WO2021217537A1 - 一种乐伐替尼游离碱晶型及其制备方法 - Google Patents

一种乐伐替尼游离碱晶型及其制备方法 Download PDF

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WO2021217537A1
WO2021217537A1 PCT/CN2020/087941 CN2020087941W WO2021217537A1 WO 2021217537 A1 WO2021217537 A1 WO 2021217537A1 CN 2020087941 W CN2020087941 W CN 2020087941W WO 2021217537 A1 WO2021217537 A1 WO 2021217537A1
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crystal form
cancer
water
dimethyl sulfoxide
ethanol
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PCT/CN2020/087941
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French (fr)
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贾慧娟
陈岩
张琦
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天津睿创康泰生物技术有限公司
北京睿创康泰医药研究院有限公司
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Priority to PCT/CN2020/087941 priority Critical patent/WO2021217537A1/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

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  • the present invention relates to the field of crystal formations, in particular to a crystal form of lenovatinib free base that is safer and more stable at room temperature, and its preparation method and application.
  • Lovatinib mesylate is an anticancer drug developed by Eisai Co., Ltd., code: E7080, which is an oral multi-receptor tyrosine kinase (RTK) inhibitor.
  • Lovatinib is a multi-target drug, the main targets include VEGFR-1, VEGFR-2, VEGFR-3, FGFR1, PDGFR, cKit, Ret.
  • the FDA has approved lenvatinib for the treatment of kidney cancer, thyroid cancer and liver cancer.
  • the active ingredient of the product on the market is the methanesulfonate of levatinib.
  • the methanesulfonate needs to be stored at 2-8°C, otherwise it will degrade and produce genotoxic impurities (LVTN-ZZ-H ), especially under the conditions of damp heat (40°C/RH75%), this degradation will be aggravated, and the control limit of this genotoxic impurity in the raw material of levatinib mesylate is 60ppm.
  • the storage conditions of the crystal form C bulk drug of lenvatinib mesylate used in the current marketed products are 2-8°C; in addition, the active ingredients on the market exist in the form of mesylate, which is used in the preparation of medicines.
  • it may undergo an esterification reaction with the lower alcohol introduced in the excipients to form genotoxic impurities of alkyl methanesulfonate.
  • Patent CN100569753C reported on the crystal form of the free base of levatinib, in which the crystallization solvent of the free base is a mixed solvent of dimethyl sulfoxide, acetone, and water.
  • Patent US2007117842 reports six different crystal forms of free base, and the crystallization solvent is also a mixed solvent of dimethyl sulfoxide, acetone, and water.
  • the stability of the drug crystal form is very important to the quality, safety and effectiveness of the pharmaceutical composition or pharmaceutical preparation.
  • the chemical stability, physical stability, storage conditions and shelf life of the active ingredients are also very important factors.
  • it is ideal to provide the drug in a fully crystalline and stable form. In fact, it is usually impossible to predict what kind of crystallization behavior of a compound will occur from the molecular structure alone, which is generally determined empirically.
  • the present invention provides a crystal form of levatinib free base with better safety and stability, and the crystal form is suitable for making related pharmaceutical compositions for the treatment of diseases such as cancer .
  • the present invention provides a crystal form of lenvatinib free base, the structure of which is shown in formula I and exists in an anhydrous and solvent-free form;
  • the present invention exhibits at least 3 following characteristic peaks as 2 ⁇ values in any combination in an X-ray powder diffraction pattern recorded at 25°C using Cu-K ⁇ radiation: 10.16°( ⁇ 0.2° ), 12.26°( ⁇ 0.2°), 13.90°( ⁇ 0.2°), 16.40°( ⁇ 0.2°), 18.94°( ⁇ 0.2°), 21.54°( ⁇ 0.2°), 23.40°( ⁇ 0.2°), 26.54°( ⁇ 0.2°), 27.84°( ⁇ 0.2°), 29.30°( ⁇ 0.2°).
  • the characteristic peaks of the X-ray powder diffraction pattern may be between one machine and another machine and between one sample and another sample. There will be slight changes. The value may differ by about 1 unit, or by about 0.8 unit, or by about 0.5 unit, or by about 0.3 unit, or by about 0.1 unit, so the value given cannot be considered For absolute. Similarly, the values given in the differential scanning calorimetry graphs of the above-mentioned crystal forms cannot be regarded as absolute.
  • its differential scanning calorimetry curve shows an endothermic melting peak at 228.5 ⁇ 2°C.
  • its infrared spectrum has characteristic absorption peaks at 3339.5 cm -1 , 3183.14 cm -1 , 2978.79 cm -1 , 1662.55 cm -1 , 1557.79 cm -1 , and 1494.99 cm -1.
  • thermogravimetric analysis chart is shown in FIG. 3.
  • the thermogravimetric analysis curve loses 0.4% when heated to 211.8°C, and loses 2.8% when heated to 225.8°C.
  • the proton nuclear magnetic resonance spectrum is shown in FIG. 6.
  • the present invention also provides a method for preparing the crystal form.
  • the crude product of the compound represented by formula I is dissolved in a solvent for crystallization.
