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WO2020083188A1 - 一种酪氨酸激酶抑制剂的一马来酸盐的晶型及其制备方法 - Google Patents

一种酪氨酸激酶抑制剂的一马来酸盐的晶型及其制备方法 Download PDF

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WO2020083188A1
WO2020083188A1 PCT/CN2019/112216 CN2019112216W WO2020083188A1 WO 2020083188 A1 WO2020083188 A1 WO 2020083188A1 CN 2019112216 W CN2019112216 W CN 2019112216W WO 2020083188 A1 WO2020083188 A1 WO 2020083188A1
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formula
compound represented
crystal form
crystal
solvent
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PCT/CN2019/112216
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English (en)
French (fr)
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邱振均
张全良
韦艳丽
曹永兴
杨俊然
马亚辉
杜振兴
王捷
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江苏恒瑞医药股份有限公司
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Priority to MX2021004600A priority Critical patent/MX2021004600A/es
Priority to JP2021546430A priority patent/JP2022508864A/ja
Priority to EP19875274.3A priority patent/EP3872072A4/en
Priority to CN201980052673.2A priority patent/CN112566904A/zh
Priority to AU2019365166A priority patent/AU2019365166A1/en
Priority to CA3115872A priority patent/CA3115872A1/en
Priority to BR112021007477-5A priority patent/BR112021007477A2/pt
Priority to US17/287,322 priority patent/US20210355109A1/en
Priority to KR1020217014629A priority patent/KR20210081367A/ko
Publication of WO2020083188A1 publication Critical patent/WO2020083188A1/zh
Priority to ZA2021/03278A priority patent/ZA202103278B/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/145—Maleic acid
    • 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 disclosure relates to a tyrosine kinase inhibitor monomaleate crystal form and a preparation method thereof.
  • Tyrosine kinase inhibitors have been on the market since 2001 and have become a new class of anticancer drugs.
  • Epidermal growth factor receptor is a member of the receptor tyrosine kinase family.
  • the epidermal growth factor receptor pathway plays a very important role in tumorigenesis and development. It has become the most important research and One of the development targets.
  • drugs currently on the market include erlotinib (erlotinib), gefitinib (gefitinib) and lapatinib (lapatinb, Tykerb, GW572016).
  • WO2011029265A1 discloses an epidermal growth factor receptor (EGFR) inhibitor whose chemical name is (R, E) -N- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino ) -3-cyano-7-ethoxyquinolin-6-yl) -3- (1-methylpyrrolidin-2-yl) acrylamide, the drug molecule has obvious advantages of pharmacokinetics and efficacy , The structure is shown in formula (II):
  • CN102675287A discloses a monomaleate salt of a compound represented by formula (II), the structure of the salt is shown by formula (I):
  • CN102675287A also discloses the dimaleate form of the compound represented by formula (II), and the biological activity test results show that the compound dimaleate represented by formula (II) has higher activity.
  • CN103974949A discloses the crystalline form of the dimaleate salt of the compound represented by formula (II). The compound represented by formula (II) is currently developed in the form of dimaleate.
  • the crystal structure of the medicinal active ingredient often affects the chemical and physical stability of the drug. Different crystallization conditions and storage conditions may lead to changes in the crystal structure of the compound, sometimes accompanied by other forms of crystal form. Therefore, it is necessary to improve the various properties of the above products. We need to study in depth to find new crystal forms with high purity and good chemical stability.
  • the purpose of the present disclosure is to provide a new crystalline form of the compound represented by formula (I), which has good stability and can be better used in clinic.
  • the present disclosure provides a crystal form I of the compound represented by formula (I) whose X-ray powder diffraction pattern is 6.57, 8.12, 9.76, 10.77, 14.98, 15.89, 20.97, 21.64, 22.06, and 22.61 at 2 ⁇ angles There are characteristic peaks.
  • the present disclosure provides a crystal form I of the compound represented by formula (I), which has an X-ray powder diffraction pattern at 2 ⁇ angles of 6.57, 8.12, 9.76, 10.77, 14.47, 14.98, 15.28, 15.89 , 20.97, 21.64, 22.06, 22.61, 24.00, 25.62 and 26.46 have characteristic peaks.
  • the present disclosure provides a crystal form I of the compound represented by formula (I), whose X-ray powder diffraction pattern is 6.57, 8.12, 9.76, 10.77, 12.42, 13.11, 14.47, 14.98 at a 2 ⁇ angle , 15.28, 15.89, 16.29, 16.49, 17.13, 17.46, 18.92, 19.56, 19.83, 20.29, 20.97, 21.64, 22.06, 22.61, 22.99, 24.00, 24.60, 25.62, 26.46, 27.30, 27.99, 29.05, 30.19, 30.69, 31. , 33.88 and 36.07 have characteristic peaks.
  • the present disclosure provides a crystal form I of the compound represented by formula (I), whose X-ray powder diffraction pattern is shown in FIG. 1.
  • the present disclosure further provides a method for preparing the crystal form I of the compound represented by formula (I), the method comprising:
  • the solvent may be one or more of water and tetrahydrofuran; or mixing the compound represented by formula (I) with a solvent, volatile crystallization, the The solvent can be ethanol, isopropanol, n-propanol, acetone, acetonitrile, 2-butanone, dimethyl sulfoxide, nitromethane (MN), propylene glycol methyl ether (PM), isoamyl alcohol (IAA), benzene One or more of ethyl ketone (ACP); or mix the compound represented by formula (II) with maleic acid and a solvent to precipitate a solid, filter and crystallize, the solvent may be isopropanol, water, methylene chloride One or more of them are preferably an isopropyl alcohol / water mixed solvent and dichloromethane.
