WO2019149254A1 - 一种小分子免疫化合物的晶型、其制备方法和含有其的药物组合物 - Google Patents

一种小分子免疫化合物的晶型、其制备方法和含有其的药物组合物 Download PDF

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WO2019149254A1
WO2019149254A1 PCT/CN2019/074248 CN2019074248W WO2019149254A1 WO 2019149254 A1 WO2019149254 A1 WO 2019149254A1 CN 2019074248 W CN2019074248 W CN 2019074248W WO 2019149254 A1 WO2019149254 A1 WO 2019149254A1
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butyl
tert
propenylene
fluorophenyl
imidazolyl
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PCT/CN2019/074248
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English (en)
French (fr)
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唐田
黄志颖
吴婧
陈燕萍
石涛
王彦青
杨经安
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深圳海王医药科技研究院有限公司
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Priority to US16/966,419 priority Critical patent/US11192882B2/en
Priority to AU2019214168A priority patent/AU2019214168B2/en
Publication of WO2019149254A1 publication Critical patent/WO2019149254A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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 invention belongs to the technical field of medicine, in particular to a novel crystal form of a novel small molecule immune compound
  • the present invention also relates to a process for the preparation of the above novel crystalline form and a pharmaceutical composition comprising the novel crystalline form compound.
  • the compound of the present invention is capable of adhering to the colchicine binding site of tubulin, thereby inhibiting the binding of tubulin.
  • formula (1) (3Z, 6Z)-3-[((E)-3-(5-tert-butyl)-1H-imidazolyl-4-yl)methylene]- 6-((E)-3-(3-fluorophenyl)-2-propenylene)piperazine-2,5-dione, which is used to reduce vascular proliferation and vascular density, acting on tumor blood vessels, Anticancer effect.
  • the B crystal form characteristic is characterized by melting point, X-ray powder diffraction (XRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TG), infrared spectroscopy (IR), elemental analysis, and the crystal form It has the properties required to prepare a pharmaceutical preparation.
  • Another object of the invention is to provide a process for the preparation of a novel crystalline form of the compound.
  • a crude product of the compound (as shown in formula (1)) is first prepared, and then the crude material is crystallized by recrystallization to obtain a crystal form of the compound.
  • the B crystal form is included at 2.5 ⁇ 0.2°, 8.7.7 ⁇ 0.2°, 11.0 ⁇ 0.2°, 13.5 ⁇ 0.2° at 2 ⁇ °, Characteristic diffraction peaks of 16.0 ⁇ 0.2° and 16.4 ⁇ 0.2°, the relative intensities (I/I 0 ) of these peaks are all greater than or equal to 30%. Further, the crystal may further comprise characteristic diffraction peaks at 2 ⁇ ° of 18.5 ⁇ 0.2°, 21.9 ⁇ 0.2°, and 22.1 ⁇ 0.2° in X-ray powder diffraction, and the relative intensities of the peaks are greater than or equal to 15% (see Figure 1).
  • the Form B of the present invention can be characterized by an X-ray powder diffraction pattern. It is characterized in that its X-ray powder diffraction pattern has a characteristic diffraction peak represented by the above 2 ⁇ °, as shown in Table 1, and its relative intensity is close to the following values.
  • the term "proximity” as used herein refers to the uncertainty of the relative intensity measurement. Those skilled in the art understand that the uncertainty of relative intensity is highly dependent on the measurement conditions. The uncertainty of the relative intensity is very dependent on the measurement conditions. The relative intensity value can vary, for example, within ⁇ 25% or preferably within ⁇ 10%.
  • the above B crystal form has the X-ray powder diffraction pattern shown in Fig. 1.
  • the present invention uses differential scanning calorimetry (DSC) technology to characterize the B crystal form (see Fig. 2), wherein the differential scanning calorimetry analysis results show that the test sample has no obvious temperature within the detection temperature range (20-310 ° C). Endothermic or exothermic process.
  • DSC differential scanning calorimetry
  • the present invention uses a thermogravimetric analysis technique to characterize the B crystal form (see Fig. 3), wherein the thermogravimetric diagram (TG) shows a weight loss of 0.87% at room temperature to 326 ° C, and a weight loss of 39.8% at 326 ° C to 436 ° C.
