WO2016131406A1 - 一种口服丝裂原活化蛋白激酶抑制剂的晶型及其制备方法 - Google Patents

一种口服丝裂原活化蛋白激酶抑制剂的晶型及其制备方法 Download PDF

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WO2016131406A1
WO2016131406A1 PCT/CN2016/073770 CN2016073770W WO2016131406A1 WO 2016131406 A1 WO2016131406 A1 WO 2016131406A1 CN 2016073770 W CN2016073770 W CN 2016073770W WO 2016131406 A1 WO2016131406 A1 WO 2016131406A1
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crystal form
ray powder
powder diffraction
preparation
diffraction pattern
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French (fr)
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陈敏华
张炎锋
陆飞
张晓宇
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苏州晶云药物科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

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  • the present invention relates to the field of chemical medicine, in particular to 5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzene
  • the crystal form of imidazolium-6-carboxamide and a preparation method thereof is particularly useful.
  • Binimetinib (MEK162), an anticancer drug, is an oral mitogen-activated protein kinase inhibitor developed by Array Biopharma and is currently in Phase III clinical trials in the United States for the NRAS gene. Treatment of mutant melanoma, BRAF mutant melanoma, and patients with recurrent low-grade plasma ovarian cancer.
  • the chemical name of the drug is: 5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole- 6-carboxamide, the structural formula of which is represented by formula (I).
  • the inventors of the present invention surprisingly discovered two crystal forms of the compound of formula (I) during the course of the study. Moreover, the crystal form of the invention has good stability, solubility and wettability meet the requirements of medicinal requirements, and the preparation method is simple and the cost is low, which is of great value for the optimization and development of the drug in the future.
  • the crystalline germanium provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2theta values of 20.3 ° ⁇ 0.2 °, 28.3 ° ⁇ 0.2 °, and 11.1 ° ⁇ 0.2 °.
  • the crystal form A provided by the present invention is further characterized by an X-ray powder diffraction pattern of one or two of 2theta values of 16.2° ⁇ 0.2°, 11.7° ⁇ 0.2°, and 18.9° ⁇ 0.2°. There are characteristic peaks at or at three locations; preferred crystal form A provided by the present invention is further characterized by an X-ray powder diffraction pattern having a value of 16.2° ⁇ 0.2°, 11.7 ° ⁇ 0.2 °, and 18.9 ° ⁇ 0.2 °. There are characteristic peaks.
  • the crystal form A provided by the present invention is further characterized by an X-ray powder diffraction pattern of one or two of 2theta values of 23.7° ⁇ 0.2°, 9.4° ⁇ 0.2°, and 22.7° ⁇ 0.2°. There are characteristic peaks at or at three locations; preferred crystal form A provided by the present invention is further characterized by an X-ray powder diffraction pattern having a 2theta value of 23.7° ⁇ 0.2°, 9.4 ° ⁇ 0.2 °, 22.7 ° ⁇ 0.2 °. There are characteristic peaks.
  • the crystal form A provided by the present invention is further characterized in that the X-ray powder diffraction pattern is basically as shown in FIG. 1 . Shown.
  • the crystal form A provided by the present invention is characterized in that an endothermic peak begins to appear near the temperature of 221 ° C, and the differential scanning calorimetry chart is basically as shown in FIG. 2 .
  • the crystal form A provided by the present invention is characterized in that it has a weight loss gradient of about 0.7% when heated to 200 ° C, and its thermogravimetric analysis chart is basically as shown in FIG. 3 .
  • the crystal form A provided by the present invention is characterized in that the crystal form A is an anhydride.
  • Another object of the present invention is to provide a process for the preparation of Form A, characterized in that a compound of the formula (I) is added to a positive solvent and added by an anti-solvent addition or added to a suitable crystallization solvent, and the temperature is lowered by volatilization, heating or Prepared by suspension stirring.
  • the positive solvent used in the anti-solvent addition includes alcohols, ethers, ketones, hydrocarbyl nitriles, and amides
  • the anti-solvents include alcohols, esters, halogenated alkanes, and water.
