WO2021227507A1 - 一种亚胺培南原料药的制备方法 - Google Patents

一种亚胺培南原料药的制备方法 Download PDF

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WO2021227507A1
WO2021227507A1 PCT/CN2020/139223 CN2020139223W WO2021227507A1 WO 2021227507 A1 WO2021227507 A1 WO 2021227507A1 CN 2020139223 W CN2020139223 W CN 2020139223W WO 2021227507 A1 WO2021227507 A1 WO 2021227507A1
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imipenem
crude
impurity
temperature
aqueous solution
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PCT/CN2020/139223
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French (fr)
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田伟豹
林楠棋
赵鹏
张金相
王成山
黄成林
莫达
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深圳市海滨制药有限公司
新乡海滨药业有限公司
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Publication of WO2021227507A1 publication Critical patent/WO2021227507A1/zh

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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
    • 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

Definitions

  • the invention belongs to the technical field of pharmacy, and specifically relates to a preparation method of imipenem bulk medicine.
  • Imipenem (Imipenem), the chemical name is: (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[[2-[(iminomethyl)amino]ethyl] Thio]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monohydrate, is a carbapenem antibiotic, mainly used for gram-positive bacteria Respiratory tract infections, biliary tract infections, urinary system and abdominal cavity infections, skin and soft tissues, bones and joints, gynecological infections caused by, negative bacteria, anaerobic bacteria, etc., it exists in the form of monohydrate under normal conditions.
  • the CAS registration number is (74431- 23-5), the specific chemical structural formula is shown in formula (I):
  • API Active Pharmaceutical Ingredient
  • ICH Q7A any substance or mixture of substances intended to be used in the manufacture of pharmaceuticals, and when used in pharmaceuticals, it becomes an active ingredient of pharmaceuticals. Such substances have pharmacological activity or other direct effects in the diagnosis, treatment, symptom relief, treatment or prevention of diseases, or can affect the function or structure of the body.
  • Impurities in imipenem or any active pharmaceutical ingredient (API) are not required, and in extreme cases, may even be harmful to patients undergoing treatment with API-containing dosage forms, for example, the official website of the State Drug Administration The "Annual Report on National Adverse Drug Reaction Monitoring (2016)” released shows that among the reports of serious adverse drug reactions/events of chemical drugs, anti-infectives accounted for 33.3% of the reports. This is related to the lack of strict control of impurities and solvent residues. Therefore, there is an urgent need to provide an imipenem API with lower impurity content, lower solvent residues, and less adverse reactions.
  • the European Pharmacopoeia 9.0 version of the standard for imipenem monohydrate stipulates related substances, requiring impurity A (relative retention time 0.8) not to exceed 1.0%, and impurity BI (relative retention time 0.33) not to exceed 0.3 %, impurity BII (relative retention time 0.35) shall not exceed 0.3%; in terms of solvent residues, the Chinese Pharmacopoeia (2015 edition) Ch.P.
  • Four General Rules 0861 second method requires acetone and isopropanol ⁇ 0.25%; methanol ⁇ 0.5% , Dichloromethane ⁇ 0.06%.
  • imipenem Due to the low solubility of imipenem in water, in the prior art, the crude imipenem is usually dissolved in hot water at a certain temperature, then cooled, and finally an organic solvent is added to crystallize the raw material of imipenem. , But imipenem has poor thermal stability, especially when it is dissolved in higher temperature water, it will accelerate decomposition and produce more impurities, which will affect product quality and yield.
  • CN1608066A discloses a preparation method for preparing high-purity imipenem, which involves first dissolving crude imipenem in an aqueous sodium bicarbonate solution at 35-60°C, cooling, adjusting the pH value with hydrochloric acid, and then treating with activated carbon Finally, use the process of lower alcohol or acetone crystallization. Because imipenem is a ⁇ -lactam compound, it is more sensitive to acid and alkali. This process requires the use of hydrochloric acid to adjust the pH value, which increases the risk of product degradation, and the process is complex and difficult to control , Is not conducive to industrial production; furthermore, the process does not involve the problem of reducing solvent residues, and the control of solvent residues is an indicator that must be paid attention to.
  • CN101891744B discloses a method for preparing high-purity imipenem with low solvent residue, which involves dissolving crude imipenem in water at 30-70°C, adding activated carbon, rapidly cooling, filtering the activated carbon, and finally using low-grade imipenem
  • the process of crystallization of alcohols or ketones can be used to prepare imipenem with low residual organic solvents, and rapid cooling is used to reduce the risk of product degradation.
  • the purity of the imipenem prepared by this process is not ideal. And it does not involve the control of impurity A, impurity BI and impurity BII; furthermore, the industrial conditions required for rapid cooling means are harsh, which is not conducive to industrial production.
  • Nanofiltration technology refers to a technology that achieves selective separation of a mixture of molecules of different particle sizes at the molecular level when passing through a nanofiltration membrane. This technology separates the solution system on the surface of the membrane under pressure. Solvents and other small molecular solutes pass through the membrane with an asymmetric microporous structure, and macromolecular solutes or particles are trapped on the membrane surface by the filter membrane to achieve selection. Sexual separation. It is often used for seawater desalination, water softening, selective separation of solutes, and concentrated preparation of alcohols, sugars, etc.
  • the object of the present invention is to provide a method for preparing imipenem bulk drug, which comprises dissolving the crude imipenem in water at a lower temperature, and after concentrating the resulting solution by nanofiltration, adding a crystallization solvent for crystallization, Preparation of Imipenem API.
  • the present invention does not involve the high-temperature dissolving step of crude imipenem, and the process is simple, compact, and controllable, and is suitable for industrial production; at the same time, the product has high yield, high purity, can effectively reduce impurity content and solvent residues, and has low cost. Economic advantage.
  • a preparation method of imipenem bulk drug comprising the following steps:
  • step 2) Concentrate the imipenem aqueous solution obtained in step 1) by nanofiltration to obtain an aqueous imipenem concentrate;
  • step 3 Decolorizing the concentrated imipenem aqueous solution obtained in step 2) with activated carbon, filtering out the activated carbon, and crystallization;
  • step 4) The crystals precipitated in step 3) are separated, washed, and dried to obtain imipenem bulk drug.
  • impurity A (relative retention time 0.8) is not more than 1.0%
  • impurity BI (relative retention time 0.33) is not more than 0.8%
  • impurity BII (Relative retention time 0.35) is not more than 0.8%
  • the sum of impurities is not more than 3.0%
  • the content of imipenem should not be less than 94.0% based on anhydrous matter.
  • the dissolution temperature is 10-15°C.
  • the mass ratio of the water to the crude imipenem is 115 to 400:1; more preferably, the mass ratio of the water to the crude imipenem is 140 to 165:1.
  • the mass ratio of the concentrated imipenem aqueous solution to the crude imipenem in step 1) is 13-50:1; more preferably, the concentrated solution is compared with that described in step 1).
  • the mass ratio of crude imipenem is 20-30:1.
  • the temperature of the nanofiltration concentration is 5-25°C; more preferably, the temperature of the nanofiltration concentration is 5-20°C; further preferably, the temperature of the nanofiltration concentration is 10 ⁇ 15°C.
  • the time for concentration by nanofiltration is 10 minutes to 6 hours; more preferably, the time for concentration by nanofiltration is 1 to 5 hours.
  • the pressure of the nanofiltration concentration is 0.5-2.0Mpa; more preferably, the pressure of the nanofiltration concentration is 0.8-1.0Mpa.
  • the molecular weight cut-off range of the nanofiltration membrane used in the nanofiltration concentration process is 100-500; more preferably, the molecular weight cut-off range of the nanofiltration membrane used in the nanofiltration concentration process is 300.
  • the mass ratio of the activated carbon to the crude imipenem in step 1) is 0.05 to 0.35:1; more preferably, the activated carbon and the crude imipenem in step 1) The mass ratio is 0.1 ⁇ 0.2:1.
  • the decolorization temperature of the activated carbon is 5-25°C; more preferably, the decolorization temperature of the activated carbon is 10-15°C.
  • the crystallization temperature is -10 to 20°C; more preferably, the crystallization temperature is 5 to 15°C.
  • the crystallization further includes the step of adding a crystallization solvent
  • the crystallization solvent is selected from one or more of isopropanol, acetone and tetrahydrofuran;
  • the volume-to-mass ratio of the crystallization solvent to the crude imipenem in step 1) is 10-100:1; more preferably, the crystallization solvent is the same as that in step 1).
  • the volume-to-mass ratio of crude imipenem is 25-45:1.
  • the method of adding the crystallization solvent is multiple addition or dripping; more preferably, the method of adding the crystallization solvent is dripping.
  • the addition time of the crystallization solvent is 0.5 to 6 hours; more preferably, the addition time of the crystallization solvent is 1 to 3 hours.
  • the separation is to separate the precipitated crystals from the solution.
  • the separation can use any conventional separation method known in the art, such as filtration or centrifugation.
