Fully continuous synthesis device and fully continuous synthesis method of cephalosporin mother nucleus

Abstract

The invention provides a full-continuous synthesis device and a full-continuous synthesis method of cephalosporin mother nucleus. The fully continuous synthesis method comprises the following steps: carrying out continuous reaction on a reaction system comprising a cephalosporin intermediate raw material, immobilized enzyme and a reaction medium to obtain a product system comprising cephalosporin mother nucleus; carrying out continuous post-treatment on the product system to obtain a cephalosporin mother nucleus; wherein the reaction system is subjected to acid gas removal, and the pH value of the continuous reaction is regulated and controlled. In the fully continuous reaction process, the reaction system is subjected to acid gas (such as carbon dioxide) removal, so that the whole-process regulation and control of the pH in the fully continuous synthesis process of the cephalosporin mother nucleus are realized, and the stability of the whole fully continuous synthesis is ensured. The full-continuous synthesis method disclosed by the invention is high in production efficiency, low in cost, simple to operate, green and environment-friendly, and the service life of the immobilized enzyme is long.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, in particular to a fully continuous synthesis device and a fully continuous synthesis method of a cephalosporin mother nucleus. Background Art

[0002] Cephalosporin pharmaceutical intermediates belong to the upstream link of raw materials. They do not need to be produced and approved according to the drug rules, and they do not need to apply for batch numbers. They benefit from the steady development of the downstream antibiotic industry. The actual demand is large and grows rapidly every year. Cephalosporin pharmaceutical intermediates are divided into cephalosporin mother core intermediates and cephalosporin side chain intermediates. Different side chain intermediates are combined with the C3 and C7 positions of the mother core intermediates to form different cephalosporin antibiotics. Among them, the mother core intermediates are mainly divided into 7-ACA, 7-ADCA, D-7ACA, GCLE, etc., and the side chain intermediates mainly include AE-active esters, cefixime side chain acid active esters, ceftazidime side chain acid active esters, furan ammonium salts, etc. At present, most of the global production of cephalosporin pharmaceutical intermediates has been transferred to China. How to synthesize cephalosporin pharmaceutical intermediates safely, environmentally friendly and low-cost has become a hot research direction.

[0003] The process of chemical synthesis of cephalosporin intermediates requires toxic chemical reagents, harsh conditions, complex processes, many by-products, and great environmental pollution, which does not meet the requirements of sustainable development. The enzymatic preparation process has mild conditions, high yield, few side reactions, is environmentally friendly, and does not require the protection and deprotection of active groups. Therefore, more and more people are trying to use enzymatic methods to synthesize semi-synthetic β-lactam antibiotics. In the 1980s, penicillin acylase was used industrially to produce the parent nucleus (6-APA and 7-ADCA) of semi-synthetic β-lactam antibiotics. In this century, penicillin acylase is used to catalyze the semi-synthetic β-lactam parent nucleus and suitable acyl donors to produce semi-synthetic β-lactam antibiotics on a large scale. That is, the synthesis of semi-synthetic β-lactam antibiotics today has gradually changed from chemical methods that are highly harmful to the environment to enzymatic methods with simple reaction steps, less toxic and harmful reagents, and less waste.

[0004] Acylase has the advantages of high catalytic efficiency, specificity and mildness, but the free acylase has the disadvantages of easy inactivation and difficulty in separation from the product, which limits the industrial application of acylase. In order to overcome the disadvantages of free enzyme, immobilized enzyme technology appeared in the 1960s, which improved the operational stability and reusability of acylase.

[0005] .

[0006] The current mainstream process is only focused on batch catalytic processes, and a small number of continuous processes are limited to the CSTR (continuous stirred tank reactor) process. However, the CSTR process has problems such as low continuous flow reaction capacity and low equipment utilization, and difficulty in controlling PBR (packed bed reactor) continuous reactions.

[0007] Some reports have shown that 6-APA can be synthesized using a continuous reaction process, and that the PBR continuous synthesis of penicillin mother nucleus 6-APA has been achieved. However, due to environmental protection and cost pressures, the current difficulty in the continuous synthesis of cephalosporin mother nucleus lies mainly in the pH control of the reaction process. The CSTR (continuous stirred reactor) process, although simple and easy to control, has low production capacity and low equipment utilization. The PBR (packed bed reactor) continuous reaction process has high production capacity, but pH control is difficult. Currently, most of them adopt an intermittent multi-point control strategy, which makes the reaction process complicated and the capacity improvement incomplete. Summary of the invention

[0008] The main purpose of the present invention is to provide a fully continuous synthesis device and a fully continuous synthesis method for cephalosporin mother nuclei, so as to solve the problems of low production capacity, poor stability caused by difficulty in pH control, and difficulty in controlling the PBR (packed bed reactor) continuous reaction process in the synthesis method of cephalosporin mother nuclei in the prior art.