  • positive solvents include, but are not limited to, alcohols, ethers, ketones, acetonitrile, dimethylformamide
  • antisolvents include, but are not limited to, ethanol, ethyl acetate, dichloromethane, and water.
  • the crystallization solvent used for volatilization, heating, cooling or suspension stirring includes alcohols, ketones, halogenated alkanes, alkanes, ethers, aromatic hydrocarbons, esters, carboxylic acids, hydrocarbyl nitriles, water, amides.
  • alcohols include, but are not limited to, methanol, ethanol, isopropanol, ketones including but not limited to methyl ethyl ketone, methyl isobutyl ketone, halogenated alkanes including but not limited to dichloromethane, chloroform, alkanes including but not limited to Heptane, octane, ethers include, but are not limited to, methyl tert-butyl ether, aromatic hydrocarbons including, but not limited to, toluene, xylene, esters including but not limited to ethyl acetate, isopropyl acetate, carboxylic acids including But not limited to acetic acid, hydrocarbyl nitriles include, but are not limited to, acetonitrile, and amides include, but are not limited to, dimethylformamide.
  • Another object of the invention is to provide a crystalline form of the compound of formula (I), Form B.
  • the crystalline germanium provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2theta values of 25.3 ° ⁇ 0.2 °, 18.7 ° ⁇ 0.2 °, and 16.8 ° ⁇ 0.2 °.
  • the crystal form B provided by the present invention is further characterized by an X-ray powder diffraction pattern of one or two of 2theta values of 17.2° ⁇ 0.2°, 29.7° ⁇ 0.2°, and 32.5° ⁇ 0.2°. There are characteristic peaks at or at three locations; preferred crystal form A provided by the present invention is further characterized by an X-ray powder diffraction pattern having a value of 17.2° ⁇ 0.2°, 29.7° ⁇ 0.2°, 32.5 ° ⁇ 0.2°. There are characteristic peaks.
  • the crystal form B provided by the present invention is further characterized in that the X-ray powder diffraction pattern is one or two of 2theta values of 25.7° ⁇ 0.2°, 21.5° ⁇ 0.2°, and 23.0° ⁇ 0.2°. There are characteristic peaks at or at three locations; preferred crystal form A provided by the present invention is further characterized in that the X-ray powder diffraction pattern has a 2theta value of 25.7° ⁇ 0.2°, 21.5° ⁇ 0.2°, 23.0 ° ⁇ 0.2°. There are characteristic peaks.
  • crystal form B provided by the present invention is further characterized in that the X-ray powder diffraction pattern thereof is substantially as shown in FIG.
  • the crystal form B provided by the present invention is characterized in that an endothermic peak begins to appear near the temperature of 89 ° C, and the differential scanning calorimetry chart is substantially as shown in FIG. 5 .
  • the crystal form B provided by the present invention is characterized in that it has a weight loss gradient of about 21.6% when heated to 120 ° C, and the thermogravimetric analysis chart is basically as shown in FIG. 6 .
  • the present invention provides the crystalline form B, characterized in that the crystalline form B is a diacetic acid solvate.
  • Another object of the present invention is to provide a process for the preparation of Form B comprising dissolving a solid of the compound (I) in acetic acid
  • the toluene solvent is added by an anti-solvent addition method, and the mixture is stirred and crystallized.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of Form A or Form B or a mixture thereof and a pharmaceutically acceptable excipient.
  • the crystalline form A or the crystalline form B of the compound of the formula (I) or a mixture thereof can be used for the preparation of a medicament for treating cancer, in particular, a pharmaceutical preparation for melanoma and ovarian cancer. .
  • the crystal form provided by the invention has good stability and remarkable process purification effect. It can well avoid drug storage and crystal transformation during development, thus avoiding changes in bioavailability and efficacy.
  • the crystal form provided by the invention has low wettability, meets the requirements of bioavailability and efficacy, does not require special drying conditions in the preparation process, simplifies the preparation process and post-treatment process of the drug, and is not easily affected by humidity, and the storage condition The requirements are not harsh, and it is convenient for long-term storage, which greatly reduces the cost of material storage and quality control, and has strong economic value.
