WO2021238835A1 - (2e)-n-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺的晶型及其制备方法 - Google Patents

(2e)-n-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺的晶型及其制备方法 Download PDF

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WO2021238835A1
WO2021238835A1 PCT/CN2021/095425 CN2021095425W WO2021238835A1 WO 2021238835 A1 WO2021238835 A1 WO 2021238835A1 CN 2021095425 W CN2021095425 W CN 2021095425W WO 2021238835 A1 WO2021238835 A1 WO 2021238835A1
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crystal form
fluorophenyl
chloro
methoxy
amino
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French (fr)
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鲁霞
樊孝天
张晓宇
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苏州晶云药物科技股份有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • 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

Definitions

  • the invention relates to the technical field of drug crystals. Specifically, it relates to (2E)-N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-4-(1-piperidine Yl)-2-butenamide new crystal form and its preparation method and application.
  • pan-ErbB kinase family consists of four receptors, including Her1 (EGFR, ErbB1), Her2 (Neu, ErbB2), Her3 (ErbB3) and Her4 (ErbB4).
  • Her1 EGFR, ErbB1
  • Her2 Neuron, ErbB2
  • Her3 ErbB3
  • Her4 ErbB4
  • tyrosine kinases such as Ras-Raf-MAPK or PI3-K/AKT
  • (2E)-N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl)-4-(1-piperidinyl)-2- Butenamide, the compound of formula (1), is a specific and irreversible pan-ErbB family kinase inhibitor, which can inhibit EGFR signaling pathway and induce apoptosis of the H3255GR cell line containing EGFR T790M.
  • the compound can effectively act on gefitinib-sensitive and drug-resistant non-small cell lung cancer (NSCLC) cell lines.
  • NSCLC gefitinib-sensitive and drug-resistant non-small cell lung cancer
  • Different polymorphs (including solvated forms) of solid materials can have different properties, such as melting point, hygroscopicity, physical and chemical stability, particle morphology, fluidity, bulk density, compressibility, apparent solubility, and dissolution rate Wait. These properties can directly affect the ease of processing and manufacturing solid drugs, as well as the stability, dissolution, and bioavailability of drug products, which in turn affect the quality, efficacy, and safety of drug products.
  • solvates may contain organic solvents that are toxic to organisms, and their use as medicinal raw materials will cause serious safety risks; hydrates may be dehydrated under high temperature and low humidity conditions, resulting in changes in the solid form, which will cause the process to produce ,
  • the storage of raw materials and medicines poses challenges.
  • New polymorphic forms of pharmaceutically useful compounds may provide opportunities to improve the performance characteristics of pharmaceutical products.
  • Patent CN 1972688 B discloses the preparation method of the compound of formula (I) above, but does not mention the crystal form of the compound.
  • CN 107793368 A discloses a variety of solvates of the compound of formula (I), but there is no report on the non-crystalline form of the compound. According to our large number of experimental studies, the existing conventional crystal preparation methods can only obtain the solvate of the compound of formula (I), but compared with anhydrous, solvate has control over the development of pharmaceutical preparations. The difficulties and inconveniences. Therefore, it is very necessary to provide an anhydrous form of the compound of formula (I) that meets the requirements of medicinal use.
  • the existing crystal form of the compound of formula (I) has low solubility, which greatly restricts its dissolution and bioavailability, thereby affecting the efficacy of the drug. Therefore, there is also a need to provide a new crystal form of the compound of formula (I) that is not only anhydrous, but also has a significantly improved solubility.
  • the problem to be solved by the present invention is to overcome the shortcomings of the prior art and provide a (2E)-N-[4-[(3-chloro-4-fluorophenyl)amino] which not only meets the requirements of medicinal use but also has significantly improved solubility -7-Methoxy-6-quinazolinyl]-4-(1-piperidinyl)-2-butenamide is an anhydrous type.
  • the present invention also provides a (2E)-N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-4-(1-piper
  • (2E)-N-[4-[(3-chloro-4-fluorophenyl)amino]- 7-Methoxy-6-quinazolinyl]-4-(1-piperidinyl)-2-butenamide is a non-crystalline type, and the method is simple to operate.
  • the crystal form C of 2-butenamide is crystal-free and uses Cu-K ⁇ radiation.
  • the X-ray powder diffraction pattern of the crystal form C is 5.6° ⁇ 0.2°, 10.5° ⁇ 0.2° at the diffraction angle 2 ⁇ , There is a characteristic peak at 12.8° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form C has characteristic peaks at one or two or three of the diffraction angles 2 ⁇ of 18.8° ⁇ 0.2°, 23.6° ⁇ 0.2°, and 25.4° ⁇ 0.2° .
  • the X-ray powder diffraction pattern of the crystal form C has characteristic peaks at one or two or three diffraction angles 2 ⁇ of 6.8° ⁇ 0.2°, 16.7° ⁇ 0.2°, and 26.3° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form C has a diffraction angle 2 ⁇ of 5.6° ⁇ 0.2°, 6.8° ⁇ 0.2°, 10.5° ⁇ 0.2°, 12.8° ⁇ 0.2°, 16.7° There are characteristic peaks at ⁇ 0.2°, 18.8° ⁇ 0.2°, 23.6° ⁇ 0.2°, 25.4° ⁇ 0.2°, 26.3° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form C has a diffraction angle 2 ⁇ of 5.6° ⁇ 0.2°, 6.8° ⁇ 0.2°, 10.5° ⁇ 0.2°, 12.8° ⁇ 0.2°,
  • the relative intensities of the characteristic peaks at 16.7° ⁇ 0.2°, 18.8° ⁇ 0.2°, 23.6° ⁇ 0.2°, 25.4° ⁇ 0.2°, and 26.3° ⁇ 0.2° are all greater than 10%.
