WO2016019910A1 - Crystal form of anticancer compound and preparation method and use thereof - Google Patents
Crystal form of anticancer compound and preparation method and use thereof Download PDFInfo
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
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- C—CHEMISTRY; METALLURGY
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/58—Pyridine rings
Definitions
- the present invention relates to an anticancer compound (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[3-fluorophenyl-1-dimethyl Crystal form of phosphonooxy-4-yl]pyridin-2-amine and preparation method thereof.
- Lung cancer is the most common primary malignant tumor of the lung and is usually classified into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Lung cancer is the cancer with the highest morbidity and mortality. Non-small cell lung cancer accounts for 80% to 85% of the total number of lung cancers, and its mortality rate is as high as 80% to 90%. According to the statistics of the World Health Organization (WHO), there were 1,332,132 new cases of lung cancer in 2002, accounting for 12.4% of the total number of new cancer cases, ranking first, the third time announced by the Ministry of Health of China on April 29, 2008. The main results of the national death cause survey show that the mortality rate of lung cancer in China has increased by 465% in the past 30 years. At present, lung cancer has replaced liver cancer as the cause of death in the first malignant tumor in China, accounting for 22.7% of malignant tumor deaths.
- NSCLC non-small cell lung cancer
- SCLC small cell lung cancer
- the 5-year survival rate of lung cancer in developed countries is about 10% to 15%, which is lower in China. If the advanced NSCLC is not treated, the median survival time is about 4 to 5 months, and the 1-year survival rate is less than 10%.
- the standard first-line chemotherapy regimen of advanced NSCLC is equivalent to the best supportive treatment, which can effectively prolong the median survival time and increase the 1-year survival period. Survival rate.
- the current efficacy of chemotherapy seems to reach a platform, its objective efficiency is about 30%, the median survival time is 8 to 9 months, and the 1-year survival rate is 30% to 40%. Therefore, finding more effective and safe treatments has become a hot spot in current lung cancer research.
- Tumor molecular targeted therapy is a treatment for other biological pathways.
- NSCLC's targeted therapeutic drugs mainly include epidermal growth factor receptor (EGFR) family inhibitors, angiogenesis inhibitors, multi-target inhibitors, signal transduction inhibitors, and apoptosis inducers.
- EGFR epidermal growth factor receptor
- CSCO Clinical Oncology Collaborative Professional Committee
- XALKORI provides us with a new path to explore future drug development and cancer treatment,” University of Colorado, Denver Cancer Research The heads of Professor Paul Bunn and the chief physician of James Dudley pointed out.
- XALKORI is the first new drug to treat lung cancer approved by the FDA for more than 6 years, representing a shift in the treatment of non-small cell lung cancer. We are moving from a monolithic treatment regime to a treatment model through biomarker decision-making.”
- the biomarker ALK fusion gene test result of the patient's tumor is positive to improve the possibility of responding to the treatment. This first test for lung cancer treatment allows researchers to observe good results in pre-screened patient populations.
- ALK positive rate in non-small cell lung cancer is approximately 3-5%, meaning that there are approximately 6,500 to 11,000 ALK-positive non-small cell lung cancer patients in the United States each year.
- NSCLC non-small cell lung cancer
- Drug crystal research and solid-state drug development are of paramount importance in the pharmaceutical industry.
- Drug molecules usually have different solid forms, including salts, polycrystals, eutectic, amorphous, hydrates and solvates; different crystal forms of the same drug molecule, in crystal structure, stability, manufacturability and bioavailability
- any drug development requires a comprehensive system of polymorphic screening to find as many crystal forms as possible, and then use various solid-state methods to conduct in-depth research on these crystal forms to find the most suitable crystal form.
- the crystal form is Form A
- the XRPD pattern has diffraction peaks at 2 ⁇ ( ⁇ 0.2°) of 7.86, 9.60, 11.76, 12.37, 14.68, 19.61, 20.02, 21.19, 23.76, 24.89.
- the XRPD pattern of the crystalline form A is shown in FIG.
- Another object of the present invention is to provide a crystalline form A of the compound of the formula (I).
- the method comprises dissolving the compound of the formula (I) with an organic solvent A, cooling and crystallization, stirring, and filtering to obtain a target crystal form.
- Another object of the present invention is to provide an alternative method for preparing the crystalline form A of the compound of the formula (I), which comprises dissolving the compound of the formula (I) with an organic solvent B, adding an anti-solvent A, stirring and crystallization, and filtering the target. Crystal form.
- the organic solvent A is selected from the group consisting of tetrahydrofuran and/or acetone.
- the organic solvent B is selected from the group consisting of dichloromethane and/or chloroform
- the anti-solvent A is selected from the group consisting of isopropyl ether, n-heptane and/or n-hexane.
- a further object of the present invention is to provide a crystalline form B of a compound of formula (I) which is crystalline form B having an XRPD pattern of 2.82, 10.14, 11.25, 12.55, 13.50, 14.90 at 2 ⁇ ( ⁇ 0.2°). There are diffraction peaks at 16.27, 19.78, and 25.21.
- the XRPD pattern of the crystalline form B is shown in FIG.
- a vacuum drying step is also included.
- Another object of the present invention is to provide an alternative method for preparing Form B of the compound of the formula (I), which comprises dissolving the compound of the formula I with an organic solvent D, crystallization by adding an anti-solvent B, and filtering to obtain a target crystal form, optionally
- the vacuum drying step is also included after filtration.
- the vacuum drying temperature is 20-40 ° C, more preferably 20-30 ° C, and most preferably 25 ° C.