  • Figure 1 is an XRPD pattern of Form A
  • Figure 2 is a DSC diagram of Form A
  • Figure 3 is a TGA diagram of Form A
  • Figure 4 is an XRPD pattern of Form B
  • Figure 5 is a DSC diagram of Form B
  • Figure 6 is a TGA diagram of Form B
  • Figure 7 is a 1 H NMR chart of Form B
  • Figure 8 is a DVS diagram of Form A
  • Figure 9 is a comparison of XRPD under different conditions of Form A (XRPD before test from top to bottom, XRPD placed at 5 °C for 11 months, XRPD placed at 25 °C, 60% RH for 11 months, 11 months of XRPD placed at 40 ° C, 75% RH)
  • Figure 10 is a comparison of XRPD under different conditions of Form B (XRPD before test from top to bottom, XRPD placed at room temperature for 2 weeks)
  • test methods described are generally carried out under conventional conditions or conditions recommended by the manufacturer.
  • the starting compounds of the formula (I) can be obtained by known preparation methods, for example, according to the patent CN101633645B.
  • the X-ray powder diffraction pattern of the present invention was collected on a Panalytical Empyrean X-ray powder diffractometer.
  • the method parameters of the X-ray powder diffraction described in the present invention are as follows:
  • Scan range: from 3.0 to 40.0 degrees
  • the differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q2000.
  • the method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:
  • thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q5000.
  • the method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:
  • the dynamic moisture adsorption (DVS) pattern of the present invention was collected on an Intrinsic dynamic moisture adsorber manufactured by SMS Corporation (Surface Measurement Systems Ltd.).
  • the method parameters of the dynamic moisture adsorber are as follows:
  • Relative humidity range 0%RH-95%RH
  • the X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 1, and its XRPD pattern is shown in Fig. 1.
  • the wetting weight gain is not less than 15%
