WO2021072622A1 - 培南类化合物连续化后处理方法及装置 - Google Patents

培南类化合物连续化后处理方法及装置 Download PDF

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Publication number
WO2021072622A1
WO2021072622A1 PCT/CN2019/111198 CN2019111198W WO2021072622A1 WO 2021072622 A1 WO2021072622 A1 WO 2021072622A1 CN 2019111198 W CN2019111198 W CN 2019111198W WO 2021072622 A1 WO2021072622 A1 WO 2021072622A1
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continuous
extraction
inlet
liquid
heavy phase
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PCT/CN2019/111198
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English (en)
French (fr)
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洪浩
洪亮
陶建
郭金海
程希安
张岩
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凯莱英医药集团（天津）股份有限公司
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Priority to PCT/CN2019/111198 priority Critical patent/WO2021072622A1/zh
Priority to US17/769,200 priority patent/US20240115972A1/en
Priority to JP2022522846A priority patent/JP7430256B2/ja
Priority to KR1020227016230A priority patent/KR20220084114A/ko
Priority to EP19949227.3A priority patent/EP4047000A4/en
Publication of WO2021072622A1 publication Critical patent/WO2021072622A1/zh

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D9/00—Crystallisation
    • B01D9/005—Selection of auxiliary, e.g. for control of crystallisation nuclei, of crystal growth, of adherence to walls; Arrangements for introduction thereof
    • B01D9/0054—Use of anti-solvent
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D11/00—Solvent extraction
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D11/00—Solvent extraction
    • B01D11/04—Solvent extraction of solutions which are liquid
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D11/00—Solvent extraction
    • B01D11/04—Solvent extraction of solutions which are liquid
    • B01D11/0446—Juxtaposition of mixers-settlers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D11/00—Solvent extraction
    • B01D11/04—Solvent extraction of solutions which are liquid
    • B01D11/0484—Controlling means
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D11/00—Solvent extraction
    • B01D11/04—Solvent extraction of solutions which are liquid
    • B01D11/0488—Flow sheets
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D11/00—Solvent extraction
    • B01D11/04—Solvent extraction of solutions which are liquid
    • B01D11/0492—Applications, solvents used
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D9/00—Crystallisation
    • B01D9/02—Crystallisation from solutions
    • 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
    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D9/00—Crystallisation
    • B01D2009/0086—Processes or apparatus therefor

Definitions

  • the invention relates to the technical field of organic synthesis, in particular to a continuous post-treatment method and device for penem compounds.
  • the post-treatment of the reaction system is one of the studies that can never be avoided.
  • the unit operations of post-processing mainly include: extraction and separation, filter press, drying, pH adjustment, crystallization, and centrifugation.
  • the domestic chemical and pharmaceutical industry is mainly based on batch post-processing, that is, the intermittent operation of a single post-processing operation unit, which has the advantage of large single-batch processing.
  • the disadvantages are time-consuming, labor-intensive and low degree of automation. If the post-processing system deteriorates over time, the batch post-processing will lose a lot of products.
  • Commonly used penem antibiotics belong to this perishable type (for example, patent CN207845524U These problems exist in the post-processing methods provided in).
  • the post-processing technology for penem-type large-scale reaction systems is relatively simple.
  • large kettles are commonly used in workshop production for batch processing and liquid separation.
  • the time for a single operation unit is 6 hours.
  • the solvent residues NEP, TMG, isoamyl alcohol
  • the residual product dissolved in the organic phase can reach 0.3%, and secondary extraction and liquid separation operations are often performed. It can be said that the traditional batch extraction and liquid separation operation is time-consuming and laborious, and the separation effect is not very good.
  • the disadvantage of batch adjustment of pH is that the repeated addition of acetic acid and then stirring and standing, will lead to a long time.
  • the pH adjustment time of a single batch of 400L batch can reach 5-6 hours, and once the adjustment is over, the loss is very large.
  • the main purpose of the present invention is to provide a continuous post-processing method and device for penem compounds to solve the low processing speed, low efficiency and material deterioration rate in the process of batch processing of crude penem compounds in the prior art. High question.
  • a continuous post-treatment method for penem compounds includes the following steps: S1, continuous extraction of the crude reaction products of penem compounds to obtain the extracted weight S2, continuous solid-liquid separation of the extracted heavy phase to obtain a liquid phase separation; S3, continuous pH adjustment of the liquid phase separation to a pH value of 6.1 to 6.3, to obtain a pH adjustment solution S4, using the first crystallization solvent to perform continuous crystallization treatment on the pH adjustment solution to obtain a penem compound product.
  • 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; and the second crystallization solvent The added amount is 50 to 80% of the weight of the extracted heavy phase, and the temperature of the PFR reactor is controlled to -7 to 3°C.
  • the residence time of the extracted heavy phase in the PFR reactor is 2-8 min.
  • the residence time of the crude reaction product of the penem compound is 1 to 7 min, and the treatment temperature is -7 to 3°C.
  • the extracted heavy phase is divided into multiple parts, and the multiple extracted heavy phases enter different filter presses for processing in one-to-one correspondence, and the processing flux of each filter press is 1 ⁇ 2L/min, the residence time of the heavy phase of extraction is 2 ⁇ 11min.
  • the first crystallization solvent is methanol and/or n-propanol
  • the second crystallization solvent is methanol and/or n-propanol
  • the residence time of the pH adjusting solution is 2-11 min, and the treatment temperature is -22 ⁇ -12°C.
  • the reagent for adjusting the pH value of the liquid phase separation is a mixed solution of methanol and acetic acid, and the pH value is preferably 3-4.
  • the residence time of the liquid phase separator is 2 to 11 minutes, and the treatment temperature is -7 to 3°C.
  • a continuous post-processing device for penem compounds which includes: a continuous extraction and liquid separation unit provided with a penem compound crude product inlet, an extractant inlet, an extraction heavy phase outlet, and The extraction light phase outlet, the continuous extraction liquid separation unit is used to continuously extract the crude product of the penem compound reaction;
  • the continuous filter press unit is provided with a filter press inlet, a solid phase outlet and a liquid phase outlet, and a filter press inlet and extraction The heavy phase outlet is connected, and the continuous filter press unit is used for continuous solid-liquid separation of the extracted heavy phase discharged from the extraction heavy phase outlet;
  • the continuous pH adjustment unit is provided with a liquid phase inlet, a pH regulator inlet, and a regulator fluid outlet.
  • the inlet is connected to the liquid phase outlet, and the continuous pH adjustment unit is used to continuously adjust 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 adjusting liquid inlet is connected with the adjusting liquid outlet, and the continuous crystallizing unit is used to continuously crystallize the pH adjusting liquid discharged from the adjusting liquid outlet.
  • the device further includes a PFR reactor, which is arranged on the pipeline connecting the press filtrate inlet and the extraction heavy phase outlet, and the PFR reactor is also provided with a second crystallization solvent inlet.
  • the PFR reactor is a jacketed coil reactor, which includes a coil reactor and a first temperature-controlling jacket arranged outside the coil reactor.
  • the continuous pH adjustment unit is a tubular pH adjustment device
  • the continuous crystallization unit is a tubular crystallization device.
  • the device further includes: a pH value detection device, which is arranged on the pipeline connecting the adjustment liquid inlet and the adjustment liquid outlet, and is used for detecting the pH value of the pH adjustment liquid.
  • the continuous extraction and liquid separation unit includes a multi-stage continuous extraction and liquid separation device arranged in series in sequence, and each continuous extraction and liquid separation device has a liquid inlet, an extractant inlet, an extraction light phase outlet, and an extraction heavy phase outlet, and is located at the most
  • the inlet of the upstream continuous extraction and liquid separation device is the penem compound crude product inlet
  • the extraction heavy phase outlet of the continuous extraction and liquid separation device located at the most downstream is connected with the filtrate inlet, and there are two adjacent continuous extraction and liquid separation devices.
  • the extraction heavy phase outlet of the upstream stage is connected to the liquid inlet of the downstream stage.
  • the continuous filter press unit includes multi-stage filter press devices arranged in parallel, and each multi-stage filter press device is provided with a filter press inlet, a solid phase outlet, and a liquid phase outlet.
  • the device further includes: an extraction light phase receiving device connected to the extraction light phase outlet; an extraction heavy phase receiving device arranged on the pipeline connecting the extraction heavy phase outlet to the PFR reactor; a liquid phase receiving device arranged on the liquid phase The inlet is connected with the liquid phase outlet on the pipeline; and the crystallization slurry receiving device is connected with the crystallization slurry outlet.
  • the device further includes: a first mass flow meter, which is arranged on the pipeline connecting the extraction heavy phase receiving device and the PFR reactor; and a second mass flow meter, which is arranged on the pipeline connecting the liquid phase receiving device and the liquid phase inlet; And the device also includes a control unit, which is electrically connected with the pH value detection device, the first mass flow meter and the second mass flow meter.
  • the penem compound crude product inlet, the extractant inlet, the pH regulator inlet, the liquid phase inlet, the first crystallization solvent inlet, the adjusting solution inlet, the second crystallization solvent inlet, and the PFR reactor are used to pass the extraction weight.
  • the pipeline where the inlet of the phase is located is provided with a material conveying pump.