  • the separated solid is washed, and the washing solvent is selected within the range of crystallization solvents.
  • one or more mixtures of isopropanol, acetone and tetrahydrofuran can be selected, or one of isopropanol, acetone and tetrahydrofuran can be selected.
  • One or more mixed liquids with water drying, such as vacuum drying, at a drying temperature of 10-40° C., to obtain the raw material of imipenem.
  • impurity A (relative retention time 0.8) is not more than 0.8%
  • impurity BI (relative retention time 0.33) is not more than 0.1%
  • impurity BII (relative retention time 0.33) is not more than 0.1% in the imipenem API that can be obtained according to the above preparation method Retention time 0.35) is not more than 0.1%
  • the sum of impurities is not more than 1.0%
  • the content of imipenem monohydrate is 98-101% based on imipenem monohydrate
  • acetone and isopropyl The total amount of alcohol residue does not exceed 0.25%, methanol residue does not exceed 0.3%, dichloromethane residue does not exceed 0.06%, acetonitrile residue does not exceed 0.04%, ethyl acetate residue does not exceed 0.5%, and tetrahydrofuran residue does not exceed 0.07%.
  • impurity A is
  • impurity B is
  • BI and BII are the two enantiomers of impurity B.
  • the European Pharmacopoeia 9.0 version of the standard for imipenem monohydrate stipulates that the relative retention time of impurity BI is 0.33, and the relative retention time of impurity BII is 0.33. The retention time is 0.35.
  • the present invention has the following beneficial effects:
  • the raw material of imipenem prepared by the preparation method of the present invention has high purity, clear impurity status, low solvent residue, and quality control indicators to ensure that the product is effective and safe.
  • the crude imipenem is dissolved in water at 5 ⁇ 25°C and then concentrated to obtain a high-concentration crude imipenem solution, which is then crystallized, which greatly reduces the crystallization solution
  • the amount of use and the high product yield can effectively reduce the impurity content, and the solvent residue is low, while increasing the production capacity and reducing the production of waste liquid. It is environmentally friendly and meets the requirements of modern green chemical industry.
  • the preparation method of the present invention can concentrate the thermally unstable imipenem solution at a lower temperature and in a short time, greatly reducing the decomposition rate of imipenem, reducing the generation of impurities, and greatly improving Product quality and yield.
  • the preparation method of the present invention does not involve the steps of high temperature and acid-base adjustment of pH value, the process is simple, compact, easy to control, high productivity, low production cost, and the obtained imipenem API has high purity and low solvent residues, and is applicable In the industrialized large-scale production of imipenem APIs.
  • the crude imipenem can be prepared according to the method described in Example 1, or can be prepared according to CN1694885A or any method for preparing imipenem in the prior art.
  • the HPLC normalized purity was 98.43% and the impurity A content was 0.775%.
  • Impurity BI content is 0.287%
  • impurity BII content is 0.173%
  • total impurities is 1.473%
  • moisture is 7.5%; according to external standard method, the content of imipenem is 95.96% based on anhydrous; according to external standard method , Based on the monohydrate, the content of imipenem monohydrate is 93.77%.
  • Experimental method nitrogen protection, add 200g purified water to the flask, control the water temperature at the specified temperature, add 2g crude imipenem obtained in Example 1 into the flask, stir, continue to add purified water to the flask, 10g each time, until dissolved Clear, record the amount of water and time used for the clearing, and then detect the change of the normalized content of imipenem in the solution over time at this temperature. Change the dissolution temperature and repeat the experiment.
  • the specific experimental data are shown in Table 1.
  • the solubility of imipenem in water gradually increases with the increase in temperature, and the dissolution time is gradually shortened.
  • the dissolution temperature is 30°C, only 105g of water can dissolve 1g. Crude product takes 5 minutes; when the dissolution temperature is 5°C, 225g of water is needed to dissolve 1g crude product, and the time is extended to 39 minutes. Appropriately increasing the amount of solvent can help reduce the dissolution time.
  • the dissolution temperature is selected to be 5-25°C, preferably 10-15°C; the mass ratio of water to the crude imipenem is selected to be 115-400:1, preferably 140-165:1.
  • Experimental method nitrogen protection, add 2800g purified water to the flask, control the temperature at 15°C, add 20g of the crude imipenem obtained in Example 1 into the flask, stir and dissolve to obtain a crude imipenem aqueous solution, control the material during concentration
  • the liquid temperature is 10-20°C
  • the concentration pressure is controlled to 0.7Mpa
  • the crude imipenem aqueous solution is concentrated by nanofiltration, when the filtration wastewater reaches 2020g, the concentration is stopped, and the collected concentrated liquid and filtration wastewater are externally standardized.
  • the experiment is carried out.
  • the experimental data is shown in the table. 2.
  • the molecular weight cut-off of the nanofiltration membrane when it is 100-1000, the crude imipenem aqueous solution can be effectively concentrated by nanofiltration, and the product recovery rate is more than 80%; among them, the molecular weight cut-off of the nanofiltration membrane When it is 100 ⁇ 500, the product recovery rate is more than 90%, but when the molecular weight cut-off of the nanofiltration membrane is 500, the product recovery rate is the lowest; when the molecular weight cut-off of the nanofiltration membrane is 100, the concentration time is the longest.
  • the molecular weight cut-off of the filter membrane is 100-500, preferably 300.
  • the temperature is 5 to 25°C, preferably 5 to 20°C, and more preferably 10 to 15°C.
  • Experimental method nitrogen protection, add 2800g purified water to the flask, control the temperature at 15°C, add 20g of the crude imipenem obtained in Example 1 into the flask, stir and dissolve to obtain a crude imipenem aqueous solution, control the material during concentration
  • the liquid temperature is 10-15°C
  • the concentration pressure is controlled to 0.5-2.0Mpa
  • the molecular weight cut-off of the nanofiltration membrane is 300
  • the crude imipenem aqueous solution is concentrated by nanofiltration until the filtered wastewater reaches 2020g, and the concentration is adjusted during the concentration process.
  • the concentration time is 10 minutes to 7 hours under pressure, and the collected concentrated liquid and filtration wastewater are analyzed by external standard, and the content of imipenem monohydrate in the concentrated liquid and filtration wastewater and the content of the concentrated liquid are calculated.
  • the recovery rate and the experimental data are shown in Table 4.
  • the mass ratio of the concentrated solution and the crude imipenem is calculated as 13:1, add the concentrated solution to a 500ml flask, control the temperature at 15°C, add 2g of activated carbon, stir for 15min, filter, cool the filtrate to 5°C, add an appropriate amount of seed crystals, stir and crystallize for 5 hours, filter, and wash the crystals with 120ml of acetone , Vacuum drying at 20-30°C to obtain 16.98g of imipenem crude drug with a yield of 84.9%.
  • impurity A is 0.042%, impurity BI is 0.013%, impurity BII is 0.008%, and total impurities are 0.079%;
  • the external standard method based on imipenem monohydrate, the content of imipenem monohydrate was 99.91%, and organic solvent residues were not detected.
  • the mass ratio of the concentrated solution and the crude imipenem at this time is calculated as 30:1, stop concentration, add the concentrated solution to a 500ml flask, stir and control the temperature at 10°C, add 2g activated carbon, stir for 10min, filter, transfer the filtrate to a 1L flask, control the temperature at 15°C, add 100ml acetone, add appropriate amount of seed crystals , Stir the crystal for 1h, add 350ml of acetone dropwise, control the dropping rate to make the acetone dropwise finish in 3h, grow the crystal for 1h, filter, wash the crystal with 60ml of acetone, vacuum dry at 20 ⁇ 30°C to obtain 8.76g of imipenem raw material. The rate is 87.6%.
  • impurity A is 0.143%
  • impurity BI is 0.027%
  • impurity BII is 0.018%
  • total impurities is 0.213%
  • the content of South monohydrate was 99.52%
  • the residue of acetone was 0.0382%, and the residue of other solvents was not detected.
  • the mass ratio of the concentrated solution to the crude imipenem is calculated as 20:1, stop concentration, add the concentrated solution to a 500ml flask, stir to bring the temperature to 10°C, add 1g activated carbon, stir to decolorize for 10min, filter, transfer the filtrate to a 1L flask, stir to bring the temperature to 5°C, add 100ml of acetone, add Appropriate amount of seed crystals, stirring for 1h, adding 150ml of acetone dropwise, controlling the dropping rate so that the acetone is added dropwise in 1h, growing the crystals for 1h, filtering, washing the crystals with 60ml of acetone, drying under vacuum at 20 ⁇ 30°C to obtain the raw material of imipenem 8.87 g, the yield is 88.7%, the impurity A is 0.208%, the impurity BI is 0.033%, the impurity BII is 0.021%, and the total impurities are 0.308%; according to the external standard method, calculated as imipenem monohydrate
  • the mass ratio of the concentrated solution and the crude imipenem is calculated as 50:1, stop concentration, add the concentrated solution to a 500ml flask, stir and control the temperature at 25°C, add 1.0g activated carbon, stir for 5min, filter, transfer the filtrate to a 1L flask, cool the filtrate to 20°C, add 200ml tetrahydrofuran, add an appropriate amount Seed crystals, stir and grow crystals for 0.5h, add 300ml of tetrahydrofuran dropwise, control the dropping rate so that the tetrahydrofuran is added dropwise in 1h, grow the crystals for 0.5h, filter, wash 60ml of tetrahydrofuran, and dry at 20-30°C to obtain the raw material of imipenem.