  • the weight loss at 436 to 700 ° C is 54.48%, and the final remaining amount at 700 ° C is 0.85%. It is indicated that the compound degrades as the temperature increases.
  • the elemental analysis data of the B crystal form of the present invention is in agreement with the theoretical value (within ⁇ 0.3% difference), further confirming that the compound is not co-crystallized with other solvents (see Table 2).
  • a process for preparing the crystalline form of B comprises: (3Z,6Z)-3-[((E)-3-(5-tert-butyl)-1H-imidazolyl-4- a crude product of methylene]-6-((E)-3-(3-fluorophenyl)-2-propenylene)piperazine-2,5-dione, added to a C1-C4 alkyl alcohol and In the mixed solvent of the C3-C4 alkyl ketone, the mixture is heated to reflux until it is dissolved; after the solution is clarified, the temperature is lowered to precipitate a solid, and the solid is collected by filtration, and the collected solid is air-dried to obtain a B crystal form.
  • the alcohol is selected from the group consisting of methanol, ethanol, propanol, isopropanol and butanol, preferably ethanol;
  • the ketone is selected from the group consisting of acetone, methyl ethyl ketone and n-butyl ketone, etc., preferably acetone;
  • volume ratio of alcohol to ketone ( V/V) is from 5:1 to 10:1, preferably 8:1; the ratio of the crude product to the solvent is from g/ml, and the weight to volume ratio is from 1:5 to 20, preferably 1:10.
  • the solution is preferably heated to 40 to 80 ° C, more preferably a mixed solvent of a C1-C4 alkyl alcohol and a C3-C4 alkyl ketone is heated to 50 ° C; according to this embodiment, the precipitation is carried out for 2 to 8 hours, more preferably 4 hours.
  • the precipitation temperature is 0 to 40 ° C, preferably 10 to 20 ° C.
  • the drying temperature is 30 to 60 ° C, preferably 50 ° C.
  • a pharmaceutical composition comprising the novel crystalline form compound and optionally a pharmaceutically acceptable carrier and/or excipient.
  • the pharmaceutical composition can be further formulated into a form for administration according to a conventional formulation method, including an oral or parenteral administration form.
  • a therapeutically effective amount of Form B should be included.
  • therapeutically effective amount is meant that at this dose, the compounds of the invention are capable of ameliorating or alleviating the symptoms of the disease, or are capable of inhibiting or blocking the progression of the disease.
  • the crystal form of the present invention can be used alone for the preparation of a medicament for treating a proliferative disease, and can also be prepared in combination with other therapeutic agents to synergistically.
  • hyperproliferative diseases are cancers, including but not limited to Non-small cell lung cancer, colorectal cancer, refractory non-small cell lung cancer, pancreatic cancer, ovarian cancer, breast cancer, glioma, brain cancer or neck cancer.
  • the compound is a cell cycle inhibitor and acts as a tumor growth inhibitor or fungal inhibitor. It can also be used to treat or prevent related diseases such as cancer, especially non-small cell lung cancer, colorectal cancer, refractory non-small cell lung cancer, ovarian cancer, pancreatic cancer, breast cancer, glioma, brain tumor or neck cancer. .
  • the preparation of the present invention gives (3Z,6Z)-3-[((E)-3-(5-tert-butyl)-1H-imidazolyl-4-yl)methylene]-6-((E)- a new crystalline form of 3-(3-fluorophenyl)-2-propenylene)piperazine-2,5-dione, which has a stable morphology, good chemical stability, and high temperature resistance.
  • (3Z,6Z)-3-[((E)-3-(5-tert-butyl)-1H-imidazolyl-4-yl)methylene]-6-((E)-3-(3- Fluorophenyl)-2-propenylene)piperazine-2,5-dione possesses the properties required for the preparation of the preparation, is convenient to store, is simpler in production, and is easier to control in quality.
  • Example 1 is an X-ray diffraction spectrum of a novel Form B obtained in Example 1 of the present invention
  • Figure 2 is a DSC chart of the new Form B obtained in Example 1 of the present invention.