  • the present disclosure provides a crystal form II of the compound represented by formula (I), whose X-ray powder diffraction pattern has characteristic peaks at 2 ⁇ angles of 6.340, 9.030, 10.232, 11.503, 18.282, 19.399, 20.865, and 21.558 .
  • the present disclosure provides a crystal form II of the compound represented by formula (I), whose X-ray powder diffraction pattern is 6.340, 9.030, 10.232, 11.503, 12.629, 13.637, 14.526, 16.170 at a 2 ⁇ angle , 17.639, 18.282, 19.399, 20.865, 21.558, 22.078, 22.616, 23.562, 24.479, 25.801, 27.601, 28.139, 29.671, 31.893 and 33.887 have characteristic peaks.
  • the present disclosure provides a crystal form II of the compound represented by formula (I), whose X-ray powder diffraction pattern is shown in FIG. 3.
  • the present disclosure further provides a method for preparing the crystalline form II of the compound represented by formula (I).
  • the method includes: mixing and crystallizing the crystal of the compound represented by formula (I) with tetrahydrofuran to precipitate solids and filtering the crystals. It is preferred that the crystal of the compound represented by formula (I) is in the form of I crystal.
  • the present disclosure provides a III crystal form of the compound represented by formula (I), which has characteristic peaks at 2 ⁇ angles of 6.291, 6.547, 8.561, 9.908, 10.401, 17.381, 19.326, and 23.741 .
  • the present disclosure provides a crystal form III of the compound represented by formula (I), whose X-ray powder diffraction pattern is 2.864, 5.516, 6.291, 6.547, 8.068, 8.561, 9.908, 10.401 at a 2 ⁇ angle , 11.603, 13.267, 13.819, 14.725, 16.270, 17.381, 18.398, 19.326, 20.125, 21.040, 21.498, 22.250, 23.741, 24.426, 25.795, 26.765, 28.530 and 31.815 have characteristic peaks.
  • the present disclosure provides a crystal form III of the compound represented by formula (I), whose X-ray powder diffraction pattern is shown in FIG. 5.
  • the present disclosure further provides a method for preparing the crystalline form III of the compound represented by formula (I).
  • the method includes: mixing the compound represented by formula (II) with maleic acid and acetone, depositing a solid, and filtering and crystallizing.
  • the present disclosure provides an IV crystal form of the compound represented by formula (I), and its X-ray powder diffraction pattern has characteristic peaks at 2 ⁇ angles of 5.638, 9.417, 11.054, 12.386, 15.218, 15.639, 17.074, and 18.369 .
  • the present disclosure provides an IV crystal form of the compound represented by formula (I), whose X-ray powder diffraction pattern is 5.638, 9.417, 11.054, 12.386, 15.218, 15.639, 17.074, 18.369 at a 2 ⁇ angle , 22.779, 23.414, 25.384, 26.426 and 28.685 have characteristic peaks.
  • the present disclosure provides an IV crystal form of the compound represented by formula (I) whose X-ray powder diffraction pattern is 5.638, 8.268, 8.772, 9.417, 11.054, 12.386, 13.739, 15.218 at a 2 ⁇ angle , 15.639, 16.312, 17.074, 18.369, 19.152, 20.439, 21.907, 22.307, 22.779, 23.414, 24.146, 24.837, 25.384, 25.852, 26.426, 26.774, 28.685, 29.782, 31.620 and 32.482 have characteristic peaks.
  • the present disclosure provides an IV crystal form of the compound represented by formula (I), whose X-ray powder diffraction pattern is shown in FIG. 7.
  • the present disclosure further provides a method for preparing the IV crystal form of the compound represented by formula (I), the method comprising:
  • the compound represented by formula (II) is mixed with maleic acid and a solvent to precipitate a solid, which is filtered and crystallized.
  • the solvent may be one of n-propanol, isopropyl acetate, 2-butanone, isopropanol, and ethanol Or more, preferably ethanol.
  • the present disclosure provides a V crystal form of the compound represented by formula (I), and its X-ray powder diffraction pattern has 2 ⁇ angles at 5.469, 5.477, 6.512, 10.376, 11.593, 18.241, 19.386, 21.028, 22.286 Characteristic peaks.
  • the present disclosure provides a crystal form V of the compound represented by formula (I), whose X-ray powder diffraction pattern is 5.469, 5.477, 6.512, 10.376, 11.593, 13.220, 14.708, 15.600 at a 2 ⁇ angle , 16.492, 18.241, 19.386, 21.028, 22.286, 22.747, 23.758, 24.693, 25.509, 25.926, 26.563, 27.837, 29.792, 30.727, 32.086 have characteristic peaks.
  • the present disclosure provides a crystal form V of the compound represented by formula (I), whose X-ray powder diffraction pattern is shown in FIG. 9.
  • the present disclosure further provides a method for preparing the crystal form V of the compound represented by formula (I), the method comprising: mixing the compound represented by formula (II) with maleic acid and a solvent, precipitating a solid, filtering and crystallizing,
  • the solvent may be 1,4-dioxane and / or tetrahydrofuran.
