WO2022036975A1 - Preparation method for biapenem active ingredient - Google Patents

Preparation method for biapenem active ingredient Download PDF

Info

Publication number
WO2022036975A1
WO2022036975A1 PCT/CN2020/139134 CN2020139134W WO2022036975A1 WO 2022036975 A1 WO2022036975 A1 WO 2022036975A1 CN 2020139134 W CN2020139134 W CN 2020139134W WO 2022036975 A1 WO2022036975 A1 WO 2022036975A1
Authority
WO
WIPO (PCT)
Prior art keywords
biapenem
acetone
ethanol
minutes
filtrate
Prior art date
Application number
PCT/CN2020/139134
Other languages
French (fr)
Chinese (zh)
Inventor
罗文军
林楠棋
王东
胡金军
汪小华
郑春莲
欧军
周月广
黄锦钿
龙利松
Original Assignee
深圳市海滨制药有限公司
新乡海滨药业有限公司
健康元海滨药业有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 深圳市海滨制药有限公司, 新乡海滨药业有限公司, 健康元海滨药业有限公司 filed Critical 深圳市海滨制药有限公司
Publication of WO2022036975A1 publication Critical patent/WO2022036975A1/en

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C07D519/06—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 containing at least one condensed beta-lactam ring system, provided for by groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00, e.g. a penem or a cepham system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the invention belongs to the field of pharmacy, and in particular relates to a preparation method of a biapenem crude drug.
  • Biapenem (Biapenem), chemical name: (-)6-[[(4R,5S,6S)-2-carboxy-6-[(1R)-1-hydroxyethyl]-4-methyl- 7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]thio]-6,7-dihydro-5H-pyrazole[1,2-a][1,2 ,4]
  • Triazole-4-onium inner salt is a carbapenem antibiotic with a broad antibacterial spectrum and strong antibacterial activity. Compared with other marketed carbapenems, biapenem has almost zero nephrotoxicity, can be administered alone, has no central nervous system toxicity, and does not induce epileptic seizures. It is widely used in biapenem clinically. Acute and chronic infections caused by susceptible gram-negative aerobes, gram-positive aerobes and anaerobic bacteria. The specific chemical structural formula of biapenem is shown in formula (I):
  • biapenem and the solubility of biapenem during reconstitution are the main problems in its clinical application. Poor stability can easily lead to the degradation of active ingredients during storage and preparation; poor solubility can easily lead to foreign matter and insolubility when the drug is reconstituted. Microparticles, which cause a variety of adverse reactions, there are great potential drug safety hazards.
  • Chinese patent CN102268024B discloses a crystallization method of biapenem, firstly dissolving the crude biapenem in water, then adding acetone for crystallization, to prepare the biapenem bulk drug in crystal form.
  • CN102584862B discloses another crystallization method of biapenem, firstly dissolving crude biapenem in water, first adding ethanol under heating, then adding isopropanol dropwise at a specific speed, and then cooperating with a gradient cooling method to prepare a special biapenem Biapenem drug substance in crystalline form.
  • the product prepared by the above method has large crystal particles and poor water solubility, and further mechanical pulverization is required to obtain the biapenem bulk drug with good water solubility, short reconstitution time and suitable medical use.
  • the additional mechanical pulverization step will lead to inevitable product loss and increase the production cost; in addition, during the mechanical pulverization process, the particle size of the product is difficult to control, which may lead to excessively fine particles of the product, or uneven particle size distribution, It cannot fundamentally solve the problem of poor water solubility.
  • the object of the present invention is to provide a method for preparing a biapenem crude drug, which comprises dissolving a crude biapenem product in water, and after cooling down, adding an aqueous solution of the crude biapenem product to an organic solvent for crystallization, to prepare The biapenem raw material is obtained.
  • the process of the invention is simple, compact, controllable, and does not require an additional mechanical pulverization process, and the preparation of the crude drug of Apenem has high yield, high purity, moderate crystal particles, uniform particle size distribution, good water solubility, and good stability. It has good fluidity, is suitable for medical use, and has mild production conditions, which is conducive to industrial packaging and storage, and has huge economic potential.
  • the present invention provides a kind of preparation method of biapenem bulk drug, described method comprises the following steps:
  • the biapenem crude product is dissolved in water to prepare an aqueous solution of the biapenem crude product;
  • step 2) the temperature of the aqueous solution of the biapenem crude product obtained in step 1) is controlled to be T 1 or cooled to T 2 , activated carbon is added, stirred for decolorization, filtered, and the filtrate is cooled to T 3 for subsequent use;
  • step 3 adding the filtrate obtained in step 2) dropwise to the mixed solvent of acetone and ethanol cooled to T 4 in advance, and crystallizing;
  • step 5) Separating, washing and drying the crystals obtained in step 4) to obtain the biapenem bulk drug.
  • the T 1 is 20-80°C, more preferably 20-30°C, further preferably 20°C or 30°C;
  • the mass ratio of the crude biapenem to water is 1:20-80, more preferably 1:30-70, further preferably 1:45;
  • the T 2 is 15-35°C, more preferably 20-30°C, further preferably 20°C or 30°C;
  • the mass ratio of the activated carbon to the crude biapenem described in step 1) is 0.05-0.25:1, more preferably 0.05-0.1:1, more preferably 0.1:1 ;
  • the decolorization time is 5-30 minutes, more preferably 10 minutes;
  • the T 3 is 0-20°C, more preferably 5-10°C, further preferably 5°C or 10°C;
  • the volume ratio of the mixed solvent of acetone and ethanol to the water in step 1) is 0.5-3:1, more preferably 1:1;
  • the volume ratio of the acetone to ethanol is 95-50:5-50, more preferably 85:15;
  • the T 4 is 0-20°C, more preferably 10-15°C, still more preferably 10°C or 15°C;
  • the dripping method is continuous dripping or batchwise dripping
  • the dripping method is continuous dripping, and the dripping time is not less than 1.5 hours; or
  • the dripping method is batchwise dripping
  • the dropwise addition is to drop the filtrate obtained in step 2) into the mixed solvent of acetone and ethanol twice, wherein the filtrate added dropwise for the first time is the same as the water in step 1).
  • the volume ratio is 0.01-0.1:1, more preferably 0.04:1;
  • the dropwise addition is to drop the filtrate obtained in step 2) into the mixed solvent of acetone and ethanol twice, wherein, after the first dropwise addition is completed, stirring for 30 - 120 minutes, more preferably stirring for 60 minutes;
  • the dropwise addition is to drop the filtrate obtained in step 2) into the mixed solvent of acetone and ethanol twice, wherein the time for the second dropwise addition is 0.5- 3 hours, more preferably 1-1.5 hours, further preferably 1 hour or 1.5 hours;
  • the temperature of the crystallization is 0-20°C, more preferably 15-20°C, further preferably 15°C or 20°C;
  • the crystallization time is 30 minutes
  • the temperature of the crystal growing is 0-20°C, more preferably 7-12°C, further preferably 7°C or 12°C;
  • the time for growing crystals is 0.5-6 hours, more preferably 1.5 hours;
  • the separation is to separate the crystal obtained by growing the crystal from the solution.
  • the separation can be carried out using any conventional separation method known in the art, such as filtration or centrifugation.
  • the washing can be carried out with one of acetone and ethanol or a mixture thereof; further preferably, the washing can be carried out with acetone or ethanol.
  • the drying is vacuum drying at 40-50°C.
  • the D50 of the obtained biapenem drug substance is 20 ⁇ m-31 ⁇ m, more preferably 27 ⁇ m-29 ⁇ m.
  • the angle of repose of the obtained biapenem drug substance is 30°-40°, more preferably 31°-33°.
  • the reconstitution time of the obtained biapenem drug substance is not more than 60s, more preferably 30s-50s, further preferably 44s-45s.
  • the present invention also provides the biapenem raw material prepared by the above method.
  • the content of biapenem is not less than 99.5%
  • the impurity A is not more than 0.2%
  • the impurity B is not more than 0.05%.
  • the biapenem bulk drug is a crystal; more preferably, using Cu-K ⁇ radiation, the X-ray powder diffraction pattern of the biapenem bulk drug crystal at the diffraction angle 2 ⁇ is 15.54 ⁇ 0.1°, There are diffraction peaks at 16.17 ⁇ 0.1°, 20.11 ⁇ 0.1°, 20.61 ⁇ 0.1°, 22.05 ⁇ 0.1°, and 27.10 ⁇ 0.1°.
  • the D50 of the biapenem bulk drug crystal is 20 ⁇ m-31 ⁇ m, more preferably 27 ⁇ m-29 ⁇ m.
  • the angle of repose of the biapenem bulk drug crystal is 30°-40°, more preferably 31°-33°.
  • the reconstitution time of the biapenem bulk drug crystal is not more than 60s, more preferably 30s-50s, further preferably 44s-45s.
  • the present invention provides the use of the biapenem bulk drug prepared by the above-mentioned method for the treatment of acute and chronic infections caused by Gram-negative aerobic bacteria, Gram-positive aerobic bacteria and anaerobic bacteria.
  • the content of biapenem is not less than 99.5%
  • the impurity A is not more than 0.2%
  • the impurity B is not more than 0.05%
  • the reconstitution time is not more than 60% Second.
  • impurity A is
  • impurity B is
  • Impurities in drugs including exogenous impurities and drug degradation impurities, the existence of impurities will reduce the efficacy of drugs, affect the stability of drugs, and even cause various adverse reactions.
  • the ICH guidelines have strict regulations on impurities. For example, when the maximum daily dose specified in Q3A is less than or equal to 2g, the defined limit of impurities is 0.15%; when the maximum daily dose specified in Q3B is greater than 10mg-2g, the defined limit of degradation products is 0.2%.
  • the maximum daily adult dose of biapenem is 600 mg with no more than 0.2% drug degradation products.
  • Impurity A of biapenem API is a degradation product
  • impurity B is a ring-opening degradation product.
  • Impurities such as degradation products, acid hydrolysis products, and polymers in carbapenem antibiotics are the main causes of adverse drug reactions.
  • "National Adverse Drug Reaction Monitoring Annual Report (2018)” shows that in the serious adverse drug reaction/event reports of chemical drugs, anti-infective drugs account for 33.3%. Therefore, it is necessary to maximize the control of impurities in biapenem APIs. content, in order to effectively ensure the safety of people's medication.
  • the beneficial effects of the present invention at least include the following aspects:
  • the bisabenem raw material prepared by the preparation method of the present invention has high purity, clear impurity status and good stability, and can ensure the product is effective and safe.
  • the bisabenem bulk drug crystal particle prepared by the preparation method of the present invention is moderate, the particle size distribution is uniform, the water solubility is good, the reconstitution time is short, and is more suitable for medical use.
  • Apenem crude drug prepared by the preparation method of the present invention has good fluidity, which is beneficial to industrial sub-packaging and storage.
  • the preparation method of the present invention is simple, compact, easy to control, suitable for industrial application, and has huge economic potential.
  • Example 1 is a particle size distribution diagram of the biapenem bulk drug prepared in Example 2.
  • Example 2 is a particle size distribution diagram of the biapenem bulk drug prepared in Example 3.
  • Example 3 is a particle size distribution diagram of the biapenem bulk drug prepared in Example 4.
  • Example 4 is a particle size distribution diagram of the biapenem bulk drug prepared in Example 5.
  • Example 5 is a particle size distribution diagram of the biapenem bulk drug prepared in Example 6.
  • Example 6 is a particle size distribution diagram of the biapenem bulk drug prepared in Example 7.
  • Example 7 is a particle size distribution diagram of the biapenem bulk drug prepared in Example 8.
  • FIG. 8 is a particle size distribution diagram of the biapenem bulk drug prepared in Example 9.
  • FIG. 8 is a particle size distribution diagram of the biapenem bulk drug prepared in Example 9.
  • Figure 10 is a particle size distribution diagram of the biapenem bulk drug prepared in Comparative Example 2.
  • Figure 11 is a particle size distribution diagram of the biapenem bulk drug prepared in Comparative Example 3.
  • Figure 12 is a particle size distribution diagram of the biapenem bulk drug prepared in Comparative Example 4.
  • Figure 13 is a particle size distribution diagram of the biapenem bulk drug prepared in Comparative Example 5.
  • Figure 14 is a particle size distribution diagram of the biapenem bulk drug prepared in Comparative Example 6.
  • Figure 16 is a particle size distribution diagram of the biapenem bulk drug prepared in Comparative Example 8.
  • Example 17 is the X-ray powder diffraction pattern of the biapenem bulk drug prepared in Example 2.
  • the crude biapenem is prepared according to the method described in Example 1, and can also be prepared according to CN104829633A or any method for preparing biapenem in the prior art.
  • the purity of the biapenem crude product and the raw drug is detected according to the method described in CN109946396A.
  • the detection equipment used for the particle size of the biapenem bulk drug is a laser diffraction particle size analyzer.
  • the detection process is as follows: take an appropriate amount of the sample and place it in the sample tube of the laser diffraction particle size analyzer, so that the powder is just immersed in the concave surface of the sample tube, place the sample tube in the particle size analyzer, and measure the particle size of the sample according to the dry method.
  • the detection equipment used for the angle of repose of the biapenem API is an intelligent powder property tester.
  • the detection process is as follows: take an appropriate amount of the sample, set the feeding speed to 4, set the feeding time to 60 seconds, and record the results.
  • the reconstitution time detection process is as follows: weigh 0.3 g of the biapenem API, add 20 ml of purified aqueous solution (23 ⁇ 1°C), and shake at 200-210 times/min (the shaking range is 12-15 cm) for 15 seconds, rest for 5 seconds, observe the dissolution of the sample, if there is insoluble matter, repeat the above operation until the sample is completely dissolved, record the result, and the rest time is not included.
  • the detection equipment used in the X-ray diffraction detection (XRD) of the biapenem bulk drug is BTX.
  • the detection process is: set CukaPeak: 450, XRFBins: 1500, stepSize: 0.04, low Angle: 0, highAngle: 54, and the data collection time is about 20-30min.
  • HPLC normalization method The detected purity is: 96.3%, impurity A is
  • the X-ray powder diffraction pattern of the biapenem bulk drug crystal prepared in this example is similar to that in Example 2.
  • the X-ray powder diffraction pattern of the biapenem bulk drug crystal prepared in this example is similar to that in Example 2.
  • the X-ray powder diffraction pattern of the biapenem bulk drug crystal prepared in this example is similar to that in Example 2.
  • the X-ray powder diffraction pattern of the biapenem bulk drug crystal prepared in this example is similar to that in Example 2.
  • the X-ray powder diffraction pattern of the biapenem bulk drug crystal prepared in this example is similar to that in Example 2.
  • the X-ray powder diffraction pattern of the biapenem bulk drug crystal prepared in this example is similar to that in Example 2.
  • the X-ray powder diffraction pattern of the biapenem bulk drug crystal prepared in this example is similar to that in Example 2.
  • Comparative Example 4 the preparation of Comparative Example 3
  • the obtained biapenem was mechanically powdered, and the loss was serious, the yield was only 84.6%, the product particle was large (D50 was 43.41 ⁇ m), and the reconstitution time was more than 2 minutes
  • the angles of repose ( ⁇ ) are 58°, 45°, and 51° respectively; in Examples 2 to 9, the prepared biapenem particles are moderate, the particle size distribution (D50) is between 20 and 31 ⁇ m, the fluidity is good, and the The angle ( ⁇ ) is between 30 and 40°, and the reconstitution time is short, all less than 60 seconds.
  • Stability detection is carried out to the biapenem product that above-mentioned example and comparative example are obtained, and detection result is as shown in table 3 below:
  • the bisabenem raw material prepared by the preparation method of the present invention has high purity, clear impurity status and good stability, which can ensure the product is effective and safe; the product crystal particles are moderate, and the particle size distribution is uniform. It has good water solubility, short reconstitution time and good fluidity, and is suitable for medical use and industrial packaging and storage; the process is simple, compact and easy to control, suitable for industrial application and has huge economic potential.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Cephalosporin Compounds (AREA)