  • the continuous extraction and separation unit, the continuous filter press unit, the continuous pH adjustment unit, and the continuous crystallization unit are all provided with a temperature control unit, and the extraction heavy phase receiving device is provided with a second temperature control jacket, and the liquid phase receiving device is provided There is a third temperature control jacket, the crystallization slurry receiving device is provided with a fourth temperature control jacket, the control unit is also connected with the temperature control unit, the second temperature control jacket, the third temperature control jacket and the fourth temperature control jacket Electric connection.
  • the continuous post-processing device for penem compounds is a post-processing device for penem compound synthesis.
  • the present invention provides a continuous post-processing method for penem compounds, which is a continuous and integrated post-processing method.
  • the method has fast processing speed and high efficiency when post-processing the crude reaction products of penem compounds. Advantages, and the material properties are stable during the treatment process, the deterioration rate is low, and the yield and purity of the target product have better control ability.
  • the method can fit well with the properties of penem compounds, and has stronger pertinence in reducing the rate of product deterioration, improving the treatment effect, and the product yield.
  • Figure 1 shows a schematic structural diagram of a continuous post-treatment device for penem compounds according to an embodiment of the present invention.
  • Continuous extraction and separation unit 11. Continuous extraction and separation device; 20. Continuous filter press unit; 21. Filter press; 30. Continuous pH adjustment unit; 40. Continuous crystallization unit; 50. PFR reactor; 60. , PH value detection device; 70, extraction light phase receiving device; 80, extraction heavy phase receiving device; 90, liquid phase receiving device; 100, crystallization slurry receiving device; 110, first mass flow meter; 120, second mass Flowmeter; 130, material conveying pump.
  • the present invention provides a continuous post-treatment method for penem compounds, which includes the following steps: S1, continuous extraction of the crude reaction products of penem compounds to obtain an extracted heavy phase and an extracted light phase; S2, continuous solid-liquid separation of the extracted heavy phase to obtain a liquid phase separation; S3, continuous pH adjustment of the liquid phase separation to a pH value of 6.1 to 6.3 to obtain a pH adjustment solution; S4, use the first The crystallization solvent performs continuous crystallization treatment on the pH adjusting solution to obtain the penem compound product.
  • the present invention provides a continuous and integrated post-treatment method for penem compounds, which has the advantages of fast processing speed and high efficiency when post-processing the crude reaction products of penem compounds, and the nature of the materials in the process It is stable, has low deterioration rate, and has better control over the yield and purity of the target product.
  • the method can fit well with the properties of penem compounds, and has stronger pertinence in reducing the rate of product deterioration, improving the treatment effect, and the product yield.
  • the continuous extraction and liquid separation used in the present invention shortens the time by more than 50% compared with batch-type batch post-processing, and the processing effect is far better than batch processing.
  • the heat release per unit time is much lower than the batch post-processing, which means that more energy is saved and the stability of the product is guaranteed.
  • the system that has been processed in the pH adjustment stage immediately enters the crystallization stage, and the residence time is greatly shortened, which means that the product deterioration rate is greatly reduced.
  • continuous processing not only overcomes the problem of low batch post-processing efficiency.
  • the crystallization system has better advantages in the later stage of crystal shape screening than the batch processing system.
  • step S2 before the continuous solid-liquid separation is performed on the extracted heavy phase, 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; And 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 to 3°C. In this way, before the extracted heavy phase enters the filter press stage, it is pre-mixed with an analytical crystal solvent.
  • the liquid phase system plays a role of buffering and stabilizing, thereby helping to prevent the blockage of the subsequent pH adjustment process and making the continuous treatment process more stable.
  • the extraction heavy phase is a continuous flow process in the PFR reactor, and it is mixed with the second crystallization solvent while flowing, and the residence time is short.
  • the residence time of the extracted heavy phase in the PFR reactor is 2-8 min.
  • the continuous extraction process includes N times in sequence, where N ⁇ 2, and the heavy phase separated in the Mth continuous extraction process enters the M+1th continuous extraction process.
  • the specific treatment times can be selected according to the treatment volume and product concentration of the crude product, and the separation stages can also be determined according to the difficulty of extraction and separation.
  • the treatment time and the separation effect of the treatment volume are more effective than batch processes. Big advantage. More preferably, in the continuous extraction process, the residence time of the reaction crude product of the penem compound is 1 to 7 min, and the treatment temperature is -7 to 3°C.
  • the extracted heavy phase is divided into multiple parts, and the multiple extracted heavy phases respectively enter different filter presses for processing in one-to-one correspondence, and each press filter
  • the processing flux of the device is 1 to 2 L/min, and the residence time for extracting the heavy phase is 2 to 11 min. Because the filter press process is a high-pressure process, the use of multi-stage filter press devices to process the press filtrate is more conducive to alleviating the processing conditions of each filter press device.
  • the first crystallization solvent is methanol and/or n-propanol
  • the second crystallization solvent is methanol and/or n-propanol. More preferably, during the continuous crystallization treatment, the residence time of the pH adjusting solution is 2-11 min, and the treatment temperature is -22 ⁇ -12°C.
  • the reagent for adjusting the pH of the liquid phase separation is a mixture of methanol and acetic acid, preferably it The pH is 3 ⁇ 4. More preferably, in the process of adjusting the pH value of the liquid phase separator, the residence time of the liquid phase separator is 2-11 min, and the treatment temperature is -7-3°C.
  • a continuous post-treatment device for penem compounds includes a continuous extraction and liquid separation unit 10, a continuous filter press unit 20, and a continuous pH adjustment unit 30.
  • Continuous crystallization unit 40, continuous extraction and separation unit 10 is provided with penem compound crude product inlet, extractant inlet, extraction heavy phase outlet and extraction light phase outlet, continuous extraction and separation unit 10 is used for penem compounds
  • the crude product of the reaction is continuously extracted;
  • the continuous filter press unit 20 is provided with a filter press inlet, a solid phase outlet, and a liquid phase outlet.
  • the filter press inlet is connected with the extraction heavy phase outlet.
  • the continuous filter press unit 20 is used to extract the heavy phase outlet
  • the discharged heavy phase of the extraction is subjected to continuous solid-liquid separation
  • the continuous pH adjustment unit 30 is provided with a liquid phase inlet, a pH regulator inlet, and an adjustment liquid outlet.
  • the liquid phase inlet is connected to the liquid phase outlet, and the continuous pH adjustment unit 30 is used for liquid
  • the liquid discharged from the phase outlet is subjected to continuous pH adjustment
  • the continuous crystallization unit 40 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 40 is used for The pH adjustment liquid discharged from the adjustment liquid outlet is continuously crystallized.
  • the above-mentioned penem compound continuous post-processing device is a continuous integrated post-processing device, which has the advantages of fast processing speed and high efficiency when post-processing the crude product of the penem compound reaction, and the nature of the material in the process It is stable, has low deterioration rate, and has better control over the yield and purity of the target product.
  • the device can fit the properties of penem compounds well, and is more targeted in terms of reducing product deterioration, improving processing effects, and product yield.
  • the continuous extraction and liquid separation used in the present invention shortens the time by more than 50% compared with batch-type batch post-processing, and the treatment effect is far better than batch-type post-processing.
  • Times processing In the filter press stage, the heat release per unit time is much lower than the batch post-processing, which means that more energy is saved and the stability of the product is guaranteed.
  • the system that has been processed in the pH adjustment stage immediately enters the crystallization stage, and the residence time is greatly shortened, which means that the product deterioration rate is greatly reduced.
  • continuous processing not only overcomes the problem of low batch post-processing efficiency. At the same time, the crystallization system has better advantages in the later stage of crystal shape screening than the batch processing system.
  • the above-mentioned device further includes: a PFR reactor 50 (plug flow reactor), which is arranged on a pipeline connecting the inlet of the press filtrate and the outlet of the extracted heavy phase, and the PFR reacts
  • the device 50 is also provided with a second crystallization solvent inlet. In this way, before the extracted heavy phase enters the filter press stage, it is pre-mixed with an analytical crystal solvent.
  • the liquid phase system plays a role of buffering and stabilizing, thereby helping to prevent the blockage of the subsequent tubular pH adjustment process and making the continuous treatment process more stable.
  • the PFR reactor 50 is a jacketed coil reactor, which includes a coil reactor and a first temperature-controlling jacket disposed outside the coil reactor.
  • the use of a temperature-controlled jacketed coil reactor is more conducive to the mixing of the extracted heavy phase with a small amount of crystallization solvent, so that the catalyst can be more fully precipitated, and the temperature control can further ensure the stability of the system and prevent deterioration.
  • the use of a jacketed coil reactor is also beneficial to avoid the risk of local heat release and large damage to the product.
  • the continuous pH adjustment unit 30 is a tubular pH adjustment device
  • the continuous crystallization unit 40 is a tubular crystallization device.
  • the continuous pH adjustment unit 30 is a flat plug flow type or a fully mixed flow type
  • the continuous crystallization unit 40 is a flat plug flow type.
  • the above-mentioned device further includes: a pH value detecting device 60, which is arranged on the pipeline connecting the adjusting liquid inlet and the adjusting liquid outlet, and is used for detecting the pH value of the pH adjusting liquid.