  • the present disclosure further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising one or more of Form I, Form II, Form III, Form IV, Form V of the compound represented by formula (I), and one or A variety of pharmaceutically acceptable carriers, diluents or excipients.
  • the present disclosure further relates to a pharmaceutical composition consisting of one or more of the crystal form I, II, III, IV, and V of the compound represented by formula (I) described in the present disclosure , Mixed with one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present disclosure further relates to a method for preparing a pharmaceutical composition
  • a method for preparing a pharmaceutical composition comprising the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, which includes combining the crystal form I, II, and III of the compound represented by formula (I)
  • One or more of Form IV, Form IV, and Form V are mixed with one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • the pharmaceutical composition of the present disclosure can be made into any pharmaceutically acceptable dosage form.
  • the crystalline form or pharmaceutical preparation of the present disclosure can be formulated as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injection solutions, sterile powders for injection and concentrated solutions for injection ), Suppositories, inhalants or sprays.
  • the present disclosure further relates to Form I, Form II, Form III, Form IV, Form V of the compound represented by formula (I), or the pharmaceutical composition described in the present disclosure in the preparation of therapeutic and / or prophylactic and protein Use of a kinase-related disease or disorder in medicine, wherein the protein kinase is selected from EGFR receptor tyrosine kinase or HER-2 receptor tyrosine kinase, the disease or disorder is preferably cancer, and the cancer is preferably lung cancer , Breast cancer, epidermal squamous cell carcinoma or gastric cancer.
  • the crystal form obtained by the present disclosure was subjected to structure determination and crystal form study by X-ray powder diffraction pattern (XRPD) and differential scanning calorimetry (DSC).
  • XRPD X-ray powder diffraction pattern
  • DSC differential scanning calorimetry
  • the crystallization method of the crystal form in the present disclosure is conventional, for example, volatile crystallization, cooling crystallization or crystallization at room temperature.
  • the starting material used in the preparation method of the crystalline form of the present disclosure may be any form of the compound represented by formula (I), or the compound represented by formula (II) reacts with maleic acid, or the dimale of the compound represented by formula (II)
  • the maleate removes one maleic acid.
  • Specific forms include, but are not limited to: amorphous, any crystal form, hydrate, solvate, etc.
  • treating refers to a method of purifying by using a substance that has poor solubility in a solvent but good solubility of impurities in the solvent. Beating and purification can remove color, change the crystal form, or remove a small amount of impurities.
  • the “X-ray powder diffraction pattern or XRPD” described in this disclosure is a pattern obtained by using Cu-K ⁇ radiation in an X-ray powder diffractometer.
  • the “differential scanning calorimetry or DSC” mentioned in this disclosure refers to the measurement of the temperature difference and heat flow difference between the sample and the reference substance during the sample heating or constant temperature to characterize all physical changes and chemistry related to the thermal effect Change, get the phase change information of the sample.
  • the “2 ⁇ or 2 ⁇ angle” mentioned in the present disclosure refers to the diffraction angle, ⁇ is the Bragg angle, and the unit is ° or degree, and the error range of 2 ⁇ is ⁇ 0.3 or ⁇ 0.2 or ⁇ 0.1.
  • crystal plane spacing or crystal plane spacing (d value) means that the spatial lattice selects three non-parallel unit vectors a, b, and c that connect two adjacent lattice points, and they will point
  • the array is divided into juxtaposed parallelepiped units, called interplanar spacing.
  • the space lattice is divided according to the determined parallelepiped unit connection to obtain a set of straight-line grids, called space grids or lattices.
  • Lattices and lattices use geometric points and lines to reflect the periodicity of the crystal structure. Different crystal planes have different surface spacings (that is, the distance between two adjacent parallel crystal planes); the unit is Or Egypt.
  • the compounds of formula (I) prepared by the present disclosure have high purity of I and IV crystal forms, good crystal form stability under the conditions of light, high temperature and high humidity, small changes in HPLC purity and high chemical stability, which are more conducive to drugs Play a role.
  • the solid form of Form II crystal is poor, and the fluidity is poor.
  • the reproducibility of crystal forms II, III, and V is poor.
  • the new crystal form of the compound represented by formula (I) obtained in the present disclosure can meet the pharmaceutical requirements for production, transportation and storage, and the production process is stable, repeatable and controllable, and can be adapted to industrial production.
  • Figure 1 is an XRPD pattern of the crystal form I of the compound represented by formula (I);
  • Fig. 11 is an amorphous XRPD pattern of the compound represented by formula (I).
  • Heating rate 10.0 °C / min
  • Heating rate 10.0 °C / min
  • Example 1 of CN102675287A 0.5 g of the compound represented by formula (II) was added to obtain the amorphous form of the compound represented by formula (I).
  • the X-ray diffraction pattern is shown in FIG. 11.
  • the amorphous 50 mg of the compound represented by the formula (I) was placed in a reaction flask, 1 mL of tetrahydrofuran was added, the slurry was transformed into crystals, filtered with suction, and dried at 40 ° C. to obtain the crystal form I of the compound represented by the formula (I).
  • the crystal form I of the compound represented by the formula (I) is about 10 mg, 500 ⁇ L of tetrahydrofuran is added, slurried at room temperature, centrifuged, and the solid part is vacuum dried to obtain the crystal form II of the compound represented by the formula (I).