[0009] In order to achieve the above-mentioned purpose, according to one aspect of the present invention, a fully continuous synthesis method of cephalosporin mother nuclei is provided, and the fully continuous synthesis method comprises: subjecting a reaction system comprising a cephalosporin intermediate raw material, an immobilized enzyme and a reaction medium to a continuous reaction to obtain a product system comprising a cephalosporin mother nucleus; subjecting the product system to a continuous post-treatment to obtain a cephalosporin mother nucleus; wherein, acidic gas is removed from the reaction system to regulate the pH of the continuous reaction.

[0010] Furthermore, the above-mentioned continuous reaction is carried out in a packed bed reactor, which includes a reaction pipe, the immobilized enzyme is filled into the packed bed reactor, the cephalosporin intermediate raw material is input from one end of the reaction pipe through a liquid pump and output from the other end of the reaction pipe, the cephalosporin intermediate raw material is added in the form of an aqueous solution, the mass concentration of the cephalosporin intermediate aqueous solution is 1~20wt%, and / or the flow rate of the cephalosporin intermediate aqueous solution is 0.5~2CV / h, wherein "CV" represents the volume of the packed bed reactor where the continuous reaction is located.

[0011] Furthermore, the reaction medium comprises a salt solution, the pH value of the salt solution is 7.8-8.3, and / or the salt solution is selected from any one of ammonium bicarbonate with a pH value of 7.8, potassium bicarbonate with a pH value of 8.1, and sodium bicarbonate with a pH value of 8.3; and / or the molar ratio of the solute to the cephalosporin intermediate in the salt solution is 2-10:1.

[0012] Furthermore, the above-mentioned fully continuous synthesis method also includes: continuously crystallizing the product system to obtain a crystallized system; and continuously filtering the crystallized system to obtain cephalosporin mother nuclei.

[0013] Furthermore, the structural formula of the above-mentioned cephalosporin intermediate is as follows:

[0014]

[0015] Wherein, R1 is H or methoxybenzoyl; R2 is selected from any one of H, chlorine, methyl, chloromethyl, vinyl, methoxymethyl, prop-1-enyl, 1-pyridylmethyl, (2-methyl-1,3,4-thiadiazol-5-ylthio)methyl.

[0016] According to another aspect of the present invention, a fully continuous synthesis device for a cephalosporin mother nucleus is provided, the fully continuous synthesis device comprising a reaction liquid storage tank, a packed bed reactor, a continuous crystallization tank and a continuous filtration tank, the reaction liquid storage tank having a reaction liquid outlet, the reaction liquid storage tank being used to accommodate a raw material comprising a cephalosporin intermediate; the packed bed reactor having a reaction liquid inlet and a product outlet, the reaction liquid inlet being connected to the reaction liquid outlet, the packed bed reactor being used to continuously react the raw material comprising the cephalosporin intermediate and the immobilized enzyme to obtain a product system comprising the cephalosporin mother nucleus; the continuous crystallization tank having a crystallization tank inlet and a crystallization tank outlet, the crystallization tank inlet being connected to the product outlet, the continuous crystallization tank being used to continuously crystallize the product system to obtain a crystallized system; the continuous filtration tank having a filtration tank inlet and a filtration tank outlet, the filtration tank inlet being connected to the crystallization tank outlet, the continuous filtration tank being used to After crystallization, the system is continuously filtered to obtain cephalosporin mother nuclei; wherein, the raw material of the cephalosporin intermediate also includes a salt solution, and the salt solution reacts with free hydrogen ions in the product system to generate carbon dioxide; a degassing membrane is also arranged in the packed bed reactor, and the degassing membrane is interspersed in the filling area of ​​the immobilized enzyme, and the degassing membrane is an ETC fiber membrane bundle; the immobilized enzyme is filled in the packed bed reactor; the packed bed reactor has a bottom end and a top end relative to each other in the axial direction, and a sealing plate is arranged at the bottom end, and a plurality of openings corresponding to the openings of the ETC fiber membrane bundle are arranged on the sealing plate; the fully continuous synthesis device also includes a gas collecting hood, which has two opposite first opening ends and a second opening end, and the first opening end is in contact with the sealing plate and is covered on the sealing plate, and covers all the openings on the sealing plate; the second opening end is a gas extraction port, and the gas extraction port is used to extract the carbon dioxide in the packed bed reactor.