  • the present invention adopts the pH pre-feedback adjustment form, and by monitoring the pH value state of the adjusting liquid in real time, it is convenient to adjust the relative added amount of the pH adjuster in time (it can be adjusted by adjusting the added amount of the pH adjuster and/or the added amount of the product phase. ).
  • the continuous extraction and liquid separation unit 10 includes a multi-stage continuous extraction and liquid separation device 11 arranged in series, and each continuous extraction and liquid separation device 11 has a liquid inlet, an extractant inlet, and an extraction light phase outlet. And the extraction heavy phase outlet, and the inlet of the continuous extraction and liquid separation device 11 located at the most upstream is the penem compound crude product inlet, and the extraction heavy phase outlet of the continuous extraction and liquid separation device 11 located at the most downstream is connected to the filtrate inlet , In two adjacent continuous extraction and liquid separation devices 11, the extraction heavy phase outlet of the upstream stage is connected to the liquid inlet of the downstream stage.
  • the two phases are continuously separated, the light phase can be solvent recovered, and the heavy phase enters the next stage of continuous extraction.
  • the liquid separation device 11 further extracts and separates.
  • the specific continuous extraction and separation device 11 stages can be selected according to the processing volume and product concentration of the crude product, or the separation stage can be determined according to the difficulty of extraction and separation, the processing time, and the processing volume are separated. The effect has a great advantage over the batch process.
  • the scale of the continuous filter press unit 20 can be selected according to the size of the treatment volume.
  • the continuous filter press unit 20 includes a multi-stage filter press device 21 arranged in parallel, and each multi-stage filter press device 21 Both are equipped with a press filtrate inlet, a solid phase outlet and a liquid phase outlet. Since the filter press process is a high-pressure process, the use of multi-stage filter press devices 21 arranged in parallel to process the filtrate press is more conducive to alleviating the processing conditions of the filter press devices.
  • the above-mentioned device further includes: an extraction light phase receiving device 70 connected to the extraction light phase outlet; an extraction heavy phase receiving device 80 arranged on the pipeline connecting the extraction heavy phase outlet to the PFR reactor 50
  • the liquid phase receiving device 90 is arranged on the pipeline connecting the liquid phase inlet and the liquid phase outlet; the crystallizing slurry receiving device 100 is connected to the crystallizing slurry outlet.
  • the above-mentioned device further includes: a first mass flow meter 110, which is arranged on the pipeline connecting the extraction heavy phase receiving device 80 and the PFR reactor 50; a second mass flow meter 120, which is arranged on the liquid phase receiving device 90 and the liquid On the pipeline connected to the inlet; and the device further includes a control unit, which is electrically connected to the pH value detection device 60, the first mass flow meter 110, and the second mass flow meter 120.
  • the control unit can more conveniently adjust the feeding conditions of each stage, and can also monitor the operating conditions of each stage in real time, making the processing process more stable, thereby further reducing the probability of product deterioration and improving processing efficiency.
  • the penem compound crude product inlet, the extractant inlet, the pH regulator inlet, the liquid phase inlet, the first crystallizing solvent inlet, the adjusting liquid inlet, and the second analyte is provided on the pipeline where the crystal solvent inlet and the inlet of the PFR reactor 50 are used to pass the extracted heavy phase. It should be noted that during 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 forced to crystallize out, and the crystallization slurry is a solid-liquid two-phase mixed system.
  • the material conveying pump 130 is used for material-driven conveying, so that the conditioning liquid and the crystallization solvent can achieve very good mixing and turbulence, and the crystallization effect and efficiency are better than batch processing methods.
  • the above-mentioned continuous crystallizing unit 40 is a tubular flat plug flow crystallizing device, which is more conducive to improving the crystallizing effect.
  • the retention time of the single system particle in the device is extremely short after the pH adjustment is completed, which is more conducive to improving the crystallization effect.
  • the material delivery pump 130 can be used to continuously quantify the feed in advance to fill the tube-type crystallization device with the crystallization solvent, and then pass the conditioning liquid through the material delivery pump 130 to proceed. Crystallization treatment.
  • the material delivery pump 130 the large-flow and high-pressure-resistant oscillating device, continuously delivers energy to the tubular crystallization device, so that the solid-liquid mixed slurry after crystallization will not be blocked in the tubular crystallization device.
  • the system enters the crystallization slurry receiving device 100 for temporary storage at low temperature. At this time, the system is already very stable and does not deteriorate with time. After standing for a period of time, it enters the solid-liquid separation device to obtain qualified products.
  • the continuous extraction and separation unit 10, the continuous filter press unit 20, the continuous pH adjustment unit 30, and the continuous crystallization unit 40 are all provided with a temperature control unit, and the extraction heavy phase receiving device 80 is provided with a first Two temperature control jackets, 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, the control unit is also connected to the temperature control unit, the second temperature control jacket, The third temperature control jacket and the fourth temperature control jacket are electrically connected. In this way, the temperature can be controlled more accurately for each stage, thereby further improving the stability of each stage of the post-processing.
  • the above-mentioned continuous extraction and separation unit 10 continuous filter press unit 20, continuous pH adjustment unit 30, continuous crystallization unit 40, first temperature control jacket, second temperature control jacket, and third temperature control jacket
  • the fourth temperature control jacket is equipped with a temperature platinum resistance, which is used to feed back the measured temperature to the control unit, and the above-mentioned device also includes an alarm unit, and the control unit is electrically connected to the alarm unit.
  • the measured temperature can be fed back to the control unit in time through the temperature platinum resistance, and the standard range can be set for each temperature platinum resistance. If the standard range is exceeded and the abnormal range is maintained for more than 10s, the alarm linkage will trip and stop. This is more conducive to maintaining the stability of each stage of post-processing and adjusting the temperature state of each stage in time.
  • Penem products are more sensitive to temperature. The higher the temperature, the faster the deterioration rate of the product. Therefore, the entire continuous post-processing device has strict temperature control measures. All product-containing receiving devices are equipped with temperature control jackets, and all operating unit devices are also equipped with temperature control jackets. Important delivery pipelines, such as the delivery section of the adjustment liquid after pH adjustment, are also equipped with temperature control jackets and kept warm.
  • the above-mentioned device further includes a pressure detection unit for detecting the pressure inside the continuous filter press unit 20, the continuous pH adjustment unit 30, the continuous crystallization unit 40, the PFR reactor 50, and each receiving device, And the pressure detection unit is electrically connected with the control unit.
  • the pressure detection point of the pressure detection unit can be set at the inlet of the above-mentioned device.
  • the continuous filter press unit 20, the continuous pH adjustment unit 30, the continuous crystallization unit 40, and the PFR reactor 50 are all provided with a tail gas discharge pipeline. This can prevent pressure holding and at the same time avoid the accumulation of exhaust gas.
  • the above-mentioned device further includes a pressure alarm system, which is electrically connected to the pressure detection unit.
  • a pressure alarm system which is electrically connected to the pressure detection unit.
  • the materials of the above-mentioned devices, units, pipes, etc. can be designed according to the properties of the materials to be processed.
  • materials with chemical properties, temperature and pressure resistance such as titanium, tetrafluoroethylene, 304, 316, and Hastelloy can be used.
  • the connection method between pipelines and equipment in the whole process is mainly flange type, and a variety of other connection methods include: welding, quick coupling, ferrule connection and other coexisting modes.
  • the serial form of the continuous extraction and liquid separation device 11 is an overflow type, that is, the heavy phase of the previous stage of extraction enters the next stage for further extraction through the overflow form.
  • the specific type of the continuous extraction and liquid separation device 11 is preferably a centrifugal extractor, of course, a rotating disk extraction tower or a membrane separation extraction device can also be used.
  • membrane stacks or fillers are used inside the aforementioned filter press 21.
  • the above-mentioned post-treatment device provided by the present invention is more suitable for the post-treatment of products with poor product properties and easily deteriorated.
  • the above-mentioned penem compound continuous post-treatment device is a penem compound post-treatment device .
  • 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 production of these penem-like crude products from small-scale to pilot-scale continuous post-treatment.
  • the above-mentioned device provided by the present invention is a highly automated processing device, and the feeding speed, temperature, etc. can be adjusted at any time according to the processing volume of the equipment, and the overall processing time can be accurately controlled.
  • Each single operation unit is connected into a whole through an automated control program, and each unit operation is accurately connected with a feedback mass flow meter, so that the original intermittent operation process is continuous and continuous.
  • the operating unit can be increased or decreased.
  • the installation of pressure, temperature, dangerous gas alarms and other devices are simultaneously linked to set over pressure, over temperature, and excessive dangerous gas alarms for regulation, which greatly reduces the potential risk of accidents.
  • all feed ports can be cut off to control product loss and risk levels to a minimum.
  • the invention can also greatly reduce the area occupied by the equipment, labor resources, and production energy consumption. Compared with traditional batch post-processing technology, the investment cost is greatly reduced.
  • the 4L crude ertapenem system was post-processed with the device shown in Figure 1.
  • the crude ertapenem includes ertapenem, TMG (tetramethylguanidine), and NEP (N-ethyl). Pyrrolidone), isoamyl alcohol, palladium-carbon catalyst, water.
  • Continuous extraction and liquid separation section ertapenem crude product system is subjected to secondary extraction and separation, the system is automatically continuously quantified and fed, and the primary extractant (isoamyl alcohol, water, NaHCO 3 diphenyl phosphate mixed solution) Continuous quantitative feeding by automation.