  • the solvent includes one or more of dimethyl sulfoxide/acetone/water, dimethyl sulfoxide/ethanol/water, dimethyl sulfoxide/tetrahydrofuran/water
  • the solvent is dimethyl sulfoxide/ethanol/water; more preferably, the mass ratio of dimethyl sulfoxide/ethanol/water is 6/1/1.
  • the crystallization includes:
  • the method for preparing the crude product of the compound represented by formula I is as follows: lenvatinib free base is dissolved in dimethyl sulfoxide by heating, and a mixture of ethanol and water is added under insulation conditions, The crude product of the compound shown in formula I is obtained;
  • the solvent includes one or more mixed solvents of dimethyl sulfoxide/acetone/water, dimethyl sulfoxide/ethanol/water, dimethyl sulfoxide/tetrahydrofuran/water; preferably dimethyl sulfoxide /Ethanol/water; the mass ratio of dimethyl sulfoxide/ethanol/water is about 6/1/1;
  • heating temperature 40°C ⁇ 80°C.
  • the crystalline form provided by the present invention or the crystalline form prepared by the method is placed under humid and hot conditions (40°C/RH75%) for 30 days, and the genotoxic impurity LVTN-ZZ-H hardly grows.
  • the crystalline form provided by the present invention or the crystalline form prepared by the method is stored at room temperature for two years, and the detected amount of the genotoxic compound LVTN-ZZ-H will not exceed 60 ppm.
  • the present invention also provides the use of the crystal form or the crystal form prepared by the method in the preparation of RTK inhibitors and/or the preparation of drugs for preventing and/or treating cancer.
  • the cancer includes kidney cancer, thyroid cancer, liver cancer, prostate cancer, rectal cancer, bladder cancer, breast cancer, pancreatic cancer, skin cancer, ovarian cancer and lung cancer.
  • the present invention also provides a pharmaceutical composition or pharmaceutical preparation, comprising the crystal form or the crystal form prepared by the method and pharmaceutically acceptable excipients.
  • the present invention provides a safe and stable crystal form of levatinib free base, and the crystal form is suitable for making relevant pharmaceutical compositions for the treatment of diseases such as cancer.
  • FIG 1 shows the preparation method of the crude compound of formula I
  • FIG. 2 shows the DSC of the compound of formula I: 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide;
  • Figure 3 shows the compound of formula I: TGA of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide;
  • Figure 4 shows the XRPD of the compound of formula I: 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide; wherein, Figure 4(A ) Is the spectrogram, Figure 4(B) shows the spectrogram data;
  • Figure 5 shows the IR of the compound of formula I: 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide; wherein, Figure 5(A ) Is the spectrum, Figure 5(B) shows the data of the spectrum; Figure 6 shows the compound of formula I: 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy- H-NMR of 6-quinoline carboxamide;
  • Figure 7 shows the compound of formula I: XRPD of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide methanesulfonate Form C ;
  • Figure 7(A) is the spectrogram, and
  • Figure 7(B) shows the spectrogram data.
  • the invention discloses a crystal form of lenvatinib free base, a preparation method and application thereof, and those skilled in the art can learn from the content of this article and appropriately improve the process parameters to realize it.
  • all similar replacements and modifications are obvious to those skilled in the art, and they are all deemed to be included in the present invention.
  • the method and application of the present invention have been described through the preferred embodiments. It is obvious that relevant persons can make changes or appropriate changes and combinations to the methods and applications described herein without departing from the content, spirit and scope of the present invention to achieve and Apply the technology of the present invention.
  • the present invention aims to provide a crystalline lenvatinib free base, namely the compound of the following formula I:
  • the compound of formula I has a sufficient crystalline form.
  • the compound of formula I is usually named 4-(3-chloro-4-(N'-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxylic acid amide.
  • the crystal form of the compound of formula I is crystal form A, and the crystal form exists in a practically anhydrous, solvent-free form.
  • Crystal form A can be identified by its melting start point and powder X-ray diffraction pattern. The melting of crystal form A starts in the range of 228.5 ⁇ 2°C.
  • the crystal form A When the crystal form A is substantially pure and essentially anhydrous and solvent-free, it is at 12.26°( ⁇ 0.2°), 16.40°( ⁇ 0.2°), 18.94°( ⁇ 0.2°), 21.54° ( ⁇ 0.2°), 26.54°( ⁇ 0.2°), 29.30°( ⁇ 0.2°). 2 ⁇ has an X-ray powder diffraction pattern with a special high-intensity peak.
  • the crystal form A has a temperature range of 10.16°( ⁇ 0.2°), 12.26°( ⁇ 0.2°), 13.90°( ⁇ 0.2°), 16.40°( ⁇ 0.2°), 18.94°( ⁇ 0.2°), 21.54° ( ⁇ 0.2°), 23.40°( ⁇ 0.2°), 26.54°( ⁇ 0.2°), 27.84°( ⁇ 0.2°), 29.30°( ⁇ 0.2°).
  • the infrared spectrum of crystal form A has characteristic absorption peaks at 3339.5 cm -1 , 3183.14 cm -1 , 2978.79 cm -1 , 1662.55 cm -1 , 1557.79 cm -1 , and 1494.99 cm -1.