Abstract

A preparation method for a biapenem active ingredient, comprising: 1) dissolving crude biapenem in water to prepare an aqueous solution; 2) adding activated carbon, stirring for decolorization, filtering, and cooling the filtrate for use; 3) adding the filtrate dropwise in a pre-cooled mixed solvent of acetone and ethanol, and crystallizing; 4) growing crystals; and 5) separating, washing, and drying the precipitated crystals to obtain a biapenem active ingredient.

Description

一种比阿培南原料药的制备方法A kind of preparation method of biapenem crude drug
相关申请的交叉引用CROSS-REFERENCE TO RELATED APPLICATIONS
本专利申请要求于2020年8月17日提交的申请号为CN202010825365.3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。This patent application claims the priority right of the Chinese invention patent application with application number CN202010825365.3 filed on August 17, 2020, the entire contents of which are hereby incorporated by reference.
技术领域technical field
本发明属于制药领域，具体涉及一种比阿培南原料药的制备方法。The invention belongs to the field of pharmacy, and in particular relates to a preparation method of a biapenem crude drug.
背景技术Background technique
比阿培南(Biapenem)，化学名为：(-)6-[[(4R,5S,6S)-2-羧基-6-[(1R)-1-羟乙基]-4-甲基-7-氧代-1-氮杂双环[3.2.0]庚-2-烯-3-基]硫]-6,7-二氢-5H-吡唑[1,2-a][1,2,4]***-4-鎓内盐，是一种碳青霉烯类抗生素，具有抗菌谱广、抗菌活性强的特点。与其他已上市的碳青霉烯类品种相比，比阿培南的肾毒性几乎为零，能单独给药，且无中枢神经***毒性，不诱发癫痫发作，临床上广泛应用于对比阿培南敏感的革兰阴性需氧菌、革兰阳性需氧菌和厌氧菌引起的急慢性感染。比阿培南的具体化学结构式如式(I)所示：Biapenem (Biapenem), chemical name: (-)6-[[(4R,5S,6S)-2-carboxy-6-[(1R)-1-hydroxyethyl]-4-methyl- 7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]thio]-6,7-dihydro-5H-pyrazole[1,2-a][1,2 ,4] Triazole-4-onium inner salt is a carbapenem antibiotic with a broad antibacterial spectrum and strong antibacterial activity. Compared with other marketed carbapenems, biapenem has almost zero nephrotoxicity, can be administered alone, has no central nervous system toxicity, and does not induce epileptic seizures. It is widely used in biapenem clinically. Acute and chronic infections caused by susceptible gram-negative aerobes, gram-positive aerobes and anaerobic bacteria. The specific chemical structural formula of biapenem is shown in formula (I):
Figure PCTCN2020139134-appb-000001
Figure PCTCN2020139134-appb-000001
比阿培南的稳定性和使用时复溶的溶解度问题是其临床应用的主要问题，稳定性差易使药效成分在储存和配制过程中降解；溶解度差易导致药品复溶时产生异物和不溶性微粒，由此引起多种不良反应，存在较大的用药安全隐患。The stability of biapenem and the solubility of biapenem during reconstitution are the main problems in its clinical application. Poor stability can easily lead to the degradation of active ingredients during storage and preparation; poor solubility can easily lead to foreign matter and insolubility when the drug is reconstituted. Microparticles, which cause a variety of adverse reactions, there are great potential drug safety hazards.
现有技术中，通常通过先将比阿培南粗品溶于水中，得到比阿培南粗品 水溶液，然后向水溶液中加入有机溶剂进行结晶，制备得到结晶形式的比阿培南原料药。In the prior art, usually by first dissolving the biapenem crude product in water to obtain an aqueous solution of the biapenem crude product, then adding an organic solvent to the aqueous solution for crystallization to prepare the biapenem bulk drug in crystalline form.
例如，中国专利CN102268024B公开了一种比阿培南的结晶方法，先将比阿培南粗品溶解在水中，然后加入丙酮结晶，制备得到结晶形式的比阿培南原料药。CN102584862B公开了另一种比阿培南的结晶方法，先将比阿培南粗品溶解在水中，加热下先加入乙醇，再以特定速度滴加异丙醇，再配合梯度降温方式，制备得到特殊结晶形式的比阿培南原料药。For example, Chinese patent CN102268024B discloses a crystallization method of biapenem, firstly dissolving the crude biapenem in water, then adding acetone for crystallization, to prepare the biapenem bulk drug in crystal form. CN102584862B discloses another crystallization method of biapenem, firstly dissolving crude biapenem in water, first adding ethanol under heating, then adding isopropanol dropwise at a specific speed, and then cooperating with a gradient cooling method to prepare a special biapenem Biapenem drug substance in crystalline form.
然而，通过上述方法制备得到的产品晶体颗粒大，水溶性差，还需要进一步进行机械粉碎，才能得到水溶性好、复溶时间短、适合医疗用途的比阿培南原料药。但是，额外的机械粉碎步骤会导致不可避免的产品损失，增加生产成本；再则，在机械粉碎过程中，产品的粒径难以控制，这可能导致产品的颗粒过细，或者粒径分布不均，不能从根本上解决水溶性差的问题。However, the product prepared by the above method has large crystal particles and poor water solubility, and further mechanical pulverization is required to obtain the biapenem bulk drug with good water solubility, short reconstitution time and suitable medical use. However, the additional mechanical pulverization step will lead to inevitable product loss and increase the production cost; in addition, during the mechanical pulverization process, the particle size of the product is difficult to control, which may lead to excessively fine particles of the product, or uneven particle size distribution, It cannot fundamentally solve the problem of poor water solubility.
发明内容SUMMARY OF THE INVENTION
本发明的目的是提供一种比阿培南原料药的制备方法，该方法包括将比阿培南粗品溶解在水中，降温后，将比阿培南粗品水溶液加入到有机溶剂里析晶，制备得到比阿培南原料药。The object of the present invention is to provide a method for preparing a biapenem crude drug, which comprises dissolving a crude biapenem product in water, and after cooling down, adding an aqueous solution of the crude biapenem product to an organic solvent for crystallization, to prepare The biapenem raw material is obtained.
本发明工艺简单、紧凑、可控、不需要额外的机械粉碎过程，制备得到比阿培南原料药收率高、纯度高、晶体颗粒适中、粒径分布均匀、水溶性好、稳定性好、流动性好、适合医疗利用，且生产条件温和，利于工业分装及储存，具有巨大的经济潜力。The process of the invention is simple, compact, controllable, and does not require an additional mechanical pulverization process, and the preparation of the crude drug of Apenem has high yield, high purity, moderate crystal particles, uniform particle size distribution, good water solubility, and good stability. It has good fluidity, is suitable for medical use, and has mild production conditions, which is conducive to industrial packaging and storage, and has huge economic potential.
本发明的目的通过以下技术方案来实现。The object of the present invention is achieved through the following technical solutions.
一方面，本发明提供一种比阿培南原料药的制备方法，所述方法包括以下步骤：On the one hand, the present invention provides a kind of preparation method of biapenem bulk drug, described method comprises the following steps:
1)在一定溶解温度T 1下，将比阿培南粗品溶解在水中，制备得到比阿培南粗品水溶液； 1) under a certain dissolution temperature T 1 , the biapenem crude product is dissolved in water to prepare an aqueous solution of the biapenem crude product;
2)将步骤1)所得的比阿培南粗品水溶液的温度控制为T 1或降温至T 2，加入活性炭，搅拌脱色，过滤，滤液降温至T 3备用； 2) the temperature of the aqueous solution of the biapenem crude product obtained in step 1) is controlled to be T 1 or cooled to T 2 , activated carbon is added, stirred for decolorization, filtered, and the filtrate is cooled to T 3 for subsequent use;
3)将步骤2)所得的滤液滴加至预先降温至T 4的丙酮和乙醇的混合溶剂中，析晶； 3) adding the filtrate obtained in step 2) dropwise to the mixed solvent of acetone and ethanol cooled to T 4 in advance, and crystallizing;
4)养晶；4) Cultivate crystals;
5)将步骤4)中得到的晶体经分离、洗涤、干燥得到比阿培南原料药。5) Separating, washing and drying the crystals obtained in step 4) to obtain the biapenem bulk drug.
优选地，在步骤1)中，所述T 1为20-80℃，更优选地为20-30℃，进一 步优选地为20℃或30℃； Preferably, in step 1), the T 1 is 20-80°C, more preferably 20-30°C, further preferably 20°C or 30°C;
优选地，在步骤1)中，所述比阿培南粗品与水的质量比为1:20-80，更优选地为1:30-70，进一步优选地为1:45；Preferably, in step 1), the mass ratio of the crude biapenem to water is 1:20-80, more preferably 1:30-70, further preferably 1:45;
优选地，在步骤2)中，所述T 2为15-35℃，更优选地为20-30℃，进一步优选地为20℃或30℃； Preferably, in step 2), the T 2 is 15-35°C, more preferably 20-30°C, further preferably 20°C or 30°C;
优选地，步骤2)中，所述活性炭与步骤1)所述的比阿培南粗品的质量比为0.05-0.25:1，进一步优选地为0.05-0.1:1，更优选地为0.1:1；Preferably, in step 2), the mass ratio of the activated carbon to the crude biapenem described in step 1) is 0.05-0.25:1, more preferably 0.05-0.1:1, more preferably 0.1:1 ;
优选地，在步骤2)中，所述脱色的时间为5-30分钟，更优选地为10分钟；Preferably, in step 2), the decolorization time is 5-30 minutes, more preferably 10 minutes;
优选地，在步骤2)中，所述T 3为0-20℃，更优选为5-10℃，进一步优选地为5℃或10℃； Preferably, in step 2), the T 3 is 0-20°C, more preferably 5-10°C, further preferably 5°C or 10°C;
优选地，在步骤3)中，所述丙酮和乙醇的混合溶剂与步骤1)所述水的体积比为0.5-3：1，更优选地为1:1；Preferably, in step 3), the volume ratio of the mixed solvent of acetone and ethanol to the water in step 1) is 0.5-3:1, more preferably 1:1;
优选地，在步骤3)中，所述丙酮与乙醇的体积比为95-50:5-50，更优选地为85:15；Preferably, in step 3), the volume ratio of the acetone to ethanol is 95-50:5-50, more preferably 85:15;
优选地，在步骤3)中，所述T 4为0-20℃，更优选地为10-15℃，更进一步优选地为10℃或15℃； Preferably, in step 3), the T 4 is 0-20°C, more preferably 10-15°C, still more preferably 10°C or 15°C;
优选地，在步骤3)中，所述滴加的方式为连续滴加或分批次滴加；Preferably, in step 3), the dripping method is continuous dripping or batchwise dripping;
优选地，在步骤3)中，所述滴加的方式为连续滴加，滴加时间不小于1.5小时；或Preferably, in step 3), the dripping method is continuous dripping, and the dripping time is not less than 1.5 hours; or
优选地，在步骤3)中，所述滴加的方式为分批次滴加；Preferably, in step 3), the dripping method is batchwise dripping;
更优选地，所述分批次滴加为将步骤2)所得的滤液分两次滴加至丙酮和乙醇的混合溶剂中，其中，第一次滴加的滤液与步骤1)所述水的体积比为0.01-0.1:1，进一步优选地为0.04:1；More preferably, the dropwise addition is to drop the filtrate obtained in step 2) into the mixed solvent of acetone and ethanol twice, wherein the filtrate added dropwise for the first time is the same as the water in step 1). The volume ratio is 0.01-0.1:1, more preferably 0.04:1;
优选地，在步骤3)中，所述分批次滴加为将步骤2)所得的滤液分两次滴加至丙酮和乙醇的混合溶剂中，其中，第一次滴加完毕后，搅拌30-120分钟，更优选地为搅拌60分钟；Preferably, in step 3), the dropwise addition is to drop the filtrate obtained in step 2) into the mixed solvent of acetone and ethanol twice, wherein, after the first dropwise addition is completed, stirring for 30 - 120 minutes, more preferably stirring for 60 minutes;
优选地，在步骤3)中，所述分批次滴加为将步骤2)所得的滤液分两次滴加至丙酮和乙醇的混合溶剂中，其中，第二次滴加的时间为0.5-3小时，更优选地为1-1.5小时，进一步优选地为1小时或1.5小时；Preferably, in step 3), the dropwise addition is to drop the filtrate obtained in step 2) into the mixed solvent of acetone and ethanol twice, wherein the time for the second dropwise addition is 0.5- 3 hours, more preferably 1-1.5 hours, further preferably 1 hour or 1.5 hours;
