WO2019033851A1 - 一种噻吩并吡啶类衍生物硫酸氢盐的晶型 iii 及其制备方法和应用 - Google Patents

一种噻吩并吡啶类衍生物硫酸氢盐的晶型 iii 及其制备方法和应用 Download PDF

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WO2019033851A1
WO2019033851A1 PCT/CN2018/092638 CN2018092638W WO2019033851A1 WO 2019033851 A1 WO2019033851 A1 WO 2019033851A1 CN 2018092638 W CN2018092638 W CN 2018092638W WO 2019033851 A1 WO2019033851 A1 WO 2019033851A1
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formula
compound
form iii
salt form
hydrogen sulfate
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顾景凯
徐学宇
王浩
赵雪
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中荣凯特（北京）生物科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • 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
    • C07B2200/05—Isotopically modified compounds, e.g. labelled
    • 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 relates to the field of medicine, in particular to a novel crystal form of a thienopyridine derivative, a preparation method and application thereof.
  • a thienopyridine derivative of the formula I (hereinafter referred to as a compound of the formula I) having the chemical name (2S)-2-(2-chlorophenyl)-2-(6,7-dihydrothiophene [3, 2-c]pyridin-5(4H)-yl)acetate methyl ester, which can be used to prevent and treat heart, brain and other arterial circulatory disorders caused by high platelet aggregation, such as recent onset strokes, Myocardial infarction and confirmed peripheral arterial disease.
  • WO2008157563A2 discloses a compound of the formula I and pharmaceutically acceptable salts thereof (including hydrogen sulphate) which can be used for the preparation of a medicament for the treatment of coronary artery disease, peripheral vascular disease, cerebrovascular disease, and does not disclose any salts (including hydrogen sulphate). Preparation methods and crystallization characteristics.
  • CN201310533062.4 also discloses a compound of the formula I and a pharmaceutically acceptable salt thereof, and specifically discloses a preparation method of the hydrogen sulfate salt, that is, the compound of the formula I is added to acetone, stirred and dissolved, ice bath, sulfuric acid is added dropwise, and stirring is continued 2 The precipitate was gradually precipitated, filtered and dried to give the hydrogen salt of the compound of formula I as a white solid powder, but without any crystallisation.
  • a drug has more than one crystalline form, it is called a polymorphism. It is well known that different crystal forms of the same drug usually exhibit different physical properties and chemical stability. Therefore, the use of a pharmaceutically active ingredient for determining the crystalline form for formulation production plays an important role in ensuring the efficacy of the drug and reducing the incidence of side effects. To date, the undetermined crystal form of the hydrogen sulphate salt of the compound of formula I has not provided more qualitative and quantitative information for solid drug research, thus developing stable crystals of hydrogen sulphate of the compound of formula I suitable for use in pharmaceutical compositions. Type is of great significance.
  • the infrared absorption spectrum of the hydrogen sulfate salt form III of the compound of the formula I has a characteristic number of wavenumbers/cm -1 of: 2978, 1753, 1264, 1236, 1183, 1037, 935, 867, 769, 618, 568;
  • the differential scanning calorimetry pattern of the compound of the formula I hydrogen sulfate salt form II has a peak of 173.0 ° C and a melting enthalpy of 84.9 J/g.
  • the fluorene methyl group of the compound of the formula I of the present invention has a fluorene atom content of not less than 50%, preferably not less than 70%, and most preferably not less than 90%.
  • the present invention provides a compound of formula I wherein the hydrogen sulfate salt form III is prepared by adding a compound of formula I, including but not limited to n-propanol, isopropanol, n-butanol, 2-butanol and/or 2-methylpropane. 1- or one of several alcohol solvents or solvent combinations, stirred and dissolved; adding sulfuric acid; stirring at room temperature to reflux temperature; then cooling, stirring; filtering, drying to obtain the compound of formula I having hydrogen sulfate .
  • a compound of formula I including but not limited to n-propanol, isopropanol, n-butanol, 2-butanol and/or 2-methylpropane.