  • the X-ray diffraction pattern is shown in Figure 3, and the DSC pattern is shown in Figure 4.
  • the characteristic peak positions are shown in the following table:
  • the crystal form I of the compound of formula (I) was examined for stability.
  • the purity of the crystal form is detected by an Agilent1200 DAD high performance liquid chromatography system, the detection chromatographic column is Waters symmetry C18, (250 * 4.6mm, 5 ⁇ m), the mobile phase: sodium dihydrogen phosphate / ACN / H 2 O, detection wavelength: 261nm.
  • the stability of crystal forms I and IV of formula (I) was investigated.
  • the purity of the crystal form was detected by the Thermo Ultimate3000DAD high performance liquid chromatography system, the detection chromatographic column was Waters symmetry C18, (250 * 4.6mm, 5 ⁇ m), mobile phase: sodium dihydrogen phosphate / ACN / H 2 O, detection wavelength: 261nm.

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Abstract

提供一种酪氨酸激酶抑制剂的一马来酸盐的晶型及其制备方法。具体而言，提供一种式(I)所示化合物的I晶型、II晶型、III晶型、IV晶型、V晶型及其制备方法。新晶型具备良好的稳定性，可更好地用于临床治疗。（I）

Description

一种酪氨酸激酶抑制剂的一马来酸盐的晶型及其制备方法
本申请要求申请日为2018年10月22日的中国专利申请CN201811231321.7的优先权。本申请引用上述中国专利申请的全文。
技术领域
本公开涉及一种酪氨酸激酶抑制剂的一马来酸盐的晶型及其制备方法。
背景技术
研究表明，超过50％的原癌基因和癌基因产物都具有酪氨酸激酶活性，它们的异常表达将导致肿瘤发生。酪氨酸激酶抑制剂从2001年开始上市，已成为异军突起的一类新型抗癌药。
表皮生长因子受体(EGFR)是受体酪氨酸激酶家族的一员，表皮生长因子受体通路在肿瘤发生、发展过程中起非常重要的作用，目前已成为肿瘤治疗领域最主要的研究和开发靶点之一。现已经上市的此类药物有埃罗替尼(erlotinib)、吉非替尼(gefitinib)和拉帕替尼(lapatinb,Tykerb，GW572016)。
WO2011029265A1公开一种表皮生长因子受体(EGFR)抑制剂，其化学名为(R,E)-N-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基)-3-氰基-7-乙氧基喹啉-6-基)-3-(1-甲基吡咯烷基-2-基)丙烯酰胺，该药物分子具有明显的药代、药效优势，结构如式(II)所示：
Figure PCTCN2019112216-appb-000001
CN102675287A公开式(II)所示化合物的一马来酸盐，该盐的结构如式(I)所示：
Figure PCTCN2019112216-appb-000002
CN102675287A还公开式(II)所示化合物的二马来酸盐形式，生物活性试验结果显示式(II)所示化合物二马来酸盐的活性较高。CN103974949A公开了式(II)所示化合物的二马来酸盐的晶型。式(II)所示化合物目前以二马来酸盐形式开发。
Figure PCTCN2019112216-appb-000003
作为药用活性成分的晶型结构往往影响到该药物的化学和物理稳定性，结晶条件及储存条件的不同有可能导致化合物的晶体结构的变化，有时还会伴随着产生其他形态的晶型。因此，改善上述产物的各方面性质是很有必要的，我们需要深入研究找到晶型纯度较高并且具备良好化学稳定的新晶型。
发明内容
本公开的目的在于提供一种式(I)所示化合物新的晶型，其具备良好的稳定性，可更好地应用于临床。
本公开一方面提供了一种式(I)所示化合物的I晶型，其X-射线粉末衍射图谱在2θ角为6.57、8.12、9.76、10.77、14.98、15.89、20.97、21.64、22.06和22.61处有特征峰。
在某些实施方式中，本公开提供一种式(I)所示化合物的I晶型，其X-射线粉末衍射图谱在2θ角为6.57、8.12、9.76、10.77、14.47、14.98、15.28、15.89、20.97、21.64、22.06、22.61、24.00、25.62和26.46处有特征峰。