优选地，在步骤3)中，所述析晶的温度为0-20℃，更优选地为15-20℃，进一步优选地为15℃或20℃；Preferably, in step 3), the temperature of the crystallization is 0-20°C, more preferably 15-20°C, further preferably 15°C or 20°C;
优选地，在步骤3)中，所述析晶的时间为30分钟；Preferably, in step 3), the crystallization time is 30 minutes;
优选地，在步骤4)中，所述养晶的温度为0-20℃，更优选地为7-12℃，进一步优选地为7℃或12℃；Preferably, in step 4), the temperature of the crystal growing is 0-20°C, more preferably 7-12°C, further preferably 7°C or 12°C;
优选地，在步骤4)中，所述养晶的时间为0.5-6小时，更优选地为1.5小时；Preferably, in step 4), the time for growing crystals is 0.5-6 hours, more preferably 1.5 hours;
优选地，在步骤5)中，所述分离是将养晶得到的晶体与溶液分离。一般而言，所述分离可以采用本领域已知的任何常规的分离方法，比如过滤或离心进行。Preferably, in step 5), the separation is to separate the crystal obtained by growing the crystal from the solution. In general, the separation can be carried out using any conventional separation method known in the art, such as filtration or centrifugation.
优选地，在步骤5)中，所述洗涤可以采用丙酮和乙醇中的一种或它们的混合物进行；进一步优选地，所述洗涤采用丙酮或乙醇进行。Preferably, in step 5), the washing can be carried out with one of acetone and ethanol or a mixture thereof; further preferably, the washing can be carried out with acetone or ethanol.
优选地，在步骤5)中，所述干燥为在40-50℃下真空干燥。Preferably, in step 5), the drying is vacuum drying at 40-50°C.
优选地，在步骤5)中，所得到的比阿培南原料药的D50为20μm-31μm，更优选地为27μm-29μm。Preferably, in step 5), the D50 of the obtained biapenem drug substance is 20 μm-31 μm, more preferably 27 μm-29 μm.
优选地，在步骤5)中，所得到的比阿培南原料药的休止角为30°-40°，更优选地为31°-33°。Preferably, in step 5), the angle of repose of the obtained biapenem drug substance is 30°-40°, more preferably 31°-33°.
优选地，在步骤5)中，所得到的比阿培南原料药的复溶时间不大于60s，更优选地为30s-50s，进一步优选地为44s-45s。Preferably, in step 5), the reconstitution time of the obtained biapenem drug substance is not more than 60s, more preferably 30s-50s, further preferably 44s-45s.
另一方面，本发明还提供由上述方法制备的比阿培南原料药。优选地，所述比阿培南原料药中，比阿培南含量不小于99.5％，杂质A不大于0.2％，杂质B不大于0.05％。On the other hand, the present invention also provides the biapenem raw material prepared by the above method. Preferably, in the biapenem API, the content of biapenem is not less than 99.5%, the impurity A is not more than 0.2%, and the impurity B is not more than 0.05%.
优选地，所述比阿培南原料药为晶体；更优选地，使用Cu-Kα辐射，所述比阿培南原料药晶体的X-射线粉末衍射图在衍射角2θ为15.54±0.1°、16.17±0.1°、20.11±0.1°、20.61±0.1°、22.05±0.1°、27.10±0.1°处有衍射峰。Preferably, the biapenem bulk drug is a crystal; more preferably, using Cu-Kα radiation, the X-ray powder diffraction pattern of the biapenem bulk drug crystal at the diffraction angle 2θ is 15.54±0.1°, There are diffraction peaks at 16.17±0.1°, 20.11±0.1°, 20.61±0.1°, 22.05±0.1°, and 27.10±0.1°.
优选地，所述比阿培南原料药晶体的D50为20μm-31μm，更优选地为27μm-29μm。Preferably, the D50 of the biapenem bulk drug crystal is 20 μm-31 μm, more preferably 27 μm-29 μm.
优选地，所述比阿培南原料药晶体的休止角为30°-40°，更优选地为31°-33°。Preferably, the angle of repose of the biapenem bulk drug crystal is 30°-40°, more preferably 31°-33°.
优选地，所述比阿培南原料药晶体的的复溶时间为不大于60s，更优选地为30s-50s，进一步优选地为44s-45s。Preferably, the reconstitution time of the biapenem bulk drug crystal is not more than 60s, more preferably 30s-50s, further preferably 44s-45s.
又一方面，本发明提供由上述方法制备的比阿培南原料药在制备用于治疗由革兰阴性需氧菌、革兰阳性需氧菌和厌氧菌引起的急慢性感染中的用途。In yet another aspect, the present invention provides the use of the biapenem bulk drug prepared by the above-mentioned method for the treatment of acute and chronic infections caused by Gram-negative aerobic bacteria, Gram-positive aerobic bacteria and anaerobic bacteria.
根据上述制备方法可得到的比阿培南原料药中，按归一法，比阿培南含量不小于99.5％，杂质A不大于0.2％，杂质B不大于0.05％，复溶时间不 大于60秒。In the biapenem raw material obtained according to the above preparation method, according to the normalization method, the content of biapenem is not less than 99.5%, the impurity A is not more than 0.2%, the impurity B is not more than 0.05%, and the reconstitution time is not more than 60% Second.
其中，杂质A为Among them, impurity A is
Figure PCTCN2020139134-appb-000002
Figure PCTCN2020139134-appb-000002
其中，杂质B为Among them, impurity B is
Figure PCTCN2020139134-appb-000003
Figure PCTCN2020139134-appb-000003
药物中的杂质，包括外源性杂质和药物降解杂质，杂质的存在，会降低药物的疗效，影响药物的稳定性，甚至会引发各种不良反应，ICH指导原则对杂质进行了严苛的规定，如：Q3A中规定每日最大剂量≤2g时，杂质的界定限度为0.15％；Q3B中规定每日最大剂量＞10mg-2g时，降解产物的界定限度为0.2％。比阿培南的成人每日最大剂量为600mg，药物降解产物不大于0.2％。比阿培南原料药的杂质A为降解产物，杂质B为开环降解物，存在于碳青霉烯类抗生素中的降解物、酸解产物、聚合物等杂质是引起药物不良反应的主要原因，《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，抗感染药占33.3％，因此，必须最大限度的控制比阿培南原料药中杂质的含量，才能有效保证人们的用药安全性。Impurities in drugs, including exogenous impurities and drug degradation impurities, the existence of impurities will reduce the efficacy of drugs, affect the stability of drugs, and even cause various adverse reactions. The ICH guidelines have strict regulations on impurities. For example, when the maximum daily dose specified in Q3A is less than or equal to 2g, the defined limit of impurities is 0.15%; when the maximum daily dose specified in Q3B is greater than 10mg-2g, the defined limit of degradation products is 0.2%. The maximum daily adult dose of biapenem is 600 mg with no more than 0.2% drug degradation products. Impurity A of biapenem API is a degradation product, and impurity B is a ring-opening degradation product. Impurities such as degradation products, acid hydrolysis products, and polymers in carbapenem antibiotics are the main causes of adverse drug reactions. , "National Adverse Drug Reaction Monitoring Annual Report (2018)" shows that in the serious adverse drug reaction/event reports of chemical drugs, anti-infective drugs account for 33.3%. Therefore, it is necessary to maximize the control of impurities in biapenem APIs. content, in order to effectively ensure the safety of people's medication.
与现有技术相比，本发明的有益效果至少包括以下方面：Compared with the prior art, the beneficial effects of the present invention at least include the following aspects:
1)采用本发明所述的制备方法制备得到的比阿培南原料药纯度高、杂质状况清晰、稳定性好，能够保证产品有效、安全。1) The bisabenem raw material prepared by the preparation method of the present invention has high purity, clear impurity status and good stability, and can ensure the product is effective and safe.
2)采用本发明所述的制备方法制备得到的比阿培南原料药晶体颗粒适中、粒径分布均匀、水溶性好、复溶时间短、更适合医疗利用。2) The bisabenem bulk drug crystal particle prepared by the preparation method of the present invention is moderate, the particle size distribution is uniform, the water solubility is good, the reconstitution time is short, and is more suitable for medical use.
3)采用本发明所述的制备方法制备得到的比阿培南原料药流动性好，利于工业分装及储存。3) Apenem crude drug prepared by the preparation method of the present invention has good fluidity, which is beneficial to industrial sub-packaging and storage.
4)本发明所述的制备方法工艺简单、紧凑、易于控制，适合工业化运用，具有巨大的经济潜力。4) The preparation method of the present invention is simple, compact, easy to control, suitable for industrial application, and has huge economic potential.
附图说明Description of drawings
图1为实施例2制备得到的比阿培南原料药的粒径分布图。1 is a particle size distribution diagram of the biapenem bulk drug prepared in Example 2.
图2为实施例3制备得到的比阿培南原料药的粒径分布图。2 is a particle size distribution diagram of the biapenem bulk drug prepared in Example 3.
图3为实施例4制备得到的比阿培南原料药的粒径分布图。3 is a particle size distribution diagram of the biapenem bulk drug prepared in Example 4.
图4为实施例5制备得到的比阿培南原料药的粒径分布图。4 is a particle size distribution diagram of the biapenem bulk drug prepared in Example 5.
图5为实施例6制备得到的比阿培南原料药的粒径分布图。5 is a particle size distribution diagram of the biapenem bulk drug prepared in Example 6.
图6为实施例7制备得到的比阿培南原料药的粒径分布图。6 is a particle size distribution diagram of the biapenem bulk drug prepared in Example 7.
图7为实施例8制备得到的比阿培南原料药的粒径分布图。7 is a particle size distribution diagram of the biapenem bulk drug prepared in Example 8.
图8为实施例9制备得到的比阿培南原料药的粒径分布图。FIG. 8 is a particle size distribution diagram of the biapenem bulk drug prepared in Example 9. FIG.
图9为对比例1制备得到的比阿培南原料药的粒径分布图。9 is a particle size distribution diagram of the biapenem bulk drug prepared in Comparative Example 1.
图10为对比例2制备得到的比阿培南原料药的粒径分布图。Figure 10 is a particle size distribution diagram of the biapenem bulk drug prepared in Comparative Example 2.
图11为对比例3制备得到的比阿培南原料药的粒径分布图。Figure 11 is a particle size distribution diagram of the biapenem bulk drug prepared in Comparative Example 3.
图12为对比例4制备得到的比阿培南原料药的粒径分布图。Figure 12 is a particle size distribution diagram of the biapenem bulk drug prepared in Comparative Example 4.
图13为对比例5制备得到的比阿培南原料药的粒径分布图。Figure 13 is a particle size distribution diagram of the biapenem bulk drug prepared in Comparative Example 5.
图14为对比例6制备得到的比阿培南原料药的粒径分布图。Figure 14 is a particle size distribution diagram of the biapenem bulk drug prepared in Comparative Example 6.
图15为对比例7制备得到的比阿培南原料药的粒径分布图。15 is a particle size distribution diagram of the biapenem bulk drug prepared in Comparative Example 7.
图16为对比例8制备得到的比阿培南原料药的粒径分布图。Figure 16 is a particle size distribution diagram of the biapenem bulk drug prepared in Comparative Example 8.
图17为实施例2制备得到的比阿培南原料药X射线粉末衍射图。17 is the X-ray powder diffraction pattern of the biapenem bulk drug prepared in Example 2.
具体实施例方式specific embodiment
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。The present invention will be described below with reference to specific examples. Those skilled in the art can understand that these examples are only for illustrating the present invention, and they do not limit the scope of the present invention in any way.
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，均为市售购买产品。The experimental methods in the following examples are conventional methods unless otherwise specified. The raw materials, auxiliary materials, reagent materials, etc. used in the following examples are all commercially available products.
所述比阿培南粗品按照实施例1所述方法制备，也可以按照CN104829633A或者现有技术中任何制备比阿培南的方法制备。The crude biapenem is prepared according to the method described in Example 1, and can also be prepared according to CN104829633A or any method for preparing biapenem in the prior art.