  • a method for preparing the crystal form A of the compound of formula I is provided.
  • the crude compound of formula I is crystallized in a suitable solvent, and the solvent is selected from: dimethyl sulfoxide/acetone/water, dimethyl sulfoxide/ Ethanol/water, dimethylsulfoxide/tetrahydrofuran/water, more preferably the solvent is selected from: dimethylsulfoxide/ethanol/water; the mass ratio of dimethylsulfoxide/ethanol/water is about 6/1 /1.
  • a method for preparing the crystal form A of the compound of formula I is provided.
  • the compound of formula I is dissolved in dimethyl sulfoxide by heating, a mixture of ethanol and water is added dropwise under heat preservation, and crystallizing after cooling, Then, the solid crystal form is separated by conventional separation means, and after drying, the compound of formula I of crystal form A is obtained.
  • the present invention provides a safer and more stable crystal form of lenvatinib free base, and the crystal form is suitable for making relevant pharmaceutical compositions for the treatment of diseases such as cancer.
  • the present invention adopts internationally recognized X-ray powder diffraction method (XRPD), DSC, TGA, IR, H-NMR to study and characterize the crystal form A of levatinib free base.
  • XRPD X-ray powder diffraction method
  • DSC Differential Scanning Calorimetry
  • the X-ray powder diffraction pattern of the present invention is collected on a Panalytical Empyrean X-ray powder diffractometer.
  • the parameters of the X-ray powder diffraction method of the present invention are as follows:
  • Anti-scatter slit 0.15°
  • Scanning range from 3 to 40 degrees;
  • Measuring time per step 3 seconds/step.
  • the differential scanning calorimetry chart of the present invention is collected on a DSC204F1 differential scanning calorimeter.
  • the method parameters of the differential scanning calorimetry analysis of the present invention are as follows:
  • the infrared spectrogram test method of the present invention is as follows:
  • Test instrument Spectrum 65 Fourier transform infrared spectrometer
  • Instrument calibration use the infrared spectrum absorption peak of the polystyrene film to calibrate the instrument wave number (refer to the Chinese Pharmacopoeia 2015 edition of the four general rules 0402).
  • thermogravimetric analysis of the present invention are as follows:
  • Heating rate 10°C/min
  • Atmosphere nitrogen, 20 ml/min.
  • Test solvent According to the solubility and structural characteristics of this product, select deuterated DMSO as the test solvent;
  • the crystal form of lenvatinib free base provided by the present invention, its preparation method and the raw materials and reagents used in its application can all be purchased from the market.
  • Example 1 Synthesis of 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxylic acid amide (LVTN-1).
  • Example 3 Preparation of crude 4-(3-chloro-4-(N'-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxylic acid amide (LVTN).
  • Example 4 Preparation of 4-(3-chloro-4-(N'-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxamide LVTN crystal form A.
  • Comparative Example 1 Preparation of 4-(3-chloro-4-(N'-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxylic acid amide methanesulfonate crystal form C .
  • Test Example 1 Comparing lenvatinib mesylate C crystal form and lenvatinib free base crystal form A on damp-heat influence factors test
  • lenvatinib mesylate C crystal form and lenvatinib free base crystal form A were tested under humid and hot conditions of 40°C/RH75%, and samples were taken for detection on 10 and 30 days respectively, and genotoxic impurities were compared. Detected amount of LVTN-ZZ-H and detected amount of common degradation impurities. At the same time, the normal degradation impurities and genotoxic impurities of lenvatinib free base crystal form A stored at room temperature for about two years and lenvatinib mesylate crystal form C stored at 2-8°C for two years were compared. The results are shown respectively The following table.
  • the above-mentioned influencing factors data show that lenvatinib free base A crystal form left for 30 days under the condition of damp heat (40°C/RH75%), the genotoxic impurity LVTN-ZZ-H and the ordinary degradation impurity did not show an increasing trend;
  • the crystalline form C of lenvatinib sulfonate was placed for 30 days under the condition of damp heat (40°C/RH75%), the general degradation impurity LVTN-ZZ-G increased from 0.04% at 0 days to 0.10% at 30 days;
  • the genotoxic impurity LVTN -ZZ-H increased from 64ppm at 0 days to 92ppm at 30 days; free base A crystals were stored at room temperature for 2 years and lenvatinib mesylate C crystals were stored for 2 years at 2-8°C.
  • the growth rate of type genotoxic impurities is much lower than that of crystal form C of lenvatinib mesylate under refrigerated conditions, and other common degradation impurities are within control limits. Therefore, the stability and safety of crystal form A of lenvatinib free base are better than crystal form C of lenvatinib mesylate.

