, penicillin V, or their salts. Because these compounds contain a β-lactam ring, the molecular skeleton of tazobactam can be efficiently constructed by structurally modifying their side chains and thiazole rings. This is currently the most mature and widely used route for industrial scale-up. The synthetic route using non-penicillin compounds, on the other hand, involves the direct chemical synthesis of the β-lactam ring and triazole side chain. Due to its longer reaction steps, poor stereoselectivity (difficulty in controlling the chiral center of the β-lactam ring), and low yield, its industrial application is less common.

[0004] Currently, tazobactam is mainly prepared by oxidizing deoxytazobactam diphenylmethyl ester (DTE) and then removing the diphenylmethyl protection. The oxidation reaction route is as follows:

[0005] In 2010, Chinese patent (CN102020663A) first proposed using a hydrogen peroxide-cobalt acetate system to replace the high-risk peracetic acid, achieving selective oxidation of sulfides to sulfoxides at 0-5℃ with a yield of 72%-84%. In 2011, Chinese patent (CN101434609B) developed a tungstate / hydrogen peroxide catalytic system, which avoids the formation of peroxide impurities; however, its industrial application suffers from difficulties in catalyst stability and increased costs. In 2012, Chinese patent (CN102643292A) utilized potassium permanganate to oxidize acetic acid; this method achieved a balance between stability and reaction efficiency through stepwise temperature control. However, its yield only reached 49.7%. In 2025, Chinese patent (CN120329322A) introduced a palladium-proline ligand system, using molecular oxygen as an oxidant, to achieve one-step oxidative coupling of sulbactam to construct sulfone groups, with an overall yield exceeding 65%. This method uses molecular oxygen as an oxidant and produces only water as a byproduct, which significantly improves economic efficiency. However, the high cost of palladium catalysts does not address the current needs for large-scale production. Summary of the Invention

[0006] To address the aforementioned problems, this invention provides a method for synthesizing tazobactam diphenyl methyl ester using a microchannel reactor, thereby solving the problems of complex and slow feeding, long reaction time, cumbersome operation, backmixing, energy consumption, and efficiency in the prior art, which make it difficult to scale up in large-scale continuous production.

[0007] A method for synthesizing tazobactam diphenyl ester using a microchannel reactor includes the following steps: (1) Solution 1 and solution 2 are pumped into the microchannel reactor respectively, and the reaction is carried out in the microchannel reactor in sequence; (2) The material at the outlet of the microchannel reactor is obtained by quenching, extraction, distillation, pulping and crystal growth, filtration and drying.

[0008] Preferably, in step 1, solution 1 is a mixed solution of desoxytazobactam diphenylmethyl ester, organic solvent, and glacial acetic acid, with a mass ratio of 1:20-35:2-6.

[0009] The organic solvent is at least one of dichloromethane, acetone, ethyl acetate, and tetrahydrofuran.

[0010] Preferably, in step 1, solution 2 is prepared by potassium permanganate or sodium permanganate and water (preferably drinking water for process use), the ratio of potassium permanganate to sodium permanganate is 0.4-0.9 times that of desoxytazobactam diphenyl methyl ester, and the ratio of drinking water for process use is 5-10 times that of desoxytazobactam diphenyl methyl ester (its solution is in slurry form).

[0011] Preferably, in step 1, the dissolution temperature of solution 2 is 25-35℃.

[0012] Preferably, in step 1, the microchannel reactor is a tubular channel.

[0013] Preferably, in step 1, the reaction temperature of the microchannel reactor is 10-30℃.

[0014] Preferably, in step 1, the total residence time of the material in the microchannel reactor is 20-40 min.

[0015] Preferably, in step 1, the pressure of the microchannel reactor is 1-3 MPa.

[0016] Preferably, in step 1, the pumping flow rate of solution 1 is 15-35 ml / min. (36.53) Preferably, in step 1, the flow rate of solution 2 pumped in is 10-30 ml / min. (20.47) Preferably, in step 2, 30% hydrogen peroxide in the material is quenched; quenching endpoint: no black solid remains.