所述比阿培南粗品和原料药的纯度按照CN109946396A描述的方法进行检测。The purity of the biapenem crude product and the raw drug is detected according to the method described in CN109946396A.
所述比阿培南原料药的粒径使用的检测设备为激光衍射粒度仪。检测过程为：取样品适量置激光衍射粒度仪的样品管中，使粉末恰好浸没样品管的凹面，将样品管置粒度仪中，按干法测定样品的粒度。The detection equipment used for the particle size of the biapenem bulk drug is a laser diffraction particle size analyzer. The detection process is as follows: take an appropriate amount of the sample and place it in the sample tube of the laser diffraction particle size analyzer, so that the powder is just immersed in the concave surface of the sample tube, place the sample tube in the particle size analyzer, and measure the particle size of the sample according to the dry method.
所述比阿培南原料药的休止角使用的检测设备为智能粉体特性测试仪。检测过程为：取样品适量，进料速度设置为4，进料时间设置为60秒，记录结果。The detection equipment used for the angle of repose of the biapenem API is an intelligent powder property tester. The detection process is as follows: take an appropriate amount of the sample, set the feeding speed to 4, set the feeding time to 60 seconds, and record the results.
所述复溶时间检测过程为：称取比阿培南原料药0.3g，加入纯化水溶液(23±1℃)20ml，以200～210次/分振摇(振摇范围为12-15cm)15秒，静止5秒，观察样品溶解情况，如有不溶物，则重复上述操作直至样品完全溶解，记录结果，静止时间不计入内。The reconstitution time detection process is as follows: weigh 0.3 g of the biapenem API, add 20 ml of purified aqueous solution (23±1°C), and shake at 200-210 times/min (the shaking range is 12-15 cm) for 15 seconds, rest for 5 seconds, observe the dissolution of the sample, if there is insoluble matter, repeat the above operation until the sample is completely dissolved, record the result, and the rest time is not included.
所述比阿培南原料药的X-射线衍射检测(XRD)使用的检测设备为BT X。检测过程为：设置CukaPeak：450，XRFBins:1500，stepSize:0.04，low Angle:0，highAngle:54，数据收集时间为20-30min左右。The detection equipment used in the X-ray diffraction detection (XRD) of the biapenem bulk drug is BTX. The detection process is: set CukaPeak: 450, XRFBins: 1500, stepSize: 0.04, low Angle: 0, highAngle: 54, and the data collection time is about 20-30min.
实施例1比阿培南粗品的制备 The preparation of embodiment 1 biapenem crude product
Figure PCTCN2020139134-appb-000004
Figure PCTCN2020139134-appb-000004
氢化釜中加入比阿培南中间体(II)10kg、四氢呋喃89kg、纯化水200kg，搅拌溶解，加入乙酸乙酯60kg、2，6-二甲基吡啶4kg和7.5％的Pd/C 3kg，在1.0～1.2MPa、30～35℃下氢化反应2小时，反应停止，过滤，使用20kg纯化水洗涤滤饼，分相，水相转入结晶釜，降温至2～7℃，加入356kg四氢呋喃，控制加入速度，1小时滴加完毕，保温2～7℃，养晶2小时，过滤，使用10kg四氢呋喃洗涤滤饼，真空干燥得到比阿培南粗品5.02kg，收率75％，HPLC归一化法检测纯度为：96.3％，杂质A为0.59％，杂质B为0.27％。In the hydrogenation kettle, add biapenem intermediate (II) 10kg, tetrahydrofuran 89kg, purified water 200kg, stir and dissolve, add ethyl acetate 60kg, 2,6-lutidine 4kg and 7.5% Pd/C 3kg, in 1.0～1.2MPa, 30～35 ℃ of hydrogenation reactions for 2 hours, the reaction is stopped, filter, use 20kg purified water to wash the filter cake, phase separation, the water phase is transferred into the crystallization kettle, cooled to 2～7 ℃, add 356kg of tetrahydrofuran, control The rate of addition, the dropwise addition was completed in 1 hour, the temperature was kept at 2 to 7°C, the crystal was grown for 2 hours, filtered, and the filter cake was washed with 10 kg of tetrahydrofuran, and dried in vacuum to obtain 5.02 kg of crude biapenem, with a yield of 75%. HPLC normalization method The detected purity is: 96.3%, impurity A is 0.59%, impurity B is 0.27%.
实施例2Example 2
向反应瓶中加入纯化水450g，控温至20℃，搅拌下，加入实施例1得到的比阿培南粗品10g，搅拌溶解，控温至20℃，加入活性炭1g，搅拌10分钟，滤除活性炭，滤液降温至5℃，备用；Add 450 g of purified water to the reaction flask, control the temperature to 20 ° C, add 10 g of the crude biapenem obtained in Example 1 under stirring, stir to dissolve, control the temperature to 20 ° C, add 1 g of activated carbon, stir for 10 minutes, filter out Activated carbon, the filtrate was cooled to 5°C, for use;
向反应瓶中加入382.5ml的丙酮和67.5ml乙醇，降温至10℃，搅拌下，滴加上述滤液18ml，搅拌60分钟，滴加剩余的上述滤液，控制滴加速度，1小时滴加完毕，在15℃搅拌30分钟，降温至7℃，继续搅拌1.5小时，过滤，滤饼使用20g丙酮洗涤，在40～50℃下，真空干燥得到比阿培南原料药9.48g，收率94.8％，HPLC纯度为99.77％，杂质A为0.1％，杂质B为0.01％，粒径分布如图1所示，其中D10＝18.57μm、D50＝28.67μm、D90＝42.34μm。Add 382.5ml of acetone and 67.5ml of ethanol to the reaction flask, cool down to 10°C, under stirring, dropwise add 18ml of the above-mentioned filtrate, stir for 60 minutes, add the remaining above-mentioned filtrate dropwise, control the rate of addition, and complete the dropwise addition in 1 hour. Stir at 15°C for 30 minutes, cool down to 7°C, continue to stir for 1.5 hours, filter, wash the filter cake with 20 g of acetone, and vacuum dry at 40 to 50°C to obtain 9.48 g of biapenem API, yield 94.8%, HPLC The purity is 99.77%, impurity A is 0.1%, impurity B is 0.01%, and the particle size distribution is shown in Figure 1, wherein D10=18.57 μm, D50=28.67 μm, D90=42.34 μm.
本实施例制备得到的比阿培南原料药晶体的X射线粉末衍射图谱如图17所示，X射线粉末衍射图谱数据见表1：The X-ray powder diffraction pattern of the biapenem bulk drug crystal prepared in this example is shown in Figure 17, and the X-ray powder diffraction pattern data is shown in Table 1:
表1比阿培南原料药晶体的X射线粉末衍射图谱数据Table 1 X-ray powder diffraction pattern data of biapenem bulk drug crystals
序号serial number 角度2θAngle 2θ 强度计数Intensity count d值(埃)d value (Angstrom) 相对强度(％)Relative Strength(%)
11 11.8311.83 3312.953312.95 7.47357.4735 11.8711.87
22 13.4513.45 6026.676026.67 6.57946.5794 21.5821.58
33 15.5415.54 13176.3613176.36 5.69895.6989 47.1947.19
44 16.1716.17 27921.1027921.10 5.47755.4775 100.00100.00
55 17.9417.94 7245.697245.69 4.94054.9405 25.9525.95
66 18.5118.51 6618.726618.72 4.78934.7893 23.7123.71
77 20.1120.11 10147.3010147.30 4.41194.4119 36.3436.34
88 20.6120.61 14670.2114670.21 4.30524.3052 52.5452.54
99 22.0522.05 9844.419844.41 4.02814.0281 35.2635.26
1010 23.8323.83 3425.773425.77 3.73063.7306 12.2712.27
1111 24.2724.27 5721.685721.68 3.66403.6640 20.4920.49
1212 25.9025.90 3937.833937.83 3.43753.4375 14.1014.10
1313 26.7426.74 2847.332847.33 3.33163.3316 10.2010.20
1414 27.1027.10 9236.129236.12 3.28753.2875 33.0833.08
1515 28.2328.23 7535.667535.66 3.15863.1586 26.9926.99
1616 29.6629.66 5304.765304.76 3.00923.0092 19.0019.00
1717 31.4231.42 3213.493213.49 2.84492.8449 11.5111.51
1818 35.2335.23 3164.813164.81 2.54572.5457 11.3311.33
实施例3Example 3
向反应瓶中加入纯化水450g，控温至30℃，搅拌下，加入实施例1得到的比阿培南粗品10g，搅拌溶解，控温至30℃，加入活性炭1g，搅拌10分钟，滤除活性炭，滤液降温至10℃，备用；Add 450 g of purified water to the reaction flask, control the temperature to 30 ° C, add 10 g of the crude biapenem obtained in Example 1 under stirring, stir to dissolve, control the temperature to 30 ° C, add 1 g of activated carbon, stir for 10 minutes, filter out Activated carbon, the filtrate was cooled to 10°C for use;
向反应瓶中加入382.5ml的丙酮和67.5ml乙醇，降温至15℃，搅拌下，滴加上述滤液18ml，搅拌60分钟，滴加剩余的上述滤液，控制滴加速度， 1.5小时滴加完毕，在20℃搅拌30分钟，降温至12℃，继续搅拌1.5小时，过滤，滤饼使用20g乙醇洗涤，在40～50℃下，真空干燥得到比阿培南原料药9.45g，收率94.5％，HPLC纯度为99.73％，杂质A为0.11％，杂质B为0.01％，粒径分布如图2所示，其中D10＝14.56μm、D50＝27.91μm、D90＝36.30μm。Add 382.5ml of acetone and 67.5ml of ethanol to the reaction flask, cool down to 15°C, add 18ml of the above-mentioned filtrate dropwise under stirring, stir for 60 minutes, add the remaining above-mentioned filtrate dropwise, control the rate of addition, and complete the dropwise addition in 1.5 hours. Stir at 20°C for 30 minutes, cool down to 12°C, continue to stir for 1.5 hours, filter, wash the filter cake with 20 g of ethanol, and vacuum dry at 40-50°C to obtain 9.45g of biapenem API, yield 94.5%, HPLC The purity is 99.73%, impurity A is 0.11%, impurity B is 0.01%, and the particle size distribution is shown in Figure 2, wherein D10=14.56 μm, D50=27.91 μm, D90=36.30 μm.
本实施例制备得到的比阿培南原料药晶体的X射线粉末衍射图谱与实施例2相似。The X-ray powder diffraction pattern of the biapenem bulk drug crystal prepared in this example is similar to that in Example 2.
实施例4Example 4
向反应瓶中加入纯化水200g，升温至80℃，搅拌下，加入实施例1得到的比阿培南粗品10g，搅拌溶解，降温至35℃，加入活性炭2.5g，搅拌30分钟，滤除活性炭，滤液降温至20℃，备用；Add 200g of purified water to the reaction flask, heat up to 80°C, add 10g of the crude biapenem obtained in Example 1 under stirring, stir to dissolve, cool down to 35°C, add 2.5g of activated carbon, stir for 30 minutes, filter out the activated carbon , the filtrate was cooled to 20°C for use;
向反应瓶中加入300ml的丙酮和300ml乙醇，降温至20℃，搅拌下，滴加上述滤液20ml，搅拌120分钟，滴加剩余的上述滤液，控制滴加速度，0.5小时滴加完毕，在20℃搅拌30分钟后，继续在20℃搅拌6小时，过滤，滤饼使用乙醇丙酮溶液(10g乙醇、10g丙酮)洗涤，在40～50℃下，真空干燥得到比阿培南原料药9.35g，收率93.5％，HPLC纯度为99.65％，杂质A为0.12％，杂质B为0.02％，粒径分布如图3所示，其中D10＝10.81μm、D50＝25.47μm、D90＝35.04μm。Add 300ml of acetone and 300ml of ethanol to the reaction flask, cool down to 20°C, add 20ml of the above-mentioned filtrate dropwise under stirring, stir for 120 minutes, add the remaining above-mentioned filtrate dropwise, control the rate of addition, and complete the dropwise addition in 0.5 hours at 20°C. After stirring for 30 minutes, continue to stir at 20 ° C for 6 hours, filter, use ethanol acetone solution (10 g ethanol, 10 g acetone) to wash the filter cake, at 40 ~ 50 ° C, vacuum dry to obtain 9.35 g of biapenem bulk drug, which is collected. The HPLC purity is 93.5%, the HPLC purity is 99.65%, the impurity A is 0.12%, and the impurity B is 0.02%.
本实施例制备得到的比阿培南原料药晶体的X射线粉末衍射图谱与实施例2相似。The X-ray powder diffraction pattern of the biapenem bulk drug crystal prepared in this example is similar to that in Example 2.
实施例5Example 5
向反应瓶中加入纯化水800g，控温至20℃，搅拌下，加入实施例1得到的比阿培南粗品10g，搅拌溶解，降温至15℃，加入活性炭0.5g，搅拌5分钟，滤除活性炭，滤液降温至0℃，备用；Add 800 g of purified water to the reaction flask, control the temperature to 20 ° C, add 10 g of the crude biapenem obtained in Example 1 under stirring, stir to dissolve, cool down to 15 ° C, add 0.5 g of activated carbon, stir for 5 minutes, filter out Activated carbon, the filtrate is cooled to 0 ℃, for use;