  • impurity A is 0.512%
  • impurity BI is 0.052%
  • impurity BII is 0.036%
  • total impurities is 0.696%
  • the mass ratio of the concentrated solution to the crude imipenem is calculated as 25:1, stop concentration, add the concentrated solution to a 500ml flask, stir and control the temperature at 10°C, add 0.5g activated carbon, stir for 10min, filter, transfer the filtrate to a 1L flask, control the temperature at 10°C, add 50ml of isopropanol, add Appropriate amount of seed crystals, stir and grow crystals for 1h, add 200ml isopropanol dropwise, control the dropping speed to make isopropanol dropwise in 0.5h, grow crystals for 1h, filter, wash crystals with 100ml isopropanol, and vacuum dry at 20-30°C.
  • Imipenem crude drug is 8.33g, the yield is 83.3%, the impurity A is 0.395%, the impurity BI is 0.038%, the impurity BII is 0.021%, and the total impurities are 0.542%.
  • the imine Based on penem monohydrate the content of imipenem monohydrate was 99.26%; isopropanol residue was 0.0769%, and other solvent residues were not detected.
  • impurity A is 0.435%
  • impurity BI is 0.048%
  • impurity BII is 0.033%
  • total impurities are 0.674%
  • the content of imipenem monohydrate was 98.96%
  • acetone residue was 0.0280%
  • isopropanol residue was 0.0521%
  • tetrahydrofuran residue was 0.0265%, and other solvent residues were not detected.
  • the mass ratio of the concentrated solution to the crude imipenem at this time is calculated as 50:1, stop concentration, add the concentrated solution to a 1L flask, stir and control the temperature at 5°C, add 2g activated carbon, stir for 10min, filter, transfer the filtrate to a 2L flask, control the temperature at 5°C, add appropriate amount of seed crystals, stir to grow crystals 1h, add 600ml of acetone dropwise, control the dropping rate so that the acetone dripping is completed in 6h, grow the crystals for 1h, filter, wash the crystals with 60ml acetone, and vacuum-dry at 20-30°C to obtain 8.05g of imipenem crude drug with a yield of 80.5%.
  • impurity A is 0.127%
  • impurity BI is 0.015%
  • impurity BII is 0.013%
  • total impurities are 0.183%
  • imipenem monohydrate is calculated as imipenem monohydrate The content of acetone was 99.71%; acetone remained 0.0225%, and other solvent residues were not detected.
  • the mass ratio of the concentrated solution to the crude imipenem at this time is calculated as 20:1, stop concentration, add the concentrate to a 1L flask, stir and control the temperature at 25°C, add 1g activated carbon, stir for 10min, filter, transfer the filtrate to a 2L flask, control the temperature at 5°C, add appropriate seed crystals, and add acetone dropwise 300ml, control the dropping rate to make the acetone drip in 1h, cool to -10°C, add 300ml of acetone, control the dropping rate to make the acetone drip in 1h, grow the crystals at -10°C for 1h, filter, and wash the crystals with 60ml of acetone.
  • the mass ratio of the concentrated solution to the crude imipenem is calculated as 13:1, stop concentration, add the concentrated solution to a 500ml flask, stir and control the temperature at 10°C, add 2g activated carbon, stir for 10min, filter, transfer the filtrate to a 1L flask, add 100ml acetone, cool to -10°C, add appropriate amount of crystals Kind, control the temperature at -10°C, stir and cultivate the crystal for 1h, add 350ml of acetone dropwise, control the dropping speed to make the acetone drip in 3h, cultivate the crystal for 1h, filter, wash the crystal with 60ml acetone, and dry at 20-30°C to obtain the imine culture.
  • the southern bulk drug is 8.34g, with a yield of 83.4%.
  • impurity A is 0.661%
  • impurity BI is 0.035%
  • impurity BII is 0.028%
  • total impurities are 0.822%
  • the content of imipenem monohydrate was 98.77%
  • acetone remained 0.0388%, and other dissolved residues were not detected.
  • the impurity A was 0.671%, the impurity BI was 0.039%, the impurity BII was 0.031%, and the total impurities were 0.829%; according to the external standard method, based on imipenem monohydrate, imine The content of penem monohydrate was 98.75%; the acetone residue was 0.0372%, and other dissolved residues were not detected.
  • impurity A is 0.179%, impurity BI is 0.031%, impurity BII is 0.017%, total impurities are 0.237%; according to external standard method, the content of imipenem monohydrate is 99.85% based on imipenem monohydrate; acetone residue is 0.0297%, and other solvent residues are not detected .
  • the mass ratio of the concentrated solution to the crude imipenem is calculated as 13:1, stop concentration, add the concentrated solution to a 500ml flask, stir and control the temperature at 25°C, add 2g activated carbon, stir for 10min, filter, transfer the filtrate to a 1L flask, add 100ml acetone, add appropriate seed crystals at 25°C, control Warm 25°C, stir and grow crystals for 1h, add 350ml of acetone dropwise, control the dropping rate so that the acetone is added dropwise in 3h, grow crystals for 1h, filter, wash crystals with 60ml acetone, and vacuum dry at 20 ⁇ 30°C to obtain imipenem crude drug 7.42 g, the yield is 74.2%, the impurity A is 0.678%, the impurity BI is 0.214%, the impurity BII is 0.113%, and the total impurities are 1.198%; according to the external standard method, calculated as imipenem monohydrate, The content of imipenem monohydrate was 98.0
  • the preparation method of the imipenem bulk drug of the present invention is simple in process, easy to control, and effectively reduces the content of various impurities.
  • the prepared imipenem bulk drug has high purity and total Impurities are not more than 1.0%, of which impurity A is not more than 0.8%, and impurities BI and BII are not more than 0.1%;
  • Comparative Example 1 uses 58°C hot water to dissolve the crude product and quickly cool it down. After activated carbon treatment, a large amount of acetone is added to crystallize. The purity of the prepared product is not high, and the content of various impurities cannot be effectively reduced.
  • the total impurities are 1.212%, of which the impurity BI is 0.250%, and the impurity BII is 0.163%.
  • Comparative example 2 uses 25°C water to dissolve the crude product and treat it with activated carbon. Then, a large amount of acetone was added for crystallization, and the product yield was extremely low, only 6.5%;
  • Comparative Example 3 used 25°C water to dissolve the crude product, and then concentrated by nanofiltration. The mass ratio of crude amipenem is 9:1. After activated carbon treatment, acetone is added to crystallize, the product yield is extremely low, only 51.3%; Comparative Example 4 Nanofiltration concentration time is 7 hours, the product purity and yield are not ideal.
  • the preparation method of the present invention dissolves the crude product at low temperature, uses nanofiltration to concentrate to obtain a high-concentration solution, and then crystallizes, which greatly reduces the amount of crystallization solution used.
  • the process is simple, compact, easy to control, and suitable for industrialization.