  • Figure 3 is a TG spectrum of the new Form B obtained in Example 1 of the present invention.
  • Example 4 is an IR spectrum of a new crystal form B obtained in Example 1 of the present invention.
  • Figure 5 is an HPLC chart of the new Form B obtained in Example 1 of the present invention.
  • the filter cake was blast dried at 50 ° C and dried with phosphorus pentoxide. 182 g of a white solid were obtained in a yield of 91.0%. The moisture was measured by a Karl Fischer meter to be 0.1%.
  • the obtained compound is (3Z,6Z)-3-[((E)-3-(5-tert-butyl)-1H-imidazolyl-4-yl)methylene]-6-((E)-3 Form B of -(3-fluorophenyl)-2-propenylene)piperazine-2,5-dione.
  • Detection conditions Cu target K ⁇ ray, voltage 40kV, current 40mA, divergence slit 1/32°, anti-scatter slit 1/16°, anti-scatter slit 7.5mm, 2 ⁇ range: 3°-50°, step size 0.02 °, each step of stay time 40S.
  • Test basis People's Republic of China (2015 edition four) 0451 X-ray powder diffraction method
  • Test sample quality Sample 1: 2.48mg (using aluminum sample tray)
  • Test basis General rules for thermal analysis methods of JY/T 014-1996
  • thermogravimetric analyzer
  • Test conditions atmosphere: air, 20ml / min;
  • Test basis General rules for thermal analysis JY/T 014-1996
  • Test basis GB/T 6040-2002 General rules for infrared spectrum analysis
  • Mobile phase A water-mobile phase acetonitrile B (80:20)
  • Test basis "Chinese Pharmacopoeia" two appendix VD high performance liquid chromatography
  • the alcohol solvent used in the experiment preferably ethanol; the ketone solvent used in the experiment, preferably acetone; the volume ratio of the alcohol to the ketone (V/V) is 5:1 to 10:1, preferably 8:1; crude and solvent The ratio is from 1:5 to 20, preferably 1:10, in terms of g/ml.
  • the solution is preferably heated to 40 to 80 ° C, preferably to a mixed solvent of an alkyl alcohol and an alkyl ketone to 50 ° C; according to this embodiment, the precipitation is carried out for 2 to 8 hours, more preferably 4 hours.
  • the precipitation temperature is 0 to 40 ° C, preferably 10 to 20 ° C.
  • the drying temperature is 30 to 60 ° C, preferably 50 ° C.
  • the obtained B crystal form was subjected to stability investigation (10-day accelerated test), and the purity of the new crystal form, the maximum single and total impurities, and the data of 0 days were compared at 60 ° C, humidity of 92.5%, and light. Under light conditions, the purity is slightly lowered, and under other conditions, the obtained crystal form is stable.
  • the same prescription 1 process is different, and it is placed at 40 ° C for 7 days.
  • the content of nitrogen sample and the related substances did not change much, the content of nitrogen-free samples decreased, and the related substances increased significantly.
  • the stability of nitrogen-passing samples was better than that of nitrogen-free samples. Therefore, the prescription 1 was selected as the process.
