WO2023115523A1 - 一种无定型阿尼芬净的制备方法 - Google Patents

一种无定型阿尼芬净的制备方法 Download PDF

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WO2023115523A1
WO2023115523A1 PCT/CN2021/141131 CN2021141131W WO2023115523A1 WO 2023115523 A1 WO2023115523 A1 WO 2023115523A1 CN 2021141131 W CN2021141131 W CN 2021141131W WO 2023115523 A1 WO2023115523 A1 WO 2023115523A1
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anifungin
preparation
solvent
anidulafungin
amorphous
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PCT/CN2021/141131
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French (fr)
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阳凯
黄枚
孙鹏
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浙江海正药业股份有限公司
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Priority to PCT/CN2021/141131 priority Critical patent/WO2023115523A1/zh
Priority to CN202180065342.XA priority patent/CN116940584A/zh
Publication of WO2023115523A1 publication Critical patent/WO2023115523A1/zh

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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/14—Extraction; Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/14—Extraction; Separation; Purification
    • C07K1/30—Extraction; Separation; Purification by precipitation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
    • C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid

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  • the invention relates to the field of drug synthesis, in particular to a preparation method of amorphous anidulungin.
  • Echinocandin B is a new type of drug developed in the early 21st century. It has a new mechanism of action, a broad antifungal spectrum, no cross-resistance, and no obvious adverse reactions caused by its own mechanism of action. It is the safest drug so far. The highest antifungal drug is currently an ideal drug for the treatment of deep fungal infections.
  • Anidulafungin (Anidulafungin, formula I) is a semi-synthetic antifungal drug of the third generation echinocandins, which was originally developed by Vicuron Pharmaceutical Company of the United States. It passed the clinical application of FDA in May 2004, and was later approved by Pfizer Acquired by a pharmaceutical company and first listed in the United States in December 2006, the trade name is Eraxis, the dosage form is freeze-dried powder injection, and it is suitable for the following fungal infections: 1 Candidemia and other types of candida infections (abdominal abscess, peritonitis) ; 2 esophageal candidiasis. Since anidulungin does not undergo hepatic metabolism and renal clearance, it is possible to use combined medication and patients with poor liver and kidney function without dose adjustment, and the drug is safe and well tolerated, and has broad market prospects.
  • Anifungin is a semi-synthetic drug after the chemical modification of echinocandin B, a product of microbial fermentation, which produces various isomers, degradation products and other impurities in the process of biotransformation and chemical reaction (easy under high temperature and acid-base conditions) Degradation occurs), most of these impurities are close to the structure and properties of the target product, which brings great difficulties to the subsequent purification of the final product.
  • the Anifungin refining method disclosed both at home and abroad mainly contains the following types:
  • Reversed-phase liquid chromatography such as WO9527074
  • this method generally requires the use of high-pressure preparation columns and expensive packing, the amount of solvent used is large, the scale of preparation and purification is small, and the energy consumption is large. It is not suitable for industrial production, and it is concentrated to dry mode in addition The quality of the finished product obtained is not uniform (the concentrated sample has uneven particle size, the solvent may not be removed completely, and the residual solvent in it is not uniform), which does not meet the requirements of the preparation for the uniformity of the pharmaceutical raw material;
  • the invention provides a method for preparing amorphous anidulungin, which has less solvent consumption, good refining effect, high product purity and high yield, large solid particles, easy to filter and good stability, and stable process.
  • the product has good stability, simple process and convenient operation, and is suitable for industrial production.
  • a preparation method of amorphous anifungin comprising the following steps:
  • Step 1 dissolving the crude product of Anifungin in an organic solvent containing water
  • Step 2 adding anti-solvent dropwise to precipitate Anifungin, and separate to obtain pure amorphous Anifungin;
  • the water content of the dissolved system is controlled to be 0.3% to 2.5%, and the content is a mass ratio.
  • the temperature in the second step is 20-45°C, preferably 20.5-44.6°C.
  • the organic solvent in step 1 is an aprotic polar solvent, preferably tetrahydrofuran or acetone.
  • the volume-to-weight ratio of the organic solvent in step 1 to the crude product of anidulungin is 20-90:1, and the unit is mL/g.
  • the anti-solvent in step 2 is an aprotic solvent, preferably ethyl acetate or methyl tert-butyl ether.
  • the volume ratio of the anti-solvent in step 2 to the organic solvent in step 1 is 3-10:1.
  • the separation includes filtration, and the filtration uses a sieve plate with a pore size of 20-30 ⁇ m.
  • the chromatographic purity of the main peak of the crude anidulungin is greater than 97.0%.
  • the present invention adopts a kind of unconventional solvent system to dissolve the crude product of Anifungin, adopts the dissolution crystallization method to refine, the steps are simple, easy to operate, the refining effect is good (the purity is all above 99.3%), and the yield is high ( Can be as high as 95%), suitable for industrialized large-scale production.
  • the present invention avoids the crystal particles being too fine to be intercepted and filtered by controlling the moisture limit in the solvent, or the crystal system becomes jelly-like without solid precipitation.
  • the solid particles obtained by operating the method of the present invention are large and easy to filter, and the obtained crystal system can be well filtered with a 20-30 ⁇ m sieve plate, and the obtained solid finished product not only meets the requirements of the preparation for uniform quality of the raw material drug, but also has good stability of the reserved sample. .
  • the present invention also avoids the technical defects in the prior art by using reversed-phase liquid chromatography or normal phase chromatography to separate and purify Anifungin.
  • the solvent used is a commonly used solvent with less consumption and low cost. It is suitable for industrialized production, and the resulting finished product has uniform quality and high purity, and meets the general requirements for related substances, properties, and uniformity during drug registration.
  • Fig. 1 is the HPLC spectrum of the prepared crude product of Anifungin.
  • Fig. 2 is the X-ray powder diffraction spectrum of the pure product of Anifungin obtained in Example 1.
  • Fig. 3 is the HPLC collection of illustrative plates of the pure product of Anifungin obtained in Example 6.
  • the instrument for HPLC detection of Anifungin involved in the present invention is Aglient1200 type.
  • the moisture meter used for detection in the present invention is a 915KF Ti-Touch type Wantong moisture meter.
  • the X-ray powder diffraction instrument involved in the present invention is Rigaku SmartLab SE, and the test method: the working voltage is 40kV, the working current is 40mA, the step size is 0.01°, and the scanning speed is 6.00°/min.
  • the crude product of Anifungin used in the present invention is produced by Zhejiang Hisun Pharmaceutical Co., Ltd.
  • the crude anidulungin was synthesized with the self-made anidulungin mother nucleus and side chain, and the HPLC purity was 97.95%.
  • the HPLC spectrum of the obtained crude anidungin is shown in Figure 1.
  • Comparative example 1 The moisture content of the system is 0.23%
  • Comparative example 2 the moisture content of the system is 2.65%

