CN110627794A - Continuous post-treatment method and device for penem compounds - Google Patents
Continuous post-treatment method and device for penem compounds Download PDFInfo
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- CN110627794A CN110627794A CN201910979214.0A CN201910979214A CN110627794A CN 110627794 A CN110627794 A CN 110627794A CN 201910979214 A CN201910979214 A CN 201910979214A CN 110627794 A CN110627794 A CN 110627794A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/02—Preparation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
- C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
- C07D477/20—Sulfur atoms
Abstract
The invention provides a continuous post-treatment method and a continuous post-treatment device for penem compounds. The method comprises the following steps: s1, continuously extracting the reaction crude product of the penem compound to obtain an extracted heavy phase and an extracted light phase; s2, carrying out continuous solid-liquid separation on the extracted heavy phase to obtain a liquid phase separator; s3, continuously adjusting the pH value of the liquid phase separation matter to 6.1-6.3 to obtain a pH adjusting liquid; and S4, carrying out continuous crystallization treatment on the pH regulating solution by adopting a first crystallization solvent to obtain a product of the penem compound. The method has the advantages of high treatment speed and high efficiency when the method is used for carrying out aftertreatment on the reaction crude product of the penem compound, and the material property is stable in the treatment process, the deterioration rate is low, and the method has better control capability on the yield and the purity of the target product.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a continuous post-treatment method and device for penem compounds.
Background
In the field of pharmaceutical and chemical industry, the post-treatment of the reacted system is one of the inevitable researches. The unit operations of the typical post-processing mainly include: extracting, separating liquid, filter pressing, drying, regulating PH, crystallizing and centrifuging. At present, the domestic chemical and pharmaceutical industry mainly takes batch post-processing as a main part, namely, the batch-type operation of a single post-processing operation unit is carried out, and the method has the advantage of large single-batch processing capacity. The disadvantages are time and labor consuming, low automation, and the fact that the batch post-treatment will lose a lot of product if the post-treatment system deteriorates over time, and the usual penem antibiotics are of this type which are prone to deterioration (such as the post-treatment method provided in patent CN 207845524U).
Specifically, in the current industry, the post-treatment technology for a penem-type large-batch reaction system is single. In terms of extraction and liquid separation, a workshop is usually used for large-kettle batch liquid separation, the time consumption of a single operation unit is 6 hours, and the solvent residues (NEP, TMG and isoamylol) are all large in the product-containing water phase subjected to extraction and separation treatment. The product residue dissolved in the organic phase can reach 0.3 percent, and secondary extraction liquid separation operation is often carried out. The traditional batch extraction and liquid separation operation is time-consuming and labor-consuming, and the separation effect is not very good. Further, at the pH adjustment stage in the penem-type post-treatment process, the batch pH adjustment has a disadvantage that the repeated addition of acetic acid followed by stirring and standing still takes a long time. The time of the single 400L treatment amount batch pH adjusting stage can reach 5-6 hours, and once the single batch pH adjusting stage is adjusted, the loss is very large. This also means that the rate of deterioration of the penem-like product during the pH adjustment is increased (usually, before the pH adjustment stage, the rate of deterioration of the product per hour is about 0.2%, and the rate of deterioration of the product after the acid adjustment is about 1.3% per hour. In addition, the risk potential brought by the large-scale treatment of the reaction system is very much. For example, heat release, gas discharge and material leakage exist, for example, the penem products have heat release conditions of different degrees in a mixing filter pressing section and a crystallization section. The larger the batch processing amount is, the more the potential danger is brought, and if the material property to be processed is worse, the maintenance cost is greatly increased. The batch post-processing occupies a large area, and the manpower resource and energy consumption cost are very high.
In view of the above situation, there is a need to develop a post-treatment technology with high post-treatment speed, high treatment efficiency and stable material properties.
Disclosure of Invention
The invention mainly aims to provide a continuous post-treatment method and a device for penem compounds, which are used for solving the problems of low treatment speed, low efficiency and high material deterioration rate in the process of batch treatment of a crude product of the penem compounds in the prior art.
In order to achieve the above object, according to one aspect of the present invention, there is provided a continuous post-treatment method for penem compounds, which comprises the following steps: s1, continuously extracting the reaction crude product of the penem compound to obtain an extracted heavy phase and an extracted light phase; s2, carrying out continuous solid-liquid separation on the extracted heavy phase to obtain a liquid phase separator; s3, continuously adjusting the pH value of the liquid phase separation matter to 6.1-6.3 to obtain a pH adjusting liquid; and S4, carrying out continuous crystallization treatment on the pH regulating solution by adopting a first crystallization solvent to obtain a product of the penem compound.
Further, before the continuous solid-liquid separation of the extracted heavy phase, the step S2 further includes the step of adding a second crystallization solvent to the extracted heavy phase and mixing the two in the PFR reactor; the addition amount of the second crystallization solvent is 50-80% of the weight of the extracted heavy phase, and the temperature of the PFR reactor is controlled to be-7-3 ℃.
Furthermore, the residence time of the extracted heavy phase in the PFR reactor is 2-8 min.
Further, in step S1, the continuous extraction process includes sequentially performing N times, where N is greater than or equal to 2, and the heavy phase separated in the mth continuous extraction process enters the M +1 th continuous extraction process, where M is greater than or equal to 1 and is less than or equal to (N-1), and the heavy phase separated in the nth continuous extraction process is used as the extracted heavy phase in step S2; preferably, N ═ 2.
Furthermore, in the continuous extraction process, the retention time of the reaction crude product of the penem compound is 1-7 min, and the treatment temperature is-7-3 ℃.
Further, in the continuous solid-liquid separation process, the extraction heavy phase is divided into multiple parts, the multiple parts of the extraction heavy phase respectively enter different filter pressing devices for treatment in a one-to-one correspondence mode, the treatment flux of each filter pressing device is 1-2L/min, and the residence time of the extraction heavy phase is 2-11 min.
Further, the first crystallization solvent is methanol and/or n-propanol, and the second crystallization solvent is methanol and/or n-propanol.
Further, in the continuous crystallization treatment process, the retention time of the pH regulating solution is 2-11 min, and the treatment temperature is-22 to-12 ℃.