  • 1- or one of several alcohol solvents or solvent combinations stirred and dissolved; adding sulfuric acid; stirring at room temperature to reflux temperature; then cooling, stirring; filtering, drying to obtain the compound of formula I having hydrogen sulfate .
  • a crystal is a solid substance that is periodically arranged by atoms (or ions, molecules), and the crystal of an organic drug basically belongs to a molecular lattice. Different crystal forms are produced depending on the process conditions. Different crystal forms of the same drug often cause significant differences in physical and chemical properties such as appearance, solubility, melting point, density, and drug dissolution and bioavailability, thereby affecting drug stability, bioavailability, etc., drug polymorphism Research has become an indispensable part of new drug development and approval, drug production and quality control, and pre-determination of new drug types.
  • the hydrogen sulphate salt of the compound of formula I of Form III provided herein can be used in the preparation of pharmaceutical compositions for the prevention and treatment of diseases caused by thrombosis.
  • Form III is more stable, bulk solid particles are denser and less susceptible to static electricity, and have good fluidity and compressibility, so that it can be more easily used as an active ingredient in the preparation of pharmaceutical compositions.
  • the actual preparation of the preparation brings great convenience.
  • Figure 1 is a powder X-ray diffraction pattern of the hydrogen sulfate salt form III of the compound of formula I.
  • Figure 2 is a graph of the infrared absorption spectrum of the hydrogen sulfate salt form III of the compound of formula I.
  • Figure 3 is a differential scanning thermogram of Form III of the hydrogen sulfate salt of the compound of Formula I.
  • Figure 5 is a graph of the infrared absorption spectrum of Form I of the hydrogen sulfate salt of the compound of Formula I.
  • Figure 6 is a differential scanning thermogram of Form I of the hydrogen sulfate salt of the compound of Formula I.
  • the hydrogen sulphate crystals of the compound of formula I are prepared according to the methods disclosed in CN201310533062.4 and Xu, respectively, and are found to have the same crystalline character, ie crystal Type I.
  • the present invention further discovers that the new crystalline form of the hydrogen sulphate salt of the compound of formula I, Form III, differs significantly from Form I in some physical properties such as X-ray powder diffraction and infrared absorption spectroscopy.
  • the bulk solid particles of the crystalline form III of the invention are more compact and less susceptible to static electricity, have better fluidity and compressibility, and thus can be more easily used as an active ingredient. Preparation of a pharmaceutical composition.
  • the hydrogen sulphate of the compound of formula I prepared in accordance with the invention, Form I and Form III, was subjected to powder X-ray diffraction on a Rigaku D/max 2500 X-ray diffractometer (CuK ⁇ , Infrared absorption spectroscopy was performed on a Perkin Elmer Spectrum 400 Fourier transform infrared spectrometer (potassium bromide tablet), and differential scanning calorimetry was performed on a METTLER TOLEDO DSC 3+ differential scanning calorimeter (rate of temperature 10) °C/min).
  • the hydrogen sulfate salt of the compound of the formula I was obtained by the method disclosed in CN201310533062.4 or Xu et al. (Molecules 2016, 21, 704), having the same crystal form characteristic, i.e., Form I.
  • the X-ray powder diffraction pattern of the compound of the formula I, hydrogen sulfate salt form I is clearly shown in Figure 4, at 9.22°, 10.92°, 11.58°, 14.84°, 19.02°, 20.58°, 23.20° in terms of 2 ⁇ angle.
  • the melting enthalpy of the crystalline form of the compound of the formula I hydrogen sulfate is significantly higher than that of the crystalline form I, indicating that the thermal stability of the crystalline form III is better.
  • Example 5 According to the method of Example 5 in CN201310533062.4, the compound of formula I (20.0g) was added to acetone (100mL), stirred and dissolved, ice bath, sulfuric acid (6.16g) was added dropwise, stirring was continued for 2 hours, crystallization was gradually precipitated, and filtered. Drying in vacuo at 50 ° C to obtain the hydrogen sulfate salt form I (20.6 g) of the compound of formula I, the X-ray powder diffraction pattern of 9.22 °, 10.92 °, 11.58 °, 14.84 °, 19.02 °, 20.58 in 2 ⁇ angle.