  • the preparation method of the present invention can effectively reduce the content of various impurities, and the prepared product has high yield, high purity, clear impurity status, low dissolution residue, and quality control indicators can ensure that the product is effective and safe, and has a huge economy Advantages, suitable for widespread promotion.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明涉及一种亚胺培南原料药的制备方法，所述方法包括以下步骤：1)将亚胺培南粗品在5～25℃下溶解于水中，得到亚胺培南水溶液；2)将步骤1)中得到的亚胺培南水溶液经纳滤浓缩，得到亚胺培南水溶液浓缩液；3)将步骤2)得到的亚胺培南水溶液浓缩液经过活性炭脱色，滤除活性炭，析晶；4)将步骤3)中析出的晶体经分离、洗涤、干燥得到亚胺培南原料药。该方法工艺简单、紧凑、可控，同时产品收率高、纯度高、成本低，具有巨大的经济优势。

Description

一种亚胺培南原料药的制备方法
相关申请的交叉引用
本专利申请要求于2020年5月15日提交的申请号为CN202010413370.3的中国发明专利申请的优先权权益，在此将其全部内容引入作为参考。
技术领域
本发明属于制药技术领域，具体涉及一种亚胺培南原料药的制备方法。
背景技术
亚胺培南(Imipenem)，化学名称为：(5R,6S)-6-[(1R)-1-羟乙基]-3-[[2-[(亚氨基甲基)氨基]乙基]硫代]-7-氧代-1-氮杂双环[3.2.0]庚-2-烯-2-羧酸一水合物，是一种碳青霉烯类抗生素，主要用于革兰阳性菌、阴性菌、厌氧菌所致的呼吸道感染、胆道感染、泌尿系统和腹腔感染、皮肤软组织、骨和关节、妇科感染等，常态下其以一水合物形式存在，CAS登记号为(74431-23-5)，具体化学结构式如式(Ⅰ)所示：
Figure PCTCN2020139223-appb-000001
原料药英文名称为Active Pharmaceutical Ingredient，简称API，指用于生产各类制剂的原料药物，是制剂中的有效成分。原料药在ICH Q7A中的完善定义为：旨在用于药品制造中的任何一种物质或物质的混合物，而且在用于制药时，成为药品的一种活性成分。此种物质在疾病的诊断，治疗，症状缓解，处理或疾病的预防中有药理活性或者其他直接作用，或者能影响机体的功能或结构。
在亚胺培南或任何活性药物成分(API)中的杂质为不需要的，并且在 极端情况下，甚至可能对正在接受含API的剂型治疗的患者有害，例如，国家药品监督管理局官方网站发布的《国家药品不良反应监测年度报告(2018年)》显示，化学药品严重药品不良反应/事件报告中，报告数量最多的是抗感染药，占33.3％。这与杂质、溶剂残留控制不严都有一定关系，所以，迫切需要提供一种杂质含量更低、溶剂残留更低、不良反应小的亚胺培南原料药。
欧洲药典9.0版关于亚胺培南原料药(Imipenem monohydrate)的标准中对有关物质进行了规定，要求杂质A(相对保留时间0.8)不得过1.0％，杂质BI(相对保留时间0.33)不得过0.3％，杂质BII(相对保留时间0.35)不得过0.3％；在溶剂残留方面，中国药典(2015版)Ch.P.四部通则0861第二法要求丙酮和异丙醇≤0.25％；甲醇≤0.5％、二氯甲烷≤0.06％。
由于亚胺培南在水中的溶解度小，现有技术中，通常将亚胺培南粗品溶于一定温度的热水中，然后冷却，最后加入有机溶剂析晶的方式制备亚胺培南原料药，但是亚胺培南热稳定性较差，特别是当其溶解在较高温度的水中时，会加速分解，并产生较多杂质，影响产品质量及收率。
CN1608066A公开了一种制备高纯度亚胺培南的制备方法，其中涉及先将亚胺培南粗品溶解在35～60℃的碳酸氢钠水溶液中，冷却，使用盐酸调节pH值，然后进行活性炭处理，最后使用低级醇或者丙酮结晶的工艺，由于亚胺培南属于β-内酰胺类化合物，对酸碱较为敏感，该工艺需要使用盐酸调节pH值，增加产品降解风险，且工艺复杂，不易控制，不利于工业化生产；再则，该工艺未涉及降低溶剂残留的问题，而溶剂残留的控制是一项必须关注的指标。
CN101891744B公开了一种具有低溶剂残留的高纯度亚胺培南的制备方法，其中涉及将亚胺培南粗品溶解在30～70℃的水中，加入活性炭，迅速冷却，滤除活性炭，最后使用低级醇或者酮结晶的工艺，通过该工艺可以制备得到有机溶剂残留低的亚胺培南，并且采用迅速冷却手段降低产物降解的风险，但通过该工艺制备得到的亚胺培南纯度并不理想，且不涉及控制杂质A、杂质BI以及杂质BII的问题；再则，迅速冷却手段需要的工业条件苛刻，不利于工业化生产。
纳滤技术是指在分子水平上不同粒径分子的混合物在通过纳滤膜时，实现选择性分离的技术。该项技术通过将溶液体系在压力的驱动下，在膜表面发生分离，溶剂和其他小分子溶质通过具有不对称微孔机构的膜，大分子溶 质或颗粒被滤膜截留在膜表面，实现选择性分离。常用作海水淡化、水的软化、选择性分离溶质及醇、糖等的浓缩制备等。
目前，还未见将纳滤技术应用到亚胺培南制备工艺中的报道。如果直接将亚胺培南溶液进行纳滤浓缩，浓缩过程中是否会对含有大量亚胺培南的溶液稳定性产生影响，尚需考察。并且，由于亚胺培南浓度大，体积不能浓缩到很小，否则会有晶体析出造成纳滤膜堵塞，这样就需要再加入大量有机溶剂析晶，很难得到有机溶剂残留低的亚胺培南原料药。
发明内容
本发明的目的是提供一种亚胺培南原料药的制备方法，该方法包括将亚胺培南粗品溶解在较低温度的水中，所得溶液经纳滤浓缩后，加入析晶溶剂析晶，制备亚胺培南原料药。
本发明不涉及将亚胺培南粗品高温溶解步骤，且工艺简单、紧凑、可控，适合工业化生产；同时产品收率高、纯度高、可以有效降低杂质含量和溶剂残留、成本低，具有巨大的经济优势。
本发明的目的通过以下技术方案来实现。
一种亚胺培南原料药的制备方法，所述方法包括以下步骤：
1)将亚胺培南粗品在5～25℃下溶解于水中，得到亚胺培南水溶液；
2)将步骤1)中得到的亚胺培南水溶液经纳滤浓缩，得到亚胺培南水溶液浓缩液；
3)将步骤2)得到的亚胺培南水溶液浓缩液经过活性炭脱色，滤除活性炭，析晶；
4)将步骤3)中析出的晶体经分离、洗涤、干燥，得到亚胺培南原料药。
优选地，步骤1)中，所述亚胺培南粗品中，按归一法，杂质A(相对保留时间0.8)不大于1.0％，杂质BI(相对保留时间0.33)不大于0.8％，杂质BII(相对保留时间0.35)不大于0.8％，杂质总和不大于3.0％；按外标法，以无水物计，含有亚胺培南不应少于94.0％。
优选地，步骤1)中，溶解温度为10～15℃。
优选地，步骤1)中，所述水与亚胺培南粗品的质量比为115～400:1；更优选地，所述水与亚胺培南粗品的质量比为140～165:1。
优选地，步骤2)中，所述亚胺培南水溶液浓缩液与步骤1)所述亚胺培南粗品的质量比为13～50:1；更优选地，浓缩液与步骤1)所述亚胺培南粗品的质量比为20～30:1。
优选地，步骤2)中，所述纳滤浓缩的温度为5～25℃；更优选地，所述纳滤浓缩的温度为5～20℃；进一步优选地，所述纳滤浓缩的温度为10～15℃。
优选地，步骤2)中，所述纳滤浓缩的时间为10分钟～6小时；更优选地，所述纳滤浓缩的时间为1～5小时。
优选地，步骤2)中，所述纳滤浓缩的压力为0.5～2.0Mpa；更优选地，所述纳滤浓缩的压力为0.8～1.0Mpa。
优选地，步骤2)中，所述纳滤浓缩过程中使用的纳滤膜截留分子量范围为100～500；更优选地，所述纳滤浓缩过程中使用的纳滤膜截留分子量范围为300。
优选地，步骤3)中，所述活性炭与步骤1)所述亚胺培南粗品的质量比为0.05～0.35：1；更优选地，所述活性炭与步骤1)所述亚胺培南粗品的质量比为0.1～0.2：1。