Abstract

涉及乐伐替尼游离碱的晶型、其制备方法及应用。该游离碱晶型更安全、稳定性更好，常温贮藏，适用于制作相关的药物组合物，使其用于癌症等疾病的治疗。

Description

一种乐伐替尼游离碱晶型及其制备方法 技术领域
本发明涉及晶型领域，特别涉及一种更安全的、常温下稳定性更好的乐伐替尼游离碱的晶型、其制备方法及应用。
背景技术
甲磺酸乐伐替尼是由日本卫材株式会社Eisai研发的一种抗癌药物，代码：E7080，属口服多受体酪氨酸激酶(RTK)抑制剂。乐伐替尼是个多靶点的药物，主要靶点包括VEGFR-1、VEGFR-2、VEGFR-3、FGFR1、PDGFR、cKit、Ret。FDA已经批准乐伐替尼用于肾癌、甲状腺癌和肝癌的治疗。2017年6月4日，在美国临床肿瘤学会(ASCO)年会上，卫材公司公布了乐伐替尼一线治疗手术不可切除的肝细胞肝癌(uHCC)随机、开放、非劣效III期临床试验(REFLECT研究)的结果。数据显示，乐伐替尼一线治疗uHCC，在OS方面非劣效于索拉非尼，达到了主要研究终点；在次要研究终点方面PFS、TTP和ORR显著优于索拉非尼。乐伐替尼REFLECT研究巨大的成功或将改变近十年来肝癌药物治疗现状。
目前本品上市产品的活性成分是乐伐替尼的甲磺酸盐，该甲磺酸盐作为药用原料药需要在2-8℃保存，否则会降解产生基因毒性杂质(LVTN-ZZ-H)，尤其在湿热(40℃/RH75％)条件下，这种降解会加剧，该基因毒性杂质在甲磺酸乐伐替尼原料药中的控制限度为60ppm。因此，目前上市产品中所使用的甲磺酸乐伐替尼的C晶型原料药的贮藏条件为2-8℃；另外，上市的活性成分以甲磺酸盐的形式存在，在制备成药物组合物或药物制剂时，可能会与辅料中引入的低级醇发生酯化反应形成甲磺酸烷基酯类基因毒性杂质。专利CN100569753C对乐伐替尼游离碱的晶型有报道，其中游离碱的结晶溶剂为二甲亚砜、丙酮、水的混合溶剂。专利US2007117842报道了游离碱六种不同的晶型，结晶溶剂也为二甲亚砜、丙酮、水的混合溶剂。
在制备药物组合物中，药物晶型稳定对药物组合物或药物制剂的质 量、安全性和有效性是十分重要的。所述活性成分的化学稳定性、物理稳定性和储存条件和储存期限也是非常重要的因素。在生产商业上可行并且药学上可接受的药用组合物时，以一种充分结晶和稳定的形态提供药物都是理想的。事实上，通常无法单从分子结构预知化合物将发生何种结晶行为，这一般是凭经验确定的。
发明内容
有鉴于此，本发明提供提供一种安全性、稳定性更好的乐伐替尼游离碱的晶型，且该晶型适用于制作相关的药物组合物，使其用于癌症等疾病的治疗。
为了实现上述发明目的，本发明提供以下技术方案：
本发明提供了乐伐替尼游离碱的晶型，其结构如式I所示且以无水、无溶剂的形态存在；
Figure PCTCN2020087941-appb-000001
其在利用Cu-Kα辐射在25℃下记录的X射线粉末衍射图中以任何组合呈现至少3个作为2θ值的如下特殊的高强度峰：12.26°(±0.2°)、16.40°(±0.2°)、18.94°(±0.2°)、21.54°(±0.2°)、26.54°(±0.2°)、29.30°(±0.2°)。
在本发明的一些具体实施方案中，其在利用Cu-Kα辐射在25℃下记录的X射线粉末衍射图中以任何组合呈现至少3个作为2θ值的如下特征峰：10.16°(±0.2°)、12.26°(±0.2°)、13.90°(±0.2°)、16.40°(±0.2°)、18.94°(±0.2°)、21.54°(±0.2°)、23.40°(±0.2°)、26.54°(±0.2°)、27.84°(±0.2°)、29.30°(±0.2°)。
本领域技术人员应当理解，衍射的相对强度可以根据许多因素例如制备样品的方法和所用仪器的类型而变化。此外，在一定的情况下，上述峰 中的一部分可能不是可检出的。实际上，上文列出的峰仅是申请人鉴别出的显著的峰。峰的完整列表(尽管在很多情况下很小)在图4中给出。
再次申明，这是申请人所鉴别出的峰的全面列表。基于这些峰中很多峰的相对强度，技术人员将理解，由不同的研究者在另一仪器上对相同多晶型形式的分析可能无法鉴别出上文所鉴别的所有小峰，表中的峰仅作为全面列表而提供。为了鉴别的目的，认为在图4中鉴别出的峰，尤其是中强峰，对本发明的多晶型物的存在更有特征性。
值得注意的是，对于以上所述晶型的X-射线粉末衍射图，在一台机器和另一台机器之间以及一个样品和另一个样品之间，X-射线粉末衍射图的特征峰可能会略有变化，其数值可能相差大约1个单位，或者相差大约0.8个单位，或者相差大约0.5个单位，或者相差大约0.3个单位，或者相差大约0.1个单位，因此所给出的数值不能视为绝对的。同样以上所述晶型的差示扫描量热分析曲线图所给出的数值也不能视为绝对的。
在本发明的一些具体实施方案中，其差示扫描量热曲线显示在228.5±2℃有吸热熔融峰。
在本发明的一些具体实施方案中，其红外谱图在3339.5cm -1、3183.14cm -1、2978.79cm -1、1662.55cm -1、1557.79cm -1、1494.99cm -1处具有特征吸收峰。
在本发明的一些具体实施方案中，其热重分析图如图3所示。其热重分析曲线在加热到211.8℃时，失重0.4％；在加热到225.8℃时，失重2.8％。