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Peptides Or Proteins (AREA)

Abstract

本发明提供了一种无定型阿尼芬净的制备方法，该制备方法包括：阿尼芬净粗品溶解于含有一定比例水的有机溶剂中；滴加反溶剂使阿尼芬净析出，分离得到无定型阿尼芬净纯品。本发明提供的方法精制效果好，结晶收率高，所得固体颗粒大、易于过滤且稳定性好，操作简便，适合工业化生产。

Description

一种无定型阿尼芬净的制备方法 技术领域
本发明涉及药物合成领域，具体涉及一种无定型阿尼芬净的制备方法。
背景技术
近年来，随着肿瘤化疗、器官移植、艾滋病等发病率的增加，真菌感染发病率显著升高，尤其是深部真菌感染的发生率及由此引起的死亡率持续上升，严重威胁人类健康，已经成为临床较为棘手的问题之一。棘白菌素B类是21世纪初开发的新型药物，具有全新的作用机理，抗真菌谱广，无交叉耐药性，无因其本身作用机制而引发的明显不良反应，是迄今为止安全性最高的一种抗真菌药物，是目前用于治疗深度真菌感染比较理想的药物。
阿尼芬净(Anidulafungin，式Ⅰ)是第三代棘白菌素类的半合成抗真菌药物，该药最初由美国Vicuron制药公司研制，2004年5月通过FDA的临床申请，后被美国辉瑞制药公司收购，并于2006年12月在美国首次上市，商品名Eraxis，剂型为冻干粉针，适用于下列真菌感染：①念珠菌血症及其他类型的念珠菌感染(腹腔脓肿、腹膜炎)；②食管念珠菌病。由于阿尼芬净不经过肝代谢和肾清除，使得联合用药以及肝肾功能不良患者无需调整剂量成为可能，且用药安全，耐受性好，具有广阔的市场前景。
Figure PCTCN2021141131-appb-000001
阿尼芬净为微生物发酵产物棘白菌素B经过化学修饰后的半合成药物，在生物转化和化学反应过程中产生多种异构体、降解产物等杂质(在高温、酸碱条件下容易发生降解)，此类杂质大都与目标产物结构性质接近，给后续终产物的纯化带来较大的困难。国内外公开的阿尼芬净精制方法主要有以下几种：
(1)反相液相色谱法，如WO9527074，此方法普遍需要使用高压制备柱和昂贵填料，溶媒用量大，制备纯化规模小，能耗大，不适用于产业化生产，另外浓缩至干方式得到的成品质量不均一(浓缩后的样品，颗粒大小不均一，溶剂可能去除不彻底，里面残留溶剂也不均一)，不满足制剂对药品原料药均一性的要求；
(2)正相层析色谱法，如CN201310146413.6，此方法硅胶和溶媒用量大，操作时间长(硅胶正相纯化涉及装柱、上样、流动相配制、洗脱、检测合并、浓缩等步骤，且该方法为梯度洗脱，需要配制不同流动相)，能耗大，成本较高，不适合工业生产，另外浓缩至干方式得到的成品质量不均一，不满足制剂对药品原料药均一性的要求；
(3)结晶方法，Timothy N，John V等(Commercialization and Late-Stage Development of a Semisynthetic Antifungal API:Anidulafungin/D-Fructose(Eraxis)Organic Process Research&Development 2008,12,447–455)报道了制备阿尼芬净-果糖共晶复合物的方法，该工艺需要高温溶解、梯度降温、加晶种，操作较繁琐，文献中也没有报道终产物的纯度；专利CN201410335233.7公开了一种阿尼芬净结晶精制方法，该工艺以混合溶剂溶解粗品，通过降温使主成分析出，收率较低，且静置析晶时间较长，不适合工业生产。
开发一种适用于工业化生产的无定型阿尼芬净的制备方法成为本技术领域待解决的难题。
发明内容