  • the X-ray powder diffraction pattern of Form C has a relative intensity of the characteristic peaks at diffraction angles 2 ⁇ of 5.6° ⁇ 0.2°, 10.5° ⁇ 0.2°, and 12.8° ⁇ 0.2° greater than 40% , Preferably greater than 50%, more preferably greater than 60%.
  • the X-ray powder diffraction pattern of crystal form C has a relative intensity of the characteristic peaks at diffraction angles 2 ⁇ of 18.8° ⁇ 0.2°, 23.6° ⁇ 0.2°, and 25.4° ⁇ 0.2° greater than 25% , Preferably greater than 30%.
  • the typical X-ray powder diffraction pattern of the crystal form C of the present invention is basically as shown in Fig. 1 or 2.
  • thermogravimetric analysis when the crystal form C is heated to about 160° C., it has a mass loss gradient of about 1.8%, and its TGA is shown in FIG. 3.
  • the present invention also provides the aforementioned (2E)-N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-4-(1 -
  • the preparation method of the crystalline form C of piperidinyl)-2-butenamide, the method comprises the following steps:
  • the first temperature is greater than 140°C
  • the second temperature is less than or equal to 140°C
  • the difference between the first temperature and the second temperature is greater than 20°C.
  • the difference between the first temperature and the second temperature is 30°C to 200°C.
  • the difference between the first temperature and the second temperature is 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C °C, 150°C, 160°C, 170°C, 180°C, 190°C or 200°C.
  • the first temperature is 160-200°C
  • the second temperature is 5-30°C.
  • the first temperature is 175-185°C
  • the second temperature is room temperature
  • the raw material of (base)-2-butenamide is preferably the crystalline form II of dacotinib monohydrate reported in CN 107793368 A.
  • the 2 ⁇ (°) values of the X-ray powder diffraction pattern of the Dacotinib monohydrate crystal form II are: 4.5° ⁇ 0.2°, 12.8° ⁇ 0.2°, 15.4° ⁇ 0.2°, 18.4° ⁇ 0.2°, There are characteristic peaks at 21.6° ⁇ 0.2°, 22.7° ⁇ 0.2°, 24.0° ⁇ 0.2°, and 26.5° ⁇ 0.2°.
  • the raw material of -2-butenamide can be prepared by the following method: (2E)-N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6 -Quinazolinyl]-4-(1-piperidinyl)-2-butenamide is dissolved in ether solvents or chlorinated alkanes or ester solvents or is selected from alcohols, hydrocarbyl nitriles, alkanes, ketones, In a mixed solvent composed of one or more solvents in the benzene series, a solid is obtained by adding an anti-solvent, stirring and crystallization or cooling, and the solid can be used as the (2E)-N-[4-[(3- Chloro-4-fluorophen
  • the ether solvent may be tetrahydrofuran; the chloroalkane may be chloroform; the ester solvent may be ethyl acetate; the alkane may be n-heptane, the hydrocarbyl nitrile may be acetonitrile, and the alcohol may be Methanol or ethanol, the ketone may be acetone, for example, and the benzene series may be toluene, for example.
  • (2E)-N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-4-(1- Piperidinyl)-2-butenamide is dissolved in tetrahydrofuran, and forms a mixed system with methanol, n-heptane, acetonitrile, toluene, and water.
  • the anti-solvent is added or cooled or stirred, or (2E)-N- [4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-4-(1-piperidinyl)-2-butenamide dissolved in chloroform
  • the anti-solvent is added or cooled or stirred, or the solid is obtained by stirring in various alcohols, ketones, esters, and water.
  • the raw material of the invention is added or cooled or stirred, or (2E)-N- [4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-4-(1-piperidinyl)-2-butenamide dissolved in chloroform
  • step (1) it is recommended to heat at a rate of 5-30°C/min; specifically, for example, heating at a rate of 10-20°C/min.
  • step (2) the intermediate can be naturally cooled to cool to room temperature.
  • the present invention also provides a medicine for treating cancer, comprising an active ingredient, the active ingredient comprising (2E)-N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methyl as described above Form C of oxy-6-quinazolinyl]-4-(1-piperidinyl)-2-butenamide.
  • the medicine includes excipients other than the active ingredient, and the selection of excipients and the preparation of the medicine can be carried out in a well-known manner in the pharmaceutical field.
  • the active ingredient may only contain (2E)-N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-4-(1-piperidine (2E)-N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazole
  • the crystalline form C of linyl]-4-(1-piperidinyl)-2-butenamide is present in an effective amount.
  • the above-mentioned drugs for the treatment of cancer are particularly used for the treatment of drug-resistant non-small cell lung cancer.
  • (2E)-N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-4 provided by the present invention -(1-piperidinyl)-2-butenamide anhydrous new crystalline form, not only has good stability, low hygroscopicity, meets the requirements of medicinal use, and at the same time the solubility and dissolution are significantly improved, so it can be expected It is a more ideal drug choice, and it can be expected to provide better bioavailability, as well as help improve drug efficacy and reduce dosage.
  • Figure 1 is an X-ray powder diffraction pattern of crystal form C obtained in Example 1;
  • Example 2 is an X-ray powder diffraction pattern of crystal form C obtained in Example 2;
  • Figure 3 is a thermogravimetric analysis diagram of crystal form C obtained in Example 2.
  • Figure 5 is an X-ray powder diffraction pattern of crystal form C obtained in Example 3.
  • Example 6 is an X-ray powder diffraction pattern of crystal form A obtained in Example 4.
  • Fig. 7 is an X-ray powder diffraction pattern of crystal form C obtained in Example 4.
  • Figure 8 is the dissolution curve of crystal form C obtained in Example 3.