  • Humidity Wet weight gain is less than 15% but not less than 2%
  • wetting gain is less than 2% but not less than 0.2%
  • wetting gain is less than 0.2%
  • the crystalline form A of the present invention had a weight gain of 0.14% after equilibration at 80% humidity, and was of no or almost no wettability. This property indicates that the crystal form is not susceptible to humidity or deliquescence, facilitating its long-term storage placement.
  • the X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 7. Its DSC diagram is shown in Figure 5, and its TGA diagram is shown in Figure 6. The 1 H NMR chart is shown in Figure 7, and the 1 H NMR data is as follows:
  • the crystal form B sample was placed at room temperature and the XRPD and HPLC purity of the Form B sample was measured after two weeks.
  • the experimental results are shown in Table 9.
  • the XRPD comparison chart under different conditions of Form B is shown in Figure 10 (from top to bottom, XRPD before test, and XRPD for 2 weeks at room temperature).
  • Form B significantly improves the chemical purity of the sample and effectively removes many impurities in the sample.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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Abstract

本发明涉及一种治疗黑色素瘤和卵巢癌的晶型及其制备方法。本发明提供的晶型Α和晶型Β稳定性好，工艺提纯效果显著，且溶解度、引湿性符合药用要求。该晶型制备方法简单，成本低廉，对未来该药物的优化和开发具有重要价值。

Description

一种口服丝裂原活化蛋白激酶抑制剂的晶型及其制备方法 技术领域
本发明涉及化学医药领域，特别是涉及5-[(4-溴-2-氟苯基)氨基]-4-氟-N-(2-羟基乙氧基)-1-甲基-1H-苯并咪唑-6-甲酰胺的晶型及其制备方法。
背景技术
抗癌新药Binimetinib(MEK162)是由艾瑞制药(Array Biopharma)研发的一种口服丝裂原活化蛋白激酶(mitogen-activated protein kinase)抑制剂，目前在美国处于三期临床试验，用于NRAS基因突变体黑色素瘤，BRAF基因突变体黑色素瘤及复发性低级血浆卵巢癌患者的治疗。该药物的化学名称为：5-[(4-溴-2-氟苯基)氨基]-4-氟-N-(2-羟基乙氧基)-1-甲基-1H-苯并咪唑-6-甲酰胺，其结构式如式(I)所示。
Figure PCTCN2016073770-appb-000001
固体化学药物晶型不同，可造成其溶解度和稳定性不同，从而影响药物的吸收和生物利用度，并且会导致临床药效的差异。然而，目前尚无式(I)化合物的晶型的相关报导，因此，有必要对式(I)化合物进行全面***的多晶型筛选，选择最适合开发的晶型。
本发明的发明人在研究过程中惊奇的发现了式(I)化合物的两种晶型。并且本发明的晶型稳定性好，溶解度、引湿性符合药用要求，且制备方法简单，成本低廉，对未来该药物的优化和开发具有重要价值。