优选地，步骤3)中，所述活性炭脱色温度为5～25℃；更优选地，所述活性炭脱色温度为10～15℃。
优选地，步骤3)中，所述析晶温度为-10～20℃；更优选地，所述析晶温度为5～15℃。
优选地，步骤3)中，所述析晶还包括加入析晶溶剂的步骤；
优选地，步骤3)中，所述析晶溶剂选自异丙醇、丙酮和四氢呋喃中的一种或多种；
优选地，步骤3)中，所述析晶溶剂与步骤1)所述亚胺培南粗品的体积质量比为10～100:1；更优选地，所述析晶溶剂与步骤1)所述亚胺培南粗品的体积质量比为25～45:1。
优选地，步骤3)中，所述析晶溶剂加入方式为多次加入或滴加；更优选地，所述析晶溶剂加入方式为滴加。
优选地，步骤3)中，所述析晶溶剂加入时间为0.5～6小时；更优选地，析晶溶剂加入时间为1～3小时。
优选地，步骤4)中，所述分离是将析出的晶体与溶液分离。所述分离可以采用本领域已知的任何常规的分离方法，例如过滤或离心。然后将分离得到的固体洗涤，洗涤溶剂在析晶溶剂范围内选择，例如可以选择异丙醇、丙酮和四氢呋喃中的一种或一种以上的混合物，或者异丙醇、丙酮和四氢呋喃中的一种或一种以上与水的混合液。之后干燥，例如真空干燥，干燥温度为10～40℃，即得到亚胺培南原料药。
根据上述制备方法可得到的亚胺培南原料药中，按归一法，杂质A(相对保留时间0.8)不大于0.8％，杂质BI(相对保留时间0.33)不大于0.1％，杂质BII(相对保留时间0.35)不大于0.1％，杂质总和不大于1.0％；按外标法，以亚胺培南一水合物计，亚胺培南一水合物的含量为98～101％；丙酮和异丙醇的残留总量不超过0.25％，甲醇残留不超过0.3％，二氯甲烷残留不超过0.06％，乙腈残留不超过0.04％，乙酸乙酯残留不超过0.5％，四氢呋喃残留不超过0.07％。
其中，杂质A为
Figure PCTCN2020139223-appb-000002
其中，杂质B为
Figure PCTCN2020139223-appb-000003
BI，BII为杂质B的两个互为对映异构体，欧洲药典9.0版关于亚胺培南原料药(Imipenem monohydrate)的标准中规定，杂质BI的相对保留时间为0.33，杂质BII的相对保留时间为0.35。
与现有技术相比，本发明的有益效果在于：
1)采用本发明所述制备方法制备得到的亚胺培南原料药纯度高、杂质状况清晰、溶剂残留低、质量控制指标能够保证产品有效、安全。
2)本发明所述制备方法，通过将亚胺培南粗品在5～25℃下溶解于水中，然后浓缩，得到高浓度亚胺培南粗品溶液，继而结晶，大大地降低了析晶溶液的使用量，产品收率高，能有效降低杂质含量，溶剂残留低，同时增大产能、减少生产废液的产生，对环境友好，符合现代绿色化工的要求。
3)本发明所述制备方法，可在较低温度下、较短时间内浓缩对热不稳定的亚胺培南溶液，大大降低亚胺培南的分解速度，减少杂质的产生，大大提高了产品质量及收率。
4)本发明所述制备方法，不涉及高温及酸碱调节pH值步骤，工艺简单、紧凑、易于控制，产能高，生产成本低，所得亚胺培南原料药纯度高、溶剂残留低，适用于工业化大规模亚胺培南原料药的生产。
具体实施例方式
以下参照具体的实施例来说明本发明。本领域技术人员能够理解，这些实施例仅用于说明本发明，其不以任何方式限制本发明的范围。
下述实施例中的实验方法，如无特殊说明，均为常规方法。下述实施例中所用的原料、辅料、试剂材料等，如无特殊说明，均为市售购买产品。
所述亚胺培南粗品可以按照实施例1所述方法制备，也可以按照CN1694885A或者现有技术中任何制备亚胺培南的方法制备。
一、亚胺培南粗品的制备
实施例1
Figure PCTCN2020139223-appb-000004
氮气保护，向反应罐中，加入400.0kg二氯甲烷、140.0kg甲醇、5.4kg DIPEA、15.0kg硫霉素对硝基苯甲酯盐酸盐N-甲基吡咯烷酮溶剂合物，搅拌溶解，降温至-20℃，加入9.4kg亚胺苄醚盐酸盐，搅拌反应2h，停止反应，向反应罐加入300.0kg纯化水，搅拌后分相，有机相中加入240.0kg异丙醇，12.0kg N-甲基吗啉，6.6kg浓盐酸，0.9kg 7.5％钯炭，将料液转入氢化釜，在25℃、压力2.0MPa下，氢化60min，加入9.0kg 20％碳酸钠溶液，滤除钯炭，向滤液加入二氯甲烷400.0kg，萃取分相，分出的水相转入结晶罐，加入500.0L丙酮，50.0g晶种，降温至0～5℃养晶1h，加入丙酮1000.0L，控制丙酮加入速度使丙酮在2h加完，养晶1h，过滤，使用50L丙酮洗涤滤饼，真空烘干得到亚胺培南粗品5.92kg，HPLC归一纯度为98.43％，杂质 A含量为0.775％，杂质BI含量为0.287％，杂质BII含量为0.173％，总杂为1.473％；水分7.5％；按外标法，以无水物计，亚胺培南的含量为95.96％；按外标法，一水合物计，亚胺培南一水合物的含量为93.77％。
二、亚胺培南粗品溶解参数选择
实施例2
实验方法：氮气保护，向烧瓶加入200g纯化水，控制水温在指定的温度，将实施例1得到的亚胺培南粗品2g加入烧瓶，搅拌，持续向烧瓶加入纯化水，每次10g，直至溶清，记录溶清时需要的水量及用时，然后检测在该温度下，溶液中亚胺培南的归一含量随时间的变化情况。改变溶解温度，重复实验，具体实验数据见表1。
表1亚胺培南粗品水溶液稳定性试验结果
Figure PCTCN2020139223-appb-000005
从表1数据可以看出，溶解在水中的亚胺培南随着温度的升高分解速度逐渐加快，在亚胺培南粗品水溶液温度为5℃时，放置7小时，亚胺培南的归一含量无明显变化；25℃时，放置6小时，亚胺培南的归一含量稍微降低，放置至7小时，亚胺培南的归一含量明显降低，由97.07％降至96.47％；30℃时，放置6小时，亚胺培南的归一含量降低明显，由98.25％降至93.86％，放置至7小时，亚胺培南的归一含量降低加剧，由93.86％降至88.02％，由此可见，亚胺培南水溶液可在温度5～25℃，0～6小时内保持相对稳定。
再则，从表1数据可以看出，亚胺培南随着温度的升高在水中的溶解度逐渐加大，溶解时长逐渐缩短，当溶解温度为30℃时，只需要105g水就能溶解1g粗品，耗时5分钟；当溶解温度为5℃时，需要225g水才能溶解1g粗品，耗时延长至39分钟，而适当的增加溶剂的量，可有助于降低溶解耗时，综合考虑，在在溶解亚胺培南粗品时，选择溶解温度为5～ 25℃，优选10～15℃；选择水与亚胺培南粗品的质量比为115～400：1，优选140～165：1。
三、纳滤浓缩参数筛选
实施例3纳滤膜筛选
实验方法：氮气保护，向烧瓶加入2800g纯化水，控温15℃，将实施例1得到的亚胺培南粗品20g加入烧瓶，搅拌溶清，得到亚胺培南粗品水溶液，控制浓缩过程中料液温度为10～20℃，浓缩压力控制为0.7Mpa，将亚胺培南粗品水溶液进行纳滤浓缩，当滤脱废水达2020g时，停止浓缩，对收集的浓缩液和滤脱废水进行外标分析，计算亚胺培南一水合物在浓缩液和滤脱废水中的含有量、浓缩液中的回收率，使用不同截留分子量的纳滤膜，其它条件不变，进行实验，实验数据见表2。
表2不同截留分子量纳滤膜对纳滤效果的影响
Figure PCTCN2020139223-appb-000006
从表2数据可以看出，当纳滤膜截留分子量为100～1000时，均可以对亚胺培南粗品水溶液进行有效纳滤浓缩，产品回收率达80％以上；其中当纳滤膜截留分子量为100～500时，产品回收率达90％以上，但是当纳滤膜截留分子量为500时，产品回收率最低；当纳滤膜截留分子量为100时，浓缩时间最长，综合考虑，选择纳滤膜截留分子量为100～500，优选为300。
实施例4纳滤浓缩温度筛选
实验方法：氮气保护，向烧瓶加入2800g纯化水，控温15℃，将实施例1得到的亚胺培南粗品20g加入烧瓶，搅拌溶清，得到亚胺培南粗品水溶液，将溶液温度控制至测试需要温度，纳滤浓缩，纳滤膜截留分子量为300，控制为0.7Mpa，控制浓缩过程中料液温度在测试需要的温度，当收集滤脱废水为2000g时停止浓缩，统计浓缩用时，实验数据见表3。
表3温度对浓缩时间的影响
工作温度 20±2℃ 15±2℃ 10±2℃ 5±2℃