- the organic solvent C is selected from the group consisting of isopropanol and/or n-butanol.
- the organic solvent D is selected from the group consisting of isopropanol, acetone and/or 2-butanone, and the anti-solvent B is selected from n-heptane or n-hexane.
- It is still another object of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of the crystalline form and a pharmaceutically acceptable carrier.
- Another object of the present invention is to provide the use of the above crystalline form or pharmaceutical composition for the preparation of an antitumor drug, preferably for the preparation of a medicament for the treatment of lung cancer.
- the crystal form provided by the invention has high purity, good stability, low wettability and good fluidity, and is suitable for medical preparations.
- Figure 1 is (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[3-fluorophenyl-1-dimethylphosphonooxy-4 XRPD pattern of -pyrimidin-2-amine crystal form A;
- Figure 2 is (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[3-fluorophenyl-1-dimethylphosphonooxy-4 XRPD pattern of -pyridine]pyridin-2-amine Form B.
- Example 1 of the present invention The crystal form prepared in Example 1 of the present invention was used as a sample, and the stability of the crystal form was examined under different temperature conditions. The results are shown in Table 1.
- Form A has good stability at 25 ° C - 60 ° C.
- Example 5 of the present invention The crystal form prepared in Example 5 of the present invention was used as a sample, and the stability of the crystal form was examined under different temperature conditions. The results are shown in Table 2.
- Form B has good stability at 20 ° C to 50 ° C.
- the wettability test was carried out according to the Guiding Principles for Drugs' Humidity Test (Chinese Pharmacopoeia 2010 Edition Part II Appendix XIXJ). Take a dry stuffed glass weighing bottle (outer diameter 50mm, height 15mm), placed in a suitable 25 ° C ⁇ 1 ° C constant temperature dryer (lower ammonium chloride saturated solution) on the day before the test, accurately weighed Weight (m1); taken in an appropriate amount of the crystal form of the present invention, laid flat in the above weighing bottle, the thickness of the test sample is generally about 1 mm, accurately weighed (m2); the weighing bottle is opened, and the bottle The lid was placed under the above constant temperature and humidity conditions for 24 hours; the lid of the weighing bottle was covered and accurately weighed (m3).
- the (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[3-fluorophenyl-1-dimethyl group of the present invention was measured.
- the weight percent of the compound of the phosphinyloxy-4-yl]pyridin-2-amine crystal form A is 0.3%
- the weight gain percentage of the crystalline form B compound is 1.0%, indicating that the crystalline form A and the crystalline form B of the present invention are slightly It is hygroscopic and is almost unaffected by high humidity.
- the angle of repose was measured by a fixed funnel method.
- the funnel is fixed at a certain height H, and the powder is placed in the funnel.
- the pile is naturally flowed down until the tip of the cone is released to the funnel outlet.
- the radius r of the conical bottom surface is measured, and the angle of repose is calculated.
- Angle of repose arc tg (H / r). The measurement results are summarized in Table 3.
Abstract
The present invention relates to a crystal form of an anticancer compound (R)-3-[1-(2,6-dichloro-3-fluorophenyl) ethoxy]-5-[3-fluorophenyl-1-dimethyl phosphonooxy-4-yl] pyridine-2-amine and preparation method thereof, the structural formula thereof being represented by formula I. The crystal form has good stability, low hygroscopicity, and good fluidity and satisfies pharmaceutical preparation application requirements.
Description
本发明涉及一种抗癌化合物(R)-3-[1-(2,6-二氯-3-氟苯基)乙氧基]-5-[3-氟苯基-1-二甲基膦酰氧-4-基]吡啶-2-胺的晶型及其制备方法。The present invention relates to an anticancer compound (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[3-fluorophenyl-1-dimethyl Crystal form of phosphonooxy-4-yl]pyridin-2-amine and preparation method thereof.
肺癌是最常见的肺部原发性恶性肿瘤，通常分为非小细胞肺癌(NSCLC)和小细胞肺癌(SCLC)。肺癌是发病率和死亡率最高的癌症，而非小细胞肺癌占肺癌总数的80％～85％，其死亡率高达80％～90％。根据世界卫生组织(WHO)的统计，2002年全球肺癌新发病例1332132例，占全部新发癌症病例总数的12.4％，居第一位，我国***2008年4月29日公布的第三次全国死因调查主要结果显示过去30年我国肺癌死亡率上升了465％，目前肺癌已经取代肝癌成为我国首位恶性肿瘤死亡原因，占恶性肿瘤死亡的22.7％。Lung cancer is the most common primary malignant tumor of the lung and is usually classified into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Lung cancer is the cancer with the highest morbidity and mortality. Non-small cell lung cancer accounts for 80% to 85% of the total number of lung cancers, and its mortality rate is as high as 80% to 90%. According to the statistics of the World Health Organization (WHO), there were 1,332,132 new cases of lung cancer in 2002, accounting for 12.4% of the total number of new cancer cases, ranking first, the third time announced by the Ministry of Health of China on April 29, 2008. The main results of the national death cause survey show that the mortality rate of lung cancer in China has increased by 465% in the past 30 years. At present, lung cancer has replaced liver cancer as the cause of death in the first malignant tumor in China, accounting for 22.7% of malignant tumor deaths.