[0017] Furthermore, a degassing membrane is also provided in the packed bed reactor, and the degassing membrane is interspersed in the filling area of ​​the immobilized enzyme. The degassing membrane is an ETC fiber membrane bundle, and the inner diameter of the membrane fiber of the ETC fiber membrane bundle is 0.22 mm, and / or the outer diameter of the membrane fiber of the ETC fiber membrane bundle is 0.30 mm.

[0018] Furthermore, the length direction of the membrane fibers in the above-mentioned ETC fiber membrane bundle extends along the axial direction of the packed bed reactor.

[0019] Furthermore, the sum of the volume of the degassing membrane and the volume of the immobilized enzyme is equal to the volume of the containing chamber of the packed bed reactor.

[0020] Furthermore, the ratio of the mass of the degassing membrane to the mass of the immobilized enzyme is 1:1000-10000.

[0021] By applying the technical solution of the present application, in the above fully continuous reaction process, the acidic gas (such as carbon dioxide) is removed from the reaction system to achieve full process regulation of pH during the fully continuous synthesis of cephalosporin mother nuclei, so that the fully continuous synthesis system of the cephalosporin mother nuclei can maintain a specific pH value, thereby achieving continuous and stable regulation of pH value during the continuous synthesis of the cephalosporin mother nuclei reaction, further maintaining the reaction rate at an optimal state, and avoiding the loss of activity of the immobilized enzyme due to the decrease in pH, while avoiding the need for complex continuous reaction equipment. The present invention realizes full continuity from the enzyme catalysis process to the continuous separation of the product, thereby solving the problems of discontinuous full continuous synthesis of the cephalosporin mother nuclei, low production capacity, poor stability due to difficulty in pH regulation, and difficulty in controlling the continuous reaction process of the PBR (packed bed reactor), and obtaining a high-yield and high-purity cephalosporin mother nucleus product. The above fully continuous synthesis method of the present application has high production efficiency, low cost, simple operation, green environmental protection, and long service life of the immobilized enzyme. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] The drawings constituting a part of the present application are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation of the present invention. In the drawings:

[0023] Figure 1 A diagram of a fully continuous synthesis device for synthesizing cephalosporin mother nuclei provided according to Example 1 of the present invention is shown.

[0024] Figure 2 Shows Figure 1 A perspective structural schematic diagram of a packed bed reactor is shown;

[0025] Figure 3 Shows Figure 2 The packed bed reactor is shown in a cross-sectional view along its radial direction.

[0026] Among them, the above drawings include the following reference numerals:

[0027] 1. Reaction liquid storage tank; 2. Packed bed reactor; 3. Immobilized enzyme; 4. Continuous crystallization tank; 5. Continuous filtration tank; 6. Degassing membrane; 7. Gas collecting hood; 8. Vacuum outlet. DETAILED DESCRIPTION

[0028] It should be noted that, in the absence of conflict, the embodiments and features in the embodiments of the present application can be combined with each other. The present invention will be described in detail below with reference to the accompanying drawings and in combination with the embodiments.

[0029] As analyzed in the background technology of the present application, the synthesis method of cephalosporin mother nucleus in the prior art has the problems of low production capacity, poor stability caused by difficulty in pH control, and difficulty in controlling the PBR (packed bed reactor) continuous reaction process. In order to solve these problems, the present application provides a fully continuous synthesis device and a fully continuous synthesis method for cephalosporin mother nucleus.

[0030] In a typical embodiment of the present application, a fully continuous synthesis method for synthesizing cephalosporin mother nuclei is provided, and the fully continuous synthesis method comprises: subjecting a reaction system comprising a cephalosporin intermediate raw material, an immobilized enzyme and a reaction medium to a continuous reaction to obtain a product system comprising a cephalosporin mother nucleus; subjecting the product system to a continuous post-treatment to obtain a cephalosporin mother nucleus; wherein, acidic gas is removed from the reaction system to regulate the pH of the continuous reaction.

[0031] In the above fully continuous reaction process, the acidic gas (such as carbon dioxide) is removed from the reaction system to achieve full-process regulation of pH during the fully continuous synthesis of cephalosporin mother nuclei, so that the fully continuous synthesis system of the cephalosporin mother nuclei can maintain a specific pH value, thereby achieving continuous and stable regulation of pH value during the continuous synthesis of cephalosporin mother nuclei reaction, further maintaining the reaction rate at an optimal state, and avoiding the loss of activity of the immobilized enzyme due to pH reduction, while avoiding the need for complex continuous reaction equipment. The present invention realizes full continuity from the enzyme catalysis process to the continuous separation of the product, thereby solving the problems of discontinuous full continuous synthesis of cephalosporin mother nuclei, low production capacity, poor stability caused by difficulty in pH regulation, and difficulty in controlling the continuous reaction process of PBR (packed bed reactor), and obtaining a high-yield and high-purity cephalosporin mother nucleus product. The above fully continuous synthesis method of the present application has high production efficiency, low cost, simple operation, green environmental protection, and long service life of the immobilized enzyme.