  • the first-stage centrifugal extractor the first-stage automatic extraction and liquid separation are carried out.
  • the light phase waste system is collected in the receiving device, and the heavy phase directly overflows to the second-stage centrifugal extractor.
  • the second-stage extractant (isoamyl alcohol ) Continuously and quantitatively transport to the second-stage centrifugal extractor, and the same separated waste light phase enters the receiving device.
  • the heavy phase continuously enters the extraction heavy phase receiving device, and the buffer receives it and then enters the next operation unit.
  • the temperature of the extraction and separation stage is controlled at -5 to 0°C.
  • the mass flow meter and the material delivery pump are used for feedback adjustment to continuously and quantitatively deliver the extracted heavy phase to the jacketed coil reactor, and at the same time automatically and continuously deliver a small amount of methanol as the dilution solvent (the same as the subsequent crystallization solvent) )
  • the extracted heavy phase are mixed and diluted in the coil reactor, and the diluted system directly enters the parallel pressure filter device to filter out a small amount of solid impurities.
  • the clarified system enters the receiving device and then into the next operating unit.
  • the temperature of the continuous mixing and filtering stage is controlled at -5 to 0°C.
  • the pressure-filtered system is fed back and adjusted by the mass flow meter and the material transfer pump, and is continuously quantitatively transported to the tubular plug flow pH adjustment device. It is also used to transport the pH regulator (acetic acid/methanol)
  • the material conveying pump receives the measurement result of the pH value detection device online, and adjusts the feeding amount of the pH regulator according to this feedback to realize accurate feeding.
  • the two materials are fully mixed in the pH adjustment device, and the pH monitoring point is set again at the pH value detection device, and the pH value detection device has a certain volume buffer capacity, and the qualified acid adjustment system directly enters the next processing stage continuously and quantitatively. Among them, the temperature in the stage of continuous pH adjustment is controlled at -10 to -5°C.
  • the material transfer pump is used to continuously quantify the feed in advance to fill the tubular plug flow crystallization device with the crystallization solvent. Because the large-flow and high-pressure-resistant oscillating device of the material transfer pump continuously transfers energy to the tubular crystallization device, the two phases of the solid-liquid mixture after crystallization will not be blocked in it, and the slurry system enters the receiving device at low temperature temporarily. The system at this time is already very stable and will not deteriorate with time. After standing for a period of time, it enters the solid-liquid separation device to get qualified products. Among them, the temperature in the continuous crystallization stage is controlled at -20 to -15°C.
  • Example 1 The 4L pilot test in Example 1 is enlarged to a 400L pilot test.
  • the equipment and reagents used are the same as those in Example 1, except for:
  • Continuous extraction and liquid separation section The crude ertapenem system is continuously fed into a secondary centrifugal extractor with a total retention volume of 5L for continuous extraction and separation, and the residence time of the system is only 3 to 5 minutes.
  • the heavy phase is extracted and a small amount of methanol (methanol is 60% of the weight of the heavy phase of the extraction) is continuously mixed in a 3-8L jacketed coil reactor, stable and rapid continuous feeding, and the mixing section of the system stays The time is only 3 to 5 minutes. Then it enters the two-stage parallel filter device membrane stack for rapid filtration.
  • the processing flux of the membrane stack is 1L ⁇ 2L/min, which matches the feed rate of the upstream mixing.
  • the continuous pH adjustment adopts an online pH meter to realize automatic feedback adjustment, and adopts a 20L continuous stirring reaction device, and the adjusted qualified system is quickly transferred to the downstream operation through the 8L overflow pipeline.
  • the residence time of the system is only 5-8min, which greatly reduces the deterioration rate of the product.
  • an oscillating flow tube type crystallization device In the continuous crystallization stage, an oscillating flow tube type crystallization device is used, with a retention volume of 6L.
  • the system and the crystallization solvent are uniformly mixed in the device for crystallization, the crystal shape of the precipitated crystal is relatively stable, and the retention time of the system is 5-8min.