在本发明的一些具体实施方案中，其核磁共振氢谱图如图6所示。
本发明还提供了一种制备所述晶型的方法，取如式I所示化合物的粗品溶解在溶剂中结晶。
在本发明的一些具体实施方案中，所述溶剂包括二甲基亚砜/丙酮/水、二甲基亚砜/乙醇/水、二甲基亚砜/四氢呋喃/水中的一种或两者以上的混合溶剂，优选的，所述溶剂为二甲基亚砜/乙醇/水；更优选的，二甲基亚砜/乙醇/水的质量比为6/1/1。
在本发明的一些具体实施方案中，所述结晶包括：
(1)通过浓缩所述溶剂；或
(2)通过冷却至环境温度或降温至25℃～30℃中间的任一温度；或
(3)通过添加所述仑伐替尼游离碱的晶型的晶种；或
(4)通过(1)、(2)或(3)的任意组合。
在本发明的一些具体实施方案中，如式I所示化合物的粗品的制备方法为：乐伐替尼游离碱在二甲基亚砜中加热溶解，保温条件下加入乙醇和水的混合液，制得如式I所示化合物的粗品；
所述溶剂包括二甲基亚砜/丙酮/水、二甲基亚砜/乙醇/水、二甲基亚砜/四氢呋喃/水中的一种或两者以上的混合溶剂；优选二甲基亚砜/乙醇/水；二甲基亚砜/乙醇/水的质量比约为6/1/1；
所以加热的温度为40℃～80℃。
本发明提供的所述的晶型或所述方法制备的晶型在湿热条件(40℃/RH75％)放置30天，基因毒性杂质LVTN-ZZ-H几乎不增长。
本发明提供的所述的晶型或所述方法制备的晶型在室温条件下贮藏两年，基因毒性化合物LVTN-ZZ-H的检出量不会超过60ppm。
本发明还提供了所述的晶型或所述方法制备的晶型在制备氨酸激酶(RTK)抑制剂和/或制备预防和/或治疗癌症的药物中的用途。优选的，癌症包括肾癌、甲状腺癌、肝癌、前列腺癌、直肠癌、膀胱癌、乳腺癌、胰腺癌、皮肤癌、卵巢癌及肺癌。
本发明还提供了一种药物组合物或药物制剂，包含所述的晶型或所述方法制备的晶型以及药学上可接受的辅料。
本发明提供了一种安全的、稳定的乐伐替尼游离碱的晶型，且该晶型适用于制作相关的药物组合物，使其用于癌症等疾病的治疗。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍。
图1示式I化合物粗品的制备方法；
图2示式I化合物：4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰胺的DSC；
图3示式I化合物：4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰胺的TGA；
图4示式I化合物：4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰胺的XRPD；其中，图4(A)是谱图，图4(B)示谱图数据；
图5示式I化合物：4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰胺的IR；其中，图5(A)是谱图，图5(B)示谱图数据；图6示式I化合物：4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰胺的H-NMR；
图7示式I化合物：4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰胺甲磺酸盐C晶型的XRPD；其中图7(A)是谱图，图7(B)示谱图数据。
具体实施方式
本发明公开了一种乐伐替尼游离碱的晶型、其制备方法及应用，本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。本发明的方法及应用已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。
本发明旨在提供一种结晶态的乐伐替尼游离碱，即下图式I化合物：
Figure PCTCN2020087941-appb-000002
所述式I化合物存在一种充分的结晶形态。式I化合物通常命名为4-(3-氯-4-(N’-环丙基脲基)苯氧基)-7-甲氧基喹啉-6-羧酸酰胺。
在本发明的一个方面，所述式I化合物的晶型为晶型A，该晶型为实际上的无水、无溶剂形式存在。
晶型A可通过它的熔融开始点、粉末X-射线衍射图进行鉴定。晶型 A的熔融开始是在228.5±2℃的范围内。
当晶型A是实质上纯的且基本为上无水、无溶剂的形态时，它在12.26°(±0.2°)、16.40°(±0.2°)、18.94°(±0.2°)、21.54°(±0.2°)、26.54°(±0.2°)、29.30°(±0.2°)。2θ有特殊的高强度峰的X射线粉末衍射图。更进一步，晶型A具有在10.16°(±0.2°)、12.26°(±0.2°)、13.90°(±0.2°)、16.40°(±0.2°)、18.94°(±0.2°)、21.54°(±0.2°)、23.40°(±0.2°)、26.54°(±0.2°)、27.84°(±0.2°)、29.30°(±0.2°)。2θ有特征峰的X射线粉末衍射图。
晶型A的红外谱图在3339.5cm -1、3183.14cm -1、2978.79cm -1、1662.55cm -1、1557.79cm -1、1494.99cm -1处具有特征吸收峰。
本发明的另一方面，提供式I化合物的制备方法，合成路线如图1所示：