[0017] Preferably, in step 2, the quenching is followed by static extraction.

[0018] Preferably, in step 2, the extraction solvent is selected from dichloromethane and ethyl acetate.

[0019] Preferably, in step 2, water is added to the distillation flask before distillation, with a volume of 1 / 3 times that of the organic phase.

[0020] Preferably, in step 2, the distillation method is vacuum distillation, the distillation temperature is 15-35℃, and distillation stops when no condensate flows out.

[0021] Preferably, in step 2, ethyl acetate is added to the distillation flask to begin slurrying, with a volume twice that of the concentrate.

[0022] Preferably, in step 2, the pulping temperature is 30-35℃ and the pulping time is 10-20 minutes.

[0023] Preferably, in step 2, the crystal growth temperature is 0-10℃ and the crystal growth time is 20-30min.

[0024] Preferably, in step 2, the drying temperature is 40-60℃.

[0025] Compared with the prior art, the beneficial effects of the present invention are as follows: 1. This invention is the first to apply microchannel reactor technology to the synthesis of tazobactam diphenyl ester. Microchannel reactors have a high specific surface area and excellent mass and heat transfer performance, which can achieve efficient mixing of reactants. This completely solves the problem of slow reaction rate and long reaction time caused by uneven mixing of two phases, especially the slurry aqueous phase containing insoluble permanganate, in traditional batch reaction. The total reaction time (material residence time) can be shortened to 20-40 minutes, which is much lower than that of traditional batch process.

[0026] 2. This invention uses a microchannel reactor, which effectively avoids side reactions caused by excessively high local concentrations or limited mass transfer in traditional methods, such as over-oxidation. The method provided by this invention increases the synthesis yield of tazobactam diphenyl ester to over 95.0%, with a product purity of 99.5%-99.9% and a total impurity content of less than 0.5%. Compared with the existing technology using potassium permanganate oxidation method with a yield of only 49.7% (CN102643292A), this method significantly improves the yield.

[0027] 3. The present invention uses a microchannel reactor for continuous flow operation, with a small liquid holdup in the reaction system, and heat can be removed quickly. This fundamentally reduces the risk of thermal runaway caused by the cumulative heat release of potassium permanganate / sodium permanganate and organic materials in traditional large reactors. The process parameters of the entire synthesis process are controllable, the operation is simple, the labor intensity is low, and it is easy to achieve automated control.

[0028] 4. The method provided by this invention uses potassium permanganate / sodium permanganate as an oxidant, which avoids the high cost of using precious metal catalysts (such as the palladium catalyst in CN120329322A). At the same time, the high selectivity of the microchannel reactor reduces the generation of by-products, simplifies post-processing, and relatively reduces solvent consumption, which is in line with the development direction of green chemistry and clean production. Detailed Implementation

[0029] The present invention will now be described in detail through specific embodiments, but this description is not intended to limit the scope of protection of the present invention. It should be noted that, unless otherwise specified, the experimental methods used in the experimental operations involved in this invention are conventional methods in the relevant field, and the equipment, materials, reagents, etc., used in the experiments can all be obtained through commercial channels, so that those skilled in the art can understand and implement the technical solutions of the present invention based on existing conditions. The scope of protection of the present invention will be determined in accordance with the claims and relevant legal provisions, and is not limited by the specific embodiments.

[0030] Example 1 (1) Solution 1: Take 60g of deoxytazobactam diphenyl methyl ester dry powder, add 1200g of dichloromethane (20 times) and 120g of glacial acetic acid (2 times) to obtain solution 1.

[0031] Solution 2: Take 24 g of potassium permanganate (0.4 times) and add 300 g of drinking water for process use (5 times). Heat (25℃) and stir to obtain solution 2 (the solution is in slurry form).

[0032] The microchannel reactor was set to a reaction temperature of 10℃, a material residence time of 20 min, and a pressure of 2 MPa. Solution 1 was pumped into the microchannel reactor at a rate of 20 ml / min and solution 2 at a rate of 15 ml / min, respectively, and the reaction proceeded sequentially within the microchannel reactor.