Further, in step S3, the reagent for adjusting the pH of the liquid phase separation product is a mixed solution of methanol and acetic acid, and preferably has a pH of 3 to 4.
Further, in the process of adjusting the pH value of the liquid phase separator, the retention time of the liquid phase separator is 2-11 min, and the treatment temperature is-7-3 ℃.
According to another aspect of the present invention, there is provided a penem compound continuous post-treatment device, which comprises: the continuous extraction and liquid separation unit is provided with a penem compound crude product inlet, an extracting agent inlet, an extraction heavy phase outlet and an extraction light phase outlet, and is used for continuously extracting a reaction crude product of the penem compound; the continuous filter pressing unit is provided with a filter pressing liquid inlet, a solid phase outlet and a liquid phase outlet, the filter pressing liquid inlet is connected with the heavy phase extraction outlet, and the continuous filter pressing unit is used for carrying out continuous solid-liquid separation on the heavy phase extraction discharged from the heavy phase extraction outlet; the continuous pH adjusting unit is provided with a liquid phase inlet, a pH regulator inlet and an adjusting liquid outlet, the liquid phase inlet is connected with the liquid phase outlet, and the continuous pH adjusting unit is used for continuously adjusting the pH of the liquid discharged from the liquid phase outlet; and the continuous crystallization unit is provided with a regulating liquid inlet, a first crystallization solvent inlet and a crystallization slurry outlet, the regulating liquid inlet is connected with the regulating liquid outlet, and the continuous crystallization unit is used for continuously crystallizing the pH regulating liquid discharged from the regulating liquid outlet.
Further, the apparatus further comprises: and the PFR reactor is arranged on a pipeline connected with the filtrate inlet and the extraction heavy phase outlet, and is also provided with a second crystallization solvent inlet.
Further, the PFR reactor is a jacketed coil reactor comprising a coil reactor and a first temperature controlled jacket disposed outside the coil reactor.
Further, the continuous pH adjusting unit is a tubular pH adjusting device, and the continuous crystallization unit is a tubular crystallization device.
Further, the apparatus further comprises: and the pH value detection device is arranged on a pipeline connecting the regulating liquid inlet and the regulating liquid outlet and is used for detecting the pH value of the pH regulating liquid.
Furthermore, the continuous extraction and liquid separation unit comprises a plurality of stages of continuous extraction and liquid separation devices which are sequentially connected in series, each continuous extraction and liquid separation device is provided with a liquid inlet, an extractant inlet, an extraction light phase outlet and an extraction heavy phase outlet, the liquid inlet of the continuous extraction and liquid separation device positioned at the most upstream is a crude product inlet of a penem compound, the extraction heavy phase outlet of the continuous extraction and liquid separation device positioned at the most downstream is connected with a filtrate inlet, and in two adjacent continuous extraction and liquid separation devices, the extraction heavy phase outlet of one stage positioned at the upstream is connected with the liquid inlet of one stage positioned at the downstream.
Furthermore, the continuous filter pressing unit comprises multistage filter pressing devices arranged in parallel, and each multistage filter pressing device is provided with a filter pressing liquid inlet, a solid phase outlet and a liquid phase outlet.
Further, the apparatus further comprises: the extraction light phase receiving device is connected with the extraction light phase outlet; the extraction heavy phase receiving device is arranged on a pipeline connecting the extraction heavy phase outlet and the PFR reactor; the liquid phase receiving device is arranged on a pipeline connected with the liquid phase inlet and the liquid phase outlet; and a crystallization slurry receiving device connected with the crystallization slurry outlet.
Further, the apparatus further comprises: the first mass flow meter is arranged on a pipeline connecting the extraction heavy phase receiving device and the PFR reactor; the second mass flowmeter is arranged on a pipeline connected with the liquid phase inlet and the liquid phase receiving device; and the device also comprises a control unit which is electrically connected with the pH value detection device, the first mass flowmeter and the second mass flowmeter.
Furthermore, material conveying pumps are arranged on pipelines of the crude product inlet of the penem compound, the extracting agent inlet, the pH regulating agent inlet, the liquid phase inlet, the first crystallization solvent inlet, the regulating liquid inlet, the second crystallization solvent inlet and the inlet of the PFR reactor for introducing the extraction heavy phase.
Furthermore, the continuous extraction liquid separation unit, the continuous filter pressing unit, the continuous pH adjusting unit and the continuous crystallization unit are all provided with temperature control units, the extraction heavy phase receiving device is provided with a second temperature control jacket, the liquid phase receiving device is provided with a third temperature control jacket, the crystallization slurry receiving device is provided with a fourth temperature control jacket, and the control unit is also electrically connected with the temperature control units, the second temperature control jacket, the third temperature control jacket and the fourth temperature control jacket.
Furthermore, the continuous post-treatment device for the penem compounds is a post-treatment device for synthesizing the penem compounds.
The invention provides a continuous post-treatment method of a penem compound, which is a continuous integrated post-treatment method, and has the advantages of high treatment speed and high efficiency when the method is used for post-treating a reaction crude product of the penem compound, stable material property and low deterioration rate in the treatment process, and has better control capability on the yield and purity of a target product. Particularly, the method can well accord with the properties of the penem compounds, and has stronger pertinence in the aspects of reducing the deterioration rate of products, improving the treatment effect and the product yield.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this application, illustrate embodiments of the invention and, together with the description, serve to explain the invention and not to limit the invention. In the drawings:
fig. 1 shows a schematic structural diagram of a continuous post-treatment device for penem compounds according to an embodiment of the present invention.
Wherein the figures include the following reference numerals:
10. a continuous extraction and liquid separation unit; 11. a continuous extraction and liquid separation device; 20. a continuous filter pressing unit; 21. a filter pressing device; 30. a continuous pH adjustment unit; 40. a continuous crystallization unit; 50. a PFR reactor; 60. a pH value detection device; 70. an extraction light phase receiving device; 80. an extraction heavy phase receiving device; 90. a liquid phase receiving device; 100. a devitrified slurry receiving means; 110. a first mass flow meter; 120. a second mass flow meter; 130. a material transfer pump.
Detailed Description
It should be noted that the embodiments and features of the embodiments in the present application may be combined with each other without conflict. The present invention will be described in detail below with reference to the embodiments with reference to the attached drawings.