向反应瓶中加入380ml的丙酮和20ml乙醇，降温至0℃，搅拌下，滴加上述滤液8ml，搅拌30分钟，滴加剩余的上述滤液，控制滴加速度，3小时滴加完毕，在0℃搅拌30分钟后，继续在0℃搅拌0.5小时，过滤，滤饼使用乙醇丙酮溶液(5g乙醇、15g丙酮)洗涤，在40～50℃下，真空干燥得到比阿培南原料药9.13g，收率91.3％，HPLC纯度为99.63％，杂质A为0.14％，杂质B为0.02％，粒径分布如图4所示，其中D10＝13.04μm、D50＝20.69μm、D90＝27.80μm。Add 380ml of acetone and 20ml of ethanol to the reaction flask, cool down to 0°C, add 8ml of the above-mentioned filtrate dropwise under stirring, stir for 30 minutes, add the remaining above-mentioned filtrate dropwise, control the rate of addition, complete the dropwise addition in 3 hours, at 0°C After stirring for 30 minutes, continue to stir at 0 °C for 0.5 hours, filter, wash the filter cake with ethanol acetone solution (5 g ethanol, 15 g acetone), and vacuum dry at 40 ~ 50 ° C to obtain 9.13 g of biapenem API, which was collected. The HPLC purity is 91.3%, the HPLC purity is 99.63%, the impurity A is 0.14%, and the impurity B is 0.02%.
本实施例制备得到的比阿培南原料药晶体的X射线粉末衍射图谱与实施例2相似。The X-ray powder diffraction pattern of the biapenem bulk drug crystal prepared in this example is similar to that in Example 2.
实施例6Example 6
向反应瓶中加入纯化水700g，升温至40℃，搅拌下，加入实施例1得到的比阿培南粗品10g，搅拌溶解，降温至25℃，加入活性炭0.5g，搅拌20分钟，滤除活性炭，滤液降温至15℃，备用；Add 700 g of purified water to the reaction flask, heat up to 40 ° C, add 10 g of the crude biapenem obtained in Example 1 under stirring, stir to dissolve, cool down to 25 ° C, add 0.5 g of activated carbon, stir for 20 minutes, filter out the activated carbon , and the filtrate was cooled to 15°C for use;
向反应瓶中加入1120ml的丙酮和280ml乙醇，降温至5℃，搅拌下，滴加上述滤液35ml，搅拌90分钟，滴加剩余的上述滤液，控制滴加速度，2小时滴加完毕，在5℃搅拌30分钟后，继续在5℃搅拌3小时，过滤，滤饼使用乙醇丙酮溶液(15g乙醇、5g丙酮)洗涤，在40～50℃下，真空干燥得到比阿培南原料药9.21g，收率92.1％，HPLC纯度为99.71％，杂质A为0.12％，杂质B为0.02％，粒径分布如图5所示，其中D10＝12.36μm、D50＝30.63μm、D90＝43.45μm。Add 1120ml of acetone and 280ml of ethanol to the reaction flask, cool down to 5°C, add 35ml of the above-mentioned filtrate dropwise with stirring, stir for 90 minutes, add the remaining above-mentioned filtrate dropwise, control the rate of addition, the addition is completed in 2 hours, at 5°C After stirring for 30 minutes, continue to stir at 5°C for 3 hours, filter, and wash the filter cake with ethanol-acetone solution (15g ethanol, 5g acetone), and at 40～50°C, vacuum dry to obtain 9.21g of biapenem bulk drug, which is collected. The HPLC purity is 92.1%, the HPLC purity is 99.71%, the impurity A is 0.12%, and the impurity B is 0.02%.
本实施例制备得到的比阿培南原料药晶体的X射线粉末衍射图谱与实施例2相似。The X-ray powder diffraction pattern of the biapenem bulk drug crystal prepared in this example is similar to that in Example 2.
实施例7Example 7
向反应瓶中加入纯化水300g，升温至60℃，搅拌下，加入实施例1得到的比阿培南粗品10g，搅拌溶解，降温至15℃，加入活性炭1.0g，搅拌15分钟，滤除活性炭，滤液保温15℃，备用；Add 300 g of purified water to the reaction flask, heat up to 60 ° C, add 10 g of the crude biapenem obtained in Example 1 under stirring, stir to dissolve, cool down to 15 ° C, add 1.0 g of activated carbon, stir for 15 minutes, filter out the activated carbon , the filtrate was kept at 15°C for use;
向反应瓶中加入315ml的丙酮和135ml乙醇，降温至15℃，搅拌下，滴加上述滤液30ml，搅拌45分钟，滴加剩余的上述滤液，控制滴加速度，1.5小时滴加完毕，在15℃搅拌30分钟后，继续在15℃搅拌4小时，过滤，滤饼使用20g乙醇洗涤，在40～50℃下，真空干燥得到比阿培南原料药9.31g，收率93.1％，HPLC纯度为99.57％，杂质A为0.17％，杂质B为0.03％，粒径分布如图6所示，其中D10＝16.12μm、D50＝25.79μm、D90＝33.67μm。Add 315ml of acetone and 135ml of ethanol to the reaction flask, cool down to 15°C, add 30ml of the above-mentioned filtrate dropwise under stirring, stir for 45 minutes, add the remaining above-mentioned filtrate dropwise, control the rate of addition, and complete the dropwise addition in 1.5 hours at 15°C. After stirring for 30 minutes, continue stirring at 15 °C for 4 hours, filter, wash the filter cake with 20 g of ethanol, and vacuum dry at 40-50 °C to obtain 9.31 g of biapenem API, yield 93.1%, HPLC purity 99.57 %, impurity A is 0.17%, impurity B is 0.03%, the particle size distribution is shown in Figure 6, wherein D10=16.12 μm, D50=25.79 μm, D90=33.67 μm.
本实施例制备得到的比阿培南原料药晶体的X射线粉末衍射图谱与实施例2相似。The X-ray powder diffraction pattern of the biapenem bulk drug crystal prepared in this example is similar to that in Example 2.
实施例8Example 8
向反应釜中加入纯化水90kg，控温至20℃，搅拌下，加入实施例1得到的比阿培南粗品2kg，搅拌溶解，控温至20℃，加入活性炭0.2kg，搅拌 10分钟，滤除活性炭，滤液降温至5℃，备用；Add 90kg of purified water to the reaction kettle, control the temperature to 20°C, under stirring, add 2kg of the crude biapenem obtained in Example 1, stir and dissolve, control the temperature to 20°C, add 0.2kg of activated carbon, stir for 10 minutes, filter In addition to activated carbon, the filtrate was cooled to 5 °C for use;
向结晶釜中加入76.5L的丙酮和13.5L乙醇，降温至10℃，搅拌下，滴加上述滤液3.6L，搅拌60分钟，滴加剩余的上述滤液，控制滴加速度，1小时滴加完毕，在15℃搅拌30分钟，降温至7℃，继续搅拌1.5小时，过滤，滤饼使用4kg丙酮洗涤，在40～50℃下，真空干燥得到比阿培南原料药1.91g，收率95.5％，HPLC纯度为99.79％，杂质A为0.09％，杂质B为0.01％，粒径分布如图7所示，其中D10＝9.55μm、D50＝28.63μm、D90＝45.07μm。Add 76.5L of acetone and 13.5L of ethanol to the crystallization kettle, cool down to 10°C, under stirring, add 3.6L of the above-mentioned filtrate dropwise, stir for 60 minutes, add the remaining above-mentioned filtrate dropwise, control the rate of addition, and complete the dropwise addition in 1 hour, Stir at 15°C for 30 minutes, cool down to 7°C, continue stirring for 1.5 hours, filter, wash the filter cake with 4kg acetone, and vacuum dry at 40-50°C to obtain biapenem bulk drug 1.91g with a yield of 95.5%, The HPLC purity is 99.79%, impurity A is 0.09%, impurity B is 0.01%, and the particle size distribution is shown in Figure 7, wherein D10=9.55 μm, D50=28.63 μm, D90=45.07 μm.
本实施例制备得到的比阿培南原料药晶体的X射线粉末衍射图谱与实施例2相似。The X-ray powder diffraction pattern of the biapenem bulk drug crystal prepared in this example is similar to that in Example 2.
实施例9Example 9
向反应瓶中加入纯化水200g，升温至80℃，搅拌下，加入实施例1得到的比阿培南粗品10g，搅拌溶解，降温至35℃，加入活性炭2.5g，搅拌30分钟，滤除活性炭，滤液降温至20℃，备用；Add 200g of purified water to the reaction flask, heat up to 80°C, add 10g of the crude biapenem obtained in Example 1 under stirring, stir to dissolve, cool down to 35°C, add 2.5g of activated carbon, stir for 30 minutes, filter out the activated carbon , the filtrate was cooled to 20°C for use;
向反应瓶中加入300ml的丙酮和300ml乙醇，降温至20℃，搅拌下，滴加上述滤液，控制滴加速度，1.5小时滴加完毕，在20℃搅拌30分钟后，继续在20℃搅拌6小时，过滤，滤饼使用乙醇丙酮溶液(10g乙醇、10g丙酮)洗涤，在40～50℃下，真空干燥得到比阿培南原料药9.28g，收率92.8％，HPLC纯度为99.52％，杂质A为0.13％，杂质B为0.02％，粒径分布如图8所示，其中D10＝13.41μm、D50＝21.44μm、D90＝34.79μm。Add 300ml of acetone and 300ml of ethanol to the reaction flask, cool down to 20°C, add the above-mentioned filtrate dropwise with stirring, control the rate of addition, and complete the dropwise addition in 1.5 hours. After stirring at 20°C for 30 minutes, continue stirring at 20°C for 6 hours. , filtered, the filter cake was washed with ethanol and acetone solution (10g ethanol, 10g acetone), at 40～50 ℃, vacuum drying obtained biapenem bulk drug 9.28g, yield 92.8%, HPLC purity was 99.52%, impurity A is 0.13%, impurity B is 0.02%, and the particle size distribution is shown in Figure 8, wherein D10=13.41 μm, D50=21.44 μm, D90=34.79 μm.
本实施例制备得到的比阿培南原料药晶体的X射线粉末衍射图谱与实施例2相似。The X-ray powder diffraction pattern of the biapenem bulk drug crystal prepared in this example is similar to that in Example 2.
对比例1Comparative Example 1
向反应瓶中加入纯化水450g，控温至20℃，搅拌下，加入实施例1得到的比阿培南粗品10g，搅拌溶解，控温至20℃，加入活性炭1g，搅拌10分钟，滤除活性炭，滤液降温至5℃，备用；Add 450 g of purified water to the reaction flask, control the temperature to 20 ° C, add 10 g of the crude biapenem obtained in Example 1 under stirring, stir to dissolve, control the temperature to 20 ° C, add 1 g of activated carbon, stir for 10 minutes, filter out Activated carbon, the filtrate was cooled to 5°C, for use;
向反应瓶中加入450ml的丙酮，降温至10℃，搅拌下，滴加上述滤液18ml，搅拌60分钟，滴加剩余的上述滤液，控制滴加速度，2小时滴加完毕，在15℃搅拌30分钟，降温至7℃，继续搅拌1.5小时，过滤，滤饼使用20g丙酮洗涤，在40～50℃下，真空干燥得到比阿培南原料药9.25g，收率92.5％，HPLC纯度为99.64％，杂质A为0.18％，杂质B为0.04％，粒径分布如图9所示，其中D10＝0.78μm、D50＝3.62μm、D90＝8.93μm。Add 450ml of acetone to the reaction flask, cool down to 10°C, add 18ml of the above-mentioned filtrate dropwise under stirring, stir for 60 minutes, add the remaining above-mentioned filtrate dropwise, control the rate of addition, complete the dropwise addition in 2 hours, and stir at 15°C for 30 minutes , cooled to 7 °C, continued to stir for 1.5 hours, filtered, and the filter cake was washed with 20 g of acetone, and at 40 to 50 °C, vacuum-dried to obtain 9.25 g of biapenem bulk drug with a yield of 92.5% and a HPLC purity of 99.64%. The impurity A is 0.18%, the impurity B is 0.04%, and the particle size distribution is shown in Fig. 9, wherein D10=0.78 μm, D50=3.62 μm, D90=8.93 μm.
对比例2Comparative Example 2
向反应瓶中加入纯化水450g，控温至20℃，搅拌下，加入实施例1得到的比阿培南粗品10g，搅拌溶解，控温至20℃，加入活性炭1g，搅拌10分钟，滤除活性炭，滤液降温至5℃，备用；Add 450 g of purified water to the reaction flask, control the temperature to 20 ° C, add 10 g of the crude biapenem obtained in Example 1 under stirring, stir to dissolve, control the temperature to 20 ° C, add 1 g of activated carbon, stir for 10 minutes, filter out Activated carbon, the filtrate was cooled to 5°C, for use;
向反应瓶中加入450ml的乙醇，降温至10℃，搅拌下，滴加上述滤液18ml，搅拌60分钟，滴加剩余的上述滤液，控制滴加速度，2小时滴加完毕，在15℃搅拌30分钟，降温至7℃，继续搅拌1.5小时，过滤，滤饼使用20g乙醇洗涤，在40～50℃下，真空干燥得到比阿培南原料药9.16g，收率91.6％，HPLC纯度为99.68％，杂质A为0.17％，杂质B为0.03％，粒径分布如图10所示，其中D10＝9.08μm、D50＝17.86μm、D90＝26.89μm。Add 450ml of ethanol to the reaction flask, cool down to 10°C, under stirring, add 18ml of the above-mentioned filtrate dropwise, stir for 60 minutes, add the remaining above-mentioned filtrate dropwise, control the rate of addition, complete the dropwise addition in 2 hours, and stir at 15°C for 30 minutes , cooled to 7 °C, continued to stir for 1.5 hours, filtered, and the filter cake was washed with 20 g of ethanol. At 40 to 50 °C, vacuum-dried to obtain 9.16 g of biapenem raw material, with a yield of 91.6% and a HPLC purity of 99.68%. The impurity A is 0.17%, the impurity B is 0.03%, and the particle size distribution is shown in Figure 10, wherein D10=9.08 μm, D50=17.86 μm, D90=26.89 μm.
对比例3Comparative Example 3