发达国家肺癌的5年生存率约10％～15％，在我国则更低。晚期NSCLC如果不治疗，中位生存期约4～5个月，1年生存率低于10％，晚期NSCLC的标准一线化疗方案相当于最佳支持治疗能有效延长中位生存期，提高1年生存率。但目前化疗的疗效似乎到达了一个平台，其客观有效率约30％，中位生存期8～9个月，1年生存率30％～40％。因此，寻找更为有效和安全的治疗手段成为当前肺癌研究的一个热点。肿瘤分子靶向治疗是针对其他生物学途径的治疗手段。目前，NSCLC的靶向治疗药物主要有表皮生长因子受体(EGFR)家族抑制剂、血管生成抑制剂、多靶点抑制剂、信号传导抑制剂、凋亡诱导剂等。中国抗癌协会临床肿瘤学协作专业委员会(CSCO)执行委员会主任委员、著名临床肿瘤专家马军教授指出说：“由于早期具有隐蔽性，大多数非小细胞肺癌患者发现时已是局部晚期或发生转移，超过半数的肺癌患者会错过手术机会。传统放化疗疗效有限，且伴随难以
忍受的药物毒副反应，通常放化疗失败的次数越多，后续治疗的效果越差。但靶向药物的出现，给征服肺癌提供了一种新可能。”The 5-year survival rate of lung cancer in developed countries is about 10% to 15%, which is lower in China. If the advanced NSCLC is not treated, the median survival time is about 4 to 5 months, and the 1-year survival rate is less than 10%. The standard first-line chemotherapy regimen of advanced NSCLC is equivalent to the best supportive treatment, which can effectively prolong the median survival time and increase the 1-year survival period. Survival rate. However, the current efficacy of chemotherapy seems to reach a platform, its objective efficiency is about 30%, the median survival time is 8 to 9 months, and the 1-year survival rate is 30% to 40%. Therefore, finding more effective and safe treatments has become a hot spot in current lung cancer research. Tumor molecular targeted therapy is a treatment for other biological pathways. At present, NSCLC's targeted therapeutic drugs mainly include epidermal growth factor receptor (EGFR) family inhibitors, angiogenesis inhibitors, multi-target inhibitors, signal transduction inhibitors, and apoptosis inducers. Professor Ma Jun, the chairman of the Executive Committee of the Clinical Oncology Collaborative Professional Committee (CSCO) of China Anti-Cancer Association, and the famous clinical oncologist, pointed out: "Because of the early concealment, most patients with non-small cell lung cancer have been locally late or have occurred. Transfer, more than half of lung cancer patients will miss the opportunity for surgery. Traditional radiotherapy and chemotherapy has limited efficacy and is difficult to accompany
The more toxic side effects of the drug, the more often the failure of radiotherapy and chemotherapy, the worse the effect of subsequent treatment. However, the emergence of targeted drugs provides a new possibility for conquering lung cancer. ”
辉瑞公司于2011年8月26日宣布，该公司的XALKORI(crizotinib)胶囊获得美国食品药品管理局FDA批准，这是第一个对间变性淋巴瘤激酶(ALK)进行靶向治疗的药品，用于治疗通过FDA批准的检测方法诊断为ALK阳性的局部晚期或转移的非小细胞肺癌。XALKORI的疗效系基于客观缓解率(ORR)。XALKORI在获得FDA快速批准的同时，辉瑞正在进行上市后临床试验，旨在对XALKORI的临床疗效做进一步评估。根据FDA关于靶向治疗和伴随诊断的最新指导意见，辉瑞在临床试验中与FDA和雅培分子诊断业务部门进行了密切合作，确保XALKORI与雅培的诊断检测技术同时获得审评和批准。后者即雅培分子诊断业务部门的Vysis ALK Break Apart FISH(荧光原位杂交)探针试剂盒，用以发现ALK融合基因。XALKORI与雅培分子诊断业务部门的ALK FISH试剂盒同时获批，也标志着辉瑞的肿瘤药物或肿瘤治疗方案首次与诊断检测方案一起进行开发和获批。“通过真正了解NSCLC的驱动基因，如ALK，我们可以选择出最有可能对治疗反应的患者。XALKORI为我们提供了一条探索未来药物研发和癌症治疗的崭新道路，”科罗拉多大学丹佛分校癌症研究部门的负责人Paul Bunn教授和James Dudley主任医师指出。“XALKORI是6年多来FDA批准的第一个治疗肺癌的新药，代表了非小细胞肺癌治疗模式转变，我们正在从千篇一律的治疗方案转向通过生物标记物决策的治疗模式。”在XALKORI临床试验中，试验方案要求患者肿瘤的生物标记物ALK融合基因检测结果为阳性，以提高对治疗做出反应的可能性。首次用于肺癌治疗的这种检测方法可以使研究者在预先筛选的患者人群中观察到良好的治疗效果。初步的流行病学研究表明，在非小细胞肺癌中ALK阳性率大约为3-5％，意味着每年在美国大约有6500到11000名ALK阳性的非小细胞肺癌患者。通过XALKORI注册临床试验的靶向治疗，在晚期ALK阳性非小细胞肺癌患者中，客观缓解率为50到61％。Pfizer announced on August 26, 2011 that the company's XALKORI (crizotinib) capsule was approved by the US Food and Drug Administration for FDA approval, the first drug to target anaplastic lymphoma kinase (ALK). Locally advanced or metastatic non-small cell lung cancer diagnosed as ALK positive was diagnosed by an FDA-approved test. The efficacy of XALKORI is based on objective response rate (ORR). While XALKORI has received rapid FDA approval, Pfizer is conducting a post-marketing clinical trial to further evaluate the clinical efficacy of XALKORI. Based on FDA's latest guidance on targeted therapy and companion diagnostics, Pfizer has worked closely with the FDA and Abbott Molecular Diagnostics Business Units in clinical trials to ensure that XALKORI and Abbott's diagnostic testing technologies are reviewed and approved at the same time. The latter is the Vysis ALK Break Apart FISH probe kit from the Abbott Molecular Diagnostics business unit to discover the ALK fusion gene. XALKORI and the Abbott Molecular Diagnostics Business Unit's ALK FISH kit were also approved, and it also marks the first development and approval of Pfizer's oncology drug or tumor treatment program along with the diagnostic test protocol. “By truly understanding NSCLC's driver genes, such as ALK, we can select the patients most likely to respond to treatment. XALKORI provides us with a new path to explore future drug development and cancer treatment,” University of Colorado, Denver Cancer Research The heads of Professor Paul Bunn and the chief physician of James Dudley pointed out. “XALKORI is the first new drug to treat lung cancer approved by the FDA for more than 6 years, representing a shift in the treatment of non-small cell lung cancer. We are moving from a monolithic treatment regime to a treatment model through biomarker decision-making.” In the XALKORI clinical trial In the test protocol, the biomarker ALK fusion gene test result of the patient's tumor is positive to improve the possibility of responding to the treatment. This first test for lung cancer treatment allows researchers to observe good results in pre-screened patient populations. Preliminary epidemiological studies have shown that the ALK positive rate in non-small cell lung cancer is approximately 3-5%, meaning that there are approximately 6,500 to 11,000 ALK-positive non-small cell lung cancer patients in the United States each year. Targeted response to XALKORI-registered clinical trials, in patients with advanced ALK-positive non-small cell lung cancer, the objective response rate was 50 to 61%.