As described in the background art, the problems of low processing speed, low efficiency, high material deterioration rate and the like exist when batch processing is adopted for the crude products of the penem compounds in the prior art.
In order to solve the problem, the invention provides a continuous post-treatment method of penem compounds, which comprises the following steps: s1, continuously extracting the reaction crude product of the penem compound to obtain an extracted heavy phase and an extracted light phase; s2, carrying out continuous solid-liquid separation on the extracted heavy phase to obtain a liquid phase separator; s3, continuously adjusting the pH value of the liquid phase separation matter to 6.1-6.3 to obtain a pH adjusting liquid; and S4, carrying out continuous crystallization treatment on the pH regulating solution by adopting a first crystallization solvent to obtain a product of the penem compound.
The invention provides a continuous integrated post-treatment method of penem compounds, which has the advantages of high treatment speed and high efficiency when used for post-treating reaction crude products of the penem compounds, and has stable material properties, low deterioration rate and better control capability on the yield and purity of target products in the treatment process. Particularly, the method can well accord with the properties of the penem compounds, and has stronger pertinence in the aspects of reducing the deterioration rate of products, improving the treatment effect and the product yield.
Specifically, in the extraction and liquid separation stage, the continuous extraction and liquid separation adopted by the invention is shortened by more than 50% compared with batch post-treatment, and the treatment effect is far better than batch treatment. In the filter pressing stage, the heat release per unit time is far lower than that of batch post-treatment, which means that more energy is saved and the stability of the product is guaranteed. The system which is treated in the pH adjusting stage immediately enters a crystallization stage, the retention time is greatly shortened, and the deterioration rate of the product is greatly reduced. In the crystallization stage, the continuous treatment not only solves the problem of low treatment efficiency after batch treatment. Meanwhile, compared with a batch processing system, the crystallization system has better advantage in the aspect of later crystal form screening.
In a preferred embodiment, step S2 further comprises the step of adding a second crystallization solvent to the extracted heavy phase and mixing the two in the PFR reactor before subjecting the extracted heavy phase to continuous solid-liquid separation; the addition amount of the second crystallization solvent is 50-80% of the weight of the extracted heavy phase, and the temperature of the PFR reactor is controlled to be-7-3 ℃. Therefore, before the extraction heavy phase enters a filter pressing stage, the extraction heavy phase is mixed with a part of crystallization solvent in advance, on one hand, the solid phase growth of the catalyst in a crude product system is facilitated, so that the solid-liquid separation in the filter pressing stage is facilitated, on the other hand, the addition of a small amount of crystallization solvent is also facilitated, the stability of a stable product in a solution system is facilitated (the product cannot be precipitated due to the small amount of crystallization solvent, and the product is forced to be crystallized and precipitated due to the solubility problem due to the large amount of crystallization solvent added in the crystallization stage), the buffer stabilization effect is achieved on a liquid phase system of the product, so that the blockage in the subsequent pH adjusting process is facilitated to be prevented.
In the actual operation process, the PFR reactor is adopted for mixing, so that the extracted heavy phase is in a continuous flowing process in the PFR reactor and is mixed with the second crystallization solvent while flowing, and the retention time is short. In order to further increase the mixing effect, in a preferred embodiment, the residence time of the extracted heavy phase in the PFR reactor is 2 to 8 min.
In a preferred embodiment, in step S1, the continuous extraction process comprises N times, N is more than or equal to 2, and the heavy phase separated from the M continuous extraction process enters the M +1 continuous extraction process, M is more than or equal to 1 and less than or equal to (N-1), and the heavy phase separated from the N continuous extraction process is used as the extracted heavy phase in step S2; preferably, N ═ 2. Thus, after the first continuous extraction and separation of the crude reaction product of the penem compound to be treated, two phases are continuously separated, the light phase can be subjected to solvent recovery, and the heavy phase enters the next continuous extraction process. In the actual treatment process, specific treatment times can be selected according to the treatment capacity and the product concentration of the crude product, and the separation stages can also be determined according to the difficulty degree of extraction separation, so that the separation effect of the treatment time and the treatment capacity has great advantages compared with the batch process. More preferably, in the continuous extraction process, the retention time of the reaction crude product of the penem compound is 1-7 min, and the treatment temperature is-7-3 ℃.
In a preferred embodiment, in the continuous solid-liquid separation process, the extraction heavy phase is divided into a plurality of parts, the plurality of parts of the extraction heavy phase respectively enter different filter pressing devices for treatment in a one-to-one correspondence manner, the treatment flux of each filter pressing device is 1-2L/min, and the residence time of the extraction heavy phase is 2-11 min. Because the filter pressing process is a high-pressure treatment process, the multistage filter pressing device is utilized to treat the filter pressing liquid, and the treatment condition of each filter pressing device is more favorably relieved.
In a preferred embodiment, the first crystallization solvent is methanol and/or n-propanol and the second crystallization solvent is methanol and/or n-propanol. More preferably, in the continuous crystallization treatment process, the retention time of the pH regulating solution is 2-11 min, and the treatment temperature is-22 to-12 ℃.
In order to further improve the efficiency of pH adjustment and prevent precipitation during pH adjustment, in a preferred embodiment, the reagent for adjusting the pH of the liquid phase separation in step S3 is a mixture of methanol and acetic acid, preferably having a pH of 3 to 4. More preferably, in the process of adjusting the pH value of the liquid phase separator, the retention time of the liquid phase separator is 2-11 min, and the treatment temperature is-7-3 ℃.