向反应瓶中加入水3L，控温至20℃，加入实施例1得到的比阿培南粗品100g，搅拌溶解后，加入活性炭10g，升温至40℃，搅拌20分钟，过滤，滤液转到结晶瓶中，搅拌下，向结晶反应瓶内加入8L丙酮和1g晶种，缓慢降温至20℃，继续搅拌养晶2小时，过滤，用800ml丙酮洗涤滤饼，在40～50℃下，真空干燥得比阿培南89g，收率89.0％，纯度为99.67％，杂质A为0.14％，杂质B为0.02％，粒径分布如图11，其中D10＝19.74μm、D50＝54.52μm、D90＝96.17μm。Add 3L of water to the reaction flask, control the temperature to 20°C, add 100g of the crude biapenem obtained in Example 1, stir and dissolve, add 10g of activated carbon, heat up to 40°C, stir for 20 minutes, filter, and the filtrate turns to crystallization In the bottle, under stirring, add 8L of acetone and 1g of seed crystals to the crystallization reaction bottle, slowly cool down to 20°C, continue to stir and grow the crystals for 2 hours, filter, wash the filter cake with 800ml of acetone, and vacuum dry at 40～50°C Debiapenem 89g, the yield is 89.0%, the purity is 99.67%, the impurity A is 0.14%, and the impurity B is 0.02%. μm.
对比例4Comparative Example 4
取对比例3得到的比阿培南50g进行机械粉粹，得比阿培南细粉42.3g，收率84.6％，粒径分布如图12，其中D10＝17.23μm、D50＝43.41μm、D90＝72.36μm。Take 50 g of biapenem obtained in Comparative Example 3 and carry out mechanical powdering to obtain 42.3 g of biapenem fine powder with a yield of 84.6%. = 72.36 μm.
对比例5Comparative Example 5
向反应瓶中加入水110ml，升温至57℃，加入实施例1得到的比阿培南粗品10g，搅拌溶解后，加入活性炭5g，搅拌30分钟，过滤，滤液转到结晶瓶中，控温至57℃，搅拌下，向结晶反应瓶内加入33ml乙醇，搅拌10分钟后，在4～5分钟内匀速滴加17ml异丙醇，停止加热，搅拌降温，15min降温至45℃，继续搅拌降温，35min降温至14℃，静置13小时，过滤，使用10ml乙醇洗涤滤饼，在40～50℃下，真空干燥得比阿培南8.8g，收率 88.0％，纯度为99.59％，杂质A为0.19％，杂质B为0.04％，粒径分布如图13，其中D10＝16.50μm、D50＝57.10μm、D90＝104.42μm。Add 110 ml of water to the reaction flask, heat up to 57°C, add 10 g of the crude biapenem obtained in Example 1, stir and dissolve, add 5 g of activated carbon, stir for 30 minutes, filter, transfer the filtrate to a crystallizing flask, and control the temperature to 57°C, under stirring, add 33ml of ethanol into the crystallization reaction flask, after stirring for 10 minutes, add 17ml of isopropanol dropwise at a uniform rate within 4-5 minutes, stop heating, stir to cool down, cool down to 45°C for 15 minutes, continue to stir and cool down, Cool to 14°C in 35min, let stand for 13 hours, filter, wash the filter cake with 10ml ethanol, and vacuum dry at 40-50°C to obtain 8.8 g of biapenem, yield 88.0%, purity 99.59%, impurity A is 0.19%, impurity B is 0.04%, the particle size distribution is shown in Figure 13, wherein D10=16.50 μm, D50=57.10 μm, D90=104.42 μm.
对比例6Comparative Example 6
向反应瓶中加入纯化水200g，升温至80℃，搅拌下，加入实施例1得到的比阿培南粗品10g，搅拌溶解，降温至35℃，加入活性炭2.5g，搅拌30分钟，滤除活性炭，滤液转到结晶瓶中，降温至20℃，搅拌下，向反应瓶中加入600ml丙酮乙醇溶剂(丙酮300ml、乙醇300ml)，控温20℃，搅拌30分钟后，继续在20℃搅拌6小时，过滤，滤饼使用乙醇丙酮溶液(10g乙醇、10g丙酮)洗涤，在40～50℃下，真空干燥得到比阿培南原料药9.24g，收率92.4％，HPLC纯度为99.76％，杂质A为0.11％，杂质B为0.03％，粒径分布如图14，其中D10＝32.59μm、D50＝51.61μm、D90＝71.72μm。Add 200g of purified water to the reaction flask, heat up to 80°C, add 10g of the crude biapenem obtained in Example 1 under stirring, stir to dissolve, cool down to 35°C, add 2.5g of activated carbon, stir for 30 minutes, filter out the activated carbon , the filtrate was transferred to the crystallizing flask, cooled to 20°C, under stirring, added 600ml of acetone ethanol solvent (300ml of acetone, 300ml of ethanol) to the reaction flask, controlled temperature to 20°C, stirred for 30 minutes, and continued to stir at 20°C for 6 hours , filtered, the filter cake was washed with ethanol acetone solution (10g ethanol, 10g acetone), at 40 ~ 50 ℃, vacuum drying to obtain biapenem bulk drug 9.24g, yield 92.4%, HPLC purity 99.76%, impurity A is 0.11%, impurity B is 0.03%, and the particle size distribution is shown in Figure 14, wherein D10=32.59 μm, D50=51.61 μm, D90=71.72 μm.
对比例7Comparative Example 7
向反应瓶中加入注射用水500g，控温5～15℃，加入实施例1得到的比阿培南粗品10g，搅拌溶解后，加入活性炭2g，搅拌40分钟，过滤，滤液转到结晶瓶中，搅拌下，向结晶瓶内加入3000ml丙酮乙醇混合溶剂(1000ml丙酮、2000ml乙醇)，控温5～15℃，搅拌析晶3小时，过滤，在40～50℃下，真空干燥得比阿培南8.65g，收率86.5％，纯度为99.63％，杂质A为0.15％，杂质B为0.02％，粒径分布如图15，其中D10＝18.82μm、D50＝47.86μm、D90＝78.47μm。Add 500 g of water for injection to the reaction flask, control the temperature at 5 to 15 °C, add 10 g of the crude biapenem obtained in Example 1, stir and dissolve, add 2 g of activated carbon, stir for 40 minutes, filter, and transfer the filtrate to a crystallizing flask, Under stirring, add 3000ml of acetone-ethanol mixed solvent (1000ml of acetone, 2000ml of ethanol) into the crystallizing bottle, control the temperature to 5-15°C, stir and crystallize for 3 hours, filter, and vacuum-dry at 40-50°C to obtain biapenem 8.65g, the yield is 86.5%, the purity is 99.63%, the impurity A is 0.15%, and the impurity B is 0.02%.
对比例8Comparative Example 8
向反应瓶中加入注射用水500g，控温5～15℃，搅拌下，加入实施例1得到的比阿培南粗品10g，搅拌溶解，控温至5～15℃，加入活性炭2g，搅拌40分钟，滤除活性炭，滤液降温至5～15℃，备用；Add 500 g of water for injection to the reaction flask, control the temperature to 5-15 °C, add 10 g of the crude biapenem obtained in Example 1 under stirring, stir to dissolve, control the temperature to 5-15 °C, add 2 g of activated carbon, and stir for 40 minutes , filter out the activated carbon, and cool the filtrate to 5-15°C for use;
向反应瓶中加入3000ml丙酮乙醇混合溶剂(1000ml丙酮、2000ml乙醇)，降温至5～15℃，搅拌下，滴加上述滤液20ml，搅拌60分钟，滴加剩余的上述滤液，控制滴加速度，1小时滴加完毕，在5～15℃搅拌2小时，过滤，滤饼使用20g丙酮洗涤，在40～50℃下，真空干燥得到比阿培南原料药8.59g，收率85.9％，HPLC纯度为99.67％，杂质A为0.11％，杂质B为0.01％，粒径分布如图16所示，其中D10＝4.11μm、D50＝11.26μm、D90＝20.66μm。Add 3000ml acetone-ethanol mixed solvent (1000ml acetone, 2000ml ethanol) to the reaction flask, cool down to 5～15 ℃, under stirring, add 20ml of the above-mentioned filtrate dropwise, stir for 60 minutes, add the remaining above-mentioned filtrate dropwise, control the rate of addition, 1 After completion of the dropwise addition in 2 hours, stirring at 5-15°C for 2 hours, filtering, the filter cake was washed with 20 g of acetone, and vacuum-dried at 40-50°C to obtain 8.59 g of biapenem bulk drug with a yield of 85.9% and HPLC purity of 8.59 g. 99.67%, impurity A is 0.11%, impurity B is 0.01%, and the particle size distribution is shown in Figure 16, wherein D10=4.11 μm, D50=11.26 μm, D90=20.66 μm.
对上述实例及对比试验得到的比阿培南产品进行检测，检测结果如下表2所示：The biapenem product obtained by above-mentioned example and comparative test is detected, and the detection result is as shown in the following table 2:
表2比阿培南产品检测结果Table 2 Test results of biapenem products
Figure PCTCN2020139134-appb-000005
Figure PCTCN2020139134-appb-000005
由表2数据可以看出，实施例2～9，对比例1～3、5～8制备得到的比阿培南归一含量均在99.5％以上，杂质A均小于0.2％，杂质B均小于0.05％；对比例3～7制备得到的比阿培南颗粒大，粒径分布(D50)为47～58μm，复溶时间均大于2分钟；从对比例4可以看出，将对比例3制备得到的比阿培南进行机械打粉，损失严重，收率只有84.6％，产品颗粒较大(D50为43.41μm)，复溶时间大于2分钟；对比例1、2和8分别采用丙酮、乙醇和丙酮与乙醇的混合溶液(丙酮：乙醇＝1：2，V:V)结晶溶剂，虽然制备得到的比阿培南颗粒小，粒径分布(D50)小于20μm，复溶时间短，但是流动性差，休止角(θ)分别为58°、45°、51°；实施例2～9，制备得到比阿培南颗粒适中，粒径分布(D50)在20～31μm之间，流动性好，休止角(θ)在30～40°之间，复溶时间短，均小于60秒。It can be seen from the data in Table 2 that the normalized content of biapenem prepared in Examples 2 to 9, Comparative Examples 1 to 3 and 5 to 8 is all above 99.5%, impurity A is less than 0.2%, and impurity B is less than 0.2%. 0.05%; the particles prepared in Comparative Examples 3 to 7 are larger than apenem particles, the particle size distribution (D50) is 47 to 58 μm, and the reconstitution time is more than 2 minutes; it can be seen from Comparative Example 4 that the preparation of Comparative Example 3 The obtained biapenem was mechanically powdered, and the loss was serious, the yield was only 84.6%, the product particle was large (D50 was 43.41 μm), and the reconstitution time was more than 2 minutes; Comparative Examples 1, 2 and 8 were respectively used acetone, ethanol and The mixed solution of acetone and ethanol (acetone:ethanol=1:2, V:V) crystallization solvent, although the prepared crystallization solvent is smaller than apenem particles, the particle size distribution (D50) is less than 20μm, and the redissolving time is short, but the fluidity is poor. , the angles of repose (θ) are 58°, 45°, and 51° respectively; in Examples 2 to 9, the prepared biapenem particles are moderate, the particle size distribution (D50) is between 20 and 31 μm, the fluidity is good, and the The angle (θ) is between 30 and 40°, and the reconstitution time is short, all less than 60 seconds.
对上述实例及对比例得到的比阿培南产品进行稳定性检测，检测结果如下表3所示：Stability detection is carried out to the biapenem product that above-mentioned example and comparative example are obtained, and detection result is as shown in table 3 below:
表3比阿培南高温(40℃)加速试验检测结果Table 3 Test results of biapenem high temperature (40℃) accelerated test
Figure PCTCN2020139134-appb-000006
Figure PCTCN2020139134-appb-000006
Figure PCTCN2020139134-appb-000007
Figure PCTCN2020139134-appb-000007
由表3数据可以看出，实施例2～9，对比例1、3、6高温加速反应30天，产品稳定性好，产品质量变化不明显；对比例2、5、7、8，高温加速反应30天后，比阿培南纯度下降明显，降幅均超过了0.5％。As can be seen from the data in Table 3, Examples 2 to 9, Comparative Examples 1, 3, and 6 accelerated the reaction at high temperature for 30 days, the product stability was good, and the change in product quality was not obvious; Comparative Examples 2, 5, 7, 8, the high temperature accelerated reaction After 30 days of reaction, the purity of biapenem decreased significantly, and the decrease rate was more than 0.5%.
综上所述，采用本发明所述的制备方法制备得到的比阿培南原料药纯度高、杂质状况清晰、稳定性好，能够保证产品有效、安全；产品晶体颗粒适中，粒径分布均匀，水溶性好，复溶时间短，流动性好，适合医疗利用和工业分装及储存；工艺简单、紧凑、易于控制，适合工业化运用，具有巨大的经济潜力。To sum up, the bisabenem raw material prepared by the preparation method of the present invention has high purity, clear impurity status and good stability, which can ensure the product is effective and safe; the product crystal particles are moderate, and the particle size distribution is uniform. It has good water solubility, short reconstitution time and good fluidity, and is suitable for medical use and industrial packaging and storage; the process is simple, compact and easy to control, suitable for industrial application and has huge economic potential.
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。The above are the preferred embodiments of the present invention. It should be pointed out that for those skilled in the art, without departing from the principles of the present invention, several improvements and modifications can be made. It should be regarded as the protection scope of the present invention.