本发明提供了一种无定型阿尼芬净的制备方法，该方法溶剂用量少，精制效果好，产品纯度高、收率高，所得固体颗粒大、易于过滤且稳定性好，工艺稳定，产品稳定性好，工艺简单，操作方便，适用于工业化生产。
为解决上述技术问题，本发明所采取的技术方案是：
一种无定型阿尼芬净的制备方法，包括以下步骤：
步骤一：将阿尼芬净粗品溶解于含有水的有机溶剂中；
步骤二：滴加反溶剂使阿尼芬净析出，分离得到无定型阿尼芬净纯品；
所述步骤一控制溶解后体系的水分含量为0.3％～2.5％，所述含量为质量比。
优选的，所述步骤二的温度为20～45℃，优选20.5～44.6℃。
优选的，所述步骤一的有机溶剂为非质子极性溶剂，优选为四氢呋喃或丙酮。
优选的，所述步骤一的有机溶剂与阿尼芬净粗品的体积重量比为20～90:1，单位为mL/g。
优选的，所述步骤二的反溶剂为非质子溶剂，优选为乙酸乙酯或甲基叔丁基醚。
优选的，所述步骤二的反溶剂与步骤一的有机溶剂的体积比为3～10:1。
优选的，所述分离包括过滤，所述过滤使用筛板的孔径为20～30μm。
优选的，所述阿尼芬净粗品的主峰色谱纯度大于97.0％。
与现有技术相比，本发明的有益效果主要体现在：
(1)本发明采用一种非常规的溶剂体系溶解阿尼芬净粗品，采用溶析结晶法进行精制，步骤简单，操作简便，精制效果好(纯度均在99.3％以上)，收率高(可高达95％)，适宜进行工业化大生产。
(2)本发明通过控制溶剂中的水分限度来避免结晶颗粒太细而很难截留过滤，或者结晶体系变成果冻状而无固体析出。按本发明方法操作所得固体颗粒大、易于过滤，得到的结晶体系用20～30μm的筛板均可很好过滤，所得固体成品既满足制剂对原料药质量均一的要求，留样稳定性也好。
(3)本发明也避免了现有技术通过使用反相液相色谱法或者正相层析色谱法分离纯化阿尼芬净存在的技术缺陷，所用溶剂为常用溶剂，用量少，成本低，适合工业化生产，所得成品质量均一、纯度高，满足药品注册时对有关物质、性状、均匀性等的一般要求。
附图说明
图1为制备得到的阿尼芬净粗品的HPLC图谱。
图2为实施例1所得阿尼芬净纯品的X-射线粉末衍射图谱。
图3为实施例6所得阿尼芬净纯品的HPLC图谱。
具体实施方式
以下实施例对本发明作进一步说明，但有必要指出以下实施例只用于对发明内容的描述，并不构成对本发明保护范围的限制，本发明保护范围以权利要求为准。
在下列实例中，除非另有指明，所有温度为摄氏温度；除非另有指明，各种起始原料和试剂均来自市售，均不经进一步纯化直接使用；除非另有指明，各种溶剂均为工业级溶剂，不经进一步处理直接使用。
本发明涉及的阿尼芬净HPLC检测的仪器为Aglient1200型。
本发明涉及的检测用水分仪为915KF Ti-Touch型万通水分仪。
本发明涉及的X-射线粉末衍射仪器为Rigaku SmartLab SE，测试方法：工作电压为40kV，工作电流为40mA，步长为0.01°，扫描速度为6.00°/min。
本发明所使用的阿尼芬净粗品为浙江海正药业股份有限公司生产。采用WO9906062中Preparation 9A的合成路线，以自制的阿尼芬净母核和侧链合成阿尼芬净粗品，HPLC纯度为97.95％，所得阿尼芬净粗品的HPLC图谱见图1。
实施例1
取1.0g阿尼芬净粗品，加入45mL四氢呋喃及0.7mL水，搅拌使之溶清，体系水分含量为1.07％，滴加225mL甲基叔丁基醚，滴加过程中体系温度为20.5～23.0℃，滴加完毕后继续搅拌0.5h，用20μm筛板过滤，滤速快，滤液澄清，滤饼用2mL甲基叔丁基醚淋洗，抽干，室温下真空干燥得0.90g阿尼芬净纯品，收率90.0％，获得的阿尼芬净纯品的HPLC纯度为99.46％。
所得阿尼芬净纯品为无定型，其X-射线粉末衍射图谱见图2。
实施例2