发明内容
本发明的一个目的是提供一种式(I)化合物的晶型，晶型A。
本发明提供的晶型Α，其特征在于，其X射线粉末衍射图在2theta值为20.3°±0.2°、28.3°±0.2°、11.1°±0.2°处具有特征峰。
更进一步的，本发明提供的晶型A，其特征还在于，其X射线粉末衍射图在2theta值为16.2°±0.2°、11.7°±0.2°、18.9°±0.2°中的一处或两处或三处具有特征峰；优选的本发明提供的晶型A，其特征还在于，其X射线粉末衍射图在2theta值为16.2°±0.2°、11.7°±0.2°、18.9°±0.2°处具有特征峰。
更进一步的，本发明提供的晶型A，其特征还在于，其X射线粉末衍射图在2theta值为23.7°±0.2°、9.4°±0.2°、22.7°±0.2°中的一处或两处或三处具有特征峰；优选的本发明提供的晶型A，其特征还在于，其X射线粉末衍射图在2theta值为23.7°±0.2°、9.4°±0.2°、22.7°±0.2°处具有特征峰。
更进一步的，本发明提供的晶型A，其特征还在于，其X射线粉末衍射图基本如图1 所示。
本发明提供的晶型A，其特征在于，加热至221℃附近开始出现吸热峰，其差示扫描量热分析图基本如图2所示。
本发明提供的晶型A，其特征在于，加热至200℃时，具有约0.7％的重量损失梯度，其热重分析图基本如图3所示。
更进一步的，本发明提供的晶型A，其特征在于，晶型A是无水物。
本发明的另一个目的是提供晶型A的制备方法，其特征在于，将式(I)化合物加入正溶剂并通过反溶剂添加制得或加入适当的析晶溶剂中，通过挥发、加热降温或悬浮搅拌制得。
更进一步的，其中反溶剂添加所用到的正溶剂包括醇类、醚类、酮类、烃基腈、酰胺类，反溶剂包括醇类、酯类、卤代烷烃类、水。更进一步的，正溶剂包括但不限于醇类、醚类、酮类、乙腈、二甲基甲酰胺，反溶剂包括但不限于乙醇、乙酸乙酯、二氯甲烷、水。
其中挥发、加热降温或悬浮搅拌所用的析晶溶剂包括醇类、酮类、卤代烷烃类、烷烃类、醚类、芳香烃类、酯类、羧酸类、烃基腈、水、酰胺类中的一种或多种溶剂的混合溶剂。其中，醇类包括但不限于甲醇、乙醇、异丙醇，酮类包括但不限于甲乙酮、甲基异丁酮，卤代烷烃包括但不限于二氯甲烷、三氯甲烷，烷烃包括但不限于正庚烷、辛烷，醚类包括但不限于甲基叔丁基醚，芳香烃类包括但不限于甲苯、二甲苯，酯类包括但不限于乙酸乙酯、乙酸异丙酯，羧酸类包括但不限于乙酸，烃基腈包括但不限于乙腈，酰胺类包括但不限于二甲基甲酰胺。
本发明的另一个目的是提供一种式(I)化合物的晶型，晶型B。
本发明提供的晶型Β，其特征在于，其X射线粉末衍射图在2theta值为25.3°±0.2°、18.7°±0.2°、16.8°±0.2°处具有特征峰。
更进一步的，本发明提供的晶型B，其特征还在于，其X射线粉末衍射图在2theta值为17.2°±0.2°、29.7°±0.2°、32.5°±0.2°中的一处或两处或三处具有特征峰；优选的本发明提供的晶型A，其特征还在于，其X射线粉末衍射图在2theta值为17.2°±0.2°、29.7°±0.2°、32.5°±0.2°处具有特征峰。
更进一步的，本发明提供的晶型B，其特征还在于，其X射线粉末衍射图在2theta值为25.7°±0.2°、21.5°±0.2°、23.0°±0.2°中的一处或两处或三处具有特征峰；优选的本发明提供的晶型A，其特征还在于，其X射线粉末衍射图在2theta值为25.7°±0.2°、21.5°±0.2°、23.0°±0.2°处具有特征峰。
更进一步的，本发明提供的晶型B，其特征还在于，其X射线粉末衍射图基本如图4所示。
本发明提供的晶型B，其特征在于，加热至89℃附近开始出现吸热峰，其差示扫描量热分析图基本如图5所示。
本发明提供的晶型B，其特征在于，加热至120℃时，具有约21.6％的重量损失梯度，其热重分析图基本如图6所示。
更进一步的，本发明提供的晶型B，其特征在于，晶型B是二乙酸溶剂合物。
本发明的另一个目的是提供晶型B的制备方法，包括将(I)化合物的固体溶解于乙酸 中，通过反溶剂添加法加入甲苯溶剂，搅拌析晶制得。
更进一步的，本发明提供的药用组合物，其特征在于，所述药用组合物包含有效量的晶型A或晶型B或其混合物及药学上可接受的赋形剂。
更进一步的，本发明所述的药用组合物中，式(I)化合物的晶型A或晶型B或其混合物可用于制备治疗癌症药物，特别是黑色素瘤和卵巢癌药物制剂中的用途。
本发明的有益效果为：
目前尚无专利或文献报导式(I)化合物的晶型，本发明的发明人通过经过研究，突破了这一难题，找到了两种适合开发的晶型。
本发明提供的晶型稳定性好，工艺提纯效果显著。能很好地避免药物储存以及开发过程中发生转晶，从而避免生物利用度以及药效的改变。