  • Hydrogen sulfate (1.00 g) of the compound of the formula I obtained in Test Example 1 was added to a water-acetone mixture (23 mL, volume ratio 1:5) according to the method reported by Xu et al. (Molecules 2016, 21, 704), and heated to reflux. After the solid was dissolved, it was cooled to 0 ° C, stirred for 2 hours, and the precipitate precipitated was filtered and dried under vacuum at 60 ° C to obtain the hydrogen sulfate salt form I (0.62 g) of the compound of the formula I, and the X-ray powder diffraction pattern was expressed at 2 ⁇ angle.

Abstract

本发明公开了一种噻吩并吡啶类衍生物硫酸氢盐的晶型Ⅲ及其制备方法和应用。该晶型Ⅲ以 2θ 衍射角表示的X-射线粉末衍射图谱在 11.02°、13.34°、14.06°、18.26°、18.80°、20.58°、21.96°、22.90°、24.14° 显示出特征衍射峰。该晶型可作为活性成分制备药物组合物，用于预防和治疗由血栓引起的疾病。与原有晶型相比本发明的晶型Ⅲ具有更好的稳定性，散装固体颗粒更致密且不易受静电影响，流动性和可压性更好，作为活性成分用于药物组合物制备，药物制剂稳定性更强。

Description

一种噻吩并吡啶类衍生物硫酸氢盐的晶型III及其制备方法和应用 技术领域
本发明涉及医药领域，具体涉及噻吩并吡啶类衍生物的新晶型及其制备方法和应用。
技术背景
如式Ⅰ所示的噻吩并吡啶类衍生物(以下简称式Ⅰ化合物)，化学名称为(2S)-2-(2-氯苯基)-2-(6,7-二氢噻吩[3,2-c]并吡啶-5(4H)-基)乙酸氘甲基酯，可被用于预防和治疗因血小板高聚集引起的心、脑及其他动脉循环障碍疾病，如近期发作的脑卒中、心肌梗死和确诊的外周动脉疾病。
Figure PCTCN2018092638-appb-000001
WO2008157563A2公开了式Ⅰ化合物及其药学上可接受的盐(包括硫酸氢盐)，可用于制备治疗冠状动脉疾病、周边血管疾病、脑血管疾病药物，并未公开任何盐(包括硫酸氢盐)的制备方法和结晶特征。
CN201310533062.4也公开了式Ⅰ化合物及其药学上可接受的盐，并具体公开了硫酸氢盐的制备方法，即将式Ⅰ化合物加入丙酮中，搅拌溶解，冰浴，滴加硫酸，继续搅拌2小时，逐渐析出沉淀，过滤，干燥得白色固体粉末状的式Ⅰ化合物硫酸氢盐，但未公开其任何结晶特征。
Xu等(Molecules 2016,21,704)报道了向含有式Ⅰ化合物的丙酮溶液中加入硫酸，冷却至0℃，搅拌2小时，过滤析出的沉淀，再用水和丙酮重结晶，得到白色结晶性粉末状的式Ⅰ化合物的硫酸氢盐，仅测定熔点177.3-178.2(未经校正)，未有准确的晶型描述。