在某些实施方式中，本公开提供一种式(I)所示化合物的I晶型，其X-射线粉末衍射图谱在2θ角为6.57、8.12、9.76、10.77、12.42、13.11、14.47、14.98、15.28、15.89、16.29、16.49、17.13、17.46、18.92、19.56、19.83、20.29、20.97、21.64、22.06、22.61、22.99、24.00、24.60、25.62、26.46、27.30、27.99、29.05、30.19、30.69、31.90、33.88和36.07处有特征峰。
在某些的实施方案中，本公开提供一种式(I)所示化合物的I晶型，其X-射线粉末衍射图谱如图1所示。
本公开进一步提供一种制备式(I)所示化合物的I晶型的方法，所述方法包括：
将式(I)所示化合物与溶剂混合打浆，过滤结晶，所述溶剂可以为水、四氢呋喃中的一种或多种；或将式(I)所示化合物与溶剂混合，挥发结晶，所述溶剂可以为乙醇、异丙醇、正丙醇、丙酮、乙腈、2-丁酮、二甲基亚砜、硝基甲烷(MN)、丙二醇甲醚(PM)、 异戊醇(IAA)、苯乙酮(ACP)中的一种或多种；或将式(II)所示化合物与马来酸和溶剂混合，析出固体，过滤结晶，所述溶剂可以为异丙醇、水、二氯甲烷中的一种或多种，优选异丙醇/水混合溶剂、二氯甲烷。
本公开一方面提供了一种式(I)所示化合物的II晶型，其X-射线粉末衍射图谱在2θ角为6.340、9.030、10.232、11.503、18.282、19.399、20.865和21.558处有特征峰。
在某些实施方式中，本公开提供一种式(I)所示化合物的II晶型，其X-射线粉末衍射图谱在2θ角为6.340、9.030、10.232、11.503、12.629、13.637、14.526、16.170、17.639、18.282、19.399、20.865、21.558、22.078、22.616、23.562、24.479、25.801、27.601、28.139、29.671、31.893和33.887处有特征峰。
在某些的实施方案中，本公开提供一种式(I)所示化合物的II晶型，其X-射线粉末衍射图谱如图3所示。
本公开进一步提供一种制备式(I)所示化合物的II晶型的方法，所述方法包括：将式(I)所示化合物的结晶与四氢呋喃混合打浆，析出固体，过滤结晶。优选式(I)所示化合物的结晶为I晶型。
本公开一方面提供了一种式(I)所示化合物的III晶型，其X-射线粉末衍射图谱在2θ角为6.291、6.547、8.561、9.908、10.401、17.381、19.326和23.741处有特征峰。
在某些实施方式中，本公开提供一种式(I)所示化合物的III晶型，其X-射线粉末衍射图谱在2θ角为4.864、5.516、6.291、6.547、8.068、8.561、9.908、10.401、11.603、13.267、13.819、14.725、16.270、17.381、18.398、19.326、20.125、21.040、21.498、22.250、23.741、24.426、25.795、26.765、28.530和31.815处有特征峰。
在某些的实施方案中，本公开提供一种式(I)所示化合物的III晶型，其X-射线粉末衍射图谱如图5所示。
本公开进一步提供一种制备式(I)所示化合物的III晶型的方法，所述方法包括：将式(II)所示化合物与马来酸和丙酮混合，析出固体，过滤结晶。
本公开一方面提供了一种式(I)所示化合物的IV晶型，其X-射线粉末衍射图谱在2θ角为5.638、9.417、11.054、12.386、15.218、15.639、17.074和18.369处有特征峰。
在某些实施方式中，本公开提供一种式(I)所示化合物的IV晶型，其X-射线粉末衍射图谱在2θ角为5.638、9.417、11.054、12.386、15.218、15.639、17.074、18.369、22.779、23.414、25.384、26.426和28.685处有特征峰。
在某些实施方式中，本公开提供一种式(I)所示化合物的IV晶型，其X-射线粉末衍射图谱在2θ角为5.638、8.268、8.772、9.417、11.054、12.386、13.739、15.218、15.639、 16.312、17.074、18.369、19.152、20.439、21.907、22.307、22.779、23.414、24.146、24.837、25.384、25.852、26.426、26.774、28.685、29.782、31.620和32.482处有特征峰。
在某些的实施方案中，本公开提供一种式(I)所示化合物的IV晶型，其X-射线粉末衍射图谱如图7所示。
本公开进一步提供一种制备式(I)所示化合物的IV晶型的方法，所述方法包括：
将式(II)所示化合物与马来酸和溶剂混合，析出固体，过滤结晶，所述溶剂可以为正丙醇、乙酸异丙酯、2-丁酮、异丙醇、乙醇中的一种或多种，优选乙醇。
本公开一方面提供了一种式(I)所示化合物的V晶型，其X-射线粉末衍射图谱在2θ角为5.469、5.477、6.512、10.376、11.593、18.241、19.386、21.028、22.286处有特征峰。
在某些实施方式中，本公开提供一种式(I)所示化合物的V晶型，其X-射线粉末衍射图谱在2θ角为5.469、5.477、6.512、10.376、11.593、13.220、14.708、15.600、16.492、18.241、19.386、21.028、22.286、22.747、23.758、24.693、25.509、25.926、26.563、27.837、29.792、30.727、32.086处有特征峰。
在某些的实施方案中，本公开提供一种式(I)所示化合物的V晶型，其X-射线粉末衍射图谱如图9所示。
本公开进一步提供一种制备式(I)所示化合物的V晶型的方法，所述方法包括：将式(II)所示化合物与马来酸和溶剂混合，析出固体，过滤结晶，所述溶剂可以为1,4-二氧六环和/或四氢呋喃。