  • Example 9 is a diagram of the moisture absorption test (DVS) of crystal form C obtained in Example 2.
  • Example 10 is a comparison diagram of X-ray powder diffraction of the crystal form C obtained in Example 2 before and after the moisture absorption test;
  • Example 11 is a comparison diagram of X-ray powder diffraction of the crystal form C obtained in Example 2 before and after stable storage.
  • the X-ray powder diffraction pattern is characteristic for a specific crystal form.
  • the relative positions of the peaks ie 2 ⁇
  • the relative intensity of the spectrum will change due to the superior orientation effect caused by the difference in crystal conditions, particle size and other measurement conditions.
  • the low intensity peak intensity less than 20%
  • the relative intensity of the peak is not characteristic for the determination of the crystal form.
  • the relative intensity of the diffraction peak in the XRPD pattern is related to the preferred orientation of the crystal.
  • the peak intensity shown in this article is illustrative and not for absolute comparison.
  • the 2 ⁇ value of the same crystal form may have a certain measurement error, about ⁇ 0.2°. Therefore, this error should be taken into consideration when determining each crystal structure.
  • room temperature refers to the natural environmental temperature that can be reached without additional heating or cooling, and the corresponding specific temperature is usually between 10-30°C.
  • the X-ray powder diffraction pattern described in this application was collected on a PANalytical Empyrean X-ray powder diffractometer and a PANalytical X'Pert 3 X-ray powder diffractometer.
  • Scan range: from 3.0 to 40.0 degrees
  • Step size 0.0167 degrees
  • Scan range: from 3.0 to 40.0 degrees
  • the differential scanning calorimetry (DSC) data described in this application are collected from TA Instruments Q200 and Discovery DSC 2500 differential scanning calorimeters.
  • the instrument control software is Q Series and TRIOS, and the analysis software is Universal Analysis.
  • Usually 1-10 mg of sample is placed in a covered aluminum crucible (unless otherwise specified), and the sample is raised from room temperature to 300°C under the protection of 50mL/min dry N 2 at a heating rate of 10°C/min.
  • the TA software records the heat change of the sample during the heating process. In this application, the melting point is reported as the onset temperature.
  • thermogravimetric analysis (TGA) data described in this application are collected from TA Instruments Q5000 and Discovery TGA 5500 thermogravimetric analyzers.
  • the instrument control software is Q Series and TRIOS, respectively, and the analysis software is Universal Analysis.
  • 2 ⁇ 15mg of the sample is placed in a platinum crucible, and the method of segmented high-resolution detection is adopted.
  • the sample is raised from room temperature to 350°C at a temperature increase rate of 10°C/min under the protection of 50mL/min dry N 2.
  • the TA software records the weight change of the sample during the heating process.
  • the X-ray powder diffraction data of the obtained solid product is shown in Table 2, the XRPD pattern is shown in Figure 2, the TGA image is shown in Figure 3, and the DSC image is shown in Figure 4.
  • Table 2 the X-ray powder diffraction data of the obtained solid product is shown in Table 2, the XRPD pattern is shown in Figure 2, the TGA image is shown in Figure 3, and the DSC image is shown in Figure 4.
  • TGA data shows that the crystal form sample loses about 1.8% when heated to 160°C, and there is a single melting endothermic peak at 167°C to 200°C in DSC, indicating that the crystal form is (2E)-N -[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-4-(1-piperidinyl)-2-butenamide anhydrous Things.
  • X-ray powder diffraction data is shown in Table 4, and its XRPD pattern is shown in Figure 6.
  • Table 4 Take about 10 mg of the wet sample crystal form A and place it in a DSC aluminum crucible.
  • the sample was heated (temperature rising rate of 10°C/min) to 160°C, and then naturally cooled to room temperature (about 25°C) to obtain a solid product, which was sampled and tested.
  • Dissolution Apparatus CPE-010 Agilent 708DS method Pulp method medium pH 6.5 FaSSIF solution Medium volume 900mL Rotating speed 50rpm Medium temperature 37°C Sampling point 5,10,15,20,30,45,60,120min Supplementary medium No
  • Example 2 About 10 mg of the crystal form C prepared in Example 2 was taken, and its hygroscopicity was tested with a dynamic moisture adsorption (DVS) instrument. The experimental results are shown in Table 9. The DVS diagram of the moisture absorption experiment is shown in Figure 9, and the XRPD comparison diagram of the sample before and after the test is shown in Figure 10.
  • DVS dynamic moisture adsorption
  • moisture-absorbing weight gain is not less than 15%
  • moisture absorption weight gain is less than 15% but not less than 2%
  • weight gain is less than 2% but not less than 0.2%
  • weight gain is less than 0.2%
  • the crystal form C of the present application gains 1.35% in weight after equilibrium at 80% humidity, which is slightly hygroscopic according to the definition standard for hygroscopic weight gain. It shows that the crystal form C of the present application can be stable under different humidity conditions and has good moisture absorption. During the production and storage of medicines, it can be kept stable without strict humidity control, and has low requirements on the preparation process and storage conditions. Very strong application value.