药物如果具有一种以上的结晶形态，称作多晶型现象。众所周知，通常同一药物的不同晶型会表现出不同的物理性质和化学稳定性，所以使用确定结晶形态的药物活性成份用于制剂生产，对于保证药物的疗效、降低毒副作用发生率有着重要作用。迄今为止，未有确定的式Ⅰ化合物硫酸氢盐的晶型研究，不能为固体药物研究提供更多的定性定量信息，因此 开发适合于药物组合物中使用的式Ⅰ化合物硫酸氢盐的稳定晶型具有十分重要的意义。
发明内容
本发明的目的是提供式Ⅰ化合物硫酸氢盐的新晶形，即晶型Ⅲ。本发明的另一目的是提供式Ⅰ化合物硫酸氢盐晶型Ⅲ的制备方法。本发明的再一目的是提供具有晶型Ⅲ的式Ⅰ化合物硫酸氢盐的医药用途，具体为通过抑制血小板聚集，预防和治疗由血栓引起的疾病。本发明的目的是通过以下技术方案实现的。
一种式Ⅰ化合物硫酸氢盐晶型Ⅲ，所述式Ⅰ化合物硫酸氢盐晶型Ⅲ以2θ衍射角表示的X-射线粉末衍射图谱在11.02°、13.34°、14.06°、18.26°、18.80°、20.58°、21.96°、22.90°、24.14°处显示出特征衍射峰，误差范围为±0.2°。
Figure PCTCN2018092638-appb-000002
所述式Ⅰ化合物硫酸氢盐晶型Ⅲ的红外吸收光谱具有波数/cm -1为：2978、1753、1264、1236、1183、1037、935、867、769，618、568的特征峰；所述式Ⅰ化合物硫酸氢盐晶型Ⅱ的差示扫描热分析图谱的峰值为173.0℃，熔化焓为84.9J/g。
本发明的式Ⅰ化合物的氘甲基的氘原子含量不小于50％，优选不小于70％，最优选不小于90％。
本发明提供的式Ⅰ化合物硫酸氢盐晶型Ⅲ的制备方法为：将式Ⅰ化合物加入包括但不限于正丙醇、异丙醇、正丁醇、2-丁醇和/或2-甲基丙-1-醇一种或几种醇类溶剂或溶剂组合中，搅拌溶解；加入硫酸；室温至回流温度下搅拌；然后降温，搅拌；过滤，干燥得具有晶型Ⅲ的式Ⅰ化合物硫酸氢盐。
晶体是由原子(或离子、分子)在空间周期地排列构成的固体物质，有机药物的结晶基本上属于分子晶格。随着工艺条件的不同而产生不同的晶型。同一药物的不同晶型常引起药物在外观、溶解度、熔点、密度等理化性质以及药物溶出度、生物有效性等显著差异，从而影响药物稳定性、生物利用度等疗效的发挥，药物多晶型的研究已经成为新药开发和审批、药物的生产和质量控制以及新药剂型确定前设计所不可缺少的重要组成部分。
本发明的有益效果：
本发明提供的晶型Ⅲ的式Ⅰ化合物硫酸氢盐可用于制备药物组合物，用于预防和治疗由血栓引起的疾病。与晶型Ⅰ相比，晶型Ⅲ更稳定，散装固体颗粒更致密且不易受静电影响，具有良好的流动性、可压性，因此可以更容易地作为活性成分用于药物组合物制备，为实际的制剂生产带来了极大的便利。
附图说明
图1是式Ⅰ化合物硫酸氢盐晶型Ⅲ的粉末X-射线衍射图。
图2是式Ⅰ化合物硫酸氢盐晶型Ⅲ的红外吸收光谱图。
图3是式Ⅰ化合物硫酸氢盐晶型Ⅲ的差示扫描热分析图。
图4是式Ⅰ化合物硫酸氢盐晶型Ⅰ的粉末X-射线衍射图。
图5是式Ⅰ化合物硫酸氢盐晶型Ⅰ的红外吸收光谱图。
图6是式Ⅰ化合物硫酸氢盐晶型Ⅰ的差示扫描热分析图。
具体实施方式
为了开发适合于药物组合物使用的式Ⅰ化合物硫酸氢盐的结晶，分别依CN201310533062.4和Xu等公开的方法，制备了式Ⅰ化合物硫酸氢盐结晶，发现它们具有相同的结晶特征，即晶型Ⅰ。本发明进一步发现了式Ⅰ化合物硫酸氢盐的新晶型，即晶型Ⅲ，与晶型Ⅰ在一些物理性质，如X-射线粉末衍射和红外吸收光谱，存在明显不同。