本公开进一步涉及一种药物组合物，包含式(I)所示化合物的I晶型、II晶型、III晶型、IV晶型、V晶型中的一种或多种，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
本公开进一步涉及一种药物组合物，其由本公开所述的式(I)所示化合物的I晶型、II晶型、III晶型、IV晶型、V晶型中的一种或多种，与一种或多种药学上可接受的载体、稀释剂或赋形剂混合制得。
本公开进一步涉及一种包含式(I)所示化合物或其药学上可接受的盐的药物组合物的制备方法，包括将式(I)所示化合物的I晶型、II晶型、III晶型、IV晶型、V晶型中的一种或多种，与一种或多种药学上可接受的载体、稀释剂或赋形剂混合。
本公开所述药物组合物可以制成药学上可接受的任一剂型。例如，本公开的晶型或药物制剂可以配制为片剂、胶囊剂、丸剂、颗粒剂、溶液剂、混悬剂、糖浆剂、注射剂(包括注射液、注射用无菌粉末与注射用浓溶液)、栓剂、吸入剂或喷雾剂。
本公开进一步涉及式(I)所示化合物的I晶型、II晶型、III晶型、IV晶型、V晶型， 或本公开所述的药物组合物在制备治疗和/或预防与蛋白质激酶有关的疾病或病症的药物中的用途，其中所述蛋白质激酶选自EGFR受体酪氨酸激酶或HER-2受体酪氨酸激酶，所述疾病或病症优选癌症，所述癌症优选肺癌、乳腺癌、表皮鳞癌或胃癌。
通过X-射线粉末衍射图谱(XRPD)、差示扫描量热分析(DSC)对本公开所得到晶型进行结构测定、晶型研究。
本公开中晶型的析晶方法是常规的，例如挥发析晶、降温析晶或室温下析晶。
本公开晶型制备方法中所用的起始原料可以是任意形式的式(I)所示化合物，或式(II)所示化合物与马来酸反应，或式(II)所示化合物的二马来酸盐脱去一个马来酸，具体形式包括但不限于：无定形、任意晶型、水合物、溶剂合物等。
在本申请的说明书和权利要求书中，除非另有说明，否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。然而，为了更好地理解本公开，下面提供了部分相关术语的定义和解释。另外，当本申请所提供的术语的定义和解释与本领域技术人员所通常理解的含义不一致时，以本申请所提供的术语的定义和解释为准。
本公开所述的“打浆”是指利用物质在溶剂中溶解性差，但杂质在溶剂中溶解性好的特性进行纯化的方法，打浆提纯可以去色、改变晶型或去除少量杂质。
本公开所述的“X-射线粉末衍射图谱或XRPD”是指根据布拉格公式2d sinθ＝nλ(式中，λ为X射线的波长，
Figure PCTCN2019112216-appb-000004
衍射的级数n为任何正整数，一般取一级衍射峰，n＝1)，当X射线以掠射角θ(入射角的余角，又称为布拉格角)入射到晶体或部分晶体样品的某一具有d点阵平面间距的原子面上时，就能满足布拉格方程，从而测得了这组X射线粉末衍射图。
本公开所述的“X-射线粉末衍射图谱或XRPD”是通过在X-射线粉末衍射仪中使用Cu-Kα辐射得到的图谱。如上所述，
Figure PCTCN2019112216-appb-000005
本公开所述的“差示扫描量热分析或DSC”是指在样品升温或恒温过程中，测量样品与参考物之间的温度差、热流差，以表征所有与热效应有关的物理变化和化学变化，得到样品的相变信息。
本公开所述的“2θ或2θ角度”是指衍射角，θ为布拉格角，单位为°或度，2θ的误差范围为±0.3或±0.2或±0.1。
本公开所述的“晶面间距或晶面间距(d值)”是指空间点阵选择3个不相平行的连结相邻两个点阵点的单位矢量a，b，c，它们将点阵划分成并置的平行六面体单位，称为晶面间距。空间点阵按照确定的平行六面体单位连线划分，获得一套直线网格，称为空间格子或晶格。点阵和晶格是分别用几何的点和线反映晶体结构的周期性，不同的晶面， 其面间距(即相邻的两个平行晶面之间的距离)各不相同；单位为
Figure PCTCN2019112216-appb-000006
或埃。
发明的有益效果
本公开制备的式(I)所示化合物的I、IV晶型纯度高，在光照、高温、高湿的条件下晶型稳定性良好，HPLC纯度变化小、化学稳定性高，更有利于药物发挥作用。II晶型的固体性状较差，流动性较差。II、III、V晶型的重现性差。本公开得到的式(I)所示化合物新的晶型能够满足生产运输储存的药用要求，生产工艺稳定、可重复可控，能够适应于工业化生产。
附图说明
图1为式(I)所示化合物的I晶型的XRPD图谱；
图2为式(I)所示化合物的I晶型的DSC图谱；
图3为式(I)所示化合物的II晶型的XRPD图谱；
图4为式(I)所示化合物的II晶型的DSC图谱；
图5为式(I)所示化合物的III晶型的XRPD图谱；
图6为式(I)所示化合物的III晶型的DSC图谱；
图7为式(I)所示化合物的IV晶型的XRPD图谱；
图8为式(I)所示化合物的IV晶型的DSC图谱；
图9为式(I)所示化合物的V晶型的XRPD图谱；
图10为式(I)所示化合物的V晶型的DSC图谱；
图11为式(I)所示化合物无定形的XRPD图谱。
具体实施方式
以下将结合实施例更详细地解释本公开，本公开的实施例仅用于说明本公开的技术方案，并非限定本公开的实质和范围。
试验所用仪器的测试条件：
1、差示扫描量热仪(Differential Scanning Calorimeter,DSC)
仪器型号：Mettler Toledo DSC 1 STAR eSystem
吹扫气：氮气
升温速率：10.0℃/min
温度范围：40-250℃
2、差示扫描量热仪(Differential Scanning Calorimeter,DSC)
仪器型号：Mettler Toledo DSC 3+
吹扫气：氮气
升温速率：10.0℃/min
温度范围：25-300℃