  • Y2 indicates the standard colorimetric liquid yellow No. 2 (in accordance with the Chinese Pharmacopoeia 2015 edition, supervised by Shanghai Pharmaceutical Inspection Institute)

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明提供了一种小分子免疫化合物的晶型、其制备方法和含有其的药物组合物，该化合物为(3Z,6Z)-3-[((E)-3-(5-叔丁基)-1H-咪唑基-4-基)亚甲基]-6-((E)-3-(3-氟苯基)-2-丙烯亚基)哌嗪-2,5-二酮，所述的其晶型具有稳定的形态，化学稳定性好，耐高温，用于治疗过度增殖疾病，该化合物的结构式如式(I)所示。

Description

一种小分子免疫化合物的晶型、其制备方法和含有其的药物组合物 技术领域
本发明属于医药技术领域，具体地说，涉及一种新型小分子免疫化合物的新晶型；
本发明还涉及上述新晶型的制备方法以及含新晶型化合物的药物组合物。
背景技术
作为肿瘤治疗的主要手段，抗肿瘤药物为延长患者的生存时间以及改善其生命质量做出了相当的贡献。其中本发明化合物作为一种新型的小分子化合物，能够依附于微管蛋白的秋水仙碱结合位点，从而抑制微管蛋白的结合。研究表明与多西他赛联用增效减毒，能在肿瘤微环境中发挥多重功效，其中包括：1、通过激活Caspase-3直接诱导肿瘤细胞凋亡；2、促进树突状细胞成熟，从而进一步促进T细胞介导的肿瘤杀伤作用；3、促进保护中性粒细胞免于凋亡的一系列细胞因子的释放。
中国专利申请CN106565686公开了式(1)的化合物(3Z,6Z)-3-[((E)-3-(5-叔丁基)-1H-咪唑基-4-基)亚甲基]-6-((E)-3-(3-氟苯基)-2-丙烯亚基)哌嗪-2,5-二酮，该化合物用于减少血管增生和血管密度，作用于肿瘤血管，具有抗癌作用。
Figure PCTCN2019074248-appb-000001
发明内容
本发明的一个目的是提供上述化合物的新晶型，即(3Z,6Z)-3-[((E)-3-(5-叔丁基)-1H-咪唑基-4-基)亚甲基]-6-((E)-3-(3-氟苯基)-2-丙烯亚基)哌嗪-2,5-二酮(如式(1)所示)的B晶型；
Figure PCTCN2019074248-appb-000002
所述B晶型特征通过熔点、X-射线粉末衍射(XRD)、差示扫描量热分析(DSC)、热重分析(TG)、红外光谱(IR)、元素分析进行了表征，该晶型具备制备药物制剂所需要的性能。
本发明的另一个目的是提供该化合物新晶型的制备方法。
本发明的再一个目的是提供含有所述晶型化合物的药物组合物。
根据本发明的一个方面，先制备所述化合物(如式(1)所示)的粗品，然后通过重结晶的方法对该物质粗品进行结晶，获得化合物晶型。
通过对该结晶进行熔点测量、X-射线粉末衍射、DSC、TG、IR、元素分析等检测和分析，确证获得的结晶是一种新型的结晶，称为B晶型。
具体地，当用Cu辐射源进行X-射线粉末衍射时，所述的B晶型包括在位于2θ°为5.5±0.2°、8.7.7±0.2°、11.0±0.2°、13.5±0.2°、16.0±0.2°、16.4±0.2°的特征衍射峰，这些峰的相对强度(I/I 0)均大于或等于30％。更进一步地，所述结晶在X-射线粉末衍射中还可以进一步包含位于2θ°为18.5±0.2°、21.9±0.2°、22.1±0.2°的特征衍射峰，这些峰的相对强度均大于或等于15％(见图1)。
其中“±0.2°”为允许的测量误差范围。
本发明的B晶型可以通过X-射线粉末衍射图谱进行表征。其特征在于其X射线粉末衍射图谱具有上述2θ°表示的特征衍射峰，如表1所示，其相对强度接近下列数值。
表1