与式Ⅰ化合物硫酸氢盐晶型Ⅰ相比，本发明的晶型Ⅲ的散装固体颗粒更致密且不易受静电影响，流动性和可压性更好，因此可以更容易地作为活性成分用于药物组合物制备。
本发明制备的晶型Ⅰ和晶型Ⅲ的式Ⅰ化合物硫酸氢盐，粉末X-射线衍射测试在Rigaku D/max2500型X-射线衍射仪上进行(CuKα，
Figure PCTCN2018092638-appb-000003
)，红外吸收光谱测试在Perkin Elmer Spectrum400型傅里叶变换红外光谱仪上进行(溴化钾压片)，差示扫描热分析在METTLER TOLEDO DSC 3+差示扫描量热仪上进行(升温速率10℃/min)。
由CN201310533062.4或Xu等(Molecules 2016,21,704)公开的方法制得式Ⅰ化合物硫酸氢盐(详见试验例1和试验例2)，具有相同的晶型特征，即晶型Ⅰ。式Ⅰ化合物硫酸氢盐晶型Ⅰ的X-射线粉末衍射图谱清楚地示于附图4，在以2θ角度表示的9.22°、10.92°、11.58°、14.84°、19.02°、20.58°、23.20°、23.86°、25.50°有峰；红外吸收光谱清楚地示于附图5，在2986、1753、1220、1175、1077、840、716cm -1有峰；其差示扫描热分析的峰值为182.4℃，熔化焓为62.7J/g。
本发明的式Ⅰ化合物硫酸氢盐晶型Ⅲ的X-射线粉末衍射图谱清楚地示于附图1，在以2θ角度表示的11.02°、13.34°、14.06°、18.26°、18.80°、20.58°、21.96°、22.90 °、24.14°有峰；红外吸收光谱清楚地示于附图2，在2978、1753、1264、1236、1183、1037、935、867、769，618、568cm -1有峰；差示扫描热分析的峰值为173.0℃，熔化焓为84.9J/g。
式Ⅰ化合物硫酸氢盐晶型Ⅲ的熔化焓明显高于晶型Ⅰ，说明晶型Ⅲ的热稳定性更好。
试验例1
式Ⅰ化合物硫酸氢盐晶型Ⅰ的制备
依CN201310533062.4中实施例5的方法，将式Ⅰ化合物(20.0g)加入丙酮(100mL)中，搅拌溶解，冰浴，滴加硫酸(6.16g)，继续搅拌2小时，逐渐析出结晶，过滤，50℃真空干燥，得式Ⅰ化合物硫酸氢盐晶型Ⅰ(20.6g)，其X-射线粉末衍射图谱在以2θ角度表示的9.22°、10.92°、11.58°、14.84°、19.02°、20.58°、23.20°、23.86°、25.50°有峰，其红外吸收光谱在2986、1753、1220、1175、1077、840、716cm -1有峰，其差示扫描热分析的峰值为182.4℃，熔化焓为62.7J/g。
试验例2
式Ⅰ化合物硫酸氢盐晶型Ⅰ的制备
依Xu等(Molecules 2016,21,704)报道的方法，将试验例1得到的式Ⅰ化合物硫酸氢盐(1.00g)加入水-丙酮混合液(23mL，体积比1:5)中，加热至回流，固体溶解后，冷却至0℃，搅拌2小时，过滤析出的沉淀，60℃真空干燥，得式Ⅰ化合物硫酸氢盐晶型Ⅰ(0.62g)，其X-射线粉末衍射图谱在以2θ角度表示的9.06°、10.80°、11.44°、14.72°、18.86°、20.46°、23.08°、23.74°、25.36°有峰，其红外吸收光谱在2986、1753、1220、1174、1077、840、715cm -1有峰，其差示扫描热分析的峰值为181.7℃，熔化焓为57.2J/g。
下面通过具体的实施方式对本发明进一步说明，但不作为对本发明的限制。