  • Extraction and liquid separation section A 3000L kettle is used for batch extraction and liquid separation operation.
  • the residence time of the system at this stage is 6.5h, and the extraction effect is poor.
  • PH adjustment stage batch operation, using a 3000L kettle for operation, the pH of the upstream system is 7.2 to 9.5, and a methanol/acetic acid system with a pH of 3 to 4 is added to the kettle during adjustment. Each time it is added, it needs to be stirred and stood for sampling. Check until the PH of the system meets the technological requirements. At this stage, the product deterioration rate is very fast, so it needs to be carried out quickly, and the residence time of the batch operation system is longer, resulting in a higher deterioration rate.
  • Crystallization stage batch operation, carried out in a 3000L autoclave. During operation, methanol/n-propanol is added to the autoclave several times in batches. The purpose of several batches is to gradually induce the precipitation of crystal nuclei. There are two hidden dangers in this operation. One is that the concentration of the local crystallization solvent is too high, which causes the crystal shape of the precipitated crystal to be unstable. In addition, the products in the other areas of the kettle that are not in contact with the crystallization solvent are still in a state of rapid deterioration. The residence time of the operating system at this stage is also longer, and the product deterioration rate is still high.
  • the total processing time of the continuous integrated post-processing method is 76.25% shorter than that of the batch post-processing.
  • the product purity will increase by 4% to 6%, and the product yield will increase by about 5%.
  • the equipment area is reduced by 60%, and the operating human resources are reduced by 80%.
  • the continuous and integrated post-processing device of Penem products improves the traditional post-processing methods of Penem products.
  • the penem product system to be processed is very easy to deteriorate.
  • the deterioration rate per hour of the system before pH adjustment is 0.3%
  • the deterioration rate per hour after pH adjustment is 1.2% (this It is an inherent loss and cannot be changed). This loss can only be reduced by compressing the processing time.
  • the continuous and integrated post-processing mode can effectively control the output of the three wastes per unit time and reduce the potential risk factor.

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Abstract

提供了一种培南类化合物连续化后处理方法及装置。该方法包括以下步骤：S1，将培南类化合物的反应粗产物进行连续化萃取，得到萃取重相和萃取轻相；S2，对萃取重相进行连续化固液分离，得到液相分离物；S3，对液相分离物进行连续化pH调节至其pH值为6.1～6.3，得到pH调节液；S4，采用第一析晶溶剂将pH调节液进行连续化析晶处理，得到培南类化合物的产品。采用该方法对培南类化合物的反应粗产物进行后处理时具有处理速度快、效率高的优势，且处理过程中物料性质稳定，变质率低，对目标产物的收率和纯度具有更好的控制能力。

Description

培南类化合物连续化后处理方法及装置 技术领域
本发明涉及有机合成技术领域，具体而言，涉及一种培南类化合物连续化后处理方法及装置。
背景技术
当前医药化工领域中，反应完体系的后处理是永远无法避免的研究之一。通常后处理的单元操作主要包括：萃取分液、压滤、干燥、PH调节、结晶、离心。当前国内化工医药行业主要是以批次后处理为主，也就是单项后处理操作单元的间歇式进行，优点是单批处理量大。缺点为耗时耗力，自动化程度低，若后处理的体系随时间延长而发生变质，则批次后处理将会损失很多产品，常用培南类抗生素就属于这种易变质类型(比如专利CN207845524U中提供的后处理方法就存在这些问题)。
具体地，当前行业中，针对培南类大批量反应体系的后处理技术比较单一。就萃取分液来说车间生产常用大釜批次处理分液，单项操作单元的耗费时间为6小时，经萃取分离处理的含产品的水相中，溶剂残留(NEP、TMG、异戊醇)均较大。有机相中溶解的产品残留能达到0.3％，经常会进行二次萃取分液操作。可以说传统批次萃取分液操作耗时费力，分离效果也不是非常好。而且，培南类后处理流程中的pH调节阶段，批次调节pH的缺点是乙酸的反复加入再搅拌静置，这会导致耗时较长。单批400L处理量批次调节pH阶段的时间能达到5～6小时，且一旦调过了，损失则是非常大的。这也意味着调节pH期间培南类产品变质率提高(通常pH调节段之前，产品每小时的变质率约0.2％，调酸之后产品的变质率为每小时约1.3％。当前业内对于厄他培南的后处理均为批次工艺，处理时间长导致产品变质率高，收率较低)，损失增加，产品收率、产品的纯度上都会受到很大影响，这都是处理方式本身的局限性造成的结果。另外，大批量的处理反应体系，带来的风险隐患也是非常多的。比如说放热、气体排出、物料泄露，比如培南类产品在混合压滤段、析晶段都会有不同程度的放热情况。批次处理量越大，带来的潜在危险也会越多，若处理的物料性质较为恶劣时，则维护费成本会大幅提高。批次后处理占地面积大，人力资源及能耗成本都非常高。
针对这种情况亟需开发出一种后处理速度快、处理效率高、物料性质稳定的后处理技术。
发明内容
本发明的主要目的在于提供一种培南类化合物连续化后处理方法装置，以解决现有技术中采用批次处理培南类化合物粗产物过程中存在的处理速度低、效率低、物料变质率高的问题。
为了实现上述目的，根据本发明的一个方面，提供了一种培南类化合物连续化后处理方法，其包括以下步骤：S1，将培南类化合物的反应粗产物进行连续化萃取，得到萃取重相和萃取轻相；S2，对萃取重相进行连续化固液分离，得到液相分离物；S3，对液相分离物进行连续化pH调节至其pH值为6.1～6.3，得到pH调节液；S4，采用第一析晶溶剂将pH调节液进行连续化析晶处理，得到培南类化合物的产品。
进一步地，在对萃取重相进行连续化固液分离之前，步骤S2还包括在萃取重相中加入第二析晶溶剂并使二者在PFR反应器中混合的步骤；且第二析晶溶剂的加入量为萃取重相重量的50～80％，控制PFR反应器的温度为-7～3℃。
进一步地，萃取重相在PFR反应器中的停留时间为2～8min。
进一步地，步骤S1中，连续化萃取过程包括依次进行的N次，N≥2，且第M次连续化萃取过程分离出的重相进入第M+1次连续化萃取过程，1≤M≤(N-1)，将第N次连续化萃取过程分离出的重相作为步骤S2中的萃取重相；优选地，N＝2。
进一步地，连续化萃取过程中，培南类化合物的反应粗产物的停留时间为1～7min，处理温度为-7～3℃。
进一步地，连续化固液分离的过程中，将萃取重相分为多部分，多部分萃取重相分别一一对应地进入不同的压滤装置进行处理，且各压滤装置的处理通量为1～2L/min，萃取重相的停留时间为2～11min。
进一步地，第一析晶溶剂为甲醇和/或正丙醇，第二析晶溶剂为甲醇和/或正丙醇。
进一步地，连续化析晶处理过程中，pH调节液的停留时间为2～11min，处理温度为-22～-12℃。
进一步地，步骤S3中，调节液相分离物pH值的试剂为甲醇和乙酸的混合液，优选其pH值为3～4。
进一步地，调节液相分离物pH值的过程中，液相分离物的停留时间为2～11min，处理温度为-7～3℃。
根据本发明的另一个方面，提供了一种培南类化合物连续化后处理装置，其包括：连续萃取分液单元，设置有培南类化合物粗产物进口、萃取剂进口、萃取重相出口和萃取轻相出口，连续萃取分液单元用于对培南类化合物的反应粗产物进行连续化萃取；连续压滤单元，设置有压滤液进口、固相出口和液相出口，压滤液进口与萃取重相出口相连，连续压滤单元用于对萃取重相出口排出的萃取重相进行连续化固液分离；连续pH调节单元，设置有液相进口、pH调节剂进口及调节液出口，液相进口与液相出口相连，连续pH调节单元用于对液相出口排出的液体进行连续化pH调节；以及连续析晶单元，设置有调节液进口、第一析晶溶剂进口和析晶浆液出口，调节液进口与调节液出口相连，连续析晶单元用于对调节液出口排出的pH调节液进行连续化析晶。