According to another aspect of the present invention, there is also provided a continuous post-treatment device for penem compounds, as shown in fig. 1, the device comprises a continuous extraction and liquid separation unit 10, a continuous filter-pressing unit 20, a continuous pH adjustment unit 30, and a continuous crystallization unit 40, wherein the continuous extraction and liquid separation unit 10 is provided with a penem compound crude product inlet, an extractant inlet, an extraction heavy phase outlet, and an extraction light phase outlet, and the continuous extraction and liquid separation unit 10 is used for continuously extracting a reaction crude product of the penem compounds; the continuous filter pressing unit 20 is provided with a filter pressing liquid inlet, a solid phase outlet and a liquid phase outlet, the filter pressing liquid inlet is connected with the extraction heavy phase outlet, and the continuous filter pressing unit 20 is used for carrying out continuous solid-liquid separation on the extraction heavy phase discharged from the extraction heavy phase outlet; the continuous pH adjusting unit 30 is provided with a liquid phase inlet, a pH regulator inlet and a regulating liquid outlet, the liquid phase inlet is connected with the liquid phase outlet, and the continuous pH adjusting unit 30 is used for continuously adjusting the pH of the liquid discharged from the liquid phase outlet; the continuous crystallization unit 40 is provided with an adjusting liquid inlet, a first crystallization solvent inlet and a crystallization slurry outlet, the adjusting liquid inlet is connected with the adjusting liquid outlet, and the continuous crystallization unit 40 is used for continuously crystallizing the pH adjusting liquid discharged from the adjusting liquid outlet.
The continuous post-treatment device for the penem compounds is a continuous integrated post-treatment device, has the advantages of high treatment speed and high efficiency when being used for post-treating the reaction crude products of the penem compounds, and has stable material properties, low deterioration rate and better control capability on the yield and purity of target products in the treatment process. Particularly, the device can well accord with the properties of penem compounds, and has stronger pertinence in the aspects of reducing the deterioration rate of products, improving the treatment effect and the product yield.
Specifically, in the post-treatment process of the penem product, in the extraction and liquid separation stage, the continuous extraction and liquid separation adopted by the invention is shortened by more than 50% compared with batch post-treatment, and the treatment effect is far better than batch treatment. In the filter pressing stage, the heat release per unit time is far lower than that of batch post-treatment, which means that more energy is saved and the stability of the product is guaranteed. The system which is treated in the pH adjusting stage immediately enters a crystallization stage, the retention time is greatly shortened, and the deterioration rate of the product is greatly reduced. In the crystallization stage, the continuous treatment not only solves the problem of low treatment efficiency after batch treatment. Meanwhile, compared with a batch processing system, the crystallization system has better advantage in the aspect of later crystal form screening.
In a preferred embodiment, as shown in fig. 1, the apparatus further comprises: the PFR reactor 50 (plug flow reactor) is provided on a line connecting the filtrate inlet and the extract heavy phase outlet, and the PFR reactor 50 is further provided with a second crystallization solvent inlet. Therefore, before the extraction heavy phase enters a filter pressing stage, the extraction heavy phase is mixed with a part of crystallization solvent in advance, on one hand, the solid phase growth of the catalyst in a crude product system is facilitated, so that the solid-liquid separation in the filter pressing stage is facilitated, on the other hand, the addition of a small amount of crystallization solvent is also facilitated, the stability of a stable product in a solution system is facilitated (the product cannot be precipitated due to the small amount of crystallization solvent, and the product is forced to be crystallized and precipitated due to the solubility problem due to the large amount of crystallization solvent added in the crystallization stage), the buffer stabilization effect is achieved on a liquid phase system of the product, so that the blockage in the subsequent tubular pH adjusting process is facilitated to be prevented.
In a preferred embodiment, the PFR reactor 50 is a jacketed coil reactor comprising a coil reactor and a first temperature controlled jacket disposed outside the coil reactor. The temperature-controlled jacketed coil reactor is more favorable for mixing the extracted heavy phase with a small amount of crystallization solvent, so that the catalyst is more fully precipitated, and the stability of the system can be further ensured by controlling the temperature to prevent deterioration. Meanwhile, the jacketed coil reactor is also beneficial to avoiding the risk of damaging the product due to local heat release.
To further improve the continuity of the treatment process, in a preferred embodiment, the continuous pH adjustment unit 30 is a tubular pH adjustment device and the continuous crystallization unit 40 is a tubular crystallization device. By adopting the tubular equipment, the materials are mixed more uniformly along with the advance of the materials in the tubular equipment, and the treatment efficiency and the treatment effect are more advantageous. More preferably, the continuous pH adjusting unit 30 is of a plug flow type or a complete flow type, and the continuous crystallization unit 40 is of a plug flow type.
In a preferred embodiment, the above apparatus further comprises: and the pH value detection device 60 is arranged on a pipeline connecting the regulating liquid inlet and the regulating liquid outlet and is used for detecting the pH value of the pH regulating liquid. The invention adopts the pH preposed feedback adjustment mode, and facilitates the adjustment of the relative addition amount of the pH regulator in time (which can be adjusted by adjusting the addition amount of the pH regulator and/or the addition amount of the product phase) by monitoring the pH value state of the adjusting liquid in real time.
In a preferred embodiment, the continuous extraction and liquid separation unit 10 includes multiple stages of continuous extraction and liquid separation devices 11 sequentially connected in series, each continuous extraction and liquid separation device 11 has a liquid inlet, an extractant inlet, an extracted light phase outlet and an extracted heavy phase outlet, the liquid inlet of the continuous extraction and liquid separation device 11 positioned at the most upstream is a crude penem compound product inlet, the extracted heavy phase outlet of the continuous extraction and liquid separation device 11 positioned at the most downstream is connected with a filtrate inlet, and in two adjacent continuous extraction and liquid separation devices 11, the extracted heavy phase outlet of the one stage positioned at the upstream is connected with the liquid inlet of the one stage positioned at the downstream. Thus, after the crude reaction product of the penem compounds to be treated is extracted and separated in the first-stage continuous extraction and liquid separation device 11, two phases are continuously separated, the light phase can be recovered by the solvent, and the heavy phase enters the next-stage continuous extraction and liquid separation device 11 for further extraction and separation. In the actual treatment process, the specific stage number of the continuous extraction and liquid separation device 11 can be selected according to the treatment capacity and the product concentration of the crude product, and the separation stage number can also be determined according to the difficulty degree of extraction and separation, so that the treatment time and the treatment capacity separation effect have great advantages compared with batch processes.
Likewise, the continuous filter press unit 20 can be sized according to the amount of throughput, and in a preferred embodiment, the continuous filter press unit 20 includes multiple stage filter press devices 21 arranged in parallel, each of the multiple stage filter press devices 21 being provided with a filtrate inlet, a solid phase outlet, and a liquid phase outlet. Because the filter pressing process is a high-pressure treatment process, the multistage filter pressing devices 21 arranged in parallel are used for treating the filter pressing liquid, and the treatment conditions of the filter pressing devices are more favorably relieved.