实施例1
式Ⅰ化合物硫酸氢盐晶型Ⅲ的制备
式Ⅰ化合物(3.80g)加入正丙醇(16mL)，搅拌溶解，加入98％硫酸(1.19g)，搅拌1小时，降温至-10～-5℃，保温搅拌8小时，过滤，60℃真空干燥，得式Ⅰ化合物硫酸氢盐晶型Ⅲ3.15g(收率63.7％)。
实施例2
式Ⅰ化合物硫酸氢盐晶型Ⅲ的制备
式Ⅰ化合物(3.16g)加入异丙醇(32mL)，搅拌溶解，加入98％硫酸(1.03g)，加热至回流，保持回流30分钟，降温至0～5℃，搅拌10小时，过滤，60℃真空干燥，得式Ⅰ化合物硫酸氢盐晶型Ⅲ3.43g(收率83.4％)。
实施例3
式Ⅰ化合物硫酸氢盐晶型Ⅲ的制备
式Ⅰ化合物(3.11g)加入正丁醇(20mL)，搅拌溶解，加入98％硫酸(0.98g)，加热至65-70℃，保温搅拌1小时，降温至-5～0℃，过滤，65℃真空干燥，得式Ⅰ化合物硫酸氢盐晶型Ⅲ2.03g(收率50.1％)。
实施例4
式Ⅰ化合物硫酸氢盐晶型Ⅲ的制备
式Ⅰ化合物(3.33g)加入2-丁醇(35mL)，加入98％硫酸(1.31g)，加热至75-80℃，保温搅拌1小时，降温至室温，搅拌24小时，过滤，65℃真空干燥，得式Ⅰ化合物硫酸氢盐晶型Ⅲ3.22g(收率74.3％)。

Claims (10)

  1. 一种式Ⅰ化合物硫酸氢盐晶型Ⅲ，其特征在于：所述式Ⅰ化合物硫酸氢盐晶型Ⅲ以2θ衍射角表示的X-射线粉末衍射图谱在11.02°、13.34°、14.06°、18.26°、18.80°、20.58°、21.96°、22.90°、24.14°处显示出特征衍射峰。
    Figure PCTCN2018092638-appb-100001
  2. 根据权利要求1所述式Ⅰ化合物硫酸氢盐晶型Ⅲ，其特征在于：所述式Ⅰ化合物硫酸氢盐晶型Ⅲ的红外吸收光谱具有波数/cm -1为：2978、1753、1264、1236、1183、1037、935、867、769，618、568的特征峰；所述式Ⅰ化合物硫酸氢盐晶型Ⅱ的差示扫描热分析图谱的峰值为173.0℃，熔化焓为84.9J/g。
  3. 根据权利要求1所述式Ⅰ化合物硫酸氢盐晶型Ⅲ，其特征在于：其中氘甲基的氘原子丰度不小于50％。
  4. 根据权利要求1所述式Ⅰ化合物硫酸氢盐晶型Ⅲ，其特征在于：其中氘甲基的氘原子丰度不小于70％。
  5. 根据权利要求1所述式Ⅰ化合物硫酸氢盐晶型Ⅲ，其特征在于：其中氘甲基的氘原子丰度不小于90％。
  6. 根据权利要求1所述式Ⅰ化合物硫酸氢盐晶型Ⅲ，其特征在于：所述式Ⅰ化合物硫酸氢盐晶型Ⅲ显示出如附图1所示的粉末X-射线衍射图。
  7. 根据权利要求1所述式Ⅰ化合物硫酸氢盐晶型Ⅲ，其特征在于：所述式Ⅰ化合物硫酸氢盐晶型Ⅲ显示出如附图2所示的红外吸收光谱图。
  8. 权利要求1所述式Ⅰ化合物硫酸氢盐晶型Ⅲ的制备方法，其特征在于：包括以下步骤：将式Ⅰ化合物加入包括但不限于正丙醇、异丙醇、正丁醇、2-丁醇和/或2-甲基丙-1-醇一种或几种醇类类溶剂或溶剂组合中，搅拌溶解；加入硫酸；室温至回流温度下搅拌；然后降温，搅拌；分离结晶。
  9. 包含权利要求1～4中任意一项所述式Ⅰ化合物硫酸氢盐晶型Ⅲ的药物组合物。
  10. 权利要求1～4中任意一项所述式Ⅰ化合物硫酸氢盐晶型Ⅲ可作为活性成分用于制备药物组合物，用于预防和治疗由血栓引起的疾病。
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