进一步地，装置还包括：PFR反应器，设置在压滤液进口与萃取重相出口相连的管路上，且PFR反应器还设置有第二析晶溶剂进口。
进一步地，PFR反应器为夹套盘管反应器，其包括盘管反应器和设置在盘管反应器外部的第一控温夹套。
进一步地，连续pH调节单元为管式pH调节装置，连续析晶单元为管式析晶装置。
进一步地，装置还包括：pH值检测装置，设置在调节液进口与调节液出口相连的管路上，用于检测pH调节液的pH值。
进一步地，连续萃取分液单元包括依次串联设置的多级连续萃取分液装置，各连续萃取分液装置均具有进液口、萃取剂进口、萃取轻相出口和萃取重相出口，且位于最上游的连续萃取分液装置的进液口为培南类化合物粗产物进口，位于最下游的连续萃取分液装置的萃取重相出口与压滤液进口相连，相邻两个连续萃取分液装置中，位于上游的一级的萃取重相出口和位于下游的一级的进液口相连。
进一步地，连续压滤单元包括并联设置的多级压滤装置，各多级压滤装置均设置有压滤液进口、固相出口和液相出口。
进一步地，装置还包括：萃取轻相接收装置，与萃取轻相出口相连；萃取重相接收装置，设置在萃取重相出口与PFR反应器相连的管路上；液相接收装置，设置在液相进口与液相出口相连的管路上；以及析晶浆液接收装置，与析晶浆液出口相连。
进一步地，装置还包括：第一质量流量计，设置在萃取重相接收装置与PFR反应器相连的管路上；第二质量流量计，设置在液相接收装置与液相进口相连的管路上；且装置还包括控制单元，控制单元与pH值检测装置、第一质量流量计及第二质量流量计均电连接。
进一步地，培南类化合物粗产物进口、萃取剂进口、pH调节剂进口、液相进口、第一析晶溶剂进口、调节液进口、第二析晶溶剂进口及PFR反应器用于通入萃取重相的进口所在的管路上均设置有物料输送泵。
进一步地，连续萃取分液单元、连续压滤单元、连续pH调节单元及连续析晶单元均设置有控温单元，且萃取重相接收装置设置有第二控温夹套，液相接收装置设置有第三控温夹套，析晶浆液接收装置设置有第四控温夹套，控制单元还与控温单元、第二控温夹套、第三控温夹套及第四控温夹套电连接。
进一步地，培南类化合物连续化后处理装置为培南类化合物合成后处理装置。
本发明提供了一种培南类化合物连续化后处理方法，其是连续化集成的后处理方法，采用该方法对培南类化合物的反应粗产物进行后处理时具有处理速度快、效率高的优势，且处理过程中物料性质稳定，变质率低，对目标产物的收率和纯度具有更好地控制能力。尤其是该方法能够很好地契合培南类化合物的性质，在降低产品变质率，提升处理效果、产品收率方面有更强的针对性。
附图说明
构成本申请的一部分的说明书附图用来提供对本发明的进一步理解，本发明的示意性实施例及其说明用于解释本发明，并不构成对本发明的不当限定。在附图中：
图1示出了根据本发明一种实施例的培南类化合物连续化后处理装置的结构示意图。
其中，上述附图包括以下附图标记：
10、连续萃取分液单元；11、连续萃取分液装置；20、连续压滤单元；21、压滤装置；30、连续pH调节单元；40、连续析晶单元；50、PFR反应器；60、pH值检测装置；70、萃取轻相接收装置；80、萃取重相接收装置；90、液相接收装置；100、析晶浆液接收装置；110、第一质量流量计；120、第二质量流量计；130、物料输送泵。
具体实施方式
需要说明的是，在不冲突的情况下，本申请中的实施例及实施例中的特征可以相互组合。下面将参考附图并结合实施例来详细说明本发明。
正如背景技术部分所描述的，现有技术中采用批次处理培南类化合物粗产物时，存在处理速度低、效率低、物料变质率高等问题。
为了解决这一问题，本发明提供了培南类化合物连续化后处理方法，其包括以下步骤：S1，将培南类化合物的反应粗产物进行连续化萃取，得到萃取重相和萃取轻相；S2，对萃取重相进行连续化固液分离，得到液相分离物；S3，对液相分离物进行连续化pH调节至其pH值为6.1～6.3，得到pH调节液；S4，采用第一析晶溶剂将pH调节液进行连续化析晶处理，得到培南类化合物的产品。
本发明提供的是培南类化合物的连续化集成的后处理方法，采用该方法对培南类化合物的反应粗产物进行后处理时具有处理速度快、效率高的优势，且处理过程中物料性质稳定，变质率低，对目标产物的收率和纯度具有更好地控制能力。尤其是该方法能够很好地契合培南类化合物的性质，在降低产品变质率，提升处理效果、产品收率方面有更强的针对性。
具体地，在萃取分液阶段，本发明采用的连续化萃取分液要比间歇式批次后处理缩短50％以上的时间，处理效果远远优于批次处理。在压滤阶段，单位时间放热远远低于批次后处理，这意味着节约了更多的能量，产品的稳定性得到了保障。调节pH阶段已处理完的体系立即进入析晶阶段，停留时间大幅缩短，这意味着产品变质率大幅降低。析晶阶段，连续化处理不仅攻克了批次后处理效率低的问题。同时，析晶体系较之批次处理体系在后期的晶形筛选方面有更好的优势。
在一种优选的实施方式中，在对萃取重相进行连续化固液分离之前，步骤S2还包括在萃取重相中加入第二析晶溶剂并使二者在PFR反应器中混合的步骤；且第二析晶溶剂的加入量为萃取重相重量的50～80％，控制PFR反应器的温度为-7～3℃。这样，在萃取重相进入压滤阶 段之前，预先和一部分析晶溶剂混合，一方面有利于粗产物体系中催化剂固相长大，从而有利于压滤阶段的固液分离，另一方面，少量的析晶溶剂加入还有利于稳定产品在溶液体系的稳定(少量析晶溶剂不会造成产品析出，析晶阶段大量加入析晶溶液会使产物因溶解度问题被逼晶析出)，对产物的液相体系起到缓冲稳定的作用，从而有利于防止后续pH调节过程的堵塞，使连续化处理过程更稳定。
在实际操作过程中，因采用了PFR反应器进行混合，萃取重相在PFR反应器中是连续流动的过程，一边流动一边与第二析晶溶剂混合，停留时间较短。为了进一步提高混合效果，在一种优选的实施方式中，萃取重相在PFR反应器中的停留时间为2～8min。
在一种优选的实施方式中，步骤S1中，连续化萃取过程包括依次进行的N次，N≥2，且第M次连续化萃取过程分离出的重相进入第M+1次连续化萃取过程，1≤M≤(N-1)，将第N次连续化萃取过程分离出的重相作为步骤S2中的萃取重相；优选地，N＝2。这样，待处理的培南类化合物反应粗产物在进行第一次连续萃取分离后，两相连续被分出，轻相可进行溶剂回收，重相进入下一次连续萃取过程。在实际的处理过程中，可以根据粗产物的处理量和产品浓度选择具体的处理次数，也可以根据萃取分离的难易程度确定分离级数，处理时间、处理量分离效果较批次工艺具有很大优势。更优选地，连续化萃取过程中，培南类化合物的反应粗产物的停留时间为1～7min，处理温度为-7～3℃。
在一种优选的实施方式中，连续化固液分离的过程中，将萃取重相分为多部分，多部分萃取重相分别一一对应地进入不同的压滤装置进行处理，且各压滤装置的处理通量为1～2L/min，萃取重相的停留时间为2～11min。因压滤过程为高压处理过程，利用多级压滤装置处理压滤液，更有利于缓解各压滤装置的处理状况。
在一种优选的实施方式中，第一析晶溶剂为甲醇和/或正丙醇，第二析晶溶剂为甲醇和/或正丙醇。更优选地，连续化析晶处理过程中，pH调节液的停留时间为2～11min，处理温度为-22～-12℃。
为了进一步提高pH调节的效率，并防止pH调节过程中的析出，在一种优选的实施方式中，上述步骤S3中，调节液相分离物pH值的试剂为甲醇和乙酸的混合液，优选其pH值为3～4。更优选地，调节液相分离物pH值的过程中，液相分离物的停留时间为2～11min，处理温度为-7～3℃。
根据本发明的另一方面，还提供了一种培南类化合物连续化后处理装置，如图1所示，该装置包括连续萃取分液单元10、连续压滤单元20、连续pH调节单元30、连续析晶单元40，连续萃取分液单元10设置有培南类化合物粗产物进口、萃取剂进口、萃取重相出口和萃取轻相出口，连续萃取分液单元10用于对培南类化合物的反应粗产物进行连续化萃取；连续压滤单元20设置有压滤液进口、固相出口和液相出口，压滤液进口与萃取重相出口相连，连续压滤单元20用于对萃取重相出口排出的萃取重相进行连续化固液分离；连续pH调节单元30设置有液相进口、pH调节剂进口及调节液出口，液相进口与液相出口相连，连续pH调节单元30用于对液相出口排出的液体进行连续化pH调节；连续析晶单元40设置有调节液进口、第 一析晶溶剂进口和析晶浆液出口，调节液进口与调节液出口相连，连续析晶单元40用于对调节液出口排出的pH调节液进行连续化析晶。
上述培南类化合物连续化后处理装置是连续化集成的后处理装置，利用其对培南类化合物的反应粗产物进行后处理时具有处理速度快、效率高的优势，且处理过程中物料性质稳定，变质率低，对目标产物的收率和纯度具有更好地控制能力。尤其是该装置能够很好地契合培南类化合物的性质，在降低产品变质率，提升处理效果、产品收率方面有更强的针对性。
具体地，就培南类产品的后处理过程，在萃取分液阶段，本发明采用的连续化萃取分液要比间歇式批次后处理缩短50％以上的时间，处理效果远远优于批次处理。压滤阶段，单位时间放热远远低于批次后处理，这意味着节约了更多的能量，产品的稳定性得到了保障。调节pH阶段已处理完的体系立即进入析晶阶段，停留时间大幅缩短，这意味着产品变质率大幅降低。析晶阶段，连续化处理不仅攻克了批次后处理效率低的问题。同时，析晶体系较之批次处理体系在后期的晶形筛选方面有更好的优势。
在一种优选的实施方式中，如图1所示，上述装置还包括：PFR反应器50(平推流反应器)，设置在压滤液进口与萃取重相出口相连的管路上，且PFR反应器50还设置有第二析晶溶剂进口。这样，在萃取重相进入压滤阶段之前，预先和一部分析晶溶剂混合，一方面有利于粗产物体系中催化剂固相长大，从而有利于压滤阶段的固液分离，另一方面，少量的析晶溶剂加入还有利于稳定产品在溶液体系的稳定(少量析晶溶剂不会造成产品析出，析晶阶段大量加入析晶溶液会使产物因溶解度问题被逼晶析出)，对产物的液相体系起到缓冲稳定的作用，从而有利于防止后续管式pH调节过程的堵塞，使连续化处理过程更稳定。
在一种优选的实施方式中，PFR反应器50为夹套盘管反应器，其包括盘管反应器和设置在盘管反应器外部的第一控温夹套。利用控温的夹套盘管反应器更有利于萃取重相与少量析晶溶剂的混合，使催化剂更充分地析出，且通过温度控制也能够进一步保证体系的稳定性，防止变质。于此同时，采用夹套盘管反应器还有利于避免局部放热大破坏产品的风险。
为了进一步提高处理过程的连续性，在一种优选的实施方式中，连续pH调节单元30为管式pH调节装置，连续析晶单元40为管式析晶装置。采用管式设备，随物料在管式设备中的前进，物料混合更加均匀，从处理效率和效果方面更有优势。更优选地，连续pH调节单元30为平推流式或全混流式，连续析晶单元40为平推流式。
在一种优选的实施方式中，上述装置还包括：pH值检测装置60，设置在调节液进口与调节液出口相连的管路上，用于检测pH调节液的pH值。本发明采用该pH前置反馈调节形式，通过实时监测调节液的pH值状态，便于及时调整pH调节剂的相对加入量(可通过调整pH调节剂的加入量和/或产品相的加入量调节)。