In a preferred embodiment, the above apparatus further comprises: an extraction light phase receiving device 70 connected with the extraction light phase outlet; an extraction heavy phase receiving device 80 arranged on a pipeline connecting an extraction heavy phase outlet with the PFR reactor 50; a liquid phase receiving device 90 disposed on a pipeline connecting the liquid phase inlet and the liquid phase outlet; and the crystallization slurry receiving device 100 is connected with the crystallization slurry outlet. By utilizing each receiving device, a buffer device can be provided for feeding of each stage, so that the adjustment of the feeding flow of each stage is facilitated. More preferably, the above apparatus further comprises: a first mass flow meter 110 disposed on a line connecting the extraction heavy phase receiving device 80 and the PFR reactor 50; a second mass flow meter 120 provided on a pipe connecting the liquid phase receiving device 90 and the liquid phase inlet; and the device further comprises a control unit which is electrically connected with the pH value detection device 60, the first mass flow meter 110 and the second mass flow meter 120. Therefore, the feeding condition of each stage can be adjusted more conveniently through the control unit, and meanwhile, the running condition of each stage can be monitored in real time, so that the treatment process is more stable, the deterioration probability of products is further reduced, and the treatment efficiency is improved.
In a preferred embodiment, as shown in fig. 1, material transfer pumps 130 are disposed on the pipelines of the penem compound crude product inlet, the extractant inlet, the pH regulator inlet, the liquid phase inlet, the first crystallization solvent inlet, the regulating liquid inlet, the second crystallization solvent inlet and the inlet of the PFR reactor 50 for introducing the extracted heavy phase. It should be noted that, in the crystallization stage, as the conditioning liquid and a large amount of crystallization solvent are mixed in the tubular crystallization device, the target product is precipitated by forced crystallization, and the crystallization slurry is a mixed system of solid phase and liquid phase. The material conveying pump 130 is adopted for material driving conveying, so that the regulating liquid and the crystallization solvent can achieve very good mixing turbulence, and the crystallization effect and efficiency are superior to those of a batch processing mode. More preferably, the continuous crystallization unit 40 is a tubular plug-flow type crystallization device, which is more advantageous for improving the crystallization effect. In addition, the retention time of single system particles in the device after the pH adjustment is finished is very short, so that the crystallization effect is more favorably improved.
In the actual operation process, before the conditioning liquid enters, the feed is continuously quantified in advance through the material conveying pump 130 to fill the crystallization solvent in the tubular crystallization device, and then the conditioning liquid is introduced through the material conveying pump 130 to perform crystallization treatment. The material conveying pump 130 continuously conveys energy to the tubular crystallization device through the large-flow high-pressure resistant oscillation device, so that the solid-liquid mixed slurry after crystallization cannot be blocked in the tubular crystallization device, the slurry system enters the crystallization slurry receiving device 100 for low-temperature temporary storage, the system is very stable and does not deteriorate along with time, and the qualified product can be obtained after the slurry system enters the solid-liquid separation device after standing for a period of time.
In a preferred embodiment, the continuous extraction and liquid separation unit 10, the continuous filter-pressing unit 20, the continuous pH adjustment unit 30, and the continuous crystallization unit 40 are all provided with temperature control units, the extraction heavy phase receiving device 80 is provided with a second temperature control jacket, the liquid phase receiving device 90 is provided with a third temperature control jacket, the crystallization slurry receiving device 100 is provided with a fourth temperature control jacket, and the control units are further electrically connected with the temperature control units, the second temperature control jacket, the third temperature control jacket, and the fourth temperature control jacket. In this way, more precise temperature control can be performed for each stage, further improving the stability of the post-processing stages. More preferably, the continuous extraction and liquid separation unit 10, the continuous filter-pressing unit 20, the continuous pH adjustment unit 30, the continuous crystallization unit 40, the first temperature control jacket, the second temperature control jacket, the third temperature control jacket, and the fourth temperature control jacket are all provided with temperature platinum resistors for feeding back the measured temperature to the control unit, and the apparatus further comprises an alarm unit, and the control unit is electrically connected with the alarm unit. Therefore, the measured temperature can be fed back to the control unit in time through the temperature platinum resistors, a standard range can be set for each temperature platinum resistor, and alarm linkage tripping can be given if the temperature platinum resistors exceed the standard range and maintain the abnormal range for exceeding 10 s. Therefore, the stability of each stage of post-treatment is more favorably maintained, and the temperature state of each stage is timely adjusted.
The penem products are sensitive to temperature, and the higher the temperature is, the higher the deterioration rate of the products is. Therefore, the whole continuous post-treatment device has strict temperature control measures, all receiving devices containing products are provided with temperature control jackets, and all operation unit devices are also provided with temperature control jackets. Important conveying pipelines such as a conveying section for adjusting the pH value and then adjusting the liquid are also provided with a temperature control jacket and are kept warm.
In a preferred embodiment, the above apparatus further comprises a pressure detection unit for detecting the pressure inside the continuous pressure filtration unit 20, the continuous pH adjustment unit 30, the continuous crystallization unit 40, the PFR reactor 50, and each receiving apparatus, and the pressure detection unit is electrically connected to the control unit. Therefore, the operation pressure of each stage can be detected in real time, whether blockage occurs in each pressure unit or not can be fed back in time, and the operation stability of the system can be maintained. The pressure detection point of the pressure detection unit may be provided at an inlet of the above-described apparatus. More preferably, the continuous filter pressing unit 20, the continuous pH adjusting unit 30, the continuous crystallization unit 40, and the PFR reactor 50 are all provided with an off-gas discharge line. Therefore, the pressure can be prevented from being held, and the tail gas accumulation can be avoided.
More preferably, the device further comprises a pressure alarm system electrically connected with the pressure detection unit. Therefore, all pressure measuring points of the continuous post-processing device can be set with a pressure standard range, and once the conditions of overpressure or negative pressure occur, the continuous post-processing device can immediately alarm and jump to stop in a linkage manner.