本发明的另一方面，提供式I化合物晶型A的制备方法，通过式I化合物粗品在适宜的溶剂中结晶，溶剂选自：二甲基亚砜/丙酮/水、二甲基亚砜/乙醇/水、二甲基亚砜/四氢呋喃/水，更优选的所述溶剂选自：二甲基亚砜/乙醇/水；二甲基亚砜/乙醇/水的质量比约为6/1/1。
本发明的另一方面，提供了式I化合物晶型A的制备方法，将式I化合物在二甲基亚砜中通过加热溶解，保温下滴加乙醇和水的混合液，冷却后析晶，随后用常规分离手段将固体晶型分离，并干燥后得到晶型A的式I化合物。
本发明提供了一种更安全、更稳定的乐伐替尼游离碱的晶型，且该晶型适用于制作相关的药物组合物，使其用于癌症等疾病的治疗。
本发明现在将参照以下非限制性实施例而描述。
本发明采用国际上公认的X-射线粉末衍射法(XRPD)、DSC、TGA、IR、H-NMR来研究和表征乐伐替尼游离碱晶型A。
术语：
XRPD：X-射线粉末衍射；
DSC：差示扫描量热法；
TGA：热重分析；
IR：红外光谱分析；
H-NMR：核磁共振氢谱。
测定条件与方法：
其中本发明所述的X射线粉末衍射图在Panalytical Empyrean X-射线粉末衍射仪上采集。本发明所述的X射线粉末衍射的方法参数如下：
X射线反射参数：Cu-Ka；
电压：36仟伏特(kV)；
电流：20毫安培(mA)；
发散狭缝：1°；
防散射狭缝：0.15°；
扫瞄范围：自3至40度；
扫描速度：4度/分
取样步长：0.02度；
每步测量时间：3秒/步。
扫描参数如表1所示。
表1 XRPD测试参数
Figure PCTCN2020087941-appb-000003
Figure PCTCN2020087941-appb-000004
本发明所述的差示扫描量热分析图在DSC 204F1差示扫描量热仪上采集。本发明所述的差示扫描量热分析的方法参数如下：
温度范围/℃:30℃-250℃；
扫描速率/℃/分钟:10℃/分钟；
保护气体：氮气，20毫升/分钟。
本发明所述的红外谱图测试方法如下：
测试仪器：Spectrum 65傅里叶变换红外光谱仪
测试条件：KBr压片法
仪器校正：用聚苯乙烯薄膜的红外光谱吸收峰对仪器波数进行校正(参考中国药典2015年版四部通则0402)。
制样条件：KBr压片法
扫描范围：400-4000cm -1。
本发明所述的热重分析的方法参数如下：
温度范围：30-250℃；
升温速度：10℃/分钟；
气氛：氮气，20毫升/分钟。
本发明所述的核磁共振氢谱的方法参数如下：
仪器型号：Bruker-B-600核磁共振波谱仪(600HMz)；
测试溶剂：根据本品的溶解度及结构特点，选择氘代DMSO为测试 溶剂；
本发明提供的乐伐替尼游离碱的晶型、其制备方法及应用中所用原料及试剂均可由市场购得。
下面结合实施例，进一步阐述本发明：
实施例1：中间体：4-(4-氨基-3-氯苯氧基)-7-甲氧基喹啉-6-羧酸酰胺(LVTN-1)的合成。
向反应釜中加入4.40kg的DMF、0.80kg的SM1和0.58kg的SM2，控温加入0.45kg的氢氧化钠，室温搅拌，反应结束后滴加水，析出固体，过滤，滤饼淋洗后干燥，所得粗品用二甲基亚砜再次溶解，滴加丙酮和水的混合液析晶，过滤，滤饼淋洗后干燥得0.985kg的棕红色固体，即LVTN-1，收率：85％。
实施例2：中间体：(4-((6-羧酸甲酰胺基-7-甲氧基喹啉-4-基)氧)-2-氯苯基)氨基甲酸苯酯(LVTN-2)的合成。
向50.00L的反应釜中加入20.25kg的DMSO、0.91kg的吡啶和0.98kg实施例1中制备的LVTN-1，滴加1.12kg的氯甲酸苯酯，室温搅拌，反应结束后滴加水18.30kg，滴毕，过滤，滤饼淋洗后干燥得1.14kg固体，即为LVTN-2，收率：86％。
实施例3：4-(3-氯-4-(N’-环丙基脲基)苯氧基)-7-甲氧基喹啉-6-羧酸酰胺(LVTN)粗品的制备。
向反应釜中加入11.31kg的DMF，搅拌下将1.14kg实施例2中制备的LVTN-2加入，升温至50℃，控温下滴加0.30kg的环丙胺，反应结束后滴加丙酮15.33kg，室温搅拌，析晶，过滤，滤饼淋洗后于60℃鼓风干燥得0.77kg的LVTN粗品，收率：74％。
实施例4：4-(3-氯-4-(N’-环丙基脲基)苯氧基)-7-甲氧基喹啉-6-羧酸酰胺LVTN晶型A的制备。
将0.77kg实施例3中制备的LVTN粗品加入7.20kg的二甲基亚砜 中，搅拌下加热至65℃，滴加2.34kg的乙醇和水的混合液(乙醇：水＝1:1)，缓慢降温至室温，析晶完全后过滤，滤饼淋洗后于40℃鼓风干燥得539.00g的乐伐替尼游离碱，即LVTN晶型A，经DSC(图2)确定其熔融开始为228.5℃，TGA(图3)和XRPD(图4)，IR(图5)，H-NMR(图6)。
对比例1：4-(3-氯-4-(N’-环丙基脲基)苯氧基)-7-甲氧基喹啉-6-羧酸酰胺甲磺酸盐晶型C的制备。
氮气保护下，向5L三口瓶中，依次加入2352g醋酸和86g甲磺酸，开启搅拌，控温25℃，加入320g 4-(3-氯-4-(N'-环丙基脲基)苯氧基)-7-甲氧基喹啉-6-羧酸酰胺(LVTN-3)，搅拌1～2小时至溶清，过滤，收集滤液，将滤液转移至10L反应釜中，氮气保护下，控温25℃，滴加2579g正丙醇，滴加时间1～2小时。滴毕，滴加1424g醋酸异丙酯，滴加时间1～2小时。滴毕，继续控温25℃下搅拌1～2小时。过滤，滤饼用570g醋酸异丙酯、1520g乙醇淋洗，得到甲磺酸乐伐替尼的醋酸合物。