本发明提供的晶型引湿性较低，满足生物利用度和药效要求，在制备工艺中无需特殊的干燥条件，简化了药物的制备工艺和后处理工艺，且不易受湿度影响，对储存条件要求不苛刻，便于长期贮存，大大降低了物料储存以及质量控制方面的成本，具有很强的经济价值。
附图说明
图1为晶型A的XRPD图
图2为晶型A的DSC图
图3为晶型A的TGA图
图4为晶型B的XRPD图
图5为晶型B的DSC图
图6为晶型B的TGA图
图7为晶型B的1H NMR图
图8为晶型A的DVS图
图9为晶型A不同条件下XRPD对比图(从上到下依次为测试前的XRPD，5℃条件下放置11个月的XRPD，25℃、60％RH条件下放置11个月的XRPD，40℃、75％RH条件下放置11个月的XRPD)
图10为晶型B不同条件下XRPD对比图(从上到下依次为测试前的XRPD，室温条件下放置2个星期的XRPD)
具体实施方式
以下将通过具体实施例进一步阐述本发明，但并不用于限制本发明的保护范围。本领域技术人员可在权利要求范围内对制备方法和使用仪器作出改进，这些改进也应视为本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
下述实施例中，所述的试验方法通常按照常规条件或制造厂商建议的条件实施。起始的式(I)化合物可以通过已知制备方法得到，例如按照专利CN101633645B制备得到。
本发明中所用到的缩写的解释如下：
XRPD：X射线粉末衍射
DSC：差示扫描量热分析
TGA：热重分析
1H NMR：液态核磁氢谱
DVS：动态水分吸附
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,Kα
Figure PCTCN2016073770-appb-000002
1.540598；
Figure PCTCN2016073770-appb-000003
1.544426
Kα2/Kα1强度比例：0.50
电压：45仟伏特(kV)
电流：40毫安培(mA)
扫描范围：自3.0至40.0度
本发明所述的差示扫描量热分析(DSC)图在TA Q2000上采集。本发明所述的差示扫描量热分析(DSC)的方法参数如下：
扫描速率：10℃/min
保护气体：氮气
本发明所述的热重分析(TGA)图在TA Q5000上采集。本发明所述的热重分析(TGA)的方法参数如下：
扫描速率：10℃/min
保护气体：氮气
本发明所述动态水分吸附(DVS)图在由SMS公司(Surface Measurement Systems Ltd.)生产的Intrinsic动态水分吸附仪上采集。所述的动态水分吸附仪的方法参数如下：
温度：25℃
载气，流速：N2,200毫升/分钟
单位时间质量变化：0.002％/分钟
相对湿度范围：0％RH-95％RH
实施例1
式(I)化合物晶型A的制备方法：
将10.2mg的式(I)化合物溶解于1.8mL甲醇中，通过0.45μm的尼龙滤头过滤，得到清液放置于1.5mL小瓶中，在室温下挥发得到固体晶型A。
本实施例得到的晶型的X射线粉末衍射数据如表1所示，其XRPD图如图1。
表1
Figure PCTCN2016073770-appb-000004
Figure PCTCN2016073770-appb-000005
实施例2
式(I)化合物晶型A的制备方法：
将12.0mg的式(I)化合物加入1.2mL四氢呋喃中，在室温下以500r/min的速率搅拌三天，离心得到固体即为晶型A。
本实施例得到的晶型的X射线粉末衍射数据如表2所示。
表2
Figure PCTCN2016073770-appb-000006
Figure PCTCN2016073770-appb-000007
实施例3
式(I)化合物晶型A的制备方法：
将17.0mg的式(I)化合物溶解于0.1mL二甲基甲酰胺中，然后边搅拌边缓慢滴加0.2mL的水，继续搅拌两天，离心得到固体即为晶型A。
本实施例得到的晶型的X射线粉末衍射数据如表3所示。
表3
Figure PCTCN2016073770-appb-000008
Figure PCTCN2016073770-appb-000009
实施例4
式(I)化合物晶型A的引湿性实验：
在25℃条件下，取本发明晶型A约10mg进行动态水分吸附(DVS)测试其引湿性。实验结果如表4所示。引湿性实验结果的DVS图如图8所示。
表4
Figure PCTCN2016073770-appb-000010
关于引湿性特征描述与引湿性增重的界定(中国药典2010年版附录XIX J药物引湿性试验指导原则，实验条件：25℃±1℃，80％相对湿度)：