The materials of the devices, units, pipes, etc. can be designed according to the properties of the materials to be processed, and for example, titanium, tetrafluoro, 304, 316, hastelloy, etc. can be used as materials with chemical properties, temperature resistance and pressure resistance. The connection mode between whole flow pipeline and equipment is mainly with the flange formula, and multiple other connection modes include: welding, quick-operation joint, cutting ferrule connecting piece etc. coexistent mode.
Preferably, the serial form of the continuous extraction and liquid separation device 11 is a overflow serial form, i.e. the previous stage extraction heavy phase enters the next stage for further extraction through the overflow form. The specific type of the continuous extraction and separation device 11 is preferably a centrifugal extractor, but a rotating disc extraction column, a membrane separation extraction device, or the like may be used.
Preferably, the filter-pressing device 21 described above employs inside stacks of membranes or packings.
The post-treatment device provided by the invention is more suitable for post-treatment of products with poor product properties and easy deterioration, and in a preferred embodiment, the continuous post-treatment device for the penem compounds is a post-treatment device for synthesizing the penem compounds. Specific penem compounds include, but are not limited to ertapenem, imipenem, meropenem, biapenem, panipenem, and the like. The invention has been successfully applied to the continuous post-treatment small-test to pilot-test production of the penem crude products.
In addition, the device provided by the invention is a highly automatic processing device, the feeding speed, the temperature and the like can be adjusted at any time according to the processing capacity of the equipment, and the whole processing time can be accurately controlled. Each single operation unit is connected into a whole through an automatic control program, each unit operation is accurately connected with an over-feedback type mass flowmeter, the original intermittent operation flow is enabled to be continuous, and the number of the operation units can be increased or decreased according to different processing systems. In the aspect of safety, devices such as pressure, temperature and dangerous gas alarm are installed, overpressure, overtemperature and dangerous gas excess alarm are set in a linkage mode simultaneously to conduct regulation and control, and potential accident risks are greatly reduced. All feed ports can be shut off in the face of an emergency to control product loss and risk level to a minimum. The invention can also greatly reduce the occupied area of equipment, labor and human resources and production energy consumption. Compared with the traditional batch post-processing technology, the method also greatly reduces the investment cost.
The present application is described in further detail below with reference to specific examples, which should not be construed as limiting the scope of the invention as claimed.
Example 1
Small test experiment: the device shown in fig. 1 is adopted to carry out post-treatment on a 4L ertapenem crude product system, wherein the ertapenem crude product system comprises ertapenem, TMG (tetramethylguanidine), NEP (N-ethylpyrrolidone), isoamyl alcohol, a palladium carbon catalyst and water.
Continuous extraction and liquid separation, secondary extraction and liquid separation are carried out on an ertapenem crude product system, and the system is subjected to automatic continuous quantificationDissolving the feed and simultaneously extracting the first-stage extractant (isoamyl alcohol, water and NaHCO)3Diphenyl phosphate mixed solution) was automatically fed continuously and quantitatively. The first-stage automatic extraction and liquid separation are carried out in the first-stage centrifugal extractor, the light phase scrapped system enters a receiving device to be collected, the heavy phase directly overflows to the second-stage centrifugal extractor, meanwhile, the second-stage extractant (isoamyl alcohol) is continuously and quantitatively conveyed to the second-stage centrifugal extractor, and the scrapped light phase is separated out in the same way and enters the receiving device. The heavy phase is continuously sent to the extraction heavy phase receiving device, and the buffer memory receives the heavy phase and then enters the next operation unit. Wherein the temperature of the extraction liquid separation stage is controlled to be-5-0 ℃.
And in the continuous mixing and filter pressing stage, a mass flow meter and a material conveying pump are used for feedback adjustment to continuously and quantitatively convey the extraction heavy phase to the jacketed coil reactor, a small amount of methanol is automatically and continuously and quantitatively conveyed to be used as a diluting solvent (the same as a subsequent crystallization solvent) to be mixed and diluted with the extraction heavy phase in the coil reactor, and the diluted system directly enters a filter pressing device connected in parallel to filter a small amount of solid impurities. The clarified system enters the receiving unit and then the next operating unit. Wherein the temperature of the continuous mixing and filter pressing stage is controlled to be-5-0 ℃.
And in the stage of continuously adjusting the pH, the system after pressure filtration is subjected to feedback adjustment through a mass flow meter and a material delivery pump so as to be continuously and quantitatively delivered to a tubular plug flow type pH adjusting device, and meanwhile, the material delivery pump for delivering a pH adjusting agent (acetic acid/methanol) receives the measurement result of the pH value detection device on line and adjusts the feeding amount of the pH adjusting agent according to the feedback adjustment, so that accurate feeding is realized. The two materials are fully mixed in the pH adjusting device, a pH monitoring point is set again through the pH value detection device, the pH value detection device has certain volume buffering capacity, and the acid-adjusting qualified system directly, continuously and quantitatively enters the next treatment stage. Wherein the temperature of the stage of continuously adjusting the pH is controlled between-10 ℃ and-5 ℃.
And in the continuous crystallization stage, before a crystallization system enters a crystallization device, a material conveying pump is used for continuously quantifying fed materials in advance to fill a crystallization solvent into the tubular plug flow type crystallization device. The high-flow high-pressure resistant oscillation device of the material conveying pump continuously conveys energy to the tubular crystallization device, so that two phases of solid-liquid mixture after crystallization cannot be blocked in the tubular crystallization device, a slurry system enters the receiving device for temporary storage at low temperature, the system is very stable and does not deteriorate along with time, and the slurry system enters the solid-liquid separation device after standing for a period of time to obtain a qualified product. Wherein the temperature of the continuous crystallization stage is controlled between-20 ℃ and-15 ℃.
The results are shown in Table 1.
Comparative example 1
The 4L ertapenem crude product system was worked up in a batch process with the results shown in table 1.
TABLE 1
Example 2
The 4L pilot test in example 1 was scaled up to a 400L pilot test using the same equipment and reagents as in example 1, except that:
and (3) continuous extraction and liquid separation section: continuously feeding the ertapenem crude product system into a secondary centrifugal extractor with the total retention volume of 5L, and carrying out continuous extraction separation, wherein the retention time of the system is only 3-5 min.