[0032] In addition, it is preferred that the immobilized enzyme of the present application is an acylase, the continuous reactor is a packed bed reactor (PBR), and the immobilized enzyme is prepared in the PBR.

[0033] In one embodiment of the present application, the above-mentioned continuous reaction is carried out in a packed bed reactor, which includes a reaction pipe, the immobilized enzyme is filled into the packed bed reactor, the cephalosporin intermediate raw material is input from one end of the reaction pipe through a liquid pump and output from the other end of the reaction pipe, the cephalosporin intermediate raw material is added in the form of an aqueous solution, the mass concentration of the cephalosporin intermediate aqueous solution is 1~20wt%, and / or the flow rate of the cephalosporin intermediate aqueous solution is 0.5~2CV / h, wherein "CV" represents the volume of the packed bed reactor where the continuous reaction is located.

[0034] It is preferred to control the mass concentration and flow rate of the cephalosporin intermediate aqueous solution within the above ranges, which helps to achieve maximum production efficiency and space-time yield (STY).

[0035] Specifically, the cephalosporin intermediate in the above raw materials is continuously added to a continuous reactor (such as a packed bed reactor) in the form of an aqueous solution via a continuous feed pump (including but not limited to a diaphragm pump, a plunger pump, a peristaltic pump, etc.). It is preferred to control the mass concentration and flow rate of the cephalosporin intermediate solution within the above range, which helps to control the progress of the continuous reaction, thereby avoiding the problem of low reaction efficiency due to too slow reaction and the problem of poor heat control due to too fast reaction as much as possible.

[0036] In one embodiment of the present application, the reaction medium comprises a salt solution, the pH value of the salt solution is 7.8-8.3, and / or the salt solution is selected from any one or more of ammonium bicarbonate with a pH value of 7.8, potassium bicarbonate with a pH value of 8.1, and sodium bicarbonate with a pH value of 8.3; and / or the molar ratio of the solute to the cephalosporin intermediate in the salt solution is 2-10:1.

[0037] The present application adopts the above special salts. Once an acidic substance is generated in the reaction system, the free protons can react with these salts to produce carbon dioxide, thereby timely converting the free protons that have been growing in the reaction system into easily removable carbon dioxide, thereby achieving continuous regulation of pH. Among them, ammonium bicarbonate, potassium bicarbonate, and sodium bicarbonate can easily react with free protons to generate carbon dioxide through acid reactions in a short time. Ammonium carbamate is more likely to release carbon dioxide by decomposition after reacting with free protons. In addition, the above preferred salt solutions help to maintain a constant pH value in the reaction system at a low cost.

[0038] The molar ratio of the solute to the cephalosporin intermediate in the salt solution is preferably controlled within the above range, which helps to ensure that the free protons generated by the cephalosporin intermediate during the reaction can be converted into carbon dioxide in a timely manner, thereby maintaining a specific pH value in the continuous reaction system, and further achieving stable regulation of pH during the continuous synthesis of cephalosporin mother nucleus reaction.

[0039] In one embodiment of the present application, the above-mentioned fully continuous synthesis method further includes: continuously crystallizing the product system to obtain a crystallized system; and continuously filtering the crystallized system to obtain cephalosporin mother nuclei.

[0040] The above preferred post-treatment methods are helpful to improve the treatment efficiency and effect of the product system and help save energy consumption.

[0041] In one embodiment of the present application, the structural formula of the above-mentioned cephalosporin intermediate is as follows:

[0042]

[0043] Wherein, R1 is H or methoxybenzoyl; R2 is selected from any one of H, chlorine, methyl, chloromethyl, vinyl, methoxymethyl, prop-1-enyl, 1-pyridylmethyl, (2-methyl-1,3,4-thiadiazol-5-ylthio)methyl.

[0044] The above fully continuous synthesis method of cephalosporin mother nucleus has a broad spectrum, and the above preferred cephalosporin intermediates can be used to continuously, efficiently and stably synthesize the corresponding cephalosporin mother nucleus through the above reaction method.