在一种优选的实施方式中，连续萃取分液单元10包括依次串联设置的多级连续萃取分液装置11，各连续萃取分液装置11均具有进液口、萃取剂进口、萃取轻相出口和萃取重相出口，且位于最上游的连续萃取分液装置11的进液口为培南类化合物粗产物进口，位于最下游的连续萃取分液装置11的萃取重相出口与压滤液进口相连，相邻两个连续萃取分液装置11中，位 于上游的一级的萃取重相出口和位于下游的一级的进液口相连。这样，待处理的培南类化合物反应粗产物在第一级连续萃取分液装置11中进行萃取分离后，两相连续被分出，轻相可进行溶剂回收，重相进入下一级连续萃取分液装置11进一步萃取分离。在实际的处理过程中，可以根据粗产物的处理量和产品浓度选择具体的连续萃取分液装置11的级数，也可以根据萃取分离的难易程度确定分离级数，处理时间、处理量分离效果较批次工艺具有很大优势。
同样地，可以根据处理量的大小选择连续压滤单元20的规模，在一种优选的实施方式中，连续压滤单元20包括并联设置的多级压滤装置21，各多级压滤装置21均设置有压滤液进口、固相出口和液相出口。因压滤过程为高压处理过程，利用并联设置的多级压滤装置21处理压滤液，更有利于缓解各压滤装置的处理状况。
在一种优选的实施方式中，上述装置还包括：萃取轻相接收装置70，与萃取轻相出口相连；萃取重相接收装置80，设置在萃取重相出口与PFR反应器50相连的管路上；液相接收装置90，设置在液相进口与液相出口相连的管路上；析晶浆液接收装置100，与析晶浆液出口相连。利用各接收装置，能够为各阶段的进料提供缓冲装置，从而方便各阶段进料流量的调整。更优选地，上述装置还包括：第一质量流量计110，设置在萃取重相接收装置80与PFR反应器50相连的管路上；第二质量流量计120，设置在液相接收装置90与液相进口相连的管路上；且装置还包括控制单元，控制单元与pH值检测装置60、第一质量流量计110及第二质量流量计120均电连接。这样，通过控制单元能够更便捷地调整各阶段的进料情况，同时也可以实时监控各阶段的运行状况，使处理过程更为稳定，从而进一步减少产品变质几率，提高处理效率。
在一种优选的实施方式中，如图1所示，培南类化合物粗产物进口、萃取剂进口、pH调节剂进口、液相进口、第一析晶溶剂进口、调节液进口、第二析晶溶剂进口及PFR反应器50用于通入萃取重相的进口所在的管路上均设置有物料输送泵130。需说明的是，在析晶阶段，随着调节液和大量析晶溶剂在管式析晶装置中混合，目标产物被逼晶析出，析晶浆液为固液两相的混合体系。采用物料输送泵130进行物料驱动输送，使调节液与析晶溶剂能够达到非常良好的混合湍动，其析晶效果及效率优于批次处理方式。更优选地，上述连续析晶单元40为管式平推流式析晶装置，这更有利于提高析晶效果。此外，该装置中单一体系质点在pH调节完毕后停留时间极短，这样更有利于提高析晶效果。
在实际操作过程中，可以在调节液进入之前，通过物料输送泵130预先连续定量化进料将析晶溶剂充满管式析晶装置中，然后再将调节液通过物料输送泵130通入，进行析晶处理。物料输送泵130大流量耐高压的振荡装置连续不断地向管式析晶装置中输送能量，使得析晶后的固液混合的浆料在管式析晶装置中也不会堵塞，浆状的体系进入析晶浆液接收装置100中低温暂存，此时的体系已经非常稳定，不随时间变化而变质，静置一段时间后进入固液分离装置便可得到合格产品。
在一种优选的实施方式中，连续萃取分液单元10、连续压滤单元20、连续pH调节单元30及连续析晶单元40均设置有控温单元，且萃取重相接收装置80设置有第二控温夹套，液相接收装置90设置有第三控温夹套，析晶浆液接收装置100设置有第四控温夹套，控制单元 还与控温单元、第二控温夹套、第三控温夹套及第四控温夹套电连接。这样，可以针对每个阶段进行更精准地控温，从而进一步改善后处理各阶段的稳定性。更优选地，上述连续萃取分液单元10、连续压滤单元20、连续pH调节单元30、连续析晶单元40、第一控温夹套、第二控温夹套、第三控温夹套、第四控温夹套中均设置有温度铂电阻，其用于将所测温度反馈至控制单元，且上述装置还包括报警单元，控制单元与报警单元电连接。这样，通过温度铂电阻可以将所测温度及时反馈至控制单元，针对各温度铂电阻可以设置标准范围，超出标准范围并维持非正常范围超过10s则会报警联动跳停。这样更有利于维持后处理各阶段的稳定性，及时调整各阶段的温度状态。
培南类产品对温度都比较敏感，温度越高产品的变质速率越快。因此整个连续后处理装置都有严格的控温措施，所有含产品的接收装置都设置有控温夹套，所有的操作单元装置也设有控温夹套。重要的输送管路例如调节pH后调节液的输送段也安装控温夹套并保温。
在一种优选的实施方式中，上述装置还包括压力检测单元，用于检测连续压滤单元20、连续pH调节单元30、连续析晶单元40、PFR反应器50、各接收装置内部的压力，且该压力检测单元与控制单元电连接。这样可以实时检测各阶段的运行压力，及时反馈各压力单元中是否产生堵塞等现象，维持体系的运行稳定。压力检测单元的压力检测点可以设置在上述装置的进口处。更优选地，上述连续压滤单元20、连续pH调节单元30、连续析晶单元40、PFR反应器50中均设置有尾气排放管路。这样可以防止憋压，同时也能够避免尾气积聚。
更优选地，上述装置还包括压力报警系统，其与压力检测单元电连接。这样连续后处理装置所有的的测压点都可以设置压力标准范围，一旦超压或有负压的情况出现则会立即报警联动跳停。
上述各装置和单元、管道等的材质可以根据所处理的物料的性质进行设计，比如可以采用钛制、四氟、304、316、哈式合金等化学性质、耐温、耐压的材料。整个流程管道及设备间的连接方式主要是以法兰式为主，多种其他连接方式包括：焊接、快速接头、卡套连接件等并存的模式。
优选地，连续萃取分液装置11的串联形式为溢流式串联，即前一级萃取重相通过溢流形式进入下一级进一步萃取。连续萃取分液装置11的具体类型优选采用离心萃取机，当然，也可以采用转盘萃取塔或者膜分离萃取装置等。
优选地，上述压滤装置21内部采用膜堆或填料。
本发明提供的上述后处理装置更适用于产品性质恶劣，易变质的产品后处理，在一种优选的实施方式中，上述培南类化合物连续化后处理装置为培南类化合物合成后处理装置。具体的培南类化合物包括但不限于有厄他培南、亚胺培南、美罗培南、比阿培南、帕尼培南等。本发明已成功应用于这些培南类粗产物连续后处理小试到中试的生产。
此外，本发明提供的上述装置是高度自动化的处理装置，根据设备的处理量可随时对进料速度、温度等进行调整，整体的处理时间可以精确控制。每个单项的操作单元通过自动化 控制程序连接成一个整体，每个单元操作之间同过反馈式的质量流量计实现精确连接，让原本间歇的操作流程实现了连续连续化，根据处理体系不同，操作单元可增可减。在安全性方面，通过安装压力、温度、危险气体报警等装置同时联动设置超压、超温、危险气体过量报警进行调控，大幅降低事故潜在风险。在面对突发情况的时候可切断所有进料口将产品损失及风险等级控制在最低范围。本发明还能够大幅降低设备占用面积、劳动人力资源、及生产能耗。较之传统批次后处理技术还大大降低了投资成本。
以下结合具体实施例对本申请作进一步详细描述，这些实施例不能理解为限制本申请所要求保护的范围。
实施例1
小试试验：采用图1所示的装置对4L厄他培南粗产物体系进行后处理，厄他培南粗产物体包括厄他培南、TMG(四甲基胍)、NEP(N-乙基吡咯烷酮)、异戊醇、钯碳催化剂、水。
连续萃取分液段，厄他培南粗产物体系进行二级萃取分液，体系经自动化连续定量化进料，同时一级萃取剂(异戊醇、水、NaHCO 3磷酸二苯酯混合溶液)经自动化连续定量进料。在第一级离心萃取机中进行第一级自动化萃取分液，轻相报废体系进接收装置中收集，重相直接溢流至第二级离心萃取机，同时第二级萃取剂(异戊醇)连续定量输送至第二级离心萃取机，同样的分离出报废的轻相进入接收装置。重相连续化进入萃取重相接收装置，缓存接收再进入下一操作单元。其中，萃取分液阶段的温度控制在-5～0℃。
连续混合压滤阶段，使用质量流量计和物料输送泵反馈调节，以连续定量化输送萃取重相至夹套盘管反应器，同时自动化连续定量输送少量甲醇作为稀释溶剂(与后续析晶溶剂相同)与萃取重相在盘管反应器中混合稀释，稀释后的体系直接进入并联的压滤装置，过滤掉其中的少量固体杂质。澄清的体系进入接收装置，再进下一操作单元。其中，连续混合压滤阶段的温度控制在-5～0℃。
连续调节pH阶段，压滤后的体系经质量流量计和物料输送泵反馈调节，以连续定量化输送至管式平推流式pH调节装置，同时用于输送pH调节剂(乙酸/甲醇)的物料输送泵在线接收pH值检测装置的测量结果，并根据此反馈调节pH调节剂的进料量，实现精确进料。两股物料在pH调节装置中充分混合，经过pH值检测装置处再次设置pH监测点，且pH值检测装置是有一定的体积缓冲能力的，调酸合格体系直接连续定量进入下一处理阶段。其中，连续调节pH阶段的温度控制在-10～-5℃。
连续结晶阶段，待析晶体系进入析晶装置之前，通过物料输送泵预先连续定量化进料将析晶溶剂充满管式平推流式析晶装置。由于物料输送泵大流量耐高压的振荡装置连续不断的向管式析晶装置中输送能量，使得析晶后的固液混合的两相在其中不会堵塞，浆状的体系进入接收装置低温暂存，此时的体系已经非常稳定，不随时间变化而变质，静置一段时间后进入固液分离装置拿到合格产品。其中，连续结晶阶段的温度控制在-20～-15℃。
结果见表1。
对比例1
采用批次处理方式对4L厄他培南粗产物体系进行后处理，结果见表1。
表1
Figure PCTCN2019111198-appb-000001
实施例2
将实施例1中的4L小试试验放大为400L中试试验，采用的设备和试剂同实施例1相同，不同之处在于：
连续萃取分液段：将厄他培南粗产物体系连续化进料至总保留体积为5L的二级离心萃取机中，进行连续化萃取分离，体系停留时间仅为3～5min。
连续混合压滤阶段，萃取重相和少量甲醇(甲醇为萃取重相重量的60％)采用3～8L夹套盘管反应器进行连续混合，稳定快速的连续化进料，体系混合段的停留时间仅3～5min。随即进入二级并联的过滤装置膜堆快速过滤，膜堆的处理通量为1L～2L/min，匹配上游混合的进料速度。
连续调节pH阶段，连续化PH调节采用在线PH计，实现自动反馈调节，采用20L连续搅拌反应装置，调节合格体系经8L溢流管路快速转移至下游操作。调节时，体系的停留时间仅为5～8min，很大程度上缩短了产品的变质率。
连续析晶阶段，采用振荡流管式析晶装置，保留体积6L，体系与逼晶溶剂在该装置中均匀混合逼晶，析出的晶体晶形较为稳定，体系保留时间为5～8min。
结果见表2。
对比例2
采用批次处理方式对4L厄他培南粗产物体系进行后处理，具体如下：
萃取分液段：采用3000L釜进行批次的萃取分液操作，体系在此阶段的停留时间6.5h，萃取效果较差。
混合过滤段：批次操作，采用3000L釜进行体系与甲醇的混合操作，混合过程会有放热情况，批次操作会有局部放热量大破会产品的风险。
调节pH阶段：批次操作，采用3000L釜进行操作，上游体系的PH值为7.2～9.5，调节时往釜中逐次加pH为3～4的甲醇/乙酸体系，每加一次需要搅拌静置取样检测，直至体系PH达到工艺要求。此阶段产品变质速率很快因此需要快速进行，而批次操作体系的停留时间较长，导致变质率较高。
析晶阶段：批次操作，在3000L釜中进行，操作时分批多次向釜中加入甲醇/正丙醇，分批多次的目的是逐渐诱导晶核析出，这样操作有两个隐患，其一是局部逼晶溶剂浓度过高，导致析出的晶体晶形不稳定，另外釜内其他未接触到逼晶溶剂的区域产品依旧处于快速变质的状态。该阶段操作体系停留时间同样较长，产品变质率依旧较高。
结果见表2.