Figure PCTCN2019074248-appb-000003
Figure PCTCN2019074248-appb-000004
此处的术语“接近”是指相对强度测量值的不确定性。本领域技术人员理解相对强度的不确定性非常依赖于测量条件。相对强度的不确定性非常依赖于测量条件。相对强度值可以例如在±25％范围内改变或优选在±10％范围内改变。
上述B晶型具有图1所示的X射线粉末衍射图谱。
本发明采用差示扫描量热(DSC)技术对B晶型进行表征(见图2)，其中差示扫描量热分析结果表明，供试样品在检测温度范围内(20-310℃)没有明显的吸热或放热过程。
本发明采用热重分析技术对B晶型进行表征(见图3)，其中热重谱图(TG)显示在室温至326℃失重量为0.87％、326℃至436℃的失重量为39.8％、436至700℃的失重量为54.48％、700℃的最后剩余量为0.85％。说明随着温度升高，该化合物降解了。
本发明的化合物的B晶型的红外图谱如图4所示，其中在3175、3060、3007、2969、2905、1691-1634、1600、1579、1555、1503、1491、1472、1376、1277、956、810、775、681cm -1有较强吸收峰。
本发明的B晶型的元素分析数据与理论值吻合(相差±0.3％以内)，进一步确证该化合物不与其他溶剂共结晶(见表2)。
表2
Figure PCTCN2019074248-appb-000005
根据本发明的另一方面，制备所述B晶型的方法包括：将(3Z,6Z)-3-[((E)-3-(5-叔丁基)-1H-咪唑基-4-基)亚甲基]-6-((E)-3-(3-氟苯基)-2-丙烯 亚基)哌嗪-2,5-二酮的粗品，加入到C1-C4烷基醇和C3-C4烷基酮的混合溶剂中，加热回流至溶解；溶液澄清后开始降温，至析出固体，过滤收集固体，将收集的固体鼓风干燥即得B晶型。所述的醇选自甲醇、乙醇、丙醇、异丙醇和丁醇，优选乙醇；所述的酮选自丙酮、甲基乙基酮和正丁酮等，优选丙酮；醇与酮的体积比(V/V)为5:1～10:1，优选8：1；所述的粗品与溶剂的配比按g/ml计，重量体积比为1：5～20，优选为1:10。将溶液优选加热到40～80℃，更优选C1-C4烷基醇和C3-C4烷基酮混合溶剂加热至50℃；根据此实施方案，析固进行2～8小时，更优选为4小时。析固温度为0～40℃，优选10～20℃。析固完全后过滤，烘干温度为30～60℃，优选为50℃。
根据本发明的又一方面，提供一种药物组合物，该药物组合物含有所述新晶型化合物和任选的药学上可接受的载体和/或赋形剂。
所述药物组合物可进一步按照常规制剂方法配制成可供给药的形式，包括经口或胃肠外给药形式。在可供给药的形式中，应包含治疗有效量的B晶型。所谓“治疗有效量“是指在该剂量下，本发明的化合物能够改善或减轻疾病症状，或能够抑制或阻断疾病的发展。
根据经验并考虑本领域的标准方法和参考文献，本领域技术人员可以很容易地选择各种载体和/或赋形剂并确定其用量。
根据本发明的再一方面，本发明的晶型可单独用于制备治疗过渡性增殖疾病的药物，也可以和其他治疗药物联合制备，协同作用。
本发明(3Z,6Z)-3-[((E)-3-(5-叔丁基)-1H-咪唑基-4-基)亚甲基]-6-((E)-3-(3-氟苯基)-2-丙烯亚基)哌嗪-2,5-二酮的B晶型，用于治疗过度增殖性疾病，优选所述的过度增殖性疾病为癌症，包括但不限于非小细胞肺癌、结肠直肠癌、顽固性非小细胞肺癌、胰腺癌、卵巢癌、乳腺癌、神经胶质瘤、脑癌或颈部癌症。
该化合物为细胞周期抑制剂，作为肿瘤生长抑制剂或真菌抑制剂。并可用来治疗或预防相关的疾病，如癌症，特别是非小细胞肺癌、结肠直肠癌、顽固性非小细胞肺癌、卵巢癌、胰腺癌、乳腺癌、神经胶质瘤、脑瘤或颈部癌症。
有益效果：