取1.0g阿尼芬净粗品，加入20mL四氢呋喃及0.5mL水，加热搅拌使之溶清，体系水分含量为2.17％，停止加热，滴加60mL乙酸乙酯，滴加过程中体系温度为37.5～44.6℃，滴加完毕后继续搅拌0.5h，用30μm筛板过滤，滤速快，滤液澄清，滤饼用2mL乙酸乙酯淋洗，抽干，室温下真空干燥得0.95g阿尼芬净纯品，收率95.0％，获得的阿尼芬净纯品的HPLC纯度为99.38％。
所得阿尼芬净纯品为无定型，其X-射线粉末衍射图谱与图2一致。
实施例3
取1.0g阿尼芬净粗品，加入90mL四氢呋喃及2.3mL水，搅拌使之溶清，体系水分含量为2.49％，滴加900mL乙酸乙酯，滴加过程中体系温度为32.5～35.0℃，滴加完毕后继续搅拌0.5h，用20μm筛板过滤，滤速快，滤液澄清，滤饼用2mL乙酸乙酯淋洗，抽干，室温下真空干燥得0.88g阿尼芬净纯品，收率88.0％，获得的阿尼芬净纯品的HPLC纯度为99.57％。
所得阿尼芬净纯品为无定型，其X-射线粉末衍射图谱与图2一致。
实施例4
取1.0g阿尼芬净粗品，加入45mL四氢呋喃及0.2mL水，搅拌使之溶清，体系水分含量为0.30％，滴加225mL甲基叔丁基醚，滴加过程中体系温度为22.8～24.1℃，滴加完毕后继续搅拌0.5h，用20μm筛板过滤，滤速快，滤液澄清，滤饼用2mL甲基叔丁基醚淋洗，抽干，室温下真空干燥得0.91g阿尼芬净纯品，收率91.0％，获得的阿尼芬净纯品的HPLC纯度为99.41％。
所得阿尼芬净纯品为无定型，其X-射线粉末衍射图谱与图2一致。
实施例5
取1.0g阿尼芬净粗品，加入45mL丙酮及0.5mL水，搅拌使之溶清，体系水分含量为0.84％，滴加225mL甲基叔丁基醚，滴加过程中体系温度为24.0～27.5℃，滴加完毕后继续搅拌0.5h，用30μm筛板过滤，滤速快，滤液澄清，滤饼用2mL甲基叔丁基醚淋洗，抽干，室温下真空干燥得0.91g阿尼芬净纯品，收率91.0％，获得的阿尼芬净纯品的HPLC纯度为 99.39％。
所得阿尼芬净纯品为无定型，其X-射线粉末衍射图谱与图2一致。
实施例6
取40.0g阿尼芬净粗品，加入800mL四氢呋喃及15mL水，搅拌使之溶清，体系水分含量为2.20％，滴加4000mL甲基叔丁基醚，滴加过程中体系温度为26.1～29.7℃，滴加完毕后继续搅拌0.5h，用20μm筛板过滤，滤速快，滤液澄清，滤饼用80mL甲基叔丁基醚淋洗，抽干，室温下真空干燥得37.1g阿尼芬净纯品，收率92.8％，获得的阿尼芬净纯品的HPLC纯度为99.54％。
所得阿尼芬净纯品为无定型，其X-射线粉末衍射图谱与图2一致。
所得阿尼芬净纯品的HPLC图谱见图3。
实施例7
按实施例6制备方法操作得到的阿尼芬净纯品在2～8℃及-20±5℃的稳定性数据如下：
Figure PCTCN2021141131-appb-000002
对比例1：体系水分含量为0.23％
取1.0g阿尼芬净粗品，加入45mL四氢呋喃及0.1mL水，搅拌使之溶清，体系水分含量为0.23％，滴加225mL甲基叔丁基醚，滴加过程中体系温度为24.3～26.4℃，滴加完毕后继续搅拌0.5h，用20μm筛板过滤，滤液浑浊，滤饼用2mL甲基叔丁基醚淋洗，抽干，室温下真空干燥得0.11g阿尼芬净纯品，收率11.0％，获得的阿尼芬净纯品的HPLC纯度为99.44％。
所得阿尼芬净纯品为无定型，其X-射线粉末衍射图谱与图2一致。
对比例2：体系水分含量为2.65％
取1.0g阿尼芬净粗品，加入45mL四氢呋喃及1.2mL水，搅拌使之溶清，体系水分含量为2.65％，滴加225mL甲基叔丁基醚，滴加过程中体系温度为21.6～23.1℃，滴加过程中无固体析出，体系变为果冻状，滴加完毕后继续搅拌5h，体系仍未有固体析出。