  • Placement conditions Set time Crystal form change Relative purity 25°C, 60% relative humidity 45 days constant 101.4% 40°C, 75% relative humidity 45 days constant 100.8% 80°C 24 hours constant 100.2%

Abstract

本发明涉及一种(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺的晶型C及其制备方法和含有其的药物，所述晶型C为无水物，使用Cu-Kα辐射，晶型C的X-射线粉末衍射图在衍射角2θ为5.6°±0.2°,10.5°±0.2°,12.8°±0.2°处有特征峰。本发明的晶型C是无水物，相比现有的溶剂化物，其在药物开发中具有明显优势，此外，本发明的晶型C在保持好的稳定性的前提下，溶解度相比现有的溶剂化合物有显著提高。

Description

(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺的晶型及其制备方法 技术领域
本发明涉及药物晶体技术领域。具体而言，涉及(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺新晶型及其制备方法和用途。
技术背景
泛ErbB激酶家族由四种受体组成，包括Her1(EGFR，ErbB1)，Her2(Neu，ErbB2)，Her3(ErbB3)和Her4(ErbB4)。在细胞信号传导过程中，ErbB激酶家族蛋白与相应配体结合后，会诱发酪氨酸激酶下游信号传导通路的级联反应，如Ras-Raf-MAPK或PI3-K/AKT等，进而导致对细胞凋亡过程的抑制以及细胞增殖过程的促进。在多种肿瘤的发生与发展过程中，都伴随着泛ErbB家族蛋白的过度表达，该受体也成为了肿瘤干预治疗中的重要靶点。
(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺的化学结构如式(I)所示：
Figure PCTCN2021095425-appb-000001
(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺即式(1)化合物是一种特异性、不可逆泛ErbB家族激酶抑制剂，能够抑制EGFR信号通路传导，并诱导包含EGFR T790M的H3255GR细胞系凋亡。该化合物能够有效作用于对gefitinib-敏感的和耐药的非小细胞肺癌(NSCLC)细胞系。2018年，FDA批准该化合物作为一线用药，用于非小细胞肺癌的治疗。
固体材料的不同多晶型(包括溶剂化形式)可具有不同的性质，例如熔点、吸湿性、物理化学稳定性、颗粒形貌、流动性、堆密度、可压性、表观溶解度和溶出速率等。这些性质可直接影响加工和制造固体药物的难易程度，以及药物产品的稳定性、溶出和生物利用度，进而影响药物产品的品质、功效和安全性。例如，溶剂合物中可能含有对生物体存在毒性的有机溶剂，作为药用原材料使用会导致严重的安全风险；水合物有可能在高温低湿度条件下脱水，发生固体形态的改变，给工艺生产、原材料与药品的储存带来挑战。药学上有用的化合物的新的多晶型可以提供改善药物产品的性能特征的机会。
专利CN 1972688 B中公开了上述式(I)化合物的制备方法，但未提及该化合物的晶体形态。CN 107793368 A中公开了上述式(I)化合物的多种溶剂合物，但未见对该化合物无水晶型的报道。根据我们大量的实验研究，采用现有的常规晶型制备方法均只能得到式 (I)化合物的溶剂合物，然而溶剂合物相较无水物而言，在药物制剂的开发上存在控制的困难和不便。因此，非常有必要提供满足药用要求的式(I)化合物的无水晶型。此外，现有的式(I)化合物的晶型，溶解性较低，会在很大程度上制约了其溶出和生物利用度，从而影响药效。因此，还需要提供不仅是无水的，而且溶解度可以显著提高的式(I)化合物的新晶型。
发明内容
本发明所要解决的问题是克服现有技术的不足，提供一种不仅满足药用要求且溶解度显著提高的(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺的无水晶型。
本发明同时提供一种(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺的无水晶型的制备方法，通过该方法可以稳定可控地得到(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺的无水晶型，且该方法操作简单。
为解决以上技术问题，本发明采取的一种技术方案是：
一种(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺的晶型C，为无水晶型，使用Cu-Kα辐射，所述晶型C的X-射线粉末衍射图在衍射角2θ为5.6°±0.2°,10.5°±0.2°,12.8°±0.2°处有特征峰。
进一步的，所述晶型C的X-射线粉末衍射图在衍射角2θ为18.8°±0.2°,23.6°±0.2°,25.4°±0.2°中的一处或两处或三处有特征峰。
更进一步的，所述晶型C的X-射线粉末衍射图在衍射角2θ为6.8°±0.2°,16.7°±0.2°,26.3°±0.2°一处或两处或三处有特征峰。
在一个优选的实施方案中，所述晶型C的X-射线粉末衍射在衍射角2θ为5.6°±0.2°,6.8°±0.2°,10.5°±0.2°,12.8°±0.2°,16.7°±0.2°,18.8°±0.2°,23.6°±0.2°,25.4°±0.2°,26.3°±0.2°处有特征峰。
在更进一步优选的实施方案中，所述晶型C的X-射线粉末衍射图在衍射角2θ为5.6°±0.2°,6.8°±0.2°,10.5°±0.2°,12.8°±0.2°,16.7°±0.2°,18.8°±0.2°,23.6°±0.2°,25.4°±0.2°,26.3°±0.2°处特征峰的相对强度均大于10％。
在一些具体的实施方式中，晶型C的X-射线粉末衍射图在衍射角2θ为5.6°±0.2°,10.5°±0.2°,12.8°±0.2°处的特征峰的相对强度大于40％，优选大于50％，更优选大于60％。
在一些具体的实施方式中，晶型C的X-射线粉末衍射图在衍射角2θ为18.8°±0.2°,23.6°±0.2°,25.4°±0.2°处的特征峰的相对强度大于25％，优选大于30％。
本发明的晶型C，其典型的X射线粉末衍射图基本如图1或2所示。
在根据本发明的一些具体实施方式中，当进行热重分析时，晶型C加热至约160℃时，具有约1.8％的质量损失梯度，其TGA如附图3所示。