And in the continuous mixing and filter pressing stage, the extracted heavy phase and a small amount of methanol (the methanol accounts for 60 percent of the weight of the extracted heavy phase) are continuously mixed by adopting a 3-8L jacketed coil reactor, so that continuous feeding is stable and rapid, and the retention time of a system mixing section is only 3-5 min. Then the mixture enters a second-stage parallel filter device to be rapidly filtered, the treatment flux of the membrane stack is 1L-2L/min, and the feed rate of the upstream mixing is matched.
And in the stage of continuously adjusting the pH, an online pH meter is adopted for continuously adjusting the pH to realize automatic feedback adjustment, and a 20L continuous stirring reaction device is adopted to quickly transfer an adjusted qualified system to downstream operation through an 8L overflow pipeline. During adjustment, the retention time of the system is only 5-8 min, and the deterioration rate of the product is greatly shortened.
In the continuous crystallization stage, an oscillating flow tube crystallization device is adopted, the retention volume is 6L, the system and the detrusor solvent are uniformly mixed in the device for detrusor, the crystal form of the precipitated crystal is stable, and the retention time of the system is 5-8 min.
The results are shown in Table 2.
Comparative example 2
The 4L ertapenem crude product system is subjected to post-treatment in a batch treatment mode, which specifically comprises the following steps:
an extraction liquid separation section: A3000L kettle is adopted for extraction and liquid separation operation of batches, the retention time of the system at the stage is 6.5 hours, and the extraction effect is poor.
A mixing and filtering section: batch operation, adopting 3000L cauldron to carry out the mixing operation of system and methyl alcohol, the mixing process has exothermic condition, and batch operation has the risk that local heat release is big to break the product.
And (3) pH adjusting stage: and (3) batch operation, wherein a 3000L kettle is adopted for operation, the pH value of an upstream system is 7.2-9.5, a methanol/acetic acid system with the pH value of 3-4 is gradually added into the kettle during adjustment, and stirring, standing, sampling and detection are needed each time until the pH value of the system meets the process requirements. The rate of deterioration of the product at this stage is fast and therefore needs to be rapid, while the residence time of the batch system is long, resulting in a high rate of deterioration.
A crystallization stage: batch operation is carried out in a 3000L kettle, methanol/n-propanol is added into the kettle in batches for multiple times during operation, and the purpose of batch multiple times is to gradually induce crystal nucleus to be precipitated, so that two hidden dangers exist in the operation, one is that the concentration of local detrusor solvent is too high, the crystal form of precipitated crystals is unstable, and in addition, other products in the kettle, which are not contacted with the detrusor solvent, are still in a fast deterioration state. The operation system in the stage has the same longer retention time, and the deterioration rate of the product is still higher.
The results are shown in Table 2.
TABLE 2
As a result, it was found that: for the 400L pilot scale of the ertapenem work-up system, the total processing time of the continuous integrated work-up procedure was reduced by 76.25% compared to the batch work-up. The product purity is improved by 4-6%, and the product yield is improved by about 5%. The occupied area of the equipment is reduced by 60 percent, and the operating human resources are reduced by 80 percent.
From the above data, it can be seen that:
1. the continuous integrated post-treatment device for the penem products improves the traditional post-treatment mode of the penem products. It is known that the systems of the penem type products to be treated are very susceptible to deterioration, in the case of ertapenem, the rate of deterioration per hour of the system before the adjustment of the pH is 0.3%, and the rate of deterioration per hour after the adjustment of the pH is 1.2% (which is an inherent loss, which cannot be changed), and this loss can only be reduced by compressing the treatment time.
2. The traditional batch post-processing penem product has 6-10% loss due to deterioration. Mainly because the processing time of each operation unit is too long. The continuous integrated post-processing shortens the processing time of all the operating units. Adjusting the operation time of extraction liquid separation and mixing and pressure filtration before PH. At the same throughput of 400L, the batch required 12 hours of product loss of 4% and only 4 hours of product loss of 1% were required continuously.
3. The advantages of the continuous integrated penem-type post-treatment device can be greatly reflected in the pH adjusting section. In the continuous post-treatment, the residence time of the single particle in the system after the pH adjustment is 8min, and the residence time of the single particle in the batch is 4 h. Directly reducing the loss by about 5%.
4. The amount of organic three wastes after the post-treatment of the penem product is very large (the product system: the three wastes are 1: 5; volume ratio), a large amount of organic three wastes can be accumulated in a short time during batch treatment, and the potential risk coefficient is high. And the continuous integrated post-treatment mode can effectively control the output of three wastes in unit time and reduce the potential risk coefficient.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (21)
1. A continuous post-treatment method for penem compounds is characterized by comprising the following steps:
s1, continuously extracting the reaction crude product of the penem compound to obtain an extracted heavy phase and an extracted light phase;
s2, carrying out continuous solid-liquid separation on the extracted heavy phase to obtain a liquid phase separator;
s3, continuously adjusting the pH value of the liquid phase separator to 6.1-6.3 to obtain a pH adjusting solution;
and S4, carrying out continuous crystallization treatment on the pH regulating solution by adopting a first crystallization solvent to obtain the product of the penem compound.
2. The process of claim 1, wherein said step S2 further comprises the step of adding a second crystallization solvent to said extracted heavy phase and mixing both in a PFR reactor prior to said continuous solid-liquid separation of said extracted heavy phase; and the addition amount of the second crystallization solvent is 50-80% of the weight of the extracted heavy phase, and the temperature in the PFR reactor is controlled to be-7-3 ℃.
3. The process of claim 2, wherein the residence time of the extracted heavy phase in the PFR reactor is 2-8 min.
4. The method as claimed in any one of claims 1 to 3, wherein in step S1, the continuous extraction process comprises N times, N is greater than or equal to 2, and the M times of the continuous extraction process separate out the heavy phase into the M +1 times of the continuous extraction process, 1 is greater than or equal to M less than or equal to (N-1), and the N times of the continuous extraction process separate out the heavy phase as the extracted heavy phase in step S2; preferably, N ═ 2.
5. The method according to claim 4, wherein in the continuous extraction process, the retention time of the reaction crude product of the penem compound is 1-7 min, and the treatment temperature is-7-3 ℃.