Claims (13)

  1. 一种比阿培南原料药的制备方法，所述方法包括以下步骤：A preparation method of biapenem bulk drug, the method comprises the following steps:
    1)在一定溶解温度T 1下，将比阿培南粗品溶解在水中，制备得到比阿培南粗品水溶液； 1) under a certain dissolution temperature T 1 , the biapenem crude product is dissolved in water to prepare an aqueous solution of the biapenem crude product;
    2)将步骤1)所得的比阿培南粗品水溶液的温度控制为T 1或降温至T 2，加入活性炭，搅拌脱色，过滤，滤液降温至T 3备用； 2) the temperature of the aqueous solution of the biapenem crude product obtained in step 1) is controlled to be T 1 or cooled to T 2 , activated carbon is added, stirred for decolorization, filtered, and the filtrate is cooled to T 3 for subsequent use;
    3)将步骤2)所得的滤液滴加至预先降温至T 4的丙酮和乙醇的混合溶剂中，析晶； 3) adding the filtrate obtained in step 2) dropwise to the mixed solvent of acetone and ethanol cooled to T 4 in advance, and crystallizing;
    4)养晶；4) Cultivate crystals;
    5)将步骤4)中得到的晶体经分离、洗涤、干燥得到比阿培南原料药。5) Separating, washing and drying the crystals obtained in step 4) to obtain the biapenem bulk drug.
  2. 根据权利要求1所述的方法，其中，在步骤1)中，所述T 1为20-80℃，优选地为20-30℃，进一步优选地为20℃或30℃； The method according to claim 1, wherein, in step 1), the T 1 is 20-80°C, preferably 20-30°C, more preferably 20°C or 30°C;
    优选地，在步骤1)中，所述比阿培南粗品与水的质量比为1:20-80，更优选地为1:30-70，进一步优选地为1:45。Preferably, in step 1), the mass ratio of the crude biapenem to water is 1:20-80, more preferably 1:30-70, further preferably 1:45.
  3. 根据权利要求1或2所述的方法，其中，在步骤2)中，所述T 2为15-35℃，优选地为20-30℃，进一步优选地为20℃或30℃； The method according to claim 1 or 2, wherein, in step 2), the T 2 is 15-35°C, preferably 20-30°C, more preferably 20°C or 30°C;
    优选地，步骤2)中，所述活性炭与步骤1)所述的比阿培南粗品的质量比为0.05-0.25:1，进一步优选地为0.05-0.1:1，更优选地为0.1:1；Preferably, in step 2), the mass ratio of the activated carbon to the crude biapenem described in step 1) is 0.05-0.25:1, more preferably 0.05-0.1:1, more preferably 0.1:1 ;
    优选地，在步骤2)中，所述脱色的时间为5-30分钟，更优选地为10分钟；Preferably, in step 2), the decolorization time is 5-30 minutes, more preferably 10 minutes;
    优选地，在步骤2)中，所述T 3为0-20℃，更优选为5-10℃，进一步优选地为5℃或10℃。 Preferably, in step 2), the T 3 is 0-20°C, more preferably 5-10°C, further preferably 5°C or 10°C.
  4. 根据权利要求1-3中任一项所述的方法，其中，在步骤3)中，所述丙酮和乙醇的混合溶剂与步骤1)所述水的体积比为0.5-3:1，优选地为1:1；The method according to any one of claims 1-3, wherein, in step 3), the volume ratio of the mixed solvent of acetone and ethanol to the water described in step 1) is 0.5-3:1, preferably is 1:1;
    优选地，在步骤3)中，所述丙酮与乙醇的体积比为95-50:5-50，更优选地为85:15；Preferably, in step 3), the volume ratio of the acetone to ethanol is 95-50:5-50, more preferably 85:15;
    优选地，在步骤3)中，所述T 4为0-20℃，更优选地为10-15℃，更进一步优选地为10℃或15℃。 Preferably, in step 3), the T 4 is 0-20°C, more preferably 10-15°C, still more preferably 10°C or 15°C.
  5. 根据权利要求1-4中任一项所述的方法，其中，在步骤3)中，所述滴加的方式为连续滴加或分批滴加；The method according to any one of claims 1-4, wherein, in step 3), the dripping mode is continuous dripping or batchwise dripping;
    优选地，在步骤3)中，所述滴加的方式为连续滴加，滴加时间不小于1.5小时；或Preferably, in step 3), the dripping method is continuous dripping, and the dripping time is not less than 1.5 hours; or
    优选地，在步骤3)中，所述滴加的方式为分批次滴加；Preferably, in step 3), the dripping method is batchwise dripping;
    更优选地，所述分批次滴加为将步骤2)所得的滤液分两次滴加至丙酮和乙醇的混合溶剂中，其中，第一次滴加的滤液与步骤1)所述水的体积比为0.01-0.1:1，进一步优选地为0.04:1；More preferably, the dropwise addition is to drop the filtrate obtained in step 2) into the mixed solvent of acetone and ethanol twice, wherein the filtrate added dropwise for the first time is the same as the water in step 1). The volume ratio is 0.01-0.1:1, more preferably 0.04:1;
    优选地，在步骤3)中，所述分批次滴加为将步骤2)所得的滤液分两次滴加至丙酮和乙醇的混合溶剂中，其中，第一次滴加完毕后，搅拌30-120分钟，更优选地为搅拌60分钟；Preferably, in step 3), the dropwise addition is to drop the filtrate obtained in step 2) into the mixed solvent of acetone and ethanol twice, wherein, after the first dropwise addition is completed, stirring for 30 -120 minutes, more preferably stirring for 60 minutes;
    优选地，在步骤3)中，所述分批次滴加为将步骤2)所得的滤液分两次滴加至丙酮和乙醇的混合溶剂中，其中，第二次滴加的时间为0.5-3小时，更优选地为1-1.5小时，进一步优选地为1小时或1.5小时。Preferably, in step 3), the dropwise addition is to drop the filtrate obtained in step 2) into the mixed solvent of acetone and ethanol twice, wherein the time for the second dropwise addition is 0.5- 3 hours, more preferably 1-1.5 hours, further preferably 1 hour or 1.5 hours.
  6. 根据权利要求1-5中任一项所述的方法，其中，在步骤3)中，所述析晶的温度为0-20℃，优选地为15-20℃，进一步优选地为15℃或20℃；The method according to any one of claims 1-5, wherein, in step 3), the temperature of the crystallization is 0-20°C, preferably 15-20°C, more preferably 15°C or 20℃;
    优选地，在步骤3)中，所述析晶的时间为30分钟。Preferably, in step 3), the crystallization time is 30 minutes.
  7. 根据权利要求1-6中任一项所述的方法，其中，在步骤4)中，所述养晶的温度为0-20℃，优选地为7-12℃，进一步优选地为7℃或12℃；The method according to any one of claims 1-6, wherein, in step 4), the temperature of the crystal growing is 0-20°C, preferably 7-12°C, more preferably 7°C or 12℃;
    优选地，在步骤4)中，所述养晶的时间为0.5-6小时，更优选地为1.5小时。Preferably, in step 4), the time for growing the crystals is 0.5-6 hours, more preferably 1.5 hours.
  8. 根据权利要求1-7中任一项所述的方法，其中，在步骤5)中，所述分离是将养晶得到的晶体与溶液分离。The method according to any one of claims 1-7, wherein, in step 5), the separation is to separate the crystal obtained by growing the crystal from the solution.
  9. 根据权利要求1-8中任一项所述的方法，其中，在步骤5)中，所述洗涤可以采用丙酮和乙醇中的一种或它们的混合物进行；优选地，所述洗涤采用丙酮或乙醇进行；The method according to any one of claims 1-8, wherein, in step 5), the washing can be carried out with one of acetone and ethanol or a mixture thereof; preferably, the washing is carried out with acetone or Ethanol;
    优选地，在步骤5)中，所述干燥为在40-50℃下真空干燥。Preferably, in step 5), the drying is vacuum drying at 40-50°C.
  10. 根据权利要求1-9中任一项所述的方法，其中，所述方法包括以下步骤：The method according to any one of claims 1-9, wherein the method comprises the steps of:
    1)在一定溶解温度T 1下，将比阿培南粗品溶解在水中，制备得到比阿培南粗品水溶液； 1) under a certain dissolution temperature T 1 , the biapenem crude product is dissolved in water to prepare an aqueous solution of the biapenem crude product;
    2)将步骤1)所得的比阿培南粗品水溶液的温度控制为T 1或降温至T 2，加入活性炭，搅拌脱色，过滤，滤液降温至T 3备用； 2) the temperature of the aqueous solution of the biapenem crude product obtained in step 1) is controlled to be T 1 or cooled to T 2 , activated carbon is added, stirred for decolorization, filtered, and the filtrate is cooled to T 3 for subsequent use;
    3)将步骤2)所得的滤液滴加至预先降温至T 4的丙酮和乙醇的混合溶剂中，析晶； 3) adding the filtrate obtained in step 2) dropwise to the mixed solvent of acetone and ethanol cooled to T 4 in advance, and crystallizing;
    4)养晶；4) Cultivate crystals;
    5)将步骤4)中得到的晶体经分离、洗涤、干燥得到比阿培南原料药；5) the crystal obtained in step 4) is separated, washed and dried to obtain the biapenem bulk drug;
    其中，在步骤1)中，所述T 1为20-80℃；所述比阿培南粗品与水的质量比为1:20-80； Wherein, in step 1), the T 1 is 20-80 ° C; the mass ratio of the crude biapenem to water is 1:20-80;
    在步骤2)中，所述T 2为15-35℃；所述活性炭与步骤1)所述的比阿培南粗品的质量比为0.05-0.25:1；所述脱色的时间为5-30分钟；所述T 3为0-20℃； In step 2 ), the T2 is 15-35°C; the mass ratio of the activated carbon to the crude biapenem described in step 1) is 0.05-0.25:1; the decolorization time is 5-30 minutes; the T 3 is 0-20°C;
    在步骤3)中，所述丙酮和乙醇的混合溶剂与步骤1)所述水的体积比为0.5-3:1；所述丙酮与乙醇的体积比为95-50:5-50；所述T 4为0-20℃； In step 3), the volume ratio of the mixed solvent of acetone and ethanol to the water described in step 1) is 0.5-3:1; the volume ratio of the acetone and ethanol is 95-50:5-50; the T4 is 0-20℃ ;
    在步骤3)中，所述滴加的方式为分批次滴加；In step 3), the mode of described dripping is to drip in batches;
    在步骤3)中，所述析晶的温度为0-20℃；In step 3), the temperature of the crystallization is 0-20°C;
    在步骤4)中，所述养晶的温度为0-20℃；所述养晶的时间为0.5-6小时；In step 4), the temperature of the crystal growing is 0-20°C; the crystal growing time is 0.5-6 hours;
    在步骤5)中，所述洗涤可以采用丙酮和乙醇中的一种或它们的混合物进行。In step 5), the washing can be carried out with one of acetone and ethanol or a mixture thereof.
  11. 根据权利要求1-10中任一项所述的方法，其中，所述方法包括以下步骤：The method according to any one of claims 1-10, wherein the method comprises the steps of:
    1)在一定溶解温度T 1下，将比阿培南粗品溶解在水中，制备得到比阿培南粗品水溶液； 1) under a certain dissolution temperature T 1 , the biapenem crude product is dissolved in water to prepare an aqueous solution of the biapenem crude product;
    2)将步骤1)所得的比阿培南粗品水溶液的温度控制为T 1或降温至T 2，加入活性炭，搅拌脱色，过滤，滤液降温至T 3备用； 2) the temperature of the aqueous solution of the biapenem crude product obtained in step 1) is controlled to be T 1 or cooled to T 2 , activated carbon is added, stirred for decolorization, filtered, and the filtrate is cooled to T 3 for subsequent use;
    3)将步骤2)所得的滤液滴加至预先降温至T 4的丙酮和乙醇的混合溶剂中，析晶； 3) adding the filtrate obtained in step 2) dropwise to the mixed solvent of acetone and ethanol cooled to T 4 in advance, and crystallizing;
    4)养晶；4) Cultivate crystals;
    5)将步骤4)中得到的晶体经分离、洗涤、干燥得到比阿培南原料药；5) the crystal obtained in step 4) is separated, washed and dried to obtain the biapenem bulk drug;
    其中，在步骤1)中，所述T 1为20℃或30℃；所述比阿培南粗品与水的质量比为1:30-70； Wherein, in step 1), the T 1 is 20°C or 30°C; the mass ratio of the crude biapenem to water is 1:30-70;
    在步骤2)中，所述T 2为20℃或30℃；所述活性炭与步骤1)所述的比阿培南粗品的质量比为0.05-0.1:1；所述脱色的时间为10分钟；所述T 3为5-10℃； In step 2), the T 2 is 20°C or 30°C; the mass ratio of the activated carbon to the crude biapenem described in step 1) is 0.05-0.1:1; the decolorization time is 10 minutes ; Described T 3 is 5-10 ℃;
    在步骤3)中，所述丙酮和乙醇的混合溶剂与步骤1)所述水的体积比为1:1；所述丙酮与乙醇的体积比为85:15；所述T 4为10-15℃； In step 3), the volume ratio of the mixed solvent of acetone and ethanol to the water described in step 1) is 1: 1 ; the volume ratio of the acetone to ethanol is 85:15; the T is 10-15 °C;
    在步骤3)中，所述滴加的方式为分批次滴加，所述分批次滴加为将步骤2)所得的滤液分两次滴加至丙酮和乙醇的混合溶剂中，其中，第一次滴加的滤液与步骤1)所述水的体积比为0.01-0.1:1；所述分批次滴加为将步骤 2)所得的滤液分两次滴加至丙酮和乙醇的混合溶剂中，其中，第一次滴加完毕后，搅拌30-120分钟；所述分批次滴加为将步骤2)所得的滤液分两次滴加至丙酮和乙醇的混合溶剂中，其中，第二次滴加的时间为0.5-3小时；In step 3), the mode of the dropwise addition is dropwise addition in batches, and the dropwise addition in batches is to drop the filtrate obtained in step 2) into the mixed solvent of acetone and ethanol twice, wherein, The volume ratio of the filtrate added dropwise for the first time to the water described in step 1) is 0.01-0.1:1; the batchwise dropwise addition is that the filtrate obtained in step 2) is added dropwise to a mixture of acetone and ethanol twice. In a solvent, wherein, after the first dropwise addition is completed, stirring is performed for 30-120 minutes; the batchwise dropwise addition is to drop the filtrate obtained in step 2) into the mixed solvent of acetone and ethanol twice, wherein, The time of the second dripping is 0.5-3 hours;
    在步骤3)中，所述析晶的温度为15-20℃；所述析晶的时间为30分钟；In step 3), the temperature of the crystallization is 15-20°C; the time of the crystallization is 30 minutes;
    在步骤4)中，所述养晶的温度为7-12℃；所述养晶的时间为1.5小时；In step 4), the temperature of the crystal growing is 7-12°C; the crystal growing time is 1.5 hours;
    在步骤5)中，所述洗涤采用丙酮或乙醇进行；所述干燥为在40-50℃下真空干燥。In step 5), the washing is performed with acetone or ethanol; and the drying is vacuum drying at 40-50°C.
  12. 根据权利要求1-11中任一项所述的方法，其中，所述方法包括以下步骤：The method of any one of claims 1-11, wherein the method comprises the steps of:
    1)在一定溶解温度T 1下，将比阿培南粗品溶解在水中，制备得到比阿培南粗品水溶液； 1) under a certain dissolution temperature T 1 , the biapenem crude product is dissolved in water to prepare an aqueous solution of the biapenem crude product;
    2)将步骤1)所得的比阿培南粗品水溶液的温度控制为T 1或降温至T 2，加入活性炭，搅拌脱色，过滤，滤液降温至T 3备用； 2) the temperature of the aqueous solution of the biapenem crude product obtained in step 1) is controlled to be T 1 or cooled to T 2 , activated carbon is added, stirred for decolorization, filtered, and the filtrate is cooled to T 3 for subsequent use;
    3)将步骤2)所得的滤液滴加至预先降温至T 4的丙酮和乙醇的混合溶剂中，析晶； 3) adding the filtrate obtained in step 2) dropwise to the mixed solvent of acetone and ethanol cooled to T 4 in advance, and crystallizing;
    4)养晶；4) Cultivate crystals;
    5)将步骤4)中得到的晶体经分离、洗涤、干燥得到比阿培南原料药；5) the crystal obtained in step 4) is separated, washed and dried to obtain the biapenem bulk drug;
    其中，在步骤1)中，所述T 1为20-30℃；所述比阿培南粗品与水的质量比为1:45； Wherein, in step 1), the T 1 is 20-30 ° C; the mass ratio of the crude biapenem to water is 1:45;
    在步骤2)中，所述T 2为20-30℃；所述活性炭与步骤1)所述的比阿培南粗品的质量比为0.1:1；所述脱色的时间为10分钟；所述T 3为5℃或10℃； In step 2), the T 2 is 20-30°C; the mass ratio of the activated carbon to the crude biapenem described in step 1) is 0.1:1; the decolorization time is 10 minutes; the T3 is 5 °C or 10°C;
    在步骤3)中，所述丙酮和乙醇的混合溶剂与步骤1)所述水的体积比为1:1；所述丙酮与乙醇的体积比为85:15；所述T 4为10℃或15℃； In step 3), the volume ratio of the mixed solvent of acetone and ethanol to the water described in step 1) is 1:1; the volume ratio of the acetone to ethanol is 85:15; the T is 10 ° C. or 15℃;
    在步骤3)中，所述滴加的方式为分批次滴加，所述分批次滴加为将步骤2)所得的滤液分两次滴加至丙酮和乙醇的混合溶剂中，其中，第一次滴加的滤液与步骤1)所述水的体积比为0.04:1；所述分批次滴加为将步骤2)所得的滤液分两次滴加至丙酮和乙醇的混合溶剂中，其中，第一次滴加完毕后，搅拌60分钟；所述分批次滴加为将步骤2)所得的滤液分两次滴加至丙酮和乙醇的混合溶剂中，其中，第二次滴加的时间为1小时或1.5小时；In step 3), the mode of the dropwise addition is dropwise addition in batches, and the dropwise addition in batches is to drop the filtrate obtained in step 2) into the mixed solvent of acetone and ethanol twice, wherein, The volume ratio of the filtrate added dropwise for the first time to the water described in step 1) is 0.04:1; the batchwise dropwise addition is that the filtrate obtained in step 2) is added dropwise to the mixed solvent of acetone and ethanol twice. , wherein, after the first dropwise addition is completed, stir for 60 minutes; the batchwise dropwise addition is to drop the filtrate obtained in step 2) into the mixed solvent of acetone and ethanol in two drops, wherein the second dropwise addition The added time is 1 hour or 1.5 hours;
    在步骤3)中，所述析晶的温度为15℃或20℃；所述析晶的时间为30分钟；In step 3), the crystallization temperature is 15°C or 20°C; the crystallization time is 30 minutes;
    在步骤4)中，所述养晶的温度为7℃或12℃；所述养晶的时间为1.5 小时；In step 4), the temperature of the crystal growing is 7°C or 12°C; the crystal growing time is 1.5 hours;
    在步骤5)中，所述洗涤采用丙酮或乙醇进行；所述干燥为在40-50℃下真空干燥。In step 5), the washing is performed with acetone or ethanol; and the drying is vacuum drying at 40-50°C.
  13. 由权利要求1至12中任一项所述的方法制备的比阿培南原料药；The biapenem bulk drug prepared by the method according to any one of claims 1 to 12;
    优选地，所述比阿培南原料药中，比阿培南含量不小于99.5％，杂质A不大于0.2％，杂质B不大于0.05％。Preferably, in the biapenem API, the content of biapenem is not less than 99.5%, the impurity A is not more than 0.2%, and the impurity B is not more than 0.05%.
PCT/CN2020/139134 2020-08-17 2020-12-24 Preparation method for biapenem active ingredient WO2022036975A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202010825365.3 2020-08-17
CN202010825365.3A CN111875622B (en) 2020-08-17 2020-08-17 Preparation method of biapenem raw material medicine