本发明还提供一种前述的(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺的晶型C的制备方法，该述方法包括如下步骤：
(1)将(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺原料在惰性气体保护下加热至第一温度得到中间物；
(2)对所述中间物进行降温，使其冷却至第二温度，得到晶型C；
其中第一温度大于140℃，所述第二温度小于等于140℃，且第一温度与第二温度的差值大于20℃。
优选地，第一温度与所述第二温度的差值为30℃-200℃。具体地，例如，第一温度与第二温度的差值为30℃，40℃，50℃，60℃，70℃，80℃，90℃，100℃，110℃，120℃，130℃，140℃，150℃，160℃，170℃，180℃，190℃或200℃。
根据本发明的一个优选方面，所述第一温度为160-200℃，所述第二温度为5-30℃。
在一个具体实施方式中，所述第一温度为175-185℃，所述第二温度为室温。
进一步地，所述(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺原料优选是CN 107793368 A报道的达可替尼一水合物晶型II。该达可替尼一水合物晶型II的X-射线粉末衍射图谱在2θ(°)值为：4.5°±0.2°、12.8°±0.2°、15.4°±0.2°、18.4°±0.2°、21.6°±0.2°、22.7°±0.2°、24.0°±0.2°和26.5°±0.2°处具有特征峰。此外，也可以采用其他(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺原料，例如(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺的其他溶剂化物(例如可以是CN 107793368 A所报道的那些或者通过其他常规结晶方法制备的晶型)，或者还可以是无定形。
作为举例，(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺原料可以是以下方法制得的：将化学合成的(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺溶解于醚类溶剂或氯代烷烃或酯类溶剂或与选自醇类、烃基腈、烷烃、酮类、苯系物中的一种或多种溶剂组成的混合溶剂中，通过反溶剂添加、搅拌析晶或降温得到固体，该固体可作为本发明的(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺原料。其中所述醚类溶剂例如可以为四氢呋喃；氯代烷烃例如可以是氯仿；酯类溶剂例如可以是乙酸乙酯；烷烃例如可以是为正庚烷，烃基腈例如可以是乙腈，醇类例如可以是甲醇或乙醇，酮类例如可以是丙酮，苯系物例如可以是甲苯。在一些具体操作中，将(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺溶解于四氢呋喃中，与甲醇、正庚烷、乙腈、甲苯、水组成混合体系，通过反溶剂添加或降温或搅拌的方式，或将(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺溶解于氯仿中，与乙酸异丙酯、正庚烷、乙腈、甲苯组成混合体系反溶剂添加或降温或搅拌的方式，或在各醇类、酮类、酯类、水中搅拌得到固体，将该固体作为本发明的原料。
进一步地，本发明方法中，升温和降温的速率对于晶型C的形成不具有决定性影响。 然而，综合产业实施等多方面的考虑，步骤(1)中，建议以5～30℃/min的速率进行加热；具体例如以10～20℃/min的速率进行加热。步骤(2)中，则可以对所述中间物进行自然降温，使其冷却至室温。
本发明还提供一种治疗癌症的药物，包含活性成分，该活性成分包含如上所述的(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺的晶型C。
通常，药物包括活性成分之外的辅料，辅料的选择、药物的制备等均可以制药领域中熟知的方式进行。
活性成分可以仅包含(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺的晶型C，此时，(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺的晶型C以有效量存在。与现有的包含(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺的药物相比，本发明由于晶型C具有显著提高的溶解性，因而在辅料的选择上可以更加灵活，在使用剂量上有望降低。
上述的治疗癌症的药物，具体特别是用于治疗抗药性非小细胞肺癌药物。
与现有技术相比，本发明提供的(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺的无水新晶型，不仅稳定性好，引湿性低，满足药用要求，且同时溶解度与溶出度有显著提高，由此可以期望其是更理想的药物选择，而且可期望提供更好的生物利用度，以及有助于提高药效和降低剂量。
附图说明
图1为实施例1中所得晶型C的X射线粉末衍射图；
图2为实施例2中所得晶型C的X射线粉末衍射图；
图3为实施例2中所得晶型C的热重分析图；
图4为为实施例2中所得晶型C的差式扫描量热图；
图5为实施例3中所得晶型C的X射线粉末衍射图；
图6为实施例4中所得晶型A的X射线粉末衍射图；
图7为实施例4中所得晶型C的X射线粉末衍射图；
图8为实施例3中所得晶型C的溶出曲线；
图9为实施例2中所得晶型C的引湿性测试(DVS)图；
图10为实施例2中所得晶型C引湿性测试前后的X射线粉末衍射对比图；
图11为实施例2中所得晶型C稳定性放置前后的X射线粉末衍射对比图。
具体实施方式
为了帮助理解本申请公开的各种实施方案，提供以下说明：
X-射线粉末衍射图谱对于特定的晶型具有特征性。判断是否与已知晶型相同时，应该注意的是峰的相对位置(即2θ)而不是它们的相对强度。这是由于谱图的相对强度会因为晶 体条件、粒径和其它测定条件的差异产生的优势取向效果而变化，特别是低强度峰值(强度小于20％)在某些情况下可能不存在，衍射峰的相对强度对晶型的确定并非是特征性的，事实上，XRPD图谱中衍射峰的相对强度与晶体的择优取向有关，本文所示的峰强度为说明性而非用于绝对比较。另外，本领域知道，用X射线衍射测定化合物的结晶时，由于测定的仪器或测定的条件等的影响，同一个晶型的2θ值可存在一定的测量误差，约为±0.2°。因此，在确定每种结晶结构时，应该将此误差考虑在内。在XRD图谱中通常用2θ角或晶面距d值表示峰位置，两者之间具有简单的换算关系：d＝λ/2sinθ，其中d代表晶面间距d值，λ代表入射X射线的波长，θ为衍射角。还应特别指出的是，在混合物的鉴定中，由于含量下降等因素会造成部分衍射线缺失。另外，由于样品高度等实验因素的影响，会造成峰角度的整体偏移，通常允许一定的偏移。因而，本领域技术人员可以理解的是，本申请所指晶型的X射线衍射图不必和这里所指的例子中的X射线衍射图完全一致，本文所述“XRPD图相同”并非指绝对相同，相同峰位置可相差±0.2°(或更大误差)且峰强度允许一定可变性。任何具有和这些图谱中的特征峰相同或相似的图的晶型均属于本申请的范畴之内。本领域技术人员能够将本申请所列的图谱和一个未知晶型的图谱相比较，以证实这两组图谱反映的是相同还是不同的晶型。