Claims (7)

  1. 一种无定型阿尼芬净的制备方法，其特征在于，所述制备方法包括以下步骤：
    步骤一：将阿尼芬净粗品溶解于含有水的有机溶剂中；
    步骤二：滴加反溶剂使阿尼芬净析出，分离得到无定型阿尼芬净纯品；
    所述步骤一控制溶解后体系的水分含量为0.3％～2.5％，所述含量为质量比。
  2. 根据权利要求1所述的制备方法，其特征在于，所述步骤二的温度为20～45℃。
  3. 根据权利要求1或2所述的制备方法，其特征在于，所述步骤一的有机溶剂为非质子极性溶剂，优选为四氢呋喃或丙酮。
  4. 根据权利要求1-3任一项所述的制备方法，其特征在于，所述步骤一的有机溶剂与阿尼芬净粗品的体积重量比为20～90:1，单位为mL/g。
  5. 根据权利要求1-4任一项所述的制备方法，其特征在于，所述步骤二的反溶剂为非质子溶剂，优选为乙酸乙酯或甲基叔丁基醚。
  6. 根据权利要求1-5任一项所述的制备方法，其特征在于，所述步骤二的反溶剂与步骤一的有机溶剂的体积比为3～10:1。
  7. 根据权利要求1-6任一项所述的制备方法，其特征在于，所述分离包括过滤，所述过滤使用筛板的孔径为20～30μm。
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