[0045] In another typical embodiment of the present application, Figures 1 to 3As shown, a fully continuous synthesis device for a cephalosporin mother nucleus is provided, the fully continuous synthesis device comprising a reaction liquid storage tank 1, a packed bed reactor 2, a continuous crystallization tank 4 and a continuous filtration tank 5, wherein the reaction liquid storage tank 1 has a reaction liquid outlet, and the reaction liquid storage tank 1 is used to accommodate a raw material including a cephalosporin intermediate; the packed bed reactor 2 has a reaction liquid inlet and a product outlet, the reaction liquid inlet is connected to the reaction liquid outlet, the packed bed reactor 2 is used to continuously react the raw material including the cephalosporin intermediate and the immobilized enzyme 3 to obtain a product system including the cephalosporin mother nucleus; the continuous crystallization tank 4 has a crystallization tank inlet and a crystallization tank outlet, the crystallization tank inlet is connected to the product outlet, the continuous crystallization tank 4 is used to continuously crystallize the product system to obtain a crystallized system; the continuous filtration tank 5 has a filtration tank inlet and a filtration tank outlet, the filtration tank inlet is connected to the crystallization tank outlet, the continuous filtration tank 5 is used to treat the crystallized product system The system is continuously filtered to obtain cephalosporin mother nuclei; wherein the raw material of the cephalosporin intermediate also includes a salt solution, and the salt solution reacts with free hydrogen ions in the product system to generate carbon dioxide; a degassing membrane 6 is also provided in the packed bed reactor 2, and the degassing membrane 6 is interspersed in the filling area of ​​the immobilized enzyme 3, and the degassing membrane 6 is an ETC fiber membrane bundle; the immobilized enzyme 3 is filled in the packed bed reactor 2; the packed bed reactor 2 has a bottom end and a top end relative to each other in the axial direction, and a sealing plate is provided at the bottom end, and a plurality of openings corresponding to the openings of the ETC fiber membrane bundle are provided on the sealing plate; the fully continuous synthesis device also includes a gas collecting hood 7, which has two opposite first opening ends and a second opening end, and the first opening end is in contact with the sealing plate and is covered on the sealing plate, and covers all the openings on the sealing plate; the second opening end is an exhaust port 8, and the exhaust port 8 is used to extract the carbon dioxide in the packed bed reactor 2.

[0046] The above fully continuous synthesis device of cephalosporin mother nucleus is helpful to realize the continuous reaction of cephalosporin intermediate raw material to cephalosporin mother nucleus through reaction liquid storage tank 1, packed bed reactor 2, continuous crystallization tank 4 and continuous filtration tank 5. The preferred air extraction port 8 can remove the carbon dioxide in the packed bed reactor 2 in a timely manner, so that the reaction can be realized in a fully continuous process and the continuous reaction can be kept stable. The packed bed reactor 2 of the present invention helps to realize the continuous synthesis of cephalosporin intermediates and continuous pH regulation, which can improve the reaction speed and extend the service life of the enzyme. Thereby solving the problems of discontinuous preparation of continuous flow reaction and immobilized enzyme 3, low enzyme-catalyzed batch reaction capacity, complex operation, large energy consumption, poor stability and low reaction efficiency.

[0047] Of course, as embodied in the preparation principle of the above cephalosporin mother nuclei of the present application, in a similar reaction system, if hydrogen ions are also generated and are detrimental to the reaction system in which they are located, a salt solution with a certain pH value can also be used as a reaction medium to remove the hydrogen ions to reduce the adverse effects of hydrogen ions on the reaction system.

[0048] In one embodiment of the present application, the inner diameter of the membrane filaments of the above-mentioned ETC fiber membrane bundle is 0.22 mm, and / or the outer diameter of the membrane filaments of the ETC fiber membrane bundle is 0.30 mm.

[0049] It is preferred to set an ETC fiber membrane bundle of the above size in the packed bed reactor 2, which helps to timely adsorb and accumulate the carbon dioxide generated in the packed bed reactor 2 in the ETC fiber membrane bundle, so that the ETC fiber membrane bundle can be used as a temporary storage and circulation pipeline for carbon dioxide, thereby making it easier to centrally remove the carbon dioxide in the packed bed reactor 2.

[0050] In one embodiment of the present application, the length direction of the membrane fibers in the above-mentioned ETC fiber membrane bundle extends along the axial direction of the packed bed reactor 2.

[0051] The preferred extending direction of the ETC fiber membrane bundle helps to keep carbon dioxide flowing better in the ETC fiber membrane bundle, thereby making it easier to remove carbon dioxide from the ETC fiber membrane bundle.

[0052] In one embodiment of the present application, the sum of the volume of the degassing membrane 6 and the volume of the immobilized enzyme 3 is equal to the volume of the containing chamber of the packed bed reactor 2, and / or the ratio of the mass of the degassing membrane 6 to the mass of the immobilized enzyme 3 is 1:1000~10000.