本发明制备得到了(3Z,6Z)-3-[((E)-3-(5-叔丁基)-1H-咪唑基-4-基)亚甲基]-6-((E)-3-(3-氟苯基)-2-丙烯亚基)哌嗪-2,5-二酮的新晶型，其具有稳定的形态，化学稳定性好，耐高温，这种新晶型的(3Z,6Z)-3-[((E)-3-(5-叔丁基)-1H-咪唑基-4- 基)亚甲基]-6-((E)-3-(3-氟苯基)-2-丙烯亚基)哌嗪-2,5-二酮具备了制备制剂所需要的性能，且贮存方便，生产操作更为简便，质量更易控制。
附图说明
图1是本发明实施例1所得的新晶型B的X射线衍射图谱；
图2是本发明实施例1所得的新晶型B的DSC图谱；
图3是本发明实施例1所得的新晶型B的TG图谱；
图4是本发明实施例1所得的新晶型B的IR图谱；
图5是本发明实施例1所得的新晶型B的HPLC图谱。
具体实施方式
所有原料和试剂均为商业购买。
粗品制备：
(3Z,6Z)-3-[((E)-3-(5-叔丁基)-1H-咪唑基-4-基)亚甲基]-6-((E)-3-(3-氟苯基)-2-丙烯亚基)哌嗪-2,5-二酮粗品的制备，以1,4-二乙酰基哌嗪-2,5-二酮、5-叔丁基-1H-咪唑-4-甲醛为起始原料，参考专利申请(CN106565686)的方法来制备。
【实施例1】
取200g(3Z,6Z)-3-[((E)-3-(5-叔丁基)-1H-咪唑基-4-基)亚甲基]-6-((E)-3-(3-氟苯基)-2-丙烯亚基)哌嗪-2,5-二酮粗品加入到反应瓶中，加入2000ml的乙醇和丙酮的混合溶剂中(V/V＝8：1)，搅拌下升温回流至50℃。溶解后搅拌10min，再降温至20～25℃，至固体析出再搅拌析晶4h，抽滤，滤饼用丙酮淋洗。滤饼于50℃鼓风干燥，用五氧化二磷助干。得类白色固体182g，收率91.0％。用卡尔费休测定仪检测水分为0.1％。得到的化合物为(3Z,6Z)-3-[((E)-3-(5-叔丁基)-1H-咪唑基-4-基)亚甲基]-6-((E)-3-(3-氟苯基)-2-丙烯亚基)哌嗪-2,5-二酮的B晶型。
化合物性状鉴定如图1～图5所示。
实施例样品的测试条件：
XRD：
检测仪器：锐影(Empyrean)X射线衍射仪
检测条件：Cu靶Kα射线，电压40kV，电流40mA，发散狭缝1/32°，防散射狭缝1/16°，防散射狭缝7.5mm，2θ范围：3°-50°，步长0.02°，每步停留时间40S。
检测依据：中华人民共和国(2015年版四部)0451X射线粉末衍射法
检测结果：如图1。
(二)DSC：
检测仪器：德国NETZSCH公司DSC 214差示扫描量热仪
检测条件：气氛：N2，40ml/min
扫描程序：从室温以10℃/min升温至250℃，记录升温曲线。
检测样品质量：样品1：2.48mg(使用铝质样品盘)
检测依据：JY/T 014-1996热分析方法通则
检测结果：如图2。
(三)TG：
检测仪器：德国NETZSCH公司TG209热重分析仪
检测条件：气氛：空气，20ml/min；
扫描程序：室温～800℃，升温速率：10℃/min。
检测依据：热分析方法通则JY/T 014-1996
检测结果：如图3。
红外光谱：
检测仪器：FT-IR NICOLET 6700(美国)
检测条件：溴化钾压片法
检测依据：GB/T 6040-2002红外光谱分析方法通则
检测结果：如图4。
HPLC
检测仪器：Agilent 1260series(美国)
检测条件：
色谱柱：Waters Sunfire C18
流动相A：水-流动相乙腈B(80:20)
柱温：40℃检测波长：390nm。
检测依据：《中国药典》二部附录VD高效液相色谱法
检测结果：如图5
【实施例2】
各取20g(3Z,6Z)-3-[((E)-3-(5-叔丁基)-1H-咪唑基-4-基)亚甲基]-6-((E)-3-(3-氟苯基)-2-丙烯亚基)哌嗪-2,5-二酮粗品加入到反应瓶中，参考实施例1的实验操作进行以下实验：
表3
Figure PCTCN2019074248-appb-000006
Figure PCTCN2019074248-appb-000007