[0033] (2) After the reaction is completed, the material is collected through the outlet and quenched by slowly adding 30% hydrogen peroxide under stirring until there is no black solid in the reaction solution. The mixture is allowed to stand and separate into two phases. It is extracted with dichloromethane and the organic phase is distilled under reduced pressure with water. When no condensate flows out, the distillation is stopped. Ethyl acetate is added to the distillation flask for slurrying. The temperature is set at 30℃. After slurrying for 10 min, the temperature is lowered to 0℃ for crystal growth. After crystal growth for 20 min, the mixture is filtered. After filtration, the mixture is dried at 40℃ until constant weight is obtained to obtain 62.1 g of tazobactam diphenyl methyl ester dry powder.

[0034] Example 2

[0035] (1) Solution 1: Take 100g of deoxytazobactam diphenyl methyl ester dry powder, add 3000g of acetone (30 times) and 500g of glacial acetic acid (5 times) to obtain solution 1.

[0036] Solution 2: Take 80 g of potassium permanganate (0.8 times) and add 900 g of drinking water for process use (9 times). Heat (25℃) and stir to obtain solution 2 (the solution is in slurry form).

[0037] The microchannel reactor was set to a reaction temperature of 25℃, a material residence time of 40 min, and a pressure of 2 MPa. Solution 1 was pumped into the microchannel reactor at a rate of 35 ml / min and solution 2 at a rate of 30 ml / min, respectively, and the reaction proceeded sequentially within the microchannel reactor.

[0038] (2) After the reaction is completed, the material is collected through the outlet and quenched by slowly adding 30% hydrogen peroxide under stirring until there is no black solid in the reaction solution. The mixture is allowed to stand and separate into phases, and extracted with ethyl acetate. The organic phase is added to water and distilled under reduced pressure. When no condensate flows out, the distillation is stopped. Ethyl acetate is added to the distillation flask for slurrying. The temperature is set at 35℃. After slurrying for 20 min, the temperature is lowered to 10℃ for crystal growth. After crystal growth for 30 min, the mixture is filtered. After filtration, the mixture is dried at 50℃ until constant weight is obtained, yielding 103.8 g of tazobactam diphenylmethyl ester dry powder.

[0039] Example 3 (1) Solution 1: Take 500g of deoxytazobactam diphenyl methyl ester dry powder, add 12500g of ethyl acetate (25 times) and 1500g of glacial acetic acid (3 times), and dissolve to obtain solution 1.

[0040] Solution 2: Take 300 g of sodium permanganate (0.6 times) and add 3000 g of drinking water for process use (6 times). Heat (25℃) and stir to obtain solution 2 (the solution is in slurry form).

[0041] The microchannel reactor was set to a reaction temperature of 15 °C, a material residence time of 25 min, and a pressure of 2 MPa. Solution 1 was pumped into the microchannel reactor at a rate of 20 ml / min and solution 2 at a rate of 15 ml / min, respectively, and the reaction proceeded sequentially through the microchannel reactor.

[0042] (2) After the reaction is completed, the material is collected through the outlet and quenched by slowly adding 30% hydrogen peroxide under stirring until there is no black solid in the reaction solution. The mixture is allowed to stand and separate into two phases. It is extracted with dichloromethane and the organic phase is distilled under reduced pressure with water. When no condensate flows out, the distillation is stopped. Ethyl acetate is added to the distillation flask for slurrying. The temperature is set at 30℃. After slurrying for 20 min, the temperature is lowered to 0℃ for crystal growth. After crystal growth for 20 min, the mixture is filtered. After filtration, the mixture is dried at 60℃ until constant weight is obtained, yielding 510.8 g of tazobactam diphenylmethyl ester dry powder.

[0043] Example 4 (1) Solution 1: Take 800g of deoxytazobactam diphenylmethyl ester dry powder, add 28000g of tetrahydrofuran (35 times) and 4800g of glacial acetic acid (6 times) to obtain solution 1.