[0053] In fact, the use of immobilized acylase batch stirring to produce cephalosporin mother nuclei has been widely used, but batch stirring to prepare immobilized enzyme 3, batch stirring reaction to produce cephalosporin mother nuclei is cumbersome, energy consumption is large, and a lot of time is wasted in the operation process, rather than the reaction process. The present invention adopts the above fully continuous synthesis device to carry out continuous enzyme catalytic reaction, and realizes online pH regulation. The raw material solution system flows through the immobilized enzyme 3 at a certain flow rate and is converted by enzyme catalysis to generate products. In this process, the amount of enzyme is greatly excessive, and the reaction speed can be increased by tens or even hundreds of times, thereby improving the reaction speed and production efficiency. The packed bed reactor 2 does not need to be stirred, so there is no need to reserve space, the reactor has no dead volume, and the catalytic efficiency of the enzyme is high, so that under the same volume, the capacity of the packed bed reactor 2 is improved by tens to thousands of times compared with the batch stirred tank reactor. And due to timely regulation, the service life and catalytic capacity of the immobilized enzyme 3 are greatly improved.

[0054] Therefore, preferably, the sum of the volume of the above degassing membrane 6 and the volume of the immobilized enzyme 3 is equal to the volume of the containing cavity of the packed bed reactor 2, that is, there is no empty volume in the packed bed reactor 2, and the space of the entire packed bed reactor 2 is utilized, thereby improving the efficiency of the reaction in the packed bed reactor 2.

[0055] In one embodiment of the present application, the ratio of the mass of the degassing membrane 6 to the mass of the immobilized enzyme 3 is 1:1000-10000.

[0056] The preferred ratio of the mass of the degassing membrane 6 to the mass of the immobilized enzyme 3 is within the above range, which helps to ensure a higher content of the immobilized enzyme 3 in the packed bed reactor 2 on the basis of removing the carbon dioxide in the packed bed reactor 2 as much as possible. In addition, it is preferred that the above-mentioned exhaust port 8 is connected to an exhaust pump, which is conducive to providing power for the exhaust process, thereby ensuring the efficiency and effect of the removal of carbon dioxide.

[0057] The beneficial effects of the present application will be described below in conjunction with specific embodiments and comparative examples.

[0058] Examples 1 to 9

[0059] according to Figure 1 The fully continuous synthesis device diagram of the synthetic cephalosporin mother nucleus shown in FIG. Figure 2 The perspective structural diagram of the packed bed reactor 2 is shown and Figure 3The packed bed reactor 2 is shown in a cross-sectional view along its radial direction), and the fully continuous synthesis device comprises a reaction liquid storage tank 1, a packed bed reactor 2, a continuous crystallization tank 4 and a continuous filtration tank 5, wherein the reaction liquid storage tank 1 has an outlet for a cephalosporin mother nucleus intermediate reaction substrate aqueous solution, and the reaction liquid storage tank 1 is used to accommodate the cephalosporin mother nucleus intermediate reaction substrate aqueous solution; the packed bed reactor 2 has an inlet for an intermediate reaction substrate aqueous solution of the cephalosporin mother nucleus and a product outlet, the inlet for the intermediate reaction substrate aqueous solution of the cephalosporin mother nucleus is connected to the outlet for the intermediate reaction substrate aqueous solution of the cephalosporin mother nucleus, and the packed bed reactor 2 is used to continuously react the cephalosporin mother nucleus intermediate reaction substrate aqueous solution and acylase to obtain a product system including the cephalosporin mother nucleus; the continuous crystallization tank 4 has a crystallization tank inlet and a crystallization tank outlet, the crystallization tank inlet is connected to the product outlet, and the continuous crystallization tank 4 is used to continuously crystallize the product system of the cephalosporin mother nucleus to obtain a crystallized system; the continuous filtration tank 5 has a filtration tank inlet and a filtration tank outlet, and the filtration tank The inlet is connected to the outlet of the crystallization tank, and the continuous filtration tank 5 is used to continuously filter the system after crystallization to obtain the cephalosporin mother nucleus; wherein, the raw material of the cephalosporin intermediate also includes a sodium bicarbonate solution with a pH value of 8.3, and the molar ratio of the solute in the sodium bicarbonate solution to the cephalosporin intermediate is 4:1; a degassing membrane 6 is also provided in the packed bed reactor 2, and the degassing membrane 6 is interspersed in the filling area of ​​the acylase, and the degassing membrane 6 is an ETC fiber membrane bundle; the acylase is filled in the packed bed reactor 2; the packed bed reactor 2 has a bottom end and a top end relative to each other in the axial direction, and a sealing plate is provided at the bottom end, and a plurality of openings corresponding to the openings of the ETC fiber membrane bundle are provided on the sealing plate; the fully continuous synthesis device also includes a gas collecting hood 7, which has two opposite first opening ends and a second opening end, the first opening end is in contact with the sealing plate and is covered on the sealing plate, and covers all the openings on the sealing plate; the second opening end is a gas extraction port 8, and the gas extraction port 8 is used to extract the carbon dioxide in the packed bed reactor 2. The inner diameter of the membrane filament of the ETC fiber membrane bundle is 0.22 mm, and the outer diameter of the membrane filament of the ETC fiber membrane bundle is 0.30 mm. Among them, the mass concentration of the aqueous solution of the cephalosporin nucleus intermediate reaction substrate is 10wt%, and the aqueous solution of the cephalosporin nucleus intermediate reaction substrate is continuously injected into the packed bed reactor (PBR) at 1CV / h ("CV" represents the volume of the reactor where the continuous reaction is located) through a continuous feed pump, flows through the acylase in the PBR, and the substrate raw material is hydrolyzed by the enzyme to obtain the cephalosporin nucleus. At a suitable flow rate (retention time), there is almost no raw material remaining in the solution collected at the outlet of the PBR, and the conversion rate is ≥90%. It can be operated continuously for more than 10 days, as shown in Table 1.