表2
Figure PCTCN2019111198-appb-000002
结果发现：对于厄他培南后处理体系400L中试规模来说，连续化集成的后处理方式总处理时间比批次后处理缩短76.25％。产品纯度上将提升4％～6％，产品收率上提升约5％。设备占地面积降低60％，操作人力资源降低80％。
由以上数据可知：
1、培南类产品连续化集成的后处理装置，改善了培南类产品的传统后处理方式。众所周知，待处理的培南类产品体系是非常容易变质的，就厄他培南来说，调pH前体系每小时的变质速率为0.3％，调pH之后每小时的变质速率为1.2％(这是固有损失，无法改变)，只能通过压缩处理时间，来减少这个损失量。
2、传统的批次后处理培南类产品因变质的损失量为6％～10％。主要是因为各操作单元的处理的时间太长。连续化集成的后处理缩短所有操作单元的处理时间。调节PH之前的萃取分液、混合压滤的操作时间。在同样的400L处理量下，批次需要12小时产品损失4％，连续只需要4小时产品损失1％。
3、连续化集成培南类后处理装置的优势在pH调节段能大幅体现。连续化后处理时，调完PH的体系单个质点的停留时间为8min,而批次单个质点的停留时间为4h。直接减少了约5％的损失。
4、培南类产品后处处理有机三废量是非常大的(产品体系:三废＝1:5；体积比)，批次处理会在短时间内积聚大量有机三废，潜在风险系数较高。而连续化集成的后处理模式，能有效控制单位时间内三废的产出量降低了潜在风险系数。
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (21)

  1. 一种培南类化合物连续化后处理方法，其特征在于，包括以下步骤：
    S1，将所述培南类化合物的反应粗产物进行连续化萃取，得到萃取重相和萃取轻相；
    S2，对所述萃取重相进行连续化固液分离，得到液相分离物；
    S3，对所述液相分离物进行连续化pH调节至其pH值为6.1～6.3，得到pH调节液；
    S4，采用第一析晶溶剂将所述pH调节液进行连续化析晶处理，得到所述培南类化合物的产品。
  2. 根据权利要求1所述的方法，其特征在于，在对所述萃取重相进行所述连续化固液分离之前，所述步骤S2还包括在所述萃取重相中加入第二析晶溶剂并使二者在PFR反应器中混合的步骤；且所述第二析晶溶剂的加入量为所述萃取重相重量的50～80％，控制PFR反应器中的温度为-7～3℃。
  3. 根据权利要求2所述的方法，其特征在于，所述萃取重相在PFR反应器中的停留时间为2～8min。
  4. 根据权利要求1至3中任一项所述的方法，其特征在于，所述步骤S1中，连续化萃取过程包括依次进行的N次，N≥2，且第M次所述连续化萃取过程分离出的重相进入第M+1次所述连续化萃取过程，1≤M≤(N-1)，将第N次所述连续化萃取过程分离出的重相作为所述步骤S2中的所述萃取重相；优选地，N＝2。
  5. 根据权利要求4所述的方法，其特征在于，所述连续化萃取过程中，所述培南类化合物的反应粗产物的停留时间为1～7min，处理温度为-7～3℃。
  6. 根据权利要求1至3中任一项所述的方法，其特征在于，所述连续化固液分离的过程中，将所述萃取重相分为多部分，多部分所述萃取重相分别一一对应地进入不同的压滤装置进行处理，且各所述压滤装置的处理通量为1～2L/min，所述萃取重相的停留时间为2～11min。
  7. 根据权利要求2所述的方法，其特征在于，所述第一析晶溶剂为甲醇和/或正丙醇，所述第二析晶溶剂为甲醇和/或正丙醇。
  8. 根据权利要求1至3中任一项所述的方法，其特征在于，所述连续化析晶处理过程中，所述pH调节液的停留时间为2～11min，处理温度为-22～-12℃。
  9. 根据权利要求1至3中任一项所述的方法，其特征在于，所述步骤S3中，调节所述液相分离物pH值的试剂为甲醇和乙酸的混合液，优选其pH值为3～4。
  10. 根据权利要求9所述的方法，其特征在于，调节所述液相分离物pH值的过程中，所述液相分离物的停留时间为2～11min，处理温度为-7～3℃。
  11. 一种培南类化合物连续化后处理装置，其特征在于，包括：
    连续萃取分液单元(10)，设置有培南类化合物粗产物进口、萃取剂进口、萃取重相出口和萃取轻相出口，所述连续萃取分液单元(10)用于对培南类化合物的反应粗产物进行连续化萃取；
    连续压滤单元(20)，设置有压滤液进口、固相出口和液相出口，所述压滤液进口与所述萃取重相出口相连，所述连续压滤单元(20)用于对所述萃取重相出口排出的萃取重相进行连续化固液分离；
    连续pH调节单元(30)，设置有液相进口、pH调节剂进口及调节液出口，所述液相进口与所述液相出口相连，所述连续pH调节单元(30)用于对所述液相出口排出的液体进行连续化pH调节；以及
    连续析晶单元(40)，设置有调节液进口、第一析晶溶剂进口和析晶浆液出口，所述调节液进口与所述调节液出口相连，所述连续析晶单元(40)用于对所述调节液出口排出的进行连续化析晶。
  12. 根据权利要求11所述的装置，其特征在于，所述装置还包括：
    PFR反应器(50)，设置在所述压滤液进口与所述萃取重相出口相连的管路上，且所述PFR反应器(50)还设置有第二析晶溶剂进口。
  13. 根据权利要求12所述的装置，其特征在于，所述PFR反应器(50)为夹套盘管反应器，其包括盘管反应器和设置在所述盘管反应器外部的第一控温夹套。
  14. 根据权利要求11所述的装置，其特征在于，所述连续pH调节单元(30)为管式pH调节装置，所述连续析晶单元(40)为管式析晶装置。
  15. 根据权利要求12所述的装置，其特征在于，所述装置还包括：pH值检测装置(60)，设置在所述调节液进口与所述调节液出口相连的管路上，用于检测所述pH调节液的pH值。
  16. 根据权利要求11至15中任一项所述的装置，其特征在于，所述连续萃取分液单元(10)包括依次串联设置的多级连续萃取分液装置(11)，各所述连续萃取分液装置(11)均具有进液口、所述萃取剂进口、所述萃取轻相出口和所述萃取重相出口，且位于最上游的所述连续萃取分液装置(11)的所述进液口为所述培南类化合物粗产物进口，位于最下游的所述连续萃取分液装置(11)的所述萃取重相出口与所述压滤液进口相连，相邻两个所述连续萃取分液装置(11)中，位于上游的一级的所述萃取重相出口和位于下游的一级的所述进液口相连。
  17. 根据权利要求11至15中任一项所述的装置，其特征在于，所述连续压滤单元(20)包括并联设置的多级压滤装置(21)，各所述多级压滤装置(21)均设置有所述压滤液进口、所述固相出口和所述液相出口。
  18. 根据权利要求15所述的装置，其特征在于，所述装置还包括：
    萃取轻相接收装置(70)，与所述萃取轻相出口相连；
    萃取重相接收装置(80)，设置在所述萃取重相出口与所述PFR反应器(50)相连的管路上；
    液相接收装置(90)，设置在所述液相进口与所述液相出口相连的管路上；以及
    析晶浆液接收装置(100)，与所述析晶浆液出口相连。
  19. 根据权利要求18所述的装置，其特征在于，所述装置还包括：
    第一质量流量计(110)，设置在所述萃取重相接收装置(80)与所述PFR反应器(50)相连的管路上；
    第二质量流量计(120)，设置在所述液相接收装置(90)与所述液相进口相连的管路上；
    且所述装置还包括控制单元，所述控制单元与所述pH值检测装置(60)、所述第一质量流量计(110)及所述第二质量流量计(120)均电连接。
  20. 根据权利要求12至15中任一项所述的装置，其特征在于，所述培南类化合物粗产物进口、所述萃取剂进口、所述pH调节剂进口、所述液相进口、所述第一析晶溶剂进口、所述调节液进口、所述第二析晶溶剂进口及所述PFR反应器(50)用于通入所述萃取重相的进口所在的管路上均设置有物料输送泵(130)。
  21. 根据权利要求19所述的装置，其特征在于，所述连续萃取分液单元(10)、所述连续压滤单元(20)、所述连续pH调节单元(30)及所述连续析晶单元(40)均设置有控温单元，且所述萃取重相接收装置(80)设置有第二控温夹套，所述液相接收装置(90)设置有第三控温夹套，所述析晶浆液接收装置(100)设置有第四控温夹套，所述控制单元还与所述控温单元、所述第二控温夹套、所述第三控温夹套及所述第四控温夹套电连接。
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KR1020227016230A KR20220084114A (ko) 2019-10-15 2019-10-15 페넴계 화합물 연속 후처리 방법 및 장치
EP19949227.3A EP4047000A4 (en) 2019-10-15 2019-10-15 METHOD AND DEVICE FOR THE CONTINUOUS POST-TREATMENT OF PENEM COMPOUNDS

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