浓缩用时 55min 58min 1h25min 2h5min
从表3数据可以看出，随着纳滤机工作温度的降低，浓缩速度逐渐变慢，综合考虑能耗、亚胺培南稳定性、产能等因素，并结合表1数据，选择纳滤浓缩温度为5～25℃，优选为5～20℃，更优选为10～15℃。
实施例5纳滤浓缩时间筛选
实验方法：氮气保护，向烧瓶加入2800g纯化水，控温15℃，将实施例1得到的亚胺培南粗品20g加入烧瓶，搅拌溶清，得到亚胺培南粗品水溶液，控制浓缩过程中料液温度为10～15℃，浓缩压力控制为0.5～2.0Mpa，纳滤膜截留分子量为300，将亚胺培南粗品水溶液进行纳滤浓缩至滤脱废水达2020g，在浓缩过程中通过调节浓缩压力，使浓缩时长为10分钟～7小时，对收集的浓缩液和滤脱废水进行外标分析，计算亚胺培南一水合物在浓缩液和滤脱废水中的含有量、浓缩液中的回收率，实验数据见表4。
表4不同浓缩时间对纳滤效果的影响
Figure PCTCN2020139223-appb-000007
从表4数据可以看出，通过在浓缩过程中调节浓缩压力控制浓缩时间，随着纳滤时间的延长，亚胺培南的回收率逐渐降低，浓缩至7h时，亚胺培南的回收率明显降低，综合考虑能耗、亚胺培南稳定性、设备的耐受性等因素，并结合表1数据，选择纳滤浓缩时间为10分钟～6小时，优选为1～5小时。
四、亚胺培南原料药的制备
实施例6
氮气保护，向3L烧瓶加入2800g纯化水，控温15℃，将实施例1得到的亚胺培南粗品20g加入烧瓶，搅拌溶清，得到亚胺培南粗品水溶液，纳滤浓缩，纳滤膜截留分子量为300，控制浓缩过程中料液温度为10～15℃，浓缩压力控制为0.8Mpa，浓缩5小时，得滤脱废水2560g，计算此时浓缩液与亚胺培南粗品的质量比为13：1，将浓缩液加入500ml烧瓶，控温15℃，加入活性炭2g，搅拌脱色15min，过滤，滤液降温至5℃，加入适量晶种，搅拌析晶5小时，过滤，使用120ml丙酮洗晶，20～30℃真空干燥得到亚胺培南原料药16.98g，收率84.9％，经HPLC检测，杂质A为0.042％，杂质BI为0.013％，杂质BII为0.008％，总杂为0.079％；按外标法，以亚胺培南一水合物计，亚胺培南一水合物的含量为99.91％，有机溶剂残留未检出。
实施例7
氮气保护，向2L烧瓶加入1650g纯化水，控温10℃，将实施例1得到的亚胺培南粗品10g加入烧瓶，搅拌溶清，得到亚胺培南粗品水溶液，纳滤浓缩，纳滤膜截留分子量为300，控制浓缩过程中料液温度为10～15℃，浓缩压力控制为0.8Mpa，浓缩1.5小时，得滤脱废水1360g，计算此时浓缩液与亚胺培南粗品的质量比为30：1，停止浓缩，将浓缩液加入500ml烧瓶，搅拌控温10℃，加入活性炭2g，搅拌脱色10min，过滤，将滤液转入1L烧瓶，控温15℃，加入100ml丙酮，加入适量晶种，搅拌养晶1h，滴加丙酮350ml，控制滴加速度使丙酮在3h滴加完毕，养晶1h，过滤，60ml丙酮洗晶，20～30℃真空干燥得到亚胺培南原料药8.76g，收率87.6％，经HPLC检测，杂质A为0.143％，杂质BI为0.027％，杂质BII为0.018％，总杂为0.213％；按外标法，以亚胺培南一水合物计，亚胺培南一水合物的含量为99.52％；丙酮残留0.0382％，其它溶剂残留未检出。
实施例8
氮气保护，向2L烧瓶加入1400g纯化水，控温15℃，将实施例1得到的亚胺培南粗品10g加入烧瓶，搅拌溶清，得到亚胺培南粗品水溶液，纳滤浓缩，纳滤膜截留分子量为300，控制浓缩过程中料液温度为10～15℃，浓缩压力控制为1.6Mpa，浓缩1小时，得滤脱废水1210g，计算此时浓缩液与亚胺培南粗品的质量比为20：1，停止浓缩，将浓缩液加入500ml烧瓶，搅 拌将温至10℃，加入活性炭1g，搅拌脱色10min，过滤，将滤液转入1L烧瓶，搅拌将温至5℃，加入100ml丙酮，加入适量晶种，搅拌养晶1h，滴加丙酮150ml，控制滴加速度使丙酮在1h滴加完毕，养晶1h，过滤，60ml丙酮洗晶，20～30℃真空干燥得到亚胺培南原料药8.87g，收率88.7％，经HPLC检测，杂质A为0.208％，杂质BI为0.033％，杂质BII为0.021％，总杂为0.308％；按外标法，以亚胺培南一水合物计，亚胺培南一水合物的含量为99.51％；丙酮残留0.0377％，其它溶剂残留未检出。
实施例9
氮气保护，向1L烧瓶加入650g纯化水，控温20℃，将实施例1得到的亚胺培南粗品5g加入烧瓶，搅拌溶清，得到亚胺培南粗品水溶液，纳滤浓缩，纳滤膜截留分子量为300，控制浓缩过程中料液温度为15～20℃，浓缩压力控制为0.5Mpa，浓缩10分钟，得滤脱废水405g，计算此时浓缩液与亚胺培南粗品的质量比为50：1，停止浓缩，将浓缩液加入500ml烧瓶，搅拌控温25℃，加入活性炭1.0g，搅拌脱色5min，过滤，将滤液转入1L烧瓶，滤液降温至20℃，加入四氢呋喃200ml，加入适量晶种，搅拌养晶0.5h，滴加四氢呋喃300ml，控制滴加速度使四氢呋喃在1h滴加完毕，养晶0.5h，过滤，60ml四氢呋喃洗晶，20～30℃真空干燥得到亚胺培南原料药4.12g，收率82.4％，经HPLC检测，杂质A为0.512％，杂质BI为0.052％，杂质BII为0.036％，总杂为0.696％；按外标法，以亚胺培南一水合物计，亚胺培南一水合物的含量为98.81％；四氢呋喃残留为0.0458％，其它溶剂残留未检出。
实施例10
氮气保护，向2L烧瓶加入1400g纯化水，控温15℃，将实施例1得到的亚胺培南粗品10g加入烧瓶，搅拌溶清，得到亚胺培南粗品水溶液，纳滤浓缩，纳滤膜截留分子量为500，控制浓缩过程中料液温度为20～25℃，浓缩压力控制为0.8Mpa，浓缩1小时，得滤脱废水1160g，计算此时浓缩液与亚胺培南粗品的质量比为25：1，停止浓缩，将浓缩液加入500ml烧瓶，搅拌控温10℃，加入活性炭0.5g，搅拌脱色10min，过滤，将滤液转入1L烧瓶，控温10℃，加入异丙醇50ml，加入适量晶种，搅拌养晶1h，滴加异丙 醇200ml，控制滴加速度使异丙醇在0.5h滴加完毕，养晶1h，过滤，100ml异丙醇洗晶，20～30℃真空干燥得到亚胺培南原料药8.33g，收率83.3％，经HPLC检测，杂质A为0.395％，杂质BI为0.038％，杂质BII为0.021％，总杂为0.542％；按外标法，以亚胺培南一水合物计，亚胺培南一水合物的含量为99.26％；异丙醇残留为0.0769％，其它溶剂残留未检出。
实施例11
氮气保护，向2L烧瓶加入1400g纯化水，控温15℃，将实施例1得到的亚胺培南粗品10g加入烧瓶，搅拌溶清，得到亚胺培南粗品水溶液，纳滤浓缩，纳滤膜截留分子量为300，控制浓缩过程中料液温度为20～25℃，浓缩压力控制为0.7Mpa，浓缩45分钟，得滤脱废水1110g，计算此时浓缩液与亚胺培南粗品的质量比为30：1，停止浓缩，将浓缩液加入500ml烧瓶，搅拌降温至10℃，加入活性炭3.5g，搅拌脱色10min，过滤，将滤液转入1L烧瓶，控温10℃，加入适量晶种，搅拌养晶1h，滴加100ml丙酮、100ml异丙醇和100ml四氢呋喃混合溶液，控制滴加速度使混合溶液在3h滴加完毕，养晶1h，过滤，100ml丙酮洗晶，20～30℃真空干燥得到亚胺培南原料药8.17g，收率81.7％，经HPLC检测，杂质A为0.435％，杂质BI为0.048％，杂质BII为0.033％，总杂为0.674％；按外标法，以亚胺培南一水合物计，亚胺培南一水合物的含量为98.96％；丙酮残留为0.0280％，异丙醇残留为0.0521％，四氢呋喃残留为0.0265％，其它溶剂残留未检出。
实施例12
氮气保护，向5L烧瓶加入4000g纯化水，控温5℃，将实施例1得到的亚胺培南粗品10g加入烧瓶，搅拌溶清，得到亚胺培南粗品水溶液，纳滤浓缩，纳滤膜截留分子量为300，控制浓缩过程中料液温度为5～10℃，浓缩压力控制为2.0Mpa，浓缩6小时，得滤脱废水3510g，计算此时浓缩液与亚胺培南粗品的质量比为50：1，停止浓缩，将浓缩液加入1L烧瓶，搅拌控温5℃，加入活性炭2g，搅拌脱色10min，过滤，将滤液转入2L烧瓶，控温5℃，加入适量晶种，搅拌养晶1h，滴加丙酮600ml，控制滴加速度使丙酮在6h滴加完毕，养晶1h，过滤，60ml丙酮洗晶，20～30℃真空干燥得到亚胺培南原料药8.05g，收率80.5％，经HPLC检测，杂质A为0.127％，杂 质BI为0.015％，杂质BII为0.013％，总杂为0.183％；按外标法，以亚胺培南一水合物计，亚胺培南一水合物的含量为99.71％；丙酮残留0.0225％，其它溶剂残留未检出。