[0060] Table 1

[0061]

[0062] Example 10

[0063] The difference between Example 10 and Example 1 is that the molar ratio of the solute in the sodium bicarbonate solution to the cephalosporin intermediate is 10:1, and the cephalosporin mother nucleus is finally obtained.

[0064] Embodiment 11

[0065] The difference between Example 11 and Example 1 is that the molar ratio of the solute in the sodium bicarbonate solution to the cephalosporin intermediate is 1:1, and the cephalosporin mother nucleus is finally obtained.

[0066] Example 12

[0067] The difference between Example 12 and Example 1 is that the salt solution is potassium bicarbonate with a pH value of 8.1, and cephalosporin mother nuclei are finally obtained.

[0068] Comparative Example 1

[0069] The difference from Example 1 is that no degassing membrane 6 is provided in the packed bed reactor 2 , and no gas extraction port 8 is distributed on the outer side wall of the packed bed reactor 2 .

[0070] Comparative Example 2

[0071] The difference from Example 1 is that the reaction is carried out in a batch reactor, and the reaction parameters are as follows: the mass concentration of the aqueous solution of the cephalosporin nucleus intermediate reaction substrate is 10wt%, the enzyme dosage is 100wt%, and the pH of the reaction system is controlled by a pH automatic control system to maintain 8.0-8.5. After reacting at 30°C for 10 hours, samples are taken every 2 h until the conversion rate is ≥90-99%.

[0072] Table 2

[0073]

[0074] From the above description, it can be seen that the above embodiments of the present invention achieve the following technical effects:

[0075] In the above fully continuous reaction process, the acidic gas (such as carbon dioxide) is removed from the reaction system to achieve full-process regulation of pH during the fully continuous synthesis of cephalosporin mother nuclei, so that the fully continuous synthesis system of the cephalosporin mother nuclei can maintain a specific pH value, thereby achieving continuous and stable regulation of pH value during the continuous synthesis of cephalosporin mother nuclei reaction, further maintaining the reaction rate at an optimal state, and avoiding the loss of activity of the immobilized enzyme due to pH reduction, while avoiding the need for complex continuous reaction equipment. The present invention realizes full continuity from the enzyme catalysis process to the continuous separation of the product, thereby solving the problems of discontinuous full continuous synthesis of cephalosporin mother nuclei, low production capacity, poor stability caused by difficulty in pH regulation, and difficulty in controlling the continuous reaction process of PBR (packed bed reactor), and obtaining a high-yield and high-purity cephalosporin mother nucleus product. The above fully continuous synthesis method of the present application has high production efficiency, low cost, simple operation, green environmental protection, and long service life of the immobilized enzyme.

[0076] The above are only preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A fully continuous synthesis method of cephalosporin mother nucleus, characterized in that: The fully continuous synthesis method comprises: Conducting a continuous reaction on a reaction system including a cephalosporin intermediate raw material, an immobilized enzyme and a reaction medium to obtain a product system including a cephalosporin mother nucleus; The product system is subjected to continuous post-processing to obtain cephalosporin mother nuclei; Wherein, the acidic gas is removed from the reaction system to adjust the pH of the continuous reaction.