3、X-射线衍射谱(X-ray Powder Diffraction,XRPD)
仪器型号：BRUKER D8DISCOVERY X-射线粉末衍射仪
射线：单色Cu-Kα射线(λ＝1.5406)
扫描方式：θ/2θ，扫描范围：5-48°
电压：40KV，电流：40mA
4、X-射线衍射谱(X-ray Powder Diffraction,XRPD)
仪器型号：BRUKER D8Focus X-射线粉末衍射仪
射线：单色Cu-Kα射线(λ＝1.5406)
扫描方式：θ/2θ，扫描范围：2-40°
电压：40KV，电流：40mA
其中，2θ保留2位小数的数据通过BRUKER D8Focus X-射线粉末衍射仪测得。
实施例1
根据CN102675287A实施例1方法，投入式(II)所示化合物0.5g，得到式(I)所示化合物的无定形，其X-射线衍射图谱见图11。
实施例2
将式(I)所示化合物的无定形5.0g置于反应瓶中，加入纯化水50mL，打浆转晶，抽滤，滤饼用少量纯化水洗，40℃干燥，得到式(I)所示化合物的I晶型。其X-射线衍射图谱见图1，其DSC谱图见图2，其特征峰位置如下表所示：
表1、I晶型的特征峰
Figure PCTCN2019112216-appb-000007
Figure PCTCN2019112216-appb-000008
Figure PCTCN2019112216-appb-000009
实施例3
将式(I)所示化合物的无定形50mg置于反应瓶中，加入四氢呋喃1mL，打浆转晶，抽滤，40℃干燥，得到式(I)所示化合物的I晶型。
实施例4
将式(I)所示化合物的I晶型约10mg置于反应瓶中，加入乙醇40μL溶解，室温搅拌，挥发结晶，得到式(I)所示化合物的I晶型。
实施例5
称取式(II)所示化合物约20mg，加入马来酸4mg，加入90％IPA/H 2O 200μL室温搅拌溶清，继续搅拌，析出固体，离心，固体样品真空干燥，得到式(I)所示化合物的I晶型。
实施例6
将式(I)所示化合物的I晶型约10mg，加四氢呋喃500μL，室温打浆，离心，固体部分真空干燥，得到式(I)所示化合物的II晶型。其X-射线衍射图谱见图3，其DSC谱图见图4，其特征峰位置如下表所示：
表2、II晶型的特征峰
Figure PCTCN2019112216-appb-000010
Figure PCTCN2019112216-appb-000011
实施例7
称取式(II)所示化合物约20mg，加入马来酸4mg，加入丙酮200μL室温搅拌溶清，继续搅拌，析出固体，离心，固体样品真空干燥，得到式(I)所示化合物的III晶型。其X-射线衍射图谱见图5，其DSC谱图见图6，其特征峰位置如下表所示：
表3、III晶型的特征峰
Figure PCTCN2019112216-appb-000012
Figure PCTCN2019112216-appb-000013
实施例8
称取式(II)所示化合物约20mg，加入马来酸4mg，加入乙醇200μL室温搅拌溶解，继续搅拌有固体析出，室温打浆，离心，固体样品真空干燥，得到式(I)所示化合物的IV晶型。其X-射线衍射图谱见图7，其DSC谱图见图8，其特征峰位置如下表所示：
表4、IV晶型的特征峰
Figure PCTCN2019112216-appb-000014
Figure PCTCN2019112216-appb-000015
实施例9
称取式(II)所示化合物约20mg，加入马来酸4mg，加入1,4-二氧六环400μL，升温至50℃反应，反应结束后，离心，固体样品真空干燥，得到式(I)所示化合物的V晶型。其X-射线衍射图谱见图9，其DSC谱图见图10，其特征峰位置如下表所示：
表5、V晶型的特征峰
Figure PCTCN2019112216-appb-000016
Figure PCTCN2019112216-appb-000017
实施例10
将式(I)化合物I晶型进行稳定性考察。所述晶型纯度通过Agilent1200 DAD高效液相色谱系统检测，其检测色谱柱为Waters symmetry C18，(250*4.6mm,5μm)，流动相：磷酸二氢钠/ACN/H 2O，检测波长：261nm。
表6、式(1)化合物I晶型和无定型影响因素实验结果
Figure PCTCN2019112216-appb-000018
Figure PCTCN2019112216-appb-000019
从表中可以看出，I晶型长期放置的物理、化学稳定性好；而无定形在光照和高温高湿条件下稳定性都很差。
实施例11
将式(I)化合物I、IV晶型进行稳定性考察。所述晶型纯度通过Thermo Ultimate3000DAD高效液相色谱系统检测，其检测色谱柱为Waters symmetry C18，(250*4.6mm,5μm)，流动相：磷酸二氢钠/ACN/H 2O，检测波长：261nm。
表7、式(1)化合物I、IV晶型影响因素实验结果
Figure PCTCN2019112216-appb-000020
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (19)

  1. 一种式(I)所示化合物的I晶型，其X-射线粉末衍射图谱在2θ角为6.57、8.12、9.76、10.77、14.98、15.89、20.97、21.64、22.06和22.61处有特征峰，
    Figure PCTCN2019112216-appb-100001