氮气保护下，向5L三口瓶中加入2147g乙醇，控温20～25℃，加入上述甲磺酸乐伐替尼醋酸合物，搅拌24小时，过滤，滤饼用506g乙醇淋洗，在30～35℃条件下，减压干燥12小时(真空度：-0.1MPa)，得到甲磺酸乐伐替尼成品327g，为类白色粉末，产率为：83.41％。经XRPD(图7)射线衍射确认为甲磺酸乐伐替尼的C晶型。
试验例1：将甲磺酸乐伐替尼C晶型与乐伐替尼游离碱晶型A进行湿热影响因素试验对比
将甲磺酸乐伐替尼C晶型和乐伐替尼游离碱晶型A置湿热条件40℃/RH75％条件下进行影响因素试验，分别于10天、30天取样检测，对比基因毒性杂质LVTN-ZZ-H的检出量及普通降解杂质的检出量。同时对室温放置约两年的乐伐替尼游离碱A晶型及2-8℃保存两年的甲磺酸乐伐替尼C晶型普通降解杂质和基因毒性杂质进行了对比，结果分别见下表。
表2 乐伐替尼游离碱A晶型影响因素实验
Figure PCTCN2020087941-appb-000005
表3 甲磺酸乐伐替尼C晶型影响因素实验
Figure PCTCN2020087941-appb-000006
上述影响因素数据表明，乐伐替尼游离碱A晶型在湿热(40℃/RH75％)条件下放置30天，基因毒性杂质LVTN-ZZ-H和普通降解杂质均未呈现增长趋势；而甲磺酸乐伐替尼C晶型经湿热(40℃/RH75％)条件下放置30天，普通降解杂质LVTN-ZZ-G由0天的0.04％增加至30天的0.10％；基因毒性杂质LVTN-ZZ-H由0天的64ppm增加至30天的92ppm；游离碱A晶型室温放置2年和甲磺酸乐伐替尼C晶型2-8℃放置2年相比，游离碱A晶型基因毒性杂质的增长幅度远低于冷藏条件下的甲磺酸乐伐替尼C晶型，其他普通降解杂质均在控制限度内。因此，乐伐替尼游离碱A晶型的稳定性和安全性与甲磺酸乐伐替尼C晶型相比更好。
以上对本发明所提供的乐伐替尼游离碱晶型及其制备方法进行了详细介绍。本文应用了具体个例对本发明的原理及实施方式进行了阐述，以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出，对于本技术领域技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。

Claims (14)

  1. 乐伐替尼游离碱的晶型，其特征在于，其结构如式I所示且以无水、无溶剂的形态存在；
    Figure PCTCN2020087941-appb-100001
    其在利用Cu-Kα辐射在25℃下记录的X射线粉末衍射图中以任何组合呈现至少3个作为2θ值的如下特殊的高强度峰：12.26°(±0.2°)、16.40°(±0.2°)、18.94°(±0.2°)、21.54°(±0.2°)、26.54°(±0.2°)、29.30°(±0.2°)。
  2. 如权利要求1所述的晶型，其特征在于，其在利用Cu-Kα辐射在25℃下记录的X射线粉末衍射图中以任何组合呈现至少3个作为2θ值的如下特征峰：10.16°(±0.2°)、12.26°(±0.2°)、13.90°(±0.2°)、16.40°(±0.2°)、18.94°(±0.2°)、21.54°(±0.2°)、23.40°(±0.2°)、26.54°(±0.2°)、27.84°(±0.2°)、29.30°(±0.2°)。
  3. 如权利要求1或2所述的晶型，其特征在于，其差示扫描量热曲线显示在228.5±2℃有吸热熔融峰。
  4. 如权利要求1至3任一项所述的晶型，其特征在于，其红外谱图在3339.5cm-1、3183.14cm-1、2978.79cm-1、1662.55cm-1、1557.79cm-1、1494.99cm-1处具有特征吸收峰。
  5. 一种制备如权利要求1至4任一项所述晶型的方法，其特征在于，取如式I所示化合物的粗品溶解在溶剂中结晶。
  6. 根据权利要求5所述的方法，其特征在于，所述溶剂包括二甲基亚砜/丙酮/水、二甲基亚砜/乙醇/水、二甲基亚砜/四氢呋喃/水中的一种或两者以上的混合溶剂，优选二甲基亚砜/乙醇/水；二甲基亚砜/乙醇/水的质量比约为6/1/1。
  7. 根据权利要求5或6所述的方法，其特征在于，所述结晶包括：
    (1)通过浓缩所述溶剂；或
    (2)通过冷却至环境温度或降温至25℃～30℃中间的任一温度；或
    (3)通过添加所述晶型的晶种；或
    (4)通过(1)、(2)或(3)的任意组合。
  8. 如权利要求5至7任一项所述的方法，其特征在于，如式I所示化合物的粗品的制备方法为：乐伐替尼游离碱在二甲基亚砜中加热溶解，保温条件下加入乙醇和水的混合液，制得如式I所示化合物的粗品；
    所述溶剂包括二甲基亚砜/丙酮/水、二甲基亚砜/乙醇/水、二甲基亚砜/四氢呋喃/水中的一种或两者以上的混合溶剂；优选二甲基亚砜/乙醇/水；二甲基亚砜/乙醇/水的质量比约为6/1/1；
    所以加热的温度为40℃～80℃。
  9. 如权利要求1至4任一项所述的晶型或如权力要求5-7任一项所述方法制备的晶型在湿热条件(40℃/RH75％)放置30天，基因毒性杂质LVTN-ZZ-H几乎不增长。