6. The method according to any one of claims 1 to 3, wherein in the continuous solid-liquid separation process, the extracted heavy phase is divided into a plurality of parts, the plurality of parts of the extracted heavy phase respectively enter different filter pressing devices for treatment in a one-to-one correspondence manner, the treatment flux of each filter pressing device is 1-2L/min, and the residence time of the extracted heavy phase is 2-11 min.
7. The method according to claim 2, characterized in that the first crystallization solvent is methanol and/or n-propanol and the second crystallization solvent is methanol and/or n-propanol.
8. The method according to any one of claims 1 to 3, wherein the residence time of the pH adjusting solution in the continuous crystallization treatment process is 2-11 min, and the treatment temperature is-22 to-12 ℃.
9. The method according to any one of claims 1 to 3, wherein the reagent for adjusting the pH of the liquid-phase separation product in step S3 is a mixture of methanol and acetic acid, preferably having a pH of 3 to 4.
10. The method according to claim 9, wherein the residence time of the liquid phase separator is 2 to 11min and the treatment temperature is-7 to 3 ℃ in the process of adjusting the pH of the liquid phase separator.
11. A continuous post-treatment device for penem compounds, which is characterized by comprising:
the continuous extraction and liquid separation unit (10) is provided with a penem compound crude product inlet, an extracting agent inlet, an extraction heavy phase outlet and an extraction light phase outlet, and the continuous extraction and liquid separation unit (10) is used for continuously extracting a reaction crude product of a penem compound;
the continuous filter pressing unit (20) is provided with a filter pressing liquid inlet, a solid phase outlet and a liquid phase outlet, the filter pressing liquid inlet is connected with the extraction heavy phase outlet, and the continuous filter pressing unit (20) is used for carrying out continuous solid-liquid separation on the extraction heavy phase discharged from the extraction heavy phase outlet;
the continuous pH adjusting unit (30) is provided with a liquid phase inlet, a pH regulator inlet and an adjusting liquid outlet, the liquid phase inlet is connected with the liquid phase outlet, and the continuous pH adjusting unit (30) is used for continuously adjusting the pH of the liquid discharged from the liquid phase outlet; and
the continuous crystallization unit (40) is provided with an adjusting liquid inlet, a first crystallization solvent inlet and a crystallization slurry outlet, the adjusting liquid inlet is connected with the adjusting liquid outlet, and the continuous crystallization unit (40) is used for carrying out continuous crystallization on the liquid discharged from the adjusting liquid outlet.
12. The apparatus of claim 11, further comprising:
and the PFR reactor (50) is arranged on a pipeline connecting the pressure filtrate inlet and the extraction heavy phase outlet, and the PFR reactor (50) is also provided with a second crystallization solvent inlet.
13. The apparatus according to claim 12, wherein the PFR reactor (50) is a jacketed coil reactor comprising a coil reactor and a first temperature controlled jacket disposed outside the coil reactor.
14. The apparatus according to claim 11, wherein the continuous pH adjusting unit (30) is a tubular pH adjusting apparatus and the continuous crystallization unit (40) is a tubular crystallization apparatus.
15. The apparatus of claim 12, further comprising: and the pH value detection device (60) is arranged on a pipeline connected with the regulating liquid inlet and the regulating liquid outlet and is used for detecting the pH value of the pH regulating liquid.
16. The device according to any one of claims 11 to 15, wherein the continuous extraction and liquid separation unit (10) comprises a plurality of stages of continuous extraction and liquid separation devices (11) which are sequentially arranged in series, each continuous extraction and liquid separation device (11) is provided with a liquid inlet, the extractant inlet, the extracted light phase outlet and the extracted heavy phase outlet, the liquid inlet of the continuous extraction and liquid separation device (11) positioned at the most upstream is the penem compound crude product inlet, the extracted heavy phase outlet of the continuous extraction and liquid separation device (11) positioned at the most downstream is connected with the press filtrate inlet, and the extracted heavy phase outlet of one stage positioned at the upstream is connected with the liquid inlet of one stage positioned at the downstream in two adjacent continuous extraction and liquid separation devices (11).
17. The plant according to any one of claims 11 to 15, wherein said continuous filter-press unit (20) comprises a plurality of stages of filter-press devices (21) arranged in parallel, each of said plurality of stages of filter-press devices (21) being provided with said inlet for the filter-press liquid, said outlet for the solid phase and said outlet for the liquid phase.
18. The apparatus of claim 15, further comprising:
an extraction light phase receiving device (70) connected with the extraction light phase outlet;
an extracted heavy phase receiving device (80) arranged on a pipeline connecting the extracted heavy phase outlet with the PFR reactor (50);
a liquid phase receiving device (90) arranged on a pipeline connecting the liquid phase inlet and the liquid phase outlet; and
and the crystallization slurry receiving device (100) is connected with the crystallization slurry outlet.
19. The apparatus of claim 18, further comprising:
a first mass flow meter (110) disposed on a line connecting the extracted heavy phase receiver (80) and the PFR reactor (50);
a second mass flow meter (120) disposed on a pipe connecting the liquid phase receiving device (90) and the liquid phase inlet;
and the device also comprises a control unit which is electrically connected with the pH value detection device (60), the first mass flow meter (110) and the second mass flow meter (120).
20. The apparatus according to any one of claims 12 to 15, wherein material transfer pumps (130) are arranged on the pipelines of the penem compound crude product inlet, the extractant inlet, the pH regulator inlet, the liquid phase inlet, the first crystallization solvent inlet, the regulating liquid inlet, the second crystallization solvent inlet and the inlet of the PFR reactor (50) for introducing the heavy phase.
21. The device according to claim 19, wherein the continuous extraction and liquid separation unit (10), the continuous filter pressing unit (20), the continuous pH adjusting unit (30) and the continuous crystallization unit (40) are all provided with temperature control units, the extraction heavy phase receiving device (80) is provided with a second temperature control jacket, the liquid phase receiving device (90) is provided with a third temperature control jacket, the crystallization slurry receiving device (100) is provided with a fourth temperature control jacket, and the control units are further electrically connected with the temperature control units, the second temperature control jacket, the third temperature control jacket and the fourth temperature control jacket.
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| CN114805162A (en) * | 2022-04-26 | 2022-07-29 | 湖北华洲药业有限公司 | Continuous production method and device for meropenem side chain key intermediate O powder |
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