专家预测2008-2013年期内，中国非小细胞肺癌(NSCLC)治疗市场将增长一倍以上，从3.07亿美元至6.48亿美元。结直肠癌病例治
疗的增加将加速这种增长。城市化和人口老龄化将导致2008-2018年期间，中国非小细胞肺癌发病病例增长47％，从36.15万到53.13万。最明显的增长将发生在城市，在这里未来十年的非小细胞肺癌发病病例将增加72％，与此相反，农村地区只有8％的增长。吉非替尼(阿斯利康的易瑞沙)，埃罗替尼(罗氏的特罗凯)，和内皮抑素(江苏先声药业的恩度)等靶向治疗日趋普及，和新靶向治疗药物的推出——贝伐单抗(罗氏的阿瓦斯丁)和cetuximab(默克的爱必妥)——是2008-2013年期间推动中国非小细胞肺癌市场的主要力量。跨国公司中国非小细胞肺癌治疗的市场份额将从2008年的34％上升到2013年的47％。这一增长将主要由靶向药物的引入增加而驱动。由于低价竞争激烈，跨国公司的化疗药物将失去在中国的市场。因此，作为Crizotinib的“me too”药物，式Ⅰ化合物将会有广阔的市场潜力。Experts predict that China's non-small cell lung cancer (NSCLC) treatment market will more than double in the 2008-2013 period, from $307 million to $648 million. Colorectal cancer case treatment
The increase in treatment will accelerate this growth. Urbanization and population aging will lead to a 47% increase in the incidence of non-small cell lung cancer in China between 2008 and 1818, from 361,500 to 531,300. The most obvious growth will occur in cities, where non-small cell lung cancer cases will increase by 72% in the next decade, while rural areas have only 8% growth. Gefitinib (Israel's Iressa), erlotinib (Roche's Tarceva), and endostatin (Jiangsu Xiansheng Pharmaceutical's Endo) and other targeted therapies are becoming more popular, and new targets The introduction of therapeutic drugs – bevacizumab (Ross Avastin) and cetuximab (Merck's Erbitux) – are the main forces driving the Chinese non-small cell lung cancer market during 2008-2013. The market share of multinational companies in China for non-small cell lung cancer treatment will rise from 34% in 2008 to 47% in 2013. This increase will be driven primarily by increased introduction of targeted drugs. Due to fierce competition at low prices, multinational companies' chemotherapy drugs will lose their market in China. Therefore, as a "me too" drug for Crizotinib, the compound of formula I will have broad market potential.
药物晶型研究和药物固态研发在制药业具有举足轻重的意义。药物分子通常有不同的固体形态，包括盐类，多晶，共晶，无定形，水合物和溶剂合物；同一药物分子的不同晶型，在晶体结构，稳定性，可生产性和生物利用度等性质方面可能会有显著差异，从而直接影响药物的疗效以及可开发性。因此，任何一个药品研发，都需要进行全面***的多晶型筛选，找到尽可能多的晶型，然后使用各种固态方法对这些晶型进行深入的研究，从而找到最适合开发的晶型。Drug crystal research and solid-state drug development are of paramount importance in the pharmaceutical industry. Drug molecules usually have different solid forms, including salts, polycrystals, eutectic, amorphous, hydrates and solvates; different crystal forms of the same drug molecule, in crystal structure, stability, manufacturability and bioavailability There may be significant differences in the nature of the degree, which directly affects the efficacy and developability of the drug. Therefore, any drug development requires a comprehensive system of polymorphic screening to find as many crystal forms as possible, and then use various solid-state methods to conduct in-depth research on these crystal forms to find the most suitable crystal form.
发明内容Summary of the invention
本发明的目的在于提供一种式(Ⅰ)化合物的晶型It is an object of the present invention to provide a crystalline form of a compound of formula (I)
优选的，所述晶型为晶型A，其XRPD图谱在2θ(±0.2°)为7.86、9.60、11.76、12.37、14.68、19.61、20.02、21.19、23.76、24.89处有衍射峰。Preferably, the crystal form is Form A, and the XRPD pattern has diffraction peaks at 2θ (±0.2°) of 7.86, 9.60, 11.76, 12.37, 14.68, 19.61, 20.02, 21.19, 23.76, 24.89.