潮解：吸收足量水分形成液体
极具引湿性：引湿增重不小于15％
有引湿性：引湿增重小于15％但不小于2％
略有引湿性：引湿增重小于2％但不小于0.2％
无或几乎无引湿性：引湿增重小于0.2％
结果表明，本发明的晶型A在80％湿度下平衡后增重0.14％，属于无或几乎无引湿性。该性质表明该晶型不易受湿度影响或潮解，方便其长期贮存放置。
实施例5
式(I)化合物晶型A的稳定性实验：
取晶型A样品约10mg敞口分别放置于5℃，长期稳定(25℃、60％RH)及加速稳定(40℃、75％RH)条件下，11个月测晶型A样品的XRPD和HPLC纯度。实验结果如表5所示。晶型A不同条件下XRPD对比图如图9(从上到下依次为测试前的XRPD，5℃条件下放置11个月的XRPD，25℃、60％RH条件下放置11个月的XRPD，40℃、75％RH条件下放置11个月的XRPD)。
表5
起始晶型 条件 起始纯度 放置时间 晶型 化学纯度
晶型A 5℃ 98.94％ 11月 晶型A保持不变 98.84％
晶型A 25℃、60％RH 98.94％ 11月 晶型A保持不变 98.85％
晶型A 40℃、75％RH 98.94％ 11月 晶型A保持不变 98.95％
结果表明，式(I)化合物晶型A在5℃，长期稳定(25℃、60％RH)及加速稳定(40℃、75％RH)条件下，放置过程中样品稳定，并且纯度几乎不变。
实施例6
式(I)化合物晶型B的制备方法：
将249.3mg式(I)化合物的固体溶解于4mL乙酸中，然后边搅拌边缓慢滴加13mL的甲苯，搅拌三天，过滤得到晶型B。
本实施例得到的晶型的X射线粉末衍射数据如表6所示。其XRPD图如图4。
表6
Figure PCTCN2016073770-appb-000011
Figure PCTCN2016073770-appb-000012
实施例7
式(I)化合物晶型B的制备方法：
将15.2mg式(I)化合物的固体溶解于0.2mL乙酸中，然后边搅拌边缓慢滴加0.5mL的甲苯，搅拌过夜，过滤得到晶型B。
本实施例得到的晶型的X射线粉末衍射数据如表7所示。其DSC图如图5，其TGA图如图6。其1H NMR图如图7，1H NMR数据如下：
1H NMR(400MHz,DMSO-d6)δ11.94(s,2H),11.64(s,1H),8.38(s,1H),7.83(s,1H),7.71(s,1H),7.43(d,J＝13.2Hz,1H),7.11(d,J＝9.4Hz,1H),6.39(td,J＝9.0,3.2Hz,1H),4.69(s,1H),3.87(d,J＝25.0Hz,5H),3.54(s,2H),1.91(s,5H)。
表7
Figure PCTCN2016073770-appb-000013
Figure PCTCN2016073770-appb-000014
实施例8
式(I)化合物晶型B的制备方法：
将109.1mg式(I)化合物的固体溶解于1.8mL乙酸中，然后边搅拌边缓慢滴加6.4mL的甲苯，搅拌过夜，过滤得到晶型B。
本实施例得到的晶型的X射线粉末衍射数据如表8所示。
表8
Figure PCTCN2016073770-appb-000015
Figure PCTCN2016073770-appb-000016
实施例9
式(I)化合物晶型B的稳定性实验：
取晶型B样品敞口放置于室温条件下，两个星期后测晶型B样品的XRPD和HPLC纯度。实验结果如表9所示。晶型B不同条件下XRPD对比图如图10(从上到下依次为测试前的XRPD，室温条件下放置2个星期的XRPD)。
表9
起始晶型 条件 起始纯度 放置时间 晶型 化学纯度
晶型B 室温 99.53％ 2个星期 晶型B保持不变 99.52％
结果表明，式(I)化合物晶型B在室温条件下，放置过程中样品稳定，并且纯度几乎不变。
实施例10
式(I)化合物晶型B的纯度研究：
将10.0mg式(I)化合物起始样品溶解于0.2mL乙酸中，然后边搅拌边缓慢滴加0.5mL的甲苯，搅拌过夜，过滤制备得到晶型B。用高效液相色谱仪分别检测式(I)化合物起始样品和本实施例制备得到的晶型B的纯度。结果如表10所示：
表10
Figure PCTCN2016073770-appb-000017
结果表明，晶型B显著提高了样品的化学纯度且有效去除了样品中的多种杂质。
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。

Claims (23)

  1. 一种式(I)化合物的晶型Α，
    Figure PCTCN2016073770-appb-100001
    其特征在于，其X射线粉末衍射图在2theta值为20.3°±0.2°、28.3°±0.2°、11.1°±0.2°处具有特征峰。