实施例13
氮气保护，向2L烧瓶加入1150g纯化水，控温25℃，将实施例1得到的亚胺培南粗品10g加入烧瓶，搅拌溶清，得到亚胺培南粗品水溶液，纳滤浓缩，纳滤膜截留分子量为100，控制浓缩过程中料液温度为20～25℃，浓缩压力控制为1.0Mpa，浓缩1小时，得滤脱废水960g，计算此时浓缩液与亚胺培南粗品的质量比为20：1，停止浓缩，将浓缩液加入1L烧瓶，搅拌控温25℃，加入活性炭1g，搅拌脱色10min，过滤，将滤液转入2L烧瓶，控温5℃，加入适量晶种，滴加丙酮300ml，控制滴加速度使丙酮在1h滴加完毕，降温至-10℃，滴加丙酮300ml，控制滴加速度使丙酮在1h滴加完毕，-10℃下养晶1h，过滤，60ml丙酮洗晶，20～30℃真空干燥得到亚胺培南原料药8.46g，收率84.6％，经HPLC检测，杂质A为0.641％，杂质BI为0.031％，杂质BII为0.027％，总杂为0.817％；按外标法，以亚胺培南一水合物计，亚胺培南一水合物的含量为98.83％；丙酮残留0.0537％，其它溶解残留未检出。
实施例14
氮气保护，向2L烧瓶加入4000g纯化水，控温5℃，将实施例1得到的亚胺培南粗品10g加入烧瓶，搅拌溶清，得到亚胺培南粗品水溶液，纳滤浓缩，纳滤膜截留分子量为100，控制浓缩过程中料液温度为10～15℃，浓缩压力控制为2.0Mpa，浓缩6小时，得滤脱废水3880g，计算此时浓缩液与亚胺培南粗品的质量比为13：1，停止浓缩，将浓缩液加入500ml烧瓶，搅拌控温10℃，加入活性炭2g，搅拌脱色10min，过滤，将滤液转入1L烧瓶，加入100ml丙酮，降温至-10℃，加入适量晶种，控温-10℃，搅拌养晶1h，滴加丙酮350ml，控制滴加速度使丙酮在3h滴加完毕，养晶1h，过滤，60ml丙酮洗晶，20～30℃真空干燥得到亚胺培南原料药8.34g，收率83.4％，经HPLC检测，杂质A为0.661％，杂质BI为0.035％，杂质BII为0.028％，总杂为0.822％；按外标法，以亚胺培南一水合物计，亚胺培南一水合物的 含量为98.77％；丙酮残留0.0388％，其它溶解残留未检出。
实施例15
氮气保护，向2L烧瓶加入900g纯化水，控温25℃，将实施例1得到的亚胺培南粗品10g加入烧瓶，搅拌溶清，得到亚胺培南粗品水溶液，纳滤浓缩，纳滤膜截留分子量为300，控制浓缩过程中料液温度为20～25℃，浓缩压力控制为1.0Mpa，浓缩1小时，得滤脱废水710g，计算此时浓缩液与亚胺培南粗品的质量比为20：1，停止浓缩，将浓缩液加入500ml烧瓶，搅拌控温25℃，加入活性炭2g，搅拌脱色10min，过滤，将滤液转入1L烧瓶，加入100ml丙酮，控温20℃，加入适量晶种，搅拌养晶1h，滴加丙酮350ml，控制滴加速度使丙酮在0.5h滴加完毕，养晶3h，过滤，60ml丙酮洗晶，20～30℃真空干燥得到亚胺培南原料药8.37g，收率83.7％，经HPLC检测，杂质A为0.671％，杂质BI为0.039％，杂质BII为0.031％，总杂为0.829％；按外标法，以亚胺培南一水合物计，亚胺培南一水合物的含量为98.75％；丙酮残留0.0372％，其它溶解残留未检出。
实施例16
氮气保护，向1000L反应釜中加入700kg纯化水，控温15℃，加入实施例1得到的亚胺培南粗品5.0kg，搅拌30min，纳滤浓缩，纳滤膜截留分子量为300，控制浓缩过程中料液温度为10～15℃，浓缩压力控制为1.0Mpa，浓缩1小时，得滤脱废水605kg，停止浓缩，将浓缩液加入200L反应釜中，控温至10℃，加入活性炭0.5kg，搅拌10min，过滤，将滤液转入1L结晶釜，搅拌降温至5℃，加入50L丙酮，加入10g晶种，搅拌养晶1h，滴加75L丙酮，控制滴加速度使丙酮在1h滴加完毕，搅拌养晶1h，过滤，20L丙酮洗涤滤饼，20～30℃真空干燥得到亚胺培南原料药4.53kg，收率90.6％，经HPLC检测，杂质A为0.179％，杂质BI为0.031％，杂质BII为0.017％，总杂为0.237％；按外标法，以亚胺培南一水合物计，亚胺培南一水合物的含量为99.85％；丙酮残留0.0297％，其它溶剂残留未检出。
实施例17
按实施例1所述方法制备得到亚胺培南粗品6.12kg，HPLC归一纯度为 97.1％，杂质A含量为0.993％，杂质BI含量为0.753％，杂质BII含量为0.401％，总杂为2.896％；水分6.9％；按外标法，以无水物计，亚胺培南的含量为94.23％；按外标法，一水合物计，亚胺培南一水合物的含量为92.57％。
氮气保护，向1000L反应釜中加入825kg纯化水，控温10℃，加入亚胺培南粗品5.0kg，搅拌30分钟，纳滤浓缩，纳滤膜截留分子量为300，控制浓缩过程中料液温度为10～15℃，浓缩压力控制为0.8Mpa，浓缩1.5小时，得滤脱废水1360g，停止浓缩，将浓缩液加入200L反应釜，搅拌控温15℃，加入活性炭1.0kg，搅拌10min，过滤，将滤液转入500L结晶釜，控温15℃，加入50L丙酮，加入10g晶种，搅拌养晶1h，滴加175L丙酮，控制滴加速度使丙酮在3h滴加完毕，搅拌养晶1h，过滤，20L丙酮洗涤滤饼，20～30℃真空干燥得到亚胺培南原料药4.16kg，收率83.2％，经HPLC检测，杂质A为0.188％，杂质BI为0.037％，杂质BII为0.021％，总杂为0.257％；按外标法，以亚胺培南一水合物计，亚胺培南一水合物的含量为99.42％；丙酮残留0.0353％，其它溶剂残留未检出。
对比例1
氮气保护，向250ml烧瓶加入175g纯化水，加热至58℃，将实施例1得到的亚胺培南粗品5g加入烧瓶，搅拌溶解，迅速降温至10℃，加入活性炭2g，搅拌脱色10min，过滤，将滤液转入1L烧瓶，控温10℃，加入晶种，搅拌养晶1h，滴加丙酮175ml，控制滴加速度使丙酮在2h滴完，养晶1h，过滤，60ml丙酮洗晶，20～30℃真空干燥得到亚胺培南原料药3.62g，收率72.4％，经HPLC检测，杂质A为0.640％；杂质BI为0.250％；杂质BII为0.163％，总杂为1.212％；按外标法，以亚胺培南一水合物计，亚胺培南一水合物的含量为97.95％；丙酮残留为0.0391％，其它溶剂残留未检出。
对比例2
氮气保护，向250ml烧瓶加入230g纯化水，控温25℃，将实施例1得到的亚胺培南粗品2g加入烧瓶，搅拌溶解，加入活性炭0.3g，搅拌脱色10min，过滤，将滤液转入2L烧瓶，控温5～10℃，加入丙酮230ml，加入晶种，搅拌养晶1h，滴加丙酮690ml，2个小时滴加完毕，养晶4h，过滤，10ml丙酮洗晶，20～30℃真空干燥得到亚胺培南原料药0.13g，收率6.5％，经HPLC 检测，杂质A为0.043％，杂质BI为0.007％，杂质BII为0.006％，总杂为0.068％，溶剂残留未检出。
对比例3
氮气保护，向2L烧瓶加入900g纯化水，控温25℃，将实施例1得到的亚胺培南粗品10g加入烧瓶，搅拌溶清，得到亚胺培南粗品水溶液，纳滤浓缩，纳滤膜截留分子量为300，控制浓缩过程中料液温度为10～25℃，浓缩压力控制为2.0Mpa，浓缩至得滤脱废水820g，计算此时浓缩液与亚胺培南粗品的质量比为9:1，停止浓缩，将浓缩液加入500ml烧瓶，搅拌控温25℃，加入活性炭2g，搅拌脱色10min，过滤，将滤液转入1L烧瓶，加入100ml丙酮，控温20℃，加入适量晶种，搅拌养晶1h，滴加丙酮350ml，控制滴加速度使丙酮在0.5h滴加完毕，养晶3h，过滤，60ml丙酮洗晶，20～30℃真空干燥得到亚胺培南原料药5.13g，收率51.3％，经HPLC检测，杂质A为0.661％，杂质BI为0.043％，杂质BII为0.035％，总杂为0.849％；按外标法，以亚胺培南一水合物计，亚胺培南一水合物的含量为98.55％；丙酮残留0.0354％，其它溶剂残留未检出。