[0044] Solution 2: Take 720 g of sodium permanganate (0.9 times) and add 4800 g of drinking water for process use (6 times). Heat (25℃) and stir to obtain solution 2 (the solution is in slurry form).

[0045] The microchannel reactor was set to a reaction temperature of 30 °C, a material residence time of 35 min, and a pressure of 2 MPa. Solution 1 was pumped into the microchannel reactor at a rate of 30 ml / min and solution 2 at a rate of 25 ml / min, respectively, and the reaction proceeded sequentially through the microchannel reactor.

[0046] (2) After the reaction is completed, the material is collected through the outlet and quenched by slowly adding 30% hydrogen peroxide under stirring until there is no black solid in the reaction solution. The mixture is allowed to stand and separate into phases, and extracted with ethyl acetate. The organic phase is added with water and distilled under reduced pressure. Distillation is stopped when no condensate flows out. Ethyl acetate is added to the distillation flask for slurrying. The temperature is set at 35℃. After slurrying for 20 min, the temperature is lowered to 10℃ for crystal growth. After crystal growth for 30 min, the mixture is filtered. After filtration, the mixture is dried at 50℃ until constant weight is obtained, yielding 825.7 g of tazobactam diphenylmethyl ester dry powder.

[0047] Comparative Example 1 This comparative example uses a similar raw material ratio to Example 1 of the present invention, but is carried out in a conventional stirred reactor, as follows: (1) Preparation of solution 1 (organic phase): Take 60g of deoxytazobactam diphenyl methyl ester dry powder, add 1200g of dichloromethane and 120g of glacial acetic acid, stir to dissolve, and obtain a clear solution. Place it in a constant pressure dropping funnel for later use.

[0048] Preparation of Solution 2 (Aqueous Phase): Take 24g of potassium permanganate, add 300g of drinking water for process use, stir at 25℃ to prepare a uniform slurry suspension, and transfer to a 1000 mL four-necked flask.

[0049] (2) Place the four-necked flask in an ice-water bath and control the internal temperature of the reaction system at 10°C. Stir at 300 rpm and slowly add solution 1 dropwise, controlling the dropping rate so that the total dropping time is about 90 min. After the dropping is completed, continue to maintain the reaction at 10°C, and the total reaction time (including dropping) is 350 min.

[0050] (3) After the reaction was completed, 30% hydrogen peroxide was slowly added dropwise under stirring to quench the reaction until no black solid remained in the reaction solution. The reaction solution was transferred to a separatory funnel and allowed to stand for phase separation. The organic phase was extracted once with dichloromethane. The organic phases were combined and 1 / 3 of their volume of water was added for vacuum distillation (temperature 15-35℃) until no condensate flowed out. Ethyl acetate was added to the distillation flask for stirring (30℃, 10 min), and then the temperature was lowered to 0℃ for crystal growth for 20 minutes. The mixture was filtered, and the filter cake was dried at 40℃ to constant weight to obtain 59.7 g of tazobactam diphenylmethyl ester powder.

[0051] Comparative Example 2 The difference between this comparative example and Example 1 of the present invention is that solution 1 is replaced with formic acid. The other steps are the same as in Example 1, yielding 50.1 g of tazobactam diphenylmethyl ester dry powder.

[0052] Comparative Example 3 The difference between this comparative example and Example 1 of the present invention is that solution 2 is not prepared in a slurry form. Specifically, 24g of potassium permanganate is added to a large amount of process drinking water (30 times, i.e., 1800g), heated to 40°C to completely dissolve it, resulting in a clear, dark purple solution. This solution is then cooled to 25°C for later use, yielding solution 2. Other steps are the same as in Example 1, ultimately yielding 52.6g of tazobactam diphenylmethyl ester dry powder.

[0053] The purity, total impurities, and purity of tazobactam diphenyl methyl ester in Examples 1-4 and Comparative Examples 1-3 were tested respectively, and the yield results are shown in Table 1 below.