  2. 根据权利要求1所述的晶型A，其特征还在于，其X射线粉末衍射图在2theta值为16.2°±0.2°、11.7°±0.2°、18.9°±0.2°中的一处或两处或三处具有特征峰。
  3. 根据权利要求2所述的晶型A，其特征还在于，其X射线粉末衍射图在2theta值为16.2°±0.2°、11.7°±0.2°、18.9°±0.2°处具有特征峰。
  4. 根据权利要求1-3任一项所述的晶型A，其特征还在于，其X射线粉末衍射图在2theta值为23.7°±0.2°、9.4°±0.2°、22.7°±0.2°中的一处或两处或三处具有特征峰。
  5. 根据权利要求4所述的晶型A，其特征还在于，其X射线粉末衍射图在2theta值为23.7°±0.2°、9.4°±0.2°、22.7°±0.2°处具有特征峰。
  6. 根据权利要求1所述的晶型A，其特征在于，其X射线粉末衍射图基本上与图1一致。
  7. 根据权利要求1-6中任一项所述的晶型A，其特征在于：所述晶型A为无水物。
  8. 一种如权利要求1-7任一项所述的式(I)化合物晶型A的制备方法，其特征在于，制备方法包括将式(I)化合物加入正溶剂并通过反溶剂添加制得晶型A；所述正溶剂包括醇类、醚类、酮类、烃基腈、酰胺类，所述反溶剂包括醇类、酯类、卤代烷烃类、水。
  9. 根据权利要求8所述的制备方法，其特征在于，所述正溶剂包括醇类、醚类、酮类、乙腈、二甲基甲酰胺，所述反溶剂包括乙醇、乙酸乙酯、二氯甲烷、水。
  10. 一种如权利要求1-7任一项所述的式(I)化合物晶型A的制备方法，其特征在于，制备方法包括将式(I)化合物加入析晶溶剂中，通过挥发、加热降温或悬浮搅拌制得晶型A，所述析晶溶剂为一种或多种溶剂的混合溶剂。
  11. 根据权利要求10所述的制备方法，其特征在于，所述析晶溶剂包括醇类、酮类、卤代烷烃类、烷烃类、醚类、芳香烃类、酯类、羧酸类、烃基腈、水、酰胺类的一种或多种溶剂的混合。
  12. 根据权利要求11所述的制备方法，其特征在于，所述醇类为甲醇、乙醇、异丙醇，所述酮类为甲乙酮、甲基异丁酮，所述卤代烷烃为二氯甲烷、三氯甲烷，所述烷烃为正庚烷、辛烷，所述醚类为甲基叔丁基醚，所述芳香烃类为甲苯、二甲苯，所述酯类为乙酸乙酯、乙酸异丙酯，所述羧酸类为乙酸，所述烃基腈为乙腈，所述酰胺类为二甲基甲酰胺。
  13. 一种式(I)化合物的晶型Β，其特征在于，其X射线粉末衍射图在2theta值为25.3°±0.2°、18.7°±0.2°、16.8°±0.2°处具有特征峰。
  14. 根据权利要求13所述的晶型B，其特征还在于，其X射线粉末衍射图在2theta值为17.2°±0.2°、29.7°±0.2°、32.5°±0.2°中的一处或两处或三处具有特征峰。
  15. 根据权利要求14所述的晶型B，其特征还在于，其X射线粉末衍射图在2theta值为17.2°±0.2°、29.7°±0.2°、32.5°±0.2°处具有特征峰。
  16. 根据权利要求13-15任一项所述的晶型B，其特征还在于，其X射线粉末衍射图在2theta值为25.7°±0.2°、21.5°±0.2°、23.0°±0.2°中的一处或两处或三处具有特征峰。
  17. 根据权利要求16任一项所述的晶型B，其特征还在于，其X射线粉末衍射图在2theta值为25.7°±0.2°、21.5°±0.2°、23.0°±0.2°处具有特征峰。
  18. 根据权利要求13所述的晶型B，其特征在于，其X射线粉末衍射图基本上与图4一致。
  19. 根据权利要求13-18中任一项所述的晶型B，其特征在于：所述晶型B为二乙酸溶剂合物。
  20. 一种如权利要求13-19任一项所述的式(I)化合物晶型B的制备方法，其特征在于，制备方法包括将(I)化合物的固体溶解于乙酸中，通过反溶剂添加法加入甲苯溶剂，搅拌析晶制得晶型B。
  21. 一种药用组合物，所述药用组合物包含有效量的权利要求1-7任意一项所述的晶型A或权利要求13-19任意一项所述的晶型B或两者的混合物及药学上可接受的赋形剂。
  22. 根据权利要求21所述的药用组合物，其特征在于，所述的权利要求1-7任意一项所述的晶型A或权利要求13-19任意一项所述的晶型B或两者的混合物用于制备治疗癌症药物。
  23. 根据权利要求22所述的药用组合物，其特征在于，所述的权利要求1-7任意一项所述的晶型A或权利要求13-19任意一项所述的晶型B或两者的混合物用于制备治疗黑色素瘤和卵巢癌药物制剂中的用途。
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