对比例4
氮气保护，向2L烧瓶加入4500g纯化水，控温25℃，将实施例1得到的亚胺培南粗品10g加入烧瓶，搅拌溶清，得到亚胺培南粗品水溶液，纳滤浓缩，纳滤膜截留分子量为100，控制浓缩过程中料液温度为20～25℃，浓缩压力控制为2.0Mpa，浓缩7小时，得滤脱废水4380g，计算此时浓缩液与亚胺培南粗品的质量比为13：1，停止浓缩，将浓缩液加入500ml烧瓶，搅拌控温25℃，加入活性炭2g，搅拌脱色10min，过滤，将滤液转入1L烧瓶，加入100ml丙酮，在25℃加入适量晶种，控温25℃，搅拌养晶1h，滴加丙酮350ml，控制滴加速度使丙酮在3h滴加完毕，养晶1h，过滤，60ml丙酮洗晶，20～30℃真空干燥得到亚胺培南原料药7.42g，收率74.2％，经HPLC检测，杂质A为0.678％，杂质BI为0.214％，杂质BII为0.113％，总杂为1.198％；按外标法，以亚胺培南一水合物计，亚胺培南一水合物的含量为98.01％；丙酮残留0.0397％，其它溶解残留未检出。
由以上实施例可以看出，本发明所述亚胺培南原料药的制备方法，工艺简单，易于控制，有效降低了各种杂质的含量，制备得到的亚胺培南原料药 纯度高，总杂不大于1.0％，其中杂质A不大于0.8％，杂质BI及BII均不大于0.1％；对比例1使用58℃的热水溶解粗品，迅速降温，经活性炭处理后，加入大量丙酮析晶，制备得到的产品纯度不高，不能有效降低各种杂质的含量，总杂为1.212％，其中杂质BI为0.250％，杂质BII为0.163％；对比例2使用25℃的水溶解粗品，经活性炭处理后，加入大量丙酮析晶，产物收率极低，只有6.5％；对比例3使用25℃的水溶解粗品，然后纳滤浓缩，所述亚胺培南水溶液浓缩液与步骤1)所述亚胺培南粗品的质量比为9:1，经活性炭处理后，加入丙酮析晶，产物收率极低，只有51.3％；对比例4纳滤浓缩时间7个小时，产物纯度及收率均不理想。
综上所述，本发明所述制备方法，通过低温溶解粗品，采用纳滤浓缩得到高浓度溶液，继而结晶，大大地降低了析晶溶液的使用量，工艺简单、紧凑，易于控制，适合工业化生产；本发明所述制备方法可有效降低各种杂质的含量，制备得到的产品收率高、纯度高、杂质状况清晰、溶残低，质量控制指标能够保证产品有效、安全，具有巨大的经济优势，适于广泛推广。
以上所述是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明所述原理的前提下，还可以作出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (13)

  1. 一种亚胺培南原料药的制备方法，所述方法包括以下步骤：
    1)将亚胺培南粗品在5～25℃下溶解于水中，得到亚胺培南水溶液；
    2)将步骤1)中得到的亚胺培南水溶液经纳滤浓缩，得到亚胺培南水溶液浓缩液；
    3)将步骤2)得到的亚胺培南水溶液浓缩液经过活性炭脱色，滤除活性炭，析晶；
    4)将步骤3)中析出的晶体经分离、洗涤、干燥得到亚胺培南原料药。
  2. 根据权利要求1所述的制备方法，其特征在于，步骤1)中，溶解温度为10～15℃。
  3. 根据权利要求1或2所述的制备方法，其特征在于，步骤1)中，所述水与亚胺培南粗品的质量比为115～400:1，优选为140～165:1。
  4. 根据权利要求1至3中任一项所述的制备方法，其特征在于，步骤2)中，所述亚胺培南水溶液浓缩液与步骤1)所述亚胺培南粗品的质量比为13～50:1，优选为20～30:1。
  5. 根据权利要求1至4中任一项所述的制备方法，其特征在于，步骤2)中，所述纳滤浓缩的温度为5～25℃，优选为5～20℃，更优选为10～15℃；
    优选地，步骤2)中，所述纳滤浓缩的时间为10分钟～6小时，优选为1～5小时；
    优选地，步骤2)中，所述纳滤浓缩的压力为0.5～2.0Mpa，优选为0.8～1.0Mpa；
    优选地，步骤2)中，所述纳滤浓缩使用的纳滤膜的截留分子量为100～500，优选为300。
  6. 根据权利要求1至5中任一项所述的制备方法，其特征在于，步骤3)中，所述活性炭与步骤1)所述亚胺培南粗品的质量比为0.05～0.35：1，优选为0.1～0.2：1；
    优选地，步骤3)中，所述活性炭脱色的温度为5～25℃，优选为10～15℃。
  7. 根据权利要求1至6中任一项所述的制备方法，其特征在于，步骤3)中，所述析晶的温度为-10～20℃，优选为5～15℃。
  8. 根据权利要求1至7中任一项所述的制备方法，步骤1)中，所述亚 胺培南粗品中，按归一法，杂质A不大于1.0％，杂质BI不大于0.8％，杂质BII不大于0.8％，杂质总和不大于3.0％；按外标法，以无水物计，含有亚胺培南不应少于94％。
  9. 根据权利要求1至8中任一项所述的制备方法，其特征在于，步骤3)中，所述析晶包括加入析晶溶剂的步骤；
    优选地，所述析晶溶剂选自异丙醇、丙酮和四氢呋喃中的一种或多种；
    优选地，所述析晶溶剂与步骤1)所述亚胺培南粗品的体积质量比为10～100:1，优选为25～45:1；
    优选地，所述析晶溶剂的加入方式为多次加入或滴加，优选为滴加。
  10. 根据权利要求9所述的制备方法，所述析晶溶剂的加入时长为0.5～6小时，优选为1～3小时。
  11. 一种亚胺培南原料药的制备方法，所述方法包括以下步骤：
    1)将亚胺培南粗品在5～25℃下溶解于水中，得到亚胺培南水溶液；
    2)将步骤1)中得到的亚胺培南水溶液经纳滤浓缩，得到亚胺培南水溶液浓缩液；
    3)将步骤2)得到的亚胺培南水溶液浓缩液经过活性炭脱色，滤除活性炭，析晶；
    4)将步骤3)中析出的晶体经分离、洗涤、干燥得到亚胺培南原料药；
    步骤1)中，所述水与亚胺培南粗品的质量比为115～400:1；所述亚胺培南粗品中，按归一法，杂质A不大于1.0％，杂质BI不大于0.8％，杂质BII不大于0.8％，杂质总和不大于3.0％；按外标法，以无水物计，含有亚胺培南不应少于94％；
    步骤2)中，所述亚胺培南水溶液浓缩液与步骤1)所述亚胺培南粗品的质量比为13～50:1；所述纳滤浓缩的温度为5～25℃，时间为10分钟～6小时，压力为0.5～2.0Mpa，纳滤膜的截留分子量为100～500；
    步骤3)中，所述活性炭与步骤1)所述亚胺培南粗品的质量比为0.05～0.35：1；所述活性炭脱色的温度为5～25℃，所述析晶的温度为-10～20℃。
  12. 一种亚胺培南原料药的制备方法，所述方法包括以下步骤：
    1)将亚胺培南粗品在10～15℃下溶解于水中，得到亚胺培南水溶液；
    2)将步骤1)中得到的亚胺培南水溶液经纳滤浓缩，得到亚胺培南水溶液浓缩液；
    3)将步骤2)得到的亚胺培南水溶液浓缩液经过活性炭脱色，滤除活性 炭，析晶；
    4)将步骤3)中析出的晶体经分离、洗涤、干燥得到亚胺培南原料药；
    步骤1)中，所述水与亚胺培南粗品的质量比为140～165:1；所述亚胺培南粗品中，按归一法，杂质A不大于1.0％，杂质BI不大于0.8％，杂质BII不大于0.8％，杂质总和不大于3.0％；按外标法，以无水物计，含有亚胺培南不应少于94％；
    步骤2)中，所述亚胺培南水溶液浓缩液与步骤1)所述亚胺培南粗品的质量比为20～30:1；所述纳滤浓缩的温度为5～20℃，时间为1～5小时，压力为0.8～2.0Mpa，纳滤膜的截留分子量为300；
    步骤3)中，所述活性炭与步骤1)所述亚胺培南粗品的质量比为0.1～0.2：1；所述活性炭脱色的温度为10～15℃，所述析晶的温度为5～15℃。
  13. 根据权利要求11或12所述的制备方法，其特征在于，步骤3)中，所述析晶包括加入析晶溶剂的步骤；所述析晶溶剂选自异丙醇、丙酮和四氢呋喃中的一种或多种；所述析晶溶剂与步骤1)所述亚胺培南粗品的体积质量比为10～100:1；所述析晶溶剂的加入方式为多次加入或滴加，加入时长为0.5～6小时。
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