Publications (1)

Publication Number Publication Date
WO2022036975A1 true WO2022036975A1 (en) 2022-02-24

Family

ID=73203290

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/139134 WO2022036975A1 (en) 2020-08-17 2020-12-24 Preparation method for biapenem active ingredient

Country Status (2)

Country Link
CN (1) CN111875622B (en)
WO (1) WO2022036975A1 (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111875622B (en) * 2020-08-17 2021-07-20 深圳市海滨制药有限公司 Preparation method of biapenem raw material medicine
CN114349772B (en) * 2020-10-13 2022-11-25 珠海联邦制药股份有限公司 Refining method of biapenem crude product
CN113912629A (en) * 2021-11-01 2022-01-11 石药集团中诺药业（石家庄）有限公司 Crystallization method of biapenem

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102268025A (en) * 2011-07-15 2011-12-07 海南美兰史克制药有限公司 Biapenem compound and preparation method thereof
CN102268024A (en) * 2011-06-10 2011-12-07 哈药集团制药总厂 Novel crystal form of biapenem and synthetic method thereof
CN102584862A (en) * 2011-11-16 2012-07-18 山东罗欣药业股份有限公司 Biapenem crystalline compound and composition powder-needle thereof
CN103159789A (en) * 2011-12-16 2013-06-19 四川科伦药物研究有限公司 Biapenem crystalline solid and preparation method thereof
CN111875622A (en) * 2020-08-17 2020-11-03 深圳市海滨制药有限公司 Preparation method of biapenem raw material medicine

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101121716A (en) * 2007-09-28 2008-02-13 严洁 Synthesis method for biapenem
CN103570750A (en) * 2013-11-15 2014-02-12 安徽悦康凯悦制药有限公司 Preparation process of biapenem
CN110343122B (en) * 2019-07-22 2021-01-01 山东罗欣药业集团股份有限公司 Preparation method of biapenem

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102268024A (en) * 2011-06-10 2011-12-07 哈药集团制药总厂 Novel crystal form of biapenem and synthetic method thereof
CN102268025A (en) * 2011-07-15 2011-12-07 海南美兰史克制药有限公司 Biapenem compound and preparation method thereof
CN102584862A (en) * 2011-11-16 2012-07-18 山东罗欣药业股份有限公司 Biapenem crystalline compound and composition powder-needle thereof
CN103159789A (en) * 2011-12-16 2013-06-19 四川科伦药物研究有限公司 Biapenem crystalline solid and preparation method thereof
CN111875622A (en) * 2020-08-17 2020-11-03 深圳市海滨制药有限公司 Preparation method of biapenem raw material medicine

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"Pharmaceutical Separation Engineering", 31 August 2011, EAST CHINA UNIVERSITY OF SCIENCE AND TECHNOLOGY PRESS, CN, ISBN: 978-7-5628-3066-5, article SONG, HANG ET AL.: "Passage; Pharmaceutical Separation Engineering", pages: 278 - 280, XP009534809 *
"Physical Pharmacy", 30 November 2018, CHINA TRADITIONAL CHINESE MEDICINE PRESS, CN, ISBN: 978-7-5132-5291-1, article WU, QING ET AL.: "Passage; Physical Pharmacy", pages: 165 - 181, XP009534810 *

Also Published As

Publication number Publication date
CN111875622A (en) 2020-11-03
CN111875622B (en) 2021-07-20

Similar Documents

Publication Publication Date Title
WO2022036975A1 (en) Preparation method for biapenem active ingredient
KR101929960B1 (en) Crystalline form of ertapenem sodium and preparation method therefor
CN107501268B (en) Preparation method of tebipenem pivoxil and intermediate thereof
CN111517980A (en) N- [8- (2-hydroxybenzoyl) amino ] caprylic acid monopotassium crystal type compound, preparation method and application
CN111747959B (en) Preparation method of imipenem raw material medicine
CN101914098A (en) Preparation method of Meropenem trihydrate crystals
WO2024093156A1 (en) Continuous preparation method for ceftazidime
CN109824700B (en) Preparation method of cefotetan disodium
CN109232389B (en) Method for preparing small-particle-size nifedipine crystals
CN111233893A (en) Preparation process of sulbactam sodium
EP4375285A1 (en) New crystalline form of ertapenem sodium and preparation method therefor
CN102942577A (en) Cefoxitin sodium compound-containing pharmaceutical composition
CN110396102B (en) Cefoxitin sodium compound pharmaceutical preparation and application thereof in prevention of infection before vaginal hysterectomy, abdominal hysterectomy and cesarean section (uterine)
CN111793076B (en) Preparation method of cefpirome sulfate for injection
CN110105374B (en) Crystallization method of phenylacetyl-7-amino-3-desacetoxy cephalosporanic acid with controllable granularity and crystal habit
CN108707158B (en) Method for purifying cefpirome sulfate
WO2020244148A1 (en) Doramectin crystal form a, crystal form b, and preparation method thereof
CN110804080A (en) Acetaminoavermectin crystal form A, crystal form B, amorphous and preparation method thereof
CA1339422C (en) Crystalline (5r,6s)-2-carbamoyloxymethyl-6-¬(1r)-hydroxyethyl|-2-penem-carboxylic acid and its pharmaceutical formulation
CN111909180B (en) Preparation method of ceftriaxone sodium crystal with good stability and high operability
CN114853786B (en) Preparation method of cefoxitin sodium powder
CN111777625B (en) Preparation method of ceftizoxime sodium for injection
CN103570719A (en) Meropenem raw medicine, preparation method thereof and pharmaceutical composition containing same
WO2014094659A1 (en) Process for preparation of meropenem trihydrate crystals
CN112745337B (en) Preparation method of cefuroxime acid

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20950176

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20950176

Country of ref document: EP

Kind code of ref document: A1