更优选的，所述晶型A的XRPD图谱如图1所示。More preferably, the XRPD pattern of the crystalline form A is shown in FIG.
本发明的另一目的还在于提供制备所述式(Ⅰ)化合物晶型A的
方法，包括用有机溶剂A溶解式(Ⅰ)化合物，搅拌冷却析晶，过滤得目标晶型。Another object of the present invention is to provide a crystalline form A of the compound of the formula (I).
The method comprises dissolving the compound of the formula (I) with an organic solvent A, cooling and crystallization, stirring, and filtering to obtain a target crystal form.
本发明的另一目的还在于提供一种替代的制备所述式(Ⅰ)化合物晶型A的方法，包括用有机溶剂B溶解式(Ⅰ)化合物，加入反溶剂A搅拌析晶，过滤得目标晶型。Another object of the present invention is to provide an alternative method for preparing the crystalline form A of the compound of the formula (I), which comprises dissolving the compound of the formula (I) with an organic solvent B, adding an anti-solvent A, stirring and crystallization, and filtering the target. Crystal form.
优选的，所述有机溶剂A选自四氢呋喃和/或丙酮。Preferably, the organic solvent A is selected from the group consisting of tetrahydrofuran and/or acetone.
优选的，所述有机溶剂B选自二氯甲烷和/或氯仿，所述反溶剂A选自异丙醚、正庚烷和/或正己烷。Preferably, the organic solvent B is selected from the group consisting of dichloromethane and/or chloroform, and the anti-solvent A is selected from the group consisting of isopropyl ether, n-heptane and/or n-hexane.
本发明的另一目的还在于提供式(Ⅰ)化合物的晶型B，所述晶型为晶型B，其XRPD图谱在2θ(±0.2°)为6.82、10.14、11.25、12.55、13.50、14.90、16.27、19.78、25.21处有衍射峰。A further object of the present invention is to provide a crystalline form B of a compound of formula (I) which is crystalline form B having an XRPD pattern of 2.82, 10.14, 11.25, 12.55, 13.50, 14.90 at 2θ (± 0.2°). There are diffraction peaks at 16.27, 19.78, and 25.21.
优选的，所述晶型B的XRPD图谱如图2所示。Preferably, the XRPD pattern of the crystalline form B is shown in FIG.
本发明的目的还在于提供一种制备所述式(Ⅰ)化合物晶型B的方法，包括用有机溶剂C溶解式Ⅰ化合物，搅拌冷却析晶，过滤得目标晶型，任选的，过滤后还包含真空干燥步骤。It is also an object of the present invention to provide a process for the preparation of the crystalline form B of the compound of the formula (I), which comprises dissolving the compound of the formula I with an organic solvent C, stirring and cooling to crystallize, filtering to obtain the target crystalline form, optionally, after filtration. A vacuum drying step is also included.
本发明的另一目的还在于提供一种替代的制备式(Ⅰ)化合物晶型B的方法，包括用有机溶剂D溶解式Ⅰ化合物，加入反溶剂B析晶，过滤得目标晶型，任选的，过滤后还包含真空干燥步骤。Another object of the present invention is to provide an alternative method for preparing Form B of the compound of the formula (I), which comprises dissolving the compound of the formula I with an organic solvent D, crystallization by adding an anti-solvent B, and filtering to obtain a target crystal form, optionally The vacuum drying step is also included after filtration.
优选的，所述真空干燥的温度为20-40℃，更优选20-30℃，最优选25℃。Preferably, the vacuum drying temperature is 20-40 ° C, more preferably 20-30 ° C, and most preferably 25 ° C.
优选的，所述有机溶剂C选自异丙醇和/或正丁醇。Preferably, the organic solvent C is selected from the group consisting of isopropanol and/or n-butanol.
优选的，所述有机溶剂D选自异丙醇、丙酮和/或2-丁酮，所述反溶剂B选自为正庚烷或正己烷。Preferably, the organic solvent D is selected from the group consisting of isopropanol, acetone and/or 2-butanone, and the anti-solvent B is selected from n-heptane or n-hexane.
本发明的另一目的还在于提供一种药物组合物，包含治疗有效量的所述晶型和药学上可接受的载体。It is still another object of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of the crystalline form and a pharmaceutically acceptable carrier.
本发明的另一目的还在于提供上述晶型或药物组合物用于制备抗肿瘤药物的作用，优选的，用于制备治疗肺癌药物中的应用。Another object of the present invention is to provide the use of the above crystalline form or pharmaceutical composition for the preparation of an antitumor drug, preferably for the preparation of a medicament for the treatment of lung cancer.
本发明所提供的晶型纯度高，稳定性好，引湿性低，流动性好，适合医药制剂需要。The crystal form provided by the invention has high purity, good stability, low wettability and good fluidity, and is suitable for medical preparations.
图1是(R)-3-[1-(2,6-二氯-3-氟苯基)乙氧基]-5-[3-氟苯基-1-二甲基膦酰氧-4-基]吡啶-2-胺晶型A的XRPD图谱；Figure 1 is (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[3-fluorophenyl-1-dimethylphosphonooxy-4 XRPD pattern of -pyrimidin-2-amine crystal form A;
图2是(R)-3-[1-(2,6-二氯-3-氟苯基)乙氧基]-5-[3-氟苯基-1-二甲基膦酰氧-4-基]吡啶-2-胺晶型B的XRPD图谱。Figure 2 is (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[3-fluorophenyl-1-dimethylphosphonooxy-4 XRPD pattern of -pyridine]pyridin-2-amine Form B.