在具体X线晶体衍射图谱的基础上，通常允许本领域技术人员选取几个特征峰来对晶型进行定义，而特征峰的选择是基于一定的目的可以进行综合考量的，并无严格限制，例如，本领域技术人员更倾向于选择相对强度较高的峰、相对低角度的峰和峰形较为完整的特征峰，以及选择足以与其他晶体区别的特征峰等，以使得特征峰具有被区分、识别和鉴定的意义。因此，不能仅因为所选择的特征峰的组合发生改变而断定构成了不同的晶型或超出了原有请求的晶型范围。
需要说明的是，本申请中提及的数值及数值范围不应被狭隘地理解为数值或数值范围本身，本领域技术人员应当理解其可以根据具体技术环境的不同，在不背离本申请精神和原则的基础上围绕具体数值有所浮动。
本申请所述“室温”，是指无需另外进行加热或冷却即达成的自然环境温度，对应的具体温度通常在10-30℃之间。
本申请进一步参考以下实施例限定，所述实施例详细描述本申请的晶型的制备和使用方法。对本领域技术人员显而易见的是，对于材料和方法两者的许多改变可在不脱离本申请范围的情况下实施。
采集数据所用的仪器及方法：
本申请所述的X射线粉末衍射图在PANalytical Empyrean型X射线粉末衍射仪及PANalytical X'Pert 3型X射线粉末衍射仪上采集。
Empyrean型X射线粉末衍射的方法参数如下：
X射线类型：Cu,Kα
Figure PCTCN2021095425-appb-000002
1.540598；
Figure PCTCN2021095425-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)
发散狭缝：自动
扫描模式：连续
扫描范围：自3.0至40.0度
每步扫描时间：17.780秒
步长：0.0167度
PANalytical X'Pert 3型X射线粉末衍射的方法参数如下：
X射线类型：Cu,Kα
Figure PCTCN2021095425-appb-000004
1.540598；
Figure PCTCN2021095425-appb-000005
1.544426
Kα2/Kα1强度比例：0.50
电压：45仟伏特(kV)
电流：40毫安培(mA)
发散狭缝：1/16度
扫描模式：连续
扫描范围：自3.0至40.0度
每步扫描时间：46.665秒
步长：0.0263度
本申请所述的差示扫描量热分析(DSC)数据采自于TA Instruments Q200型及Discovery DSC 2500型差示扫描量热仪，仪器控制软件分别是Q Series和TRIOS，分析软件是Universal Analysis。通常取1～10毫克的样品放置于加盖(除非特别说明)的铝坩埚内，以10℃/min的升温速度在50mL/min干燥N 2的保护下将样品从室温升至300℃，同时TA软件记录样品在升温过程中的热量变化。在本申请中，熔点是按起始温度来报告的。
本申请所述的热重分析(TGA)数据采自于TA Instruments Q5000型及Discovery TGA 5500型热重分析仪，仪器控制软件分别是Q Series和TRIOS，分析软件是Universal Analysis。通常取2～15mg的样品放置于白金坩埚内，采用分段高分辨检测的方式，以10℃/min的升温速度在50mL/min干燥N 2的保护下将样品从室温升至350℃，同时TA软件记录样品在升温过程中的重量变化。
除非特殊说明，以下实施例均在室温条件下操作。
以下具体实施例中，作为原料的(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺固体，经检测其为晶体且晶型为CN 107793368 A中所报道的一水合物晶型II。
实施例1
称取约20毫克的(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺固体置于DSC铝坩埚中，使用DSC在氮气保护下将(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺加热(升温速率为10℃/min)至约180℃，然后自然冷却降温至室温(约25℃)后得到固体产物。
经检测，本实施例所得固体的X射线粉末衍射数据如表1所示，其XRPD图如图1所示，结果表明所得固体产物为本申请所述的晶型C。
表1
编号 衍射角2θ(±0.2°) d值 相对强度％
1 5.62 15.72 100.00
2 6.76 13.09 23.66
3 8.33 10.61 4.71
4 10.46 8.46 73.12
5 12.85 6.89 85.63
6 13.56 6.53 3.45
7 15.40 5.75 2.31
8 16.74 5.30 22.67
9 17.41 5.09 4.91
10 18.04 4.92 10.20
11 18.77 4.73 38.48
12 19.65 4.52 7.12
13 20.45 4.34 11.02
14 21.03 4.22 11.26
15 21.77 4.08 11.02
16 22.79 3.90 16.59
17 23.61 3.77 38.13
18 24.88 3.58 14.26
19 25.41 3.51 40.15
20 26.31 3.39 14.58
21 27.31 3.27 4.84
22 27.93 3.19 6.60
23 29.08 3.07 4.60
24 29.84 2.99 2.65
实施例2
称取约20毫克的(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺固体置于DSC铝坩埚中，使用DSC在氮气保护下将(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺加热(升温速率为10℃/min)至180℃，然后自然冷却至室温(约25℃)后得到固体产物，平行试验20次，将20次所得固体产物混合均匀，取样检测。