  2. 根据权利要求1所述的式(I)所示化合物的I晶型，其X-射线粉末衍射图谱在2θ角为6.57、8.12、9.76、10.77、12.42、13.11、14.47、14.98、15.28、15.89、16.29、16.49、17.13、17.46、18.92、19.56、19.83、20.29、20.97、21.64、22.06、22.61、22.99、24.00、24.60、25.62、26.46、27.30、27.99、29.05、30.19、30.69、31.90、33.88和36.07处有特征峰。
  3. 根据权利要求1所述的式(I)所示化合物的I晶型，其X-射线粉末衍射图谱如图1所示。
  4. 一种式(I)所示化合物的II晶型，其X-射线粉末衍射图谱在2θ角为6.340、9.030、10.232、11.503、18.282、19.399、20.865和21.558处有特征峰，
    Figure PCTCN2019112216-appb-100002
  5. 一种式(I)所示化合物的III晶型，其X-射线粉末衍射图谱在2θ角为6.291、6.547、8.561、9.908、10.401、17.381、19.326和23.741处有特征峰，
    Figure PCTCN2019112216-appb-100003
  6. 一种式(I)所示化合物的IV晶型，其X-射线粉末衍射图谱在2θ角为5.638、9.417、11.054、12.386、15.218、15.639、17.074和18.369处有特征峰，
    Figure PCTCN2019112216-appb-100004
  7. 根据权利要求6所述的式(I)所示化合物的IV晶型，其X-射线粉末衍射图谱在2θ角为5.638、8.268、8.772、9.417、11.054、12.386、13.739、15.218、15.639、16.312、17.074、18.369、19.152、20.439、21.907、22.307、22.779、23.414、24.146、24.837、25.384、25.852、26.426、26.774、28.685、29.782、31.620和32.482处有特征峰。
  8. 根据权利要求6所述的式(I)所示化合物的IV晶型，其X-射线粉末衍射图谱如图7所示。
  9. 一种式(I)所示化合物的V晶型，其X-射线粉末衍射图谱在2θ角为5.469、5.477、6.512、10.376、11.593、18.241、19.386、21.028、22.286处有特征峰，
    Figure PCTCN2019112216-appb-100005
  10. 根据权利要求1-9任意一项所述的式(I)所示化合物的晶型，其中，所述2θ角的误差范围为±0.2。
  11. 一种药物组合物，其由权利要求1-10任意一项所述的式(I)所示化合物的I晶型、 II晶型、III晶型、IV晶型、V晶型中的一种或多种，与一种或多种药学上可接受的载体、稀释剂或赋形剂混合制得。
  12. 一种药物组合物，其包含权利要求1-10任意一项所述的式(I)所示化合物的I晶型、II晶型、III晶型、IV晶型、V晶型中的一种或多种，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
  13. 一种制备如权利要求1-3任意一项所述的式(I)所示化合物的I晶型的方法，所述方法包括：将式(I)所示化合物与溶剂混合打浆，过滤结晶，所述溶剂选自水、四氢呋喃中的一种或多种；或将式(I)所示化合物与溶剂混合，挥发结晶，所述溶剂选自乙醇、异丙醇、正丙醇、丙酮、乙腈、2-丁酮、二甲基亚砜、硝基甲烷、丙二醇甲醚、异戊醇、苯乙酮中的一种或多种；或将式(II)所示化合物与马来酸和溶剂混合，析出固体，过滤结晶，所述溶剂选自异丙醇、水、二氯甲烷中的一种或多种，优选异丙醇/水混合溶剂、二氯甲烷，
    Figure PCTCN2019112216-appb-100006
  14. 一种制备如权利要求4所述的式(I)所示化合物的II晶型的方法，所述方法包括：将式(I)所示化合物的结晶与四氢呋喃混合打浆，过滤结晶，优选式(I)所示化合物的结晶为I晶型。
  15. 一种制备如权利要求5所述的式(I)所示化合物的III晶型的方法，所述方法包括：将式(II)所示化合物与马来酸和丙酮混合，析出固体，过滤结晶，
    Figure PCTCN2019112216-appb-100007
  16. 一种制备如权利要求6-8任意一项所述的式(I)所示化合物的IV晶型的方法，所述方法包括：将式(II)所示化合物与马来酸和溶剂混合，析出固体，过滤结晶，所述溶剂可以为正丙醇、乙酸异丙酯、2-丁酮、异丙醇、乙醇中的一种或多种，优选乙醇，
    Figure PCTCN2019112216-appb-100008
  17. 一种制备如权利要求9所述的式(I)所示化合物的V晶型的方法，所述方法包括：将式(II)所示化合物与马来酸和溶剂混合，析出固体，过滤结晶，所述溶剂可以为1,4-二氧六环和/或四氢呋喃，
    Figure PCTCN2019112216-appb-100009
  18. 一种包含式(I)所示化合物或其药学上可接受的盐的药物组合物的制备方法，包括将权利要求1-10任意一项所述的式(I)所示化合物的I晶型、II晶型、III晶型、IV晶型、V晶型中的一种或多种，与一种或多种药学上可接受的载体、稀释剂或赋形剂混合。
  19. 一种如权利要求1-10任意一项所述的式(I)所示化合物的I晶型、II晶型、III晶型、IV晶型、V晶型，或权利要求11-12任意一项所述的药物组合物在制备治疗和/或预防与蛋白质激酶有关的疾病或病症的药物中的用途，其中所述蛋白质激酶选自EGFR受体酪氨酸激酶或HER-2受体酪氨酸激酶，所述疾病或病症优选癌症，所述癌症优选肺癌、乳腺癌、表皮鳞癌或胃癌。
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