实施例1Example 1
将式Ⅰ化合物粗品5.0g投入丙酮42ml中，60℃水浴搅拌溶解，然后自然冷却搅拌析晶2h。过滤，25℃真空干燥得到目标晶型A 4.1g。经检测，其XRPD图谱如图1所示。5.0 g of the crude compound of the formula I was poured into 42 ml of acetone, stirred and dissolved in a water bath at 60 ° C, and then naturally cooled and stirred for 2 h. Filtration and vacuum drying at 25 ° C gave the target crystal form A 4.1 g. After testing, its XRPD pattern is shown in Figure 1.
实施例2Example 2
将式Ⅰ化合物粗品5.0g投入四氢呋喃150ml中，60℃水浴搅拌溶解，然后自然冷却搅拌析晶2h。过滤，25℃真空干燥得到目标晶型A3.6g。经检测，其XRPD图谱基本与图1吻合，所有特征峰均在误差范围内。5.0 g of the crude compound of the formula I was poured into 150 ml of tetrahydrofuran, stirred and dissolved in a water bath at 60 ° C, and then naturally cooled and stirred for 2 h. Filtration and vacuum drying at 25 ° C gave a target crystal form A 3.6 g. After testing, its XRPD pattern is basically consistent with Figure 1, and all characteristic peaks are within the error range.
实施例3Example 3
将式Ⅰ化合物粗品5.0g投入二氯甲烷30ml中，搅拌溶解，然后加入异丙醚100ml搅拌析晶2h。过滤，25℃真空干燥得到目标晶型A4.4g。经检测，其XRPD图谱基本与图1吻合，所有特征峰均在误差范围内。5.0 g of the crude compound of the formula I was poured into 30 ml of dichloromethane, stirred and dissolved, and then 100 ml of isopropyl ether was added and stirred for 2 h. Filtration and vacuum drying at 25 ° C gave the target crystal form A 4.4 g. After testing, its XRPD pattern is basically consistent with Figure 1, and all characteristic peaks are within the error range.
实施例4Example 4
将式Ⅰ化合物粗品5.0g投入二氯甲烷30ml中，搅拌溶解，然后加入正庚烷100ml搅拌析晶2h。过滤，25℃真空干燥得到目标晶型A4.5g。经检测，其XRPD图谱基本与图1吻合，所有特征峰均在误差范围内。5.0 g of the crude compound of the formula I was poured into 30 ml of dichloromethane, stirred and dissolved, and then 100 ml of n-heptane was added to stir and crystallize for 2 h. Filtration and vacuum drying at 25 ° C gave a target crystal form A 4.5 g. After testing, its XRPD pattern is basically consistent with Figure 1, and all characteristic peaks are within the error range.
实施例5Example 5
将式Ⅰ化合物粗品5.0g投入异丙醇30ml中，60℃水浴搅拌溶解，然后自然冷却搅拌析晶2h。过滤，25℃真空干燥得到目标晶型B4.3g。经检测，其XRPD图谱如图2所示。5.0 g of the crude compound of the formula I was put into 30 ml of isopropyl alcohol, stirred and dissolved in a water bath at 60 ° C, and then naturally cooled and stirred for 2 h. Filtration and vacuum drying at 25 ° C gave the target crystal form B4.3 g. After testing, its XRPD pattern is shown in Figure 2.
实施例6
Example 6
将式Ⅰ化合物粗品5.0g投入异丙醇50ml中，然后加入正庚烷150ml搅拌析晶2h。过滤，25℃真空干燥得到目标晶型B 4.3g。经检测，其XRPD图谱基本与图2吻合，所有特征峰均在误差范围内。5.0 g of the crude compound of the formula I was put into 50 ml of isopropanol, and then 150 ml of n-heptane was added and stirred for 2 h. Filtration and vacuum drying at 25 ° C gave 4.3 g of the desired crystal form B. After testing, its XRPD pattern is basically consistent with Figure 2, and all characteristic peaks are within the error range.
实施例7Example 7
将式Ⅰ化合物粗品5.0g投入丙酮150ml中，40℃水浴搅拌溶解，然后加入正庚烷1200ml搅拌析晶2h。过滤，25℃真空干燥得到目标晶型B 4.4g。经检测，其XRPD图谱基本与图2吻合，所有特征峰均在误差范围内。5.0 g of the crude compound of the formula I was put into 150 ml of acetone, stirred and dissolved in a water bath at 40 ° C, and then stirred and crystallization for 2 h with 1200 ml of n-heptane. Filtration and vacuum drying at 25 ° C gave the desired crystalline form B 4.4 g. After testing, its XRPD pattern is basically consistent with Figure 2, and all characteristic peaks are within the error range.
实验例一、晶型A稳定性研究Experimental Example 1 Study on the Stability of Crystal Form A
以本发明实施例1所制备的晶型为样品，在不同温度条件下检测晶型的稳定性，结果如表1所示The crystal form prepared in Example 1 of the present invention was used as a sample, and the stability of the crystal form was examined under different temperature conditions. The results are shown in Table 1.
表1Table 1
| 温度temperature | 25℃25°C | 45℃45 ° C | 60℃60 ° C |
| 晶型Crystal form | AA | AA | AA |
由上表可知，晶型A在25℃-60℃条件下稳定性良好As can be seen from the above table, Form A has good stability at 25 ° C - 60 ° C.