实验结论：实验所用醇类溶剂，优选乙醇；实验所用酮类溶剂，优选丙酮；醇与酮的体积比(V/V)为5:1～10:1，优选8：1；粗品与溶剂的配比按g/ml计，重量体积比为1：5～20，优选为1:10。将溶液优选加热到40～80℃，优选烷基醇和烷基酮混合溶剂加热至50℃；根据此实施方案，析固进行2～8小时，更优选为4小时。析固温度为0～40℃，优选10～20℃。析固完全后过滤，烘干温度为30～60℃，优选为50℃。
【实施例3】
(3Z,6Z)-3-[((E)-3-(5-叔丁基)-1H-咪唑基-4-基)亚甲基]-6-((E)-3-(3-氟苯基)-2-丙烯亚基)哌嗪-2,5-二酮的B晶型的稳定性考察
将获得的B晶型进行稳定性考察(10天的加速试验)，在60℃、湿度92.5％、光照条件下对新晶型的纯度、最大单杂及总杂与0天的数据进行对比，光照条件下，纯度略有降低，其他条件下显示获得的晶型稳定。
表4B晶型影响因素试验结果
Figure PCTCN2019074248-appb-000008
将(3Z,6Z)-3-[((E)-3-(5-叔丁基)-1H-咪唑基-4-基)亚甲基]-6-((E)-3-(3-氟苯基)-2-丙烯亚基)哌嗪-2,5-二酮的粗品进行稳定性考察(10天的加速试验)，在40℃、60℃对粗品的纯度、最大单杂与0天的数据进行对比，粗品60℃5天、60℃10天的纯度低于B晶型相应条件下的纯度。
表5粗品影响因素试验结果
Figure PCTCN2019074248-appb-000009
【实施例4】
化合物B晶型注射液的制备
表6处方1
Figure PCTCN2019074248-appb-000010
Figure PCTCN2019074248-appb-000011
制法：取聚山梨酯-80，加入0.5％的经干燥处理的针用活性炭，加热至40-60℃，恒温搅拌30-60min，加热过滤，至澄明度与颜色检验合格。
取处方量的聚山梨酯-80，边滴加13％盐酸溶液，边搅拌，使测定pH值在3.5-3.9范围内，加入化合物B晶型，搅拌使化合物B溶解，将溶液经微孔滤膜进行正压滤过，至溶液澄明，测定含量和pH，合格后，将溶液在洁净条件灌装于抗生素管制瓶中，每瓶0.5ml(含化合物B)，通氮气后，压胶塞、轧铝盖，即得。
取药用乙醇，在水浴上蒸馏，弃去初馏分，收集冷凝液。称取195g冷凝液，加注射水至1500g，加入0.3％的针用活性碳，加热回流30min后，放冷，脱炭，经0.22um微孔滤膜过滤至溶液澄明，在100级洁净条件下灌装于抗生素管制瓶中，每瓶1.5ml。压胶塞，轧铝盖，即得。
【实施例5】
比较处方中不加酸与加入不同酸、及同一处方不同工艺通氮气与不通氮气对本品稳定性影响，经检测40℃放置7天的各项指标与0天比较，结果见表7，由表7可见本品处方3中不加酸，40℃放置7天后有关物质明显增加，含量下降，其它指标没有明显变化，加入13％盐酸(处方2)或50％枸橼酸(处方4)的处方明显优于不加酸的处方(处方3)，而用13％盐酸调节pH值的处方优于用50％枸橼酸调节pH值的处方，同一处方1工艺不同，40℃放置7天后通氮气样品的含量与有关物质变化不大，不通氮气的样品含量下降、有关物质明显增加，通氮气比不通氮气的样品稳定性更好，因此选择处方1为本品工艺。
表7
Figure PCTCN2019074248-appb-000012
Figure PCTCN2019074248-appb-000013
注：*pH值测定方法：取本品0.5g，加水4.5ml，搅拌15分钟，依法测定(中国药典2015版)，插入电极后搅拌15分钟，所测定的pH值。
Y2：表示标准比色液黄色2号(符合中国药典2015版，上海药品检验所监制)
以上对本发明较佳实施方式的描述并不限制本发明，本领域技术人员可以根据本发明做出各种改变或变形，只要不脱离本发明的精神，均应属于本发明所附权利要求的范围。

Claims (8)