经检测，所得固体产物的X射线粉末衍射数据如表2所示，其XRPD图如图2所示，TGA图像如图3所示，DSC图像如图4所示，结果表明所得固体产物为本申请所述的晶型C，TGA数据显示该晶型样品加热至160℃失重约1.8％，且DSC中在167℃至200℃存在单一熔化吸热峰，说明该晶型为(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺无水物。
表2
编号 衍射角2θ(±0.2°) d值 相对强度％
1 5.64 15.40 91.75
2 6.72 12.96 27.60
3 10.48 8.36 67.64
4 12.93 6.79 75.08
5 16.72 5.27 27.55
6 18.04 4.89 21.18
7 18.82 4.69 65.11
8 19.70 4.48 15.82
9 20.49 4.31 25.71
10 21.15 4.18 21.50
11 21.78 4.06 24.71
12 22.82 3.88 34.68
13 23.51 3.77 100.00
14 25.37 3.50 82.47
15 26.28 3.38 29.36
16 29.96 3.18 14.23
17 29.07 3.06 12.28
实施例3
称取约1克的(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁 烯酰胺固体置于真空干燥箱中，在真空保护下将(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺加热至170℃，然后自然冷却至室温(约25℃)后得到固体产物，取样检测。
经检测，所得固体产物的X射线粉末衍射数据如表3所示，其XRPD图如图5所示，结果表明所得固体产物为本申请所述的晶型C，且该晶型为(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺无水物。
表3
编号 衍射角2θ(±0.2°) d值 相对强度％
1 5.59 15.82 100.00
2 6.72 13.16 15.49
3 10.44 8.47 66.65
4 12.84 6.89 89.63
5 16.72 5.30 21.61
6 17.96 4.94 6.93
7 18.73 4.74 31.30
8 21.04 4.22 11.77
9 21.78 4.08 9.50
10 22.72 3.91 15.74
11 23.66 3.76 31.90
12 24.79 3.59 9.45
13 25.42 3.50 33.81
14 26.30 3.39 10.96
15 27.22 3.28 4.46
实施例4
称取约100毫克的(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺固体溶解在3毫升四氢呋喃中，所得样品超声约2分钟后使用0.22微米过滤器过滤，得到澄清溶液。缓慢滴加水至该澄清溶液中至有固体析出，将所得悬浊液室温搅拌2小时后，固液分离并弃去上清液，所得固体湿样为溶剂合物晶型A，晶型A的X射线粉末衍射数据如表4所示，其XRPD图如图6所示。取约10毫克该湿样晶型A置于DSC铝坩埚中，使用DSC在氮气保护下将样品加热(升温速率为10℃/min)至50℃，平衡10分钟，然后继续使用DSC在氮气保护下将样品加热(升温速率为10℃/min)至160℃，然后自然冷却至室温(约25℃)后得到固体产物，取样检测。
经检测，所得固体产物的X射线粉末衍射数据如表5所示，其XRPD图如图7所示。 结果表明所得固体产物为本申请所述的晶型C，且该晶型为(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺无水物。
表4
编号 衍射角2θ(±0.2°) d值 相对强度％
1 5.44 16.25 100.00
2 6.03 14.66 2.33
3 9.76 9.07 1.93
4 10.73 8.25 1.76
5 11.08 7.99 6.21
6 12.10 7.31 5.54
7 15.27 5.80 2.95
8 16.27 5.45 2.67
9 17.31 5.12 3.21
10 18.07 4.91 1.86
11 19.50 4.55 0.85
12 21.11 4.21 1.61
13 21.72 4.09 4.00
14 22.40 3.97 8.62
15 24.30 3.66 0.71
16 27.26 3.27 0.52
17 29.46 3.03 0.61
18 32.84 2.73 0.83
表5
编号 衍射角2θ(±0.2°) d值 相对强度％
1 5.61 15.75 93.76
2 6.75 13.09 18.48
3 10.41 8.50 57.79
4 12.84 6.89 86.23
5 16.73 5.30 25.51
6 18.04 4.92 27.62
7 18.78 4.73 65.74
8 19.60 4.53 24.77
9 20.57 4.32 30.89
10 21.10 4.21 28.52
11 21.85 4.07 22.70
12 22.76 3.91 47.93
13 23.57 3.78 100.00
14 24.77 3.59 38.47
15 25.38 3.51 91.81
16 26.31 3.39 34.80
17 29.00 3.08 14.25
18 31.49 2.84 7.46
19 31.91 2.80 6.29
20 33.87 2.65 12.14
21 36.20 2.48 5.70
22 36.51 2.46 10.65
23 37.10 2.42 25.58
24 38.61 2.33 15.20
实施例5：动态溶解度对比研究
在室温条件(约25℃)下，将实施例2制备的晶型C与CN107793368A中晶型II的样品分别加入到pH 6.5的FaSSIF溶液(模拟未进食状态下的人工肠液)中，分别在1个小时后，2个小时后，4个小时后和24个小时后采用高效液相色谱(HPLC)测定溶液中(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺的含量。实验结果如表6所示。
表6 动态溶解度对比研究
Figure PCTCN2021095425-appb-000006
结果表明，本申请的新晶型C与CN107793368A中晶型II相比，在FaSSIF中具有显著更高的溶解度和溶解速率。
实施例6：溶出速率对比研究
为进一步比对模拟人体环境下，晶型C与现有技术的溶出差异，在37℃条件下，将实施例3制备的晶型C与CN107793368A中晶型II的样品各400毫克分别加入到900毫升pH6.5的FaSSIF溶液(模拟未进食状态下的人工肠液)中，倒入溶出杯中，使用溶出仪测试溶出速率。溶出条件如表7所示，溶出曲线如图8所示，溶出数据如表8所示.