实验例二、晶型B稳定性研究Experimental Example 2: Study on the stability of crystal form B
以本发明实施例5所制备的晶型为样品，在不同温度条件下检测晶型的稳定性，结果如表2所示The crystal form prepared in Example 5 of the present invention was used as a sample, and the stability of the crystal form was examined under different temperature conditions. The results are shown in Table 2.
表2Table 2
|
温度 |
20℃20 ° |
30℃30 ° C | 50℃50 ° C |
| 晶型Crystal form | BB | BB | BB |
由上表可知，晶型B在20℃-50℃条件下稳定性良好As can be seen from the above table, Form B has good stability at 20 ° C to 50 ° C.
实验例三、引湿性Experimental example three, wettability
根据《药物引湿性试验指导原则》(中国药典2010版二部附录ⅪⅩJ)进行引湿性试验。取干燥的具塞玻璃称量瓶(外径为50mm，高为15mm)，于试验前一天置于适宜的25℃±1℃恒温干燥器(下部放置氯化铵饱和溶液)内，精密称定重量(m1)；取供本发明晶型适量，平铺于上述称量瓶中，供试品的厚度一般约为1mm，精密称定重量(m2)；将称量瓶敞口，并与瓶盖同置于上述恒温恒湿条件下放置24小时；盖好称量瓶盖子，精密称重(m3)。
The wettability test was carried out according to the Guiding Principles for Drugs' Humidity Test (Chinese Pharmacopoeia 2010 Edition Part II Appendix XIXJ). Take a dry stuffed glass weighing bottle (outer diameter 50mm, height 15mm), placed in a suitable 25 ° C ± 1 ° C constant temperature dryer (lower ammonium chloride saturated solution) on the day before the test, accurately weighed Weight (m1); taken in an appropriate amount of the crystal form of the present invention, laid flat in the above weighing bottle, the thickness of the test sample is generally about 1 mm, accurately weighed (m2); the weighing bottle is opened, and the bottle The lid was placed under the above constant temperature and humidity conditions for 24 hours; the lid of the weighing bottle was covered and accurately weighed (m3).
引湿性试验判断标准如下：The criteria for judging the wettability test are as follows:
潮解：吸收足量水分形成液体Deliquescence: absorb enough water to form a liquid
极易引湿性：X％≥15％；Very easy to wettability: X% ≥ 15%;
有引湿性：2％≤X％＜15％；Humidity: 2% ≤ X% < 15%;
略有引湿性：0.2％≤X％＜2％；Slightly hygroscopic: 0.2% ≤ X% < 2%;
无或几乎无引湿性：X％＜0.2％。No or almost no hygroscopicity: X% < 0.2%.
按照以上方法，测得本发明的(R)-3-[1-(2,6-二氯-3-氟苯基)乙氧基]-5-[3-氟苯基-1-二甲基膦酰氧-4-基]吡啶-2-胺晶型A化合物的增重百分率为0.3％，晶型B化合物的增重百分率为1.0％，表明本发明晶型A和晶型B略有引湿性，几乎不受高湿度影响而潮解。According to the above method, the (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[3-fluorophenyl-1-dimethyl group of the present invention was measured. The weight percent of the compound of the phosphinyloxy-4-yl]pyridin-2-amine crystal form A is 0.3%, and the weight gain percentage of the crystalline form B compound is 1.0%, indicating that the crystalline form A and the crystalline form B of the present invention are slightly It is hygroscopic and is almost unaffected by high humidity.
实施例四、流动性Embodiment 4, liquidity
取适量本发明晶型A和晶型B，进行休止角测定。Appropriate amounts of Form A and Form B of the present invention were taken to determine the angle of repose.
固定漏斗法测定休止角。即将漏斗固定在一定高度H，粉体置于漏斗中，是自然流下成堆，至圆锥体的顶端刚解除到漏斗出口为止，测定圆锥底面的半径r，计算休止角。休止角＝arc tg(H/r)。测量结果整理于表3中。The angle of repose was measured by a fixed funnel method. The funnel is fixed at a certain height H, and the powder is placed in the funnel. The pile is naturally flowed down until the tip of the cone is released to the funnel outlet. The radius r of the conical bottom surface is measured, and the angle of repose is calculated. Angle of repose = arc tg (H / r). The measurement results are summarized in Table 3.
| 晶型Crystal form | 休止角(°)Angle of repose (°) |
| 晶型ACrystal form A | 26.426.4 |
| 晶型BForm B | 23.623.6 |
结果表明，本发明晶型晶型A，晶型B具有较小的休止角，说明本发明晶型的流动性较高。
The results show that the crystalline form A of the present invention, the crystalline form B has a small angle of repose, indicating that the crystal form of the present invention has a high fluidity.
Claims (16)
- 式(Ⅰ)化合物的晶型Crystal form of the compound of formula (I)
- 根据权利要求1所述的式(Ⅰ)化合物的晶型，其特征在于，所述晶型为晶型A，其XRPD图谱在2θ(±0.2°)为7.86、9.60、11.76、12.37、14.68、19.61、20.02、21.19、23.76、24.89处有衍射峰。The crystalline form of the compound of formula (I) according to claim 1, wherein the crystalline form is crystalline form A, and its XRPD pattern is 7.86, 9.60, 11.76, 12.37, 14.68 at 2θ (±0.2°), There are diffraction peaks at 19.61, 20.02, 21.19, 23.76, and 24.89.