  10. 如权利要求1至4任一项所述的晶型或如权力要求5-7任一项所述方法制备的晶型在室温条件下贮藏两年，基因毒性化合物LVTN-ZZ-H的检出量不会超过60ppm。
  11. 如权利要求1至4任一项所述的晶型或如权力要求5-7任一项所述方法制备的晶型在制备药物组合物或药物制剂时，不会与其他成分中可能引入的低级醇，包括甲醇、乙醇、异丙醇、正丁醇等形成甲磺酸烷基酯类基因毒性杂质。
  12. 如权利要求1至4任一项所述的晶型或如权利要求5至7任一项所述方法制备的晶型在制备氨酸激酶(RTK)抑制剂和/或制备预防和/或治疗癌症的药物中的用途。
  13. 如权利要求12所述的用途，其特征在于，所述癌症包括肾癌、甲状腺癌、肝癌、前列腺癌、直肠癌、膀胱癌、乳腺癌、胰腺癌、皮肤癌、卵巢癌及肺癌。
  14. 一种药物组合物或药物制剂，其特征在于，包含如权利要求1至4任一项所述的晶型或如权利要求5至7任一项所述方法制备的晶型以 及药学上可接受的辅料。
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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1878751A (zh) * 2003-11-11 2006-12-13 卫材株式会社 脲衍生物及其制备方法
US20070117842A1 (en) * 2003-04-22 2007-05-24 Itaru Arimoto Polymorph of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6- quinolinecarboxamide and a process for the preparation of the same
CN101024627A (zh) * 2000-10-20 2007-08-29 卫材R&D管理有限公司 含氮芳环衍生物
CN106543079A (zh) * 2015-09-22 2017-03-29 天津市汉康医药生物技术有限公司 乐伐替尼化合物
CN106660964A (zh) * 2014-08-28 2017-05-10 卫材R&D管理有限公司 高纯度喹啉衍生物及其生产方法
WO2019111283A1 (en) * 2017-12-09 2019-06-13 Msn Laboratories Private Limited, R&D Center Novel polymorphs of 4-[3-chloro-4-(n'-cyclopropyl ureido)phenoxy]-7-methoxyquinoline-6-carboxamide, its salts and process for the preparation thereof
WO2020048963A1 (en) * 2018-09-07 2020-03-12 Indena S.P.A. Process for the preparation of lenvatinib

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101024627A (zh) * 2000-10-20 2007-08-29 卫材R&D管理有限公司 含氮芳环衍生物
US20070117842A1 (en) * 2003-04-22 2007-05-24 Itaru Arimoto Polymorph of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6- quinolinecarboxamide and a process for the preparation of the same
CN1878751A (zh) * 2003-11-11 2006-12-13 卫材株式会社 脲衍生物及其制备方法
CN106660964A (zh) * 2014-08-28 2017-05-10 卫材R&D管理有限公司 高纯度喹啉衍生物及其生产方法
CN106543079A (zh) * 2015-09-22 2017-03-29 天津市汉康医药生物技术有限公司 乐伐替尼化合物
WO2019111283A1 (en) * 2017-12-09 2019-06-13 Msn Laboratories Private Limited, R&D Center Novel polymorphs of 4-[3-chloro-4-(n'-cyclopropyl ureido)phenoxy]-7-methoxyquinoline-6-carboxamide, its salts and process for the preparation thereof
WO2020048963A1 (en) * 2018-09-07 2020-03-12 Indena S.P.A. Process for the preparation of lenvatinib

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