  1. 式(1)化合物(3Z,6Z)-3-[((E)-3-(5-叔丁基)-1H-咪唑基-4-基)亚甲基]-6-((E)-3-(3-氟苯基)-2-丙烯亚基)哌嗪-2,5-二酮的晶型，其特征在于所述晶型的X-射线粉末衍射图谱2θ衍射角在5.5±0.2°、8.7.7±0.2°、11.0±0.2°、13.5±0.2°、16.0±0.2°、16.4±0.2°、18.5±0.2°、21.9±0.2°和22.1±0.2°有特征衍射峰，
    Figure PCTCN2019074248-appb-100001
  2. 如权利要求1所述的(3Z,6Z)-3-[((E)-3-(5-叔丁基)-1H-咪唑基-4-基)亚甲基]-6-((E)-3-(3-氟苯基)-2-丙烯亚基)哌嗪-2,5-二酮的晶型，其特征在于，所述特征衍射峰的相对强度I/I 0为表1所示的数值，相对强度I/I 0在±25％范围内改变。
    表1
    Figure PCTCN2019074248-appb-100002
  3. 如权利要求2所述的(3Z,6Z)-3-[((E)-3-(5-叔丁基)-1H-咪唑基-4-基)亚甲基]-6-((E)-3-(3-氟苯基)-2-丙烯亚基)哌嗪-2,5-二酮的晶型，其特征在于，相对强度I/I0在±10％范围内改变。
  4. 如权利要求1-3任一项所述的(3Z,6Z)-3-[((E)-3-(5-叔丁基)-1H-咪唑基-4-基)亚甲基]-6-((E)-3-(3-氟苯基)-2-丙烯亚基)哌嗪-2,5-二酮的晶型，其特征在于，
    所述晶型的热重谱图显示在室温至326℃失重量为0.87％、326℃至436℃的 失重量为39.8％、436至700℃的失重量为54.48％、700℃的最后剩余量为0.85％。
  5. 如权利要求1-3任一项所述的(3Z,6Z)-3-[((E)-3-(5-叔丁基)-1H-咪唑基-4-基)亚甲基]-6-((E)-3-(3-氟苯基)-2-丙烯亚基)哌嗪-2,5-二酮的晶型，其特征在于用KBr压片测得的红外吸收图谱，所述晶型在3175、3060、3007、2969、2905、1691-1634、1600、1579、1555、1503、1491、1472、1376、1277、956、810、775、681cm -1有吸收峰。
  6. 制备权利要求1所述的(3Z,6Z)-3-[((E)-3-(5-叔丁基)-1H-咪唑基-4-基)亚甲基]-6-((E)-3-(3-氟苯基)-2-丙烯亚基)哌嗪-2,5-二酮的晶型的方法，包括以下步骤：
    1)将(3Z,6Z)-3-[((E)-3-(5-叔丁基)-1H-咪唑基-4-基)亚甲基]-6-((E)-3-(3-氟苯基)-2-丙烯亚基)哌嗪-2,5-二酮的粗品，加入到C1-C4烷基醇和C3-C4烷基酮的混合溶剂中，加热回流至溶解；
    其中所述的烷基醇选自甲醇、乙醇、丙醇、异丙醇和丁醇；
    所述的烷基酮选自丙酮、甲基乙基酮和正丁酮，烷基醇与烷基酮的体积比为5:1～10:1；
    所述的粗品与溶剂的配比按g/ml计，重量体积比为1：5～20，加热温度为40～80℃；
    2)溶液澄清后开始降温，至析出固体，过滤收集固体，将收集的固体鼓风干燥即得所述晶型；
    析固进行2～8小时，析固温度为0～40℃，析固完全后过滤，烘干温度为30～60℃。
  7. 如权利要求6所述的制备方法，其特征在于，
    步骤1)中所述的烷基醇为乙醇，所述的烷基酮为丙酮，乙醇与丙酮的体积比为8:1；
    所述的粗品与溶剂的配比按g/ml计，重量体积比为1:10，加热温度为50℃；
    步骤2)中析固进行4小时，析固温度为10～20℃，烘干温度为50℃。
  8. 含有权利要求1所述的(3Z,6Z)-3-[((E)-3-(5-叔丁基)-1H-咪唑基-4-基)亚甲基]-6-((E)-3-(3-氟苯基)-2-丙烯亚基)哌嗪-2,5-二酮的晶型的药物组合物。
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