2. The fully continuous synthesis method according to claim 1, characterized in that The continuous reaction is carried out in a packed bed reactor, which includes a reaction pipe, the immobilized enzyme is filled into the packed bed reactor, the cephalosporin intermediate raw material is input from one end of the reaction pipe through a liquid pump and output from the other end of the reaction pipe, the cephalosporin intermediate raw material is added in the form of an aqueous solution, the mass concentration of the cephalosporin intermediate aqueous solution is 1~20wt%, and / or the flow rate of the cephalosporin intermediate aqueous solution is 0.5~2CV / h, wherein "CV" represents the volume of the packed bed reactor where the continuous reaction is carried out.

3. The fully continuous synthesis method according to claim 1 or 2, characterized in that: The reaction medium comprises a salt solution, the pH value of the salt solution is 7.8-8.3, and / or the salt solution is selected from any one of ammonium bicarbonate with a pH value of 7.8, potassium bicarbonate with a pH value of 8.1, and sodium bicarbonate with a pH value of 8.3; and / or the molar ratio of the solute in the salt solution to the cephalosporin intermediate is 2-10:

1.

4. The fully continuous synthesis method according to claim 1 or 2, characterized in that: The fully continuous synthesis method also includes: The product system is subjected to continuous crystallization treatment to obtain a crystallized system; The system after crystallization is continuously filtered to obtain the cephalosporin mother nucleus.

5. The fully continuous synthesis method according to claim 1, characterized in that The structural formula of the cephalosporin intermediate is as follows: ， Wherein, R1 is H or methoxybenzoyl; R2 is selected from any one of H, chlorine, methyl, chloromethyl, vinyl, methoxymethyl, prop-1-enyl, 1-pyridylmethyl, (2-methyl-1,3,4-thiadiazol-5-ylthio)methyl.

6. A fully continuous synthesis device for cephalosporin mother nuclei, characterized in that: The fully continuous synthesis device comprises: A reaction liquid storage tank (1) having a reaction liquid outlet, wherein the reaction liquid storage tank (1) is used to contain raw materials including a cephalosporin intermediate; A packed bed reactor (2) having a reaction liquid inlet and a product outlet, wherein the reaction liquid inlet is connected to the reaction liquid outlet, and the packed bed reactor (2) is used to continuously react a raw material including a cephalosporin intermediate and an immobilized enzyme (3) to obtain a product system including a cephalosporin mother nucleus; A continuous crystallization tank (4) having a crystallization tank inlet and a crystallization tank outlet, wherein the crystallization tank inlet is connected to the product outlet, and the continuous crystallization tank (4) is used to perform continuous crystallization treatment on the product system to obtain a crystallized system; A continuous filtration tank (5) having a filtration tank inlet and a filtration tank outlet, wherein the filtration tank inlet is connected to the crystallization tank outlet, and the continuous filtration tank (5) is used to continuously filter the post-crystallization system to obtain cephalosporin mother nuclei; Wherein, the raw material of the cephalosporin intermediate also includes a salt solution, and the salt solution reacts with free hydrogen ions in the product system to generate carbon dioxide; The packed bed reactor (2) is further provided with a degassing membrane (6), the degassing membrane (6) being inserted into the filling area of ​​the immobilized enzyme (3), and the degassing membrane (6) being a bundle of ETC fiber membranes; The immobilized enzyme (3) is filled in the packed bed reactor (2); The packed bed reactor (2) has a bottom end and a top end opposite to each other in the axial direction, the bottom end is provided with an end capping plate, and the end capping plate is provided with a plurality of openings corresponding one to one to the openings of the ETC fiber membrane bundle; The fully continuous synthesis device further comprises a gas collecting hood (7) having two opposite first opening ends and a second opening end, wherein the first opening end contacts the end sealing plate and is covered on the end sealing plate, and covers all openings on the end sealing plate; The second open end is a gas extraction port (8), and the gas extraction port (8) is used to extract the carbon dioxide in the packed bed reactor (2).

7. The fully continuous synthesis device according to claim 6, characterized in that: The inner diameter of the membrane filaments of the ETC fiber membrane bundle is 0.22 mm, and / or the outer diameter of the membrane filaments of the ETC fiber membrane bundle is 0.30 mm.

8. The fully continuous synthesis device according to claim 6 or 7, characterized in that: The length direction of the membrane fibers in the ETC fiber membrane bundle extends along the axial direction of the packed bed reactor (2).

9. The fully continuous synthesis device according to claim 6 or 7, characterized in that: The sum of the volume of the degassing membrane (6) and the volume of the immobilized enzyme (3) is equal to the volume of the containing chamber of the packed bed reactor (2).

10. The fully continuous synthesis device according to claim 6 or 7, characterized in that: The ratio of the mass of the degassing membrane (6) to the mass of the immobilized enzyme (3) is 1:1000-10000.

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