- 根据权利要求2所述的式(Ⅰ)化合物的晶型，其特征在于，所述晶型A的XRPD图谱如图1所示。A crystalline form of a compound of formula (I) according to claim 2, characterized in that the XRPD pattern of said crystalline form A is shown in Figure 1.
- 制备权利要求1或2任意一项所述的式(Ⅰ)化合物晶型A的方法，包括用有机溶剂A溶解式(Ⅰ)化合物，搅拌冷却析晶，过滤得目标晶型。A process for the preparation of the crystalline form A of the compound of the formula (I) according to any one of claims 1 or 2, which comprises dissolving the compound of the formula (I) with an organic solvent A, cooling and crystallization by stirring, and filtering to obtain a target crystal form.
- 制备权利要求1或2任意一项所述的式(Ⅰ)化合物晶型A的方法，包括用有机溶剂B溶解式(Ⅰ)化合物，加入反溶剂A搅拌析晶，过滤得目标晶型。A process for the preparation of the crystalline form A of the compound of the formula (I) according to any one of claims 1 or 2, which comprises dissolving the compound of the formula (I) with an organic solvent B, adding an anti-solvent A, stirring and crystallization, and filtering to obtain a target crystal form.
- 根据权利要求4所述的制备方法，其特征在于，所述有机溶剂A选自四氢呋喃和/或丙酮。The production method according to claim 4, wherein the organic solvent A is selected from the group consisting of tetrahydrofuran and/or acetone.
- 根据权利要求5所述的制备方法，其特征在于，所述有机溶剂B选自二氯甲烷和/或氯仿，所述反溶剂A选自异丙醚、正庚烷和/或正己烷。The production method according to claim 5, wherein the organic solvent B is selected from the group consisting of dichloromethane and/or chloroform, and the anti-solvent A is selected from the group consisting of isopropyl ether, n-heptane and/or n-hexane.
- 根据权利要求1所述的式(Ⅰ)化合物的晶型，其特征在于， 所述晶型为晶型B，其XRPD图谱在2θ(±0.2°)为6.82、10.14、11.25、12.55、13.50、14.90、16.27、19.78、25.21处有衍射峰。A crystalline form of a compound of formula (I) according to claim 1 wherein The crystal form is Form B, and its XRPD pattern has diffraction peaks at 2θ (±0.2°) of 6.82, 10.14, 11.25, 12.55, 13.50, 14.90, 16.27, 19.78, 25.21.
- 根据权利要求8所述的式(Ⅰ)化合物的晶型，其特征在于，所述晶型B的XRPD图谱如图2所示。A crystalline form of a compound of formula (I) according to claim 8 wherein the XRPD pattern of Form B is as shown in Figure 2.
- 制备权利要求8或9任意一项所述的式(Ⅰ)化合物晶型B的方法，包括用有机溶剂C溶解式Ⅰ化合物，搅拌冷却析晶，过滤得目标晶型，任选的，过滤后还包含真空干燥步骤。A process for the preparation of the crystalline form B of the compound of the formula (I) according to any one of claims 8 or 9, which comprises dissolving the compound of the formula I with an organic solvent C, cooling and crystallization, stirring to obtain the target crystalline form, optionally, after filtration. A vacuum drying step is also included.
- 制备权利要求8或9任意一项所述的式(Ⅰ)化合物晶型B的方法，包括用有机溶剂D溶解式Ⅰ化合物，加入反溶剂B析晶，过滤得目标晶型，任选的，过滤后还包含真空干燥步骤。A process for the preparation of the crystalline form B of the compound of the formula (I) according to any one of claims 8 or 9, which comprises dissolving the compound of the formula I with an organic solvent D, adding the anti-solvent B to crystallization, filtering to obtain the target crystal form, optionally, A vacuum drying step is also included after filtration.
- 根据权利要求10所述的制备方法，其特征在于，所述有机溶剂C选自异丙醇和/或正丁醇。The production method according to claim 10, wherein the organic solvent C is selected from the group consisting of isopropyl alcohol and/or n-butanol.
- 根据权利要求11所述的制备方法，其特征在于，所述有机溶剂D选自异丙醇、丙酮和/或2-丁酮，所述反溶剂B选自为正庚烷或正己烷。The method according to claim 11, wherein the organic solvent D is selected from the group consisting of isopropanol, acetone, and/or 2-butanone, and the anti-solvent B is selected from n-heptane or n-hexane.
- 根据权利要求10或11所述的制备方法，其特征在于，所述真空干燥的温度为20-40℃，优选20-30℃，最优选25℃。The preparation method according to claim 10 or 11, wherein the vacuum drying temperature is 20 to 40 ° C, preferably 20 to 30 ° C, and most preferably 25 ° C.
- 一种药物组合物，包含治疗有效量的权利要求1-3或权利要求8-9任意一项所述的晶型和药学上可接受的载体。A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form of any of claims 1-3 or any of claims 8-9 and a pharmaceutically acceptable carrier.
- 权利要求1-3或权利要求8-9任意一项所述晶型或权利要求4所述药物组合物用于制备抗肿瘤药物的作用，优选的，用于制备治疗肺癌药物。 The crystalline form according to any one of claims 1 to 3 or any of claims 8 to 9 or the pharmaceutical composition according to claim 4 for use in the preparation of an antitumor drug, preferably for the preparation of a medicament for treating lung cancer.
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| CN103826641A (en) * | 2011-02-24 | 2014-05-28 | 江苏豪森药业股份有限公司 | Phosphorus containing compounds as protein kinase inhibitors |
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| CN106459111B (en) | 2019-05-31 |
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