[0054] Table 1

[0055] As shown in Table 1, the tazobactam diphenyl ester prepared by the synthesis process provided by this invention has high purity and yield. The purity of tazobactam diphenyl ester reaches a maximum of 99.9% and a minimum of 99.5%, demonstrating excellent overall purity. The total impurity content is only 0.1%-0.5%. The yield is stable with small fluctuations, and the process repeatability is good. The purity of deoxytazobactam diphenyl ester was not detected, indicating its strong reaction selectivity. This demonstrates that the process of this invention has excellent reaction selectivity and process controllability, with complete conversion of raw materials (no raw material residues detected), effectively suppressing side reactions.

[0056] Compared to traditional batch reactor processes (Comparative Example 1, yield 92.1%, purity 99.2%), this invention utilizes a microchannel reactor, significantly shortening the reaction time (20-40 minutes vs. several hours) while simultaneously improving purity and yield. This is because the superior mass transfer and mixing efficiency of the microchannel reactor solves the problems of uneven mixing and localized overheating in traditional stirred tank reactors, especially with solid-containing slurries, thereby improving the reaction rate and selectivity.

[0057] In Comparative Example 2, when glacial acetic acid was replaced with formic acid, the product purity plummeted to 95.8% and the yield dropped to 74.5%, demonstrating that glacial acetic acid is one of the keys to maintaining high selectivity in this oxidation system.

[0058] In Comparative Example 3, when the potassium permanganate slurry was changed to a clear solution, the purity and yield (97.3%, 79.5%) also decreased significantly. This indicates that using a moderate slurry feed can work synergistically with microchannels, possibly by controlling the contact and dissolution kinetics of solid particles, optimizing the reaction process, and avoiding excessive oxidation.

Claims

1. A method for synthesizing tazobactam diphenylmethyl ester using a microchannel reactor, characterized in that, Includes the following steps: (1) Prepare solution 1 and solution 2 respectively, and pump solution 1 and solution 2 into the microchannel reactor respectively for continuous reaction; Solution 1 is prepared from deoxytazobactam diphenylmethyl ester, organic solvent and glacial acetic acid; Solution 2 is prepared from permanganate and water, and is in the form of a slurry; (2) Quench, extract, distill, pulp and crystallize, filter and dry the material after step (1) to obtain tazobactam diphenyl methyl ester.

2. The method according to claim 1, characterized in that, In step (1), solution 1 is a mixed solution of deoxytazobactam diphenylmethyl ester, organic solvent, and glacial acetic acid, with a mass ratio of 1:20-35:2-6.

3. The method according to claim 2, characterized in that, In step (1), the organic solvent is selected from at least one of dichloromethane, acetone, ethyl acetate, and tetrahydrofuran.

4. The method according to claim 1, characterized in that, In step (1), in solution 2, the permanganate is potassium permanganate or sodium permanganate, and the amount of permanganate used is 0.4-0.9 times the mass of deoxytazobactam diphenyl methyl ester; the amount of water used is 5-10 times the mass of deoxytazobactam diphenyl methyl ester; and the dissolution temperature of solution 2 is 25-35℃.

5. The method according to claim 1, characterized in that, The microchannel reactor is a tubular microchannel reactor with a reaction temperature of 10-30℃, a reaction pressure of 1-3MPa, and a total residence time of the material in the reactor of 20-40 minutes.

6. The method according to claim 1, characterized in that, In step (1), the pumping flow rate of solution 1 is 15-35 mL / min, and the pumping flow rate of solution 2 is 10-30 mL / min.

7. The method according to claim 1, characterized in that, In step (2), quenching is performed using a 30% hydrogen peroxide solution, and the quenching endpoint is when there is no black solid in the reaction solution.

8. The method according to claim 1, characterized in that, In step (2), the solvent used for extraction is dichloromethane or ethyl acetate.

9. The method according to claim 1, characterized in that, In step (2), the pulping temperature is 30-35℃ and the pulping time is 10-20 minutes; the crystal growth temperature is 0-10℃ and the crystal growth time is 20-30 minutes; the drying temperature is 40-60℃.

10. The method according to any one of claims 1-9, characterized in that, The purity of the obtained tazobactam diphenyl methyl ester is not less than 99.5%, and the yield is not less than 95%.

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