表7
溶出仪 CPE-010 Agilent 708DS
方法 浆法
介质 pH 6.5 FaSSIF溶液
介质体积 900mL
转速 50rpm
介质温度 37℃
取样点 5,10,15,20,30,45,60,120min
补充介质 No
表8
Figure PCTCN2021095425-appb-000007
结果表明，本申请晶型C与现有技术CN107793368A中晶型II相比，溶出更快，从5分钟开始溶解度大于CN107793368A中晶型II，在2小时，溶解度达到CN107793368A公开的晶型II的6倍。
实施例7：晶型C的引湿性实验：
取实施例2制备的晶型C约10mg，采用动态水分吸附(DVS)仪测试其引湿性。实验结果如表9所示。引湿性实验的DVS图如图9所示，样品测试前后的XRPD对比图如图10所示。
表9 晶型C的引湿性实验
Figure PCTCN2021095425-appb-000008
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，本申请的晶型C在80％湿度下平衡后增重1.35％，根据引湿性增重的界定标准，属于略有引湿性。说明本申请晶型C在不同湿度条件下均能保持稳定，具有良好的引湿性，在药品生产与存放过程中，无需严格的湿度控制即可保持稳定，对制备工艺以及存储条件要求低，具有很强的应用价值。
实施例8：晶型C的稳定性实验
取实施例2制备的三份晶型C样品，分别敞口放置于25℃、60％相对湿度下，40℃、75％相对湿度下和80℃环境湿度下，设定时间后取样测XRPD和纯度。结果分别参见图11和表10所示。结果表明，在全部实验条件下放置，本申请的晶型C样品晶型均保持不变且纯度未见减小，表明本申请的晶型C具有优异的稳定性。
表10 晶型C的稳定性实验
放置条件 放置时间 晶型变化 相对纯度
25℃，60％相对湿度 45天 保持不变 101.4％
40℃，75％相对湿度 45天 保持不变 100.8％
80℃ 24小时 保持不变 100.2％
上述实施例只为说明本申请的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本申请的内容并据以实施，并不能以此限制本申请的保护范围。凡根据本申请精神实质所作的等效变化或修饰，都应涵盖在本申请的保护范围之内。

Claims (10)

  1. 一种(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺的晶型C，其特征在于：所述晶型C为无水物，使用Cu-Kα辐射，所述晶型C的X-射线粉末衍射图在衍射角2θ为5.6°±0.2°,10.5°±0.2°,12.8°±0.2°处有特征峰。
  2. 根据权利要求1所述的晶型C，其特征在于：所述晶型C的X-射线粉末衍射图在衍射角2θ为18.8°±0.2°处有特征峰；和/或，所述晶型C的X-射线粉末衍射图在衍射角2θ为23.6°±0.2°处有特征峰；和/或，所述晶型C的X-射线粉末衍射图在衍射角2θ为25.4°±0.2°处有特征峰；和/或，所述晶型C的X-射线粉末衍射图在衍射角2θ为6.8°±0.2°处有特征峰；和/或，所述晶型C的X-射线粉末衍射图在衍射角2θ为16.7°±0.2°处有特征峰；和/或，所述晶型C的X-射线粉末衍射图在衍射角2θ为26.3°±0.2°处有特征峰。
  3. 根据权利要求1所述的晶型C，其特征在于：所述晶型C的X-射线粉末衍射图在衍射角2θ为18.8°±0.2°、23.6°±0.2°、25.4°±0.2°处有特征峰；和/或，所述晶型C的X-射线粉末衍射图在衍射角2θ为6.8°±0.2°、16.7°±0.2°、26.3°±0.2°处有特征峰。
  4. 根据权利要求1所述的晶型C，其特征在于：所述晶型C的X-射线粉末衍射图与图1或图2保持一致。
  5. 一种如权利要求1至4中任一项权利要求所述的(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺的晶型C的制备方法，其特征在于：所述方法包括如下步骤：
    (1)将(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺原料在惰性气体保护下加热至第一温度得到中间物；
    (2)对所述中间物进行降温，使其冷却至第二温度，得到所述的晶型C；
    所述的第一温度大于140℃，所述第二温度小于等于140℃，且所述第一温度与所述第二温度的差值大于20℃。
  6. 根据权利要求5所述的(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺的晶型C的制备方法，其特征在于：所述第一温度与所述第二温度的差值为30℃-200℃。
  7. 根据权利要求5所述的(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺的晶型C的制备方法，其特征在于：所述第一温度为160-200℃，所述第二温度为5-30℃。
  8. 根据权利要求5所述的(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺的晶型C的制备方法，其特征在于：所述(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺原料为(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺的溶剂化物或无定形。
  9. 根据权利要求5所述的(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺的晶型C的制备方法，其特征在于：步骤(1)中，以5～30℃/min的速率进行加热；步骤(2)中，对所述中间物进行自然降温，使其冷却至室温。
  10. 一种治疗癌症的药物，包含活性成分，其特征在于，所述活性成分包含如权利要求1至4中任一项权利要求所述的(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺的晶型C。
PCT/CN2021/095425 2020-05-25 2021-05-24 (2e)-n-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺的晶型及其制备方法 WO2021238835A1 (zh)

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CN1972688A (zh) * 2004-05-06 2007-05-30 沃尼尔·朗伯有限责任公司 4－苯胺基－喹唑啉－6－基－酰胺类化合物
CN103288759A (zh) * 2013-05-16 2013-09-11 苏州明锐医药科技有限公司 达克米替尼的制备方法
CN107793368A (zh) * 2016-08-31 2018-03-13 四川科伦药物研究院有限公司 达可替尼溶剂化物、其新晶型及其制备方法和用途

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CN1972688A (zh) * 2004-05-06 2007-05-30 沃尼尔·朗伯有限责任公司 4－苯胺基－喹唑啉－6－基－酰胺类化合物
CN103288759A (zh) * 2013-05-16 2013-09-11 苏州明锐医药科技有限公司 达克米替尼的制备方法
CN107793368A (zh) * 2016-08-31 2018-03-13 四川科伦药物研究院有限公司 达可替尼溶剂化物、其新晶型及其制备方法和用途

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