WO2023222006A1 - Hs378晶型及其制备方法 - Google Patents

Hs378晶型及其制备方法 Download PDF

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WO2023222006A1
WO2023222006A1 PCT/CN2023/094661 CN2023094661W WO2023222006A1 WO 2023222006 A1 WO2023222006 A1 WO 2023222006A1 CN 2023094661 W CN2023094661 W CN 2023094661W WO 2023222006 A1 WO2023222006 A1 WO 2023222006A1
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crystal form
formula
compound
present
preparation
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French (fr)
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李娜
施珍娟
陈连蔚
赵美玉
杨志清
吴忠伟
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浙江海正药业股份有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C07K5/06052—Val-amino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/02—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length in solution
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention relates to the field of chemical pharmaceuticals. More specifically, the present invention relates to (1R,2S,5S)-N- ⁇ (1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]-ethyl ⁇ -6,6-Dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide Crystalline Forms A and B of (HS378) as well as preparation methods of said crystalline forms and their pharmaceutical uses.
  • HS378 is an orally bioavailable SARSCoV-2 primary protease inhibitor with in vitro coronavirus antiviral activity and excellent off-target selectivity and in vivo safety. Oral activity was demonstrated in a mouse-adapted model of novel coronavirus and oral plasma concentrations that exceeded in vitro antiviral cellular efficacy were achieved in a Phase 1 clinical trial in healthy human participants.
  • the chemical name of the compound of formula (I) is (1R,2S,5S)-N- ⁇ (1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]-ethyl ⁇ -6,6-Dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-methyl Amide (named HS378 in this application), its structural formula is as follows:
  • Crystal form 1 is methyl tert-butyl ether solvate
  • crystal form 5 is amorphous.
  • the preparation of crystal form 1, crystal form 4 and crystal form 5 all uses crystal form 2 as the substrate.
  • the present invention provides HS378 crystal form A and crystal form B, whose crystallization methods have better impurity removal effects.
  • crystal form A The X-ray powder diffraction pattern of crystal form A of HS378 according to the present invention (hereinafter referred to as crystal form A) has characteristic peaks at the following diffraction angles 2 ⁇ : 6.2 ⁇ 0.2°, 6.9 ⁇ 0.2°, 7.9 ⁇ 0.2°, 10.5 ⁇ 0.2°, 11.5 ⁇ 0.2°, 11.9 ⁇ 0.2°, 12.5 ⁇ 0.2°, 13.9 ⁇ 0.2°, 14.3 ⁇ 0.2°, 15.8 ⁇ 0.2°, 18.7 ⁇ 0.2°, 19.4 ⁇ 0.2°, 20.7 ⁇ 0.2° and 23.3 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form A of the present invention has the 2 ⁇ value, the interplanar spacing d value and the relative intensity data as shown in Table 1 below:
  • the differential scanning calorimetry (DSC) spectrum of the crystal form A of the present invention has an endothermic peak with a Peak value of 105.2°C.
  • Form A of the present invention has a DSC pattern as shown in Figure 2.
  • thermogravimetric analyzer TGA
  • Form A of the present invention has a TGA spectrum as shown in Figure 3.
  • the crystal form A of the present invention has a micrograph as shown in Figure 7.
  • the crystal habit is massive, close to a spherical shape, the friction between particles is small, and the fluidity is good.
  • Another object of the present invention is to provide a method for preparing the crystal form A, which method includes the following steps:
  • the mass and volume ratio of the crude compound of formula (I) and the mixed solvent in the above step (1) is 1:5-40, and its unit is g/ml; the volume ratio of the alcohol and isobutyl acetate (ml/ ml) is 1:7-1:100; the alcohol is C1-C2 alcohol; the mixing temperature is 25-80°C.
  • the temperature of the medium-stirring crystallization in step (2) is 5-25°C.
  • crystal form B The X-ray powder diffraction pattern of crystal form B (hereinafter referred to as crystal form B) of the compound of formula (I) of the present invention has characteristic peaks at the following diffraction angles 2 ⁇ : 6.7 ⁇ 0.2°, 7.4 ⁇ 0.2°, 9.3 ⁇ 0.2 °, 10.0 ⁇ 0.2°, 10.9 ⁇ 0.2°, 11.2 ⁇ 0.2°, 15.8 ⁇ 0.2°, 16.4 ⁇ 0.2°, 17.4 ⁇ 0.2°, 18.4 ⁇ 0.2°, 19.4 ⁇ 0.2°, 20.3 ⁇ 0.2° and 20.8 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the crystal form B of the present invention has the 2 ⁇ value, the interplanar spacing d value and the relative intensity data as shown in Table 2 below:
  • the differential scanning calorimetry (DSC) spectrum of the crystal form B of the present invention has an endothermic peak with a Peak value of 94.4°C.
  • Form B of the present invention has a DSC pattern as shown in Figure 5.
  • thermogravimetric analyzer (TGA) spectrum of the crystal form B of the present invention has a weight loss step.
  • crystal form B of the present invention has a TGA pattern as shown in Figure 6.
  • crystal form B of the present invention is an isopropyl alcohol solvate.
  • the crystal form B of the present invention has a micrograph as shown in Figure 8.
  • the crystal habit of crystal form B is columnar, the surface of the crystal habit is smooth, and the fluidity is good.
  • Another object of the present invention is to provide a method for preparing the crystal form B, which method includes the following steps:
  • the mass-to-volume ratio of the crude product to isopropyl alcohol in the above step (1) is 1:5-30, and its unit is g/ml; the mixing temperature is 25-80°C.
  • the temperature of the medium-stirring crystallization in step (2) is 5-25°C.
  • the present invention also relates to a pharmaceutical composition containing crystalline form A and/or crystalline form B of the compound of formula (I), the pharmaceutical composition comprising a therapeutically effective amount of crystalline form A and/or crystalline form B of the compound of formula (I), and One or more pharmaceutically acceptable carriers.
  • the present invention also relates to the use of crystal form A, crystal form B or their pharmaceutical compositions of the compound of formula (I) in the preparation of drugs for the treatment of novel coronavirus.
  • the two new crystal forms of crystal form A and crystal form B prepared by the preparation method of the present invention have good physical and chemical stability, regular crystal habits, good particle size uniformity and good fluidity, which can solve the problems of existing patented technologies. It has shortcomings such as cumbersome crystallization process, small particles, and uneven particles, but it has excellent properties in terms of processing adaptability. Moreover, the preparation method of the new crystal form can effectively remove difficult-to-remove impurities and obtain a sample with less impurities and high purity. It can also be used as an intermediate to make the crystallization process of the finished product simpler.
  • the crystallization process of the present invention is simple, easy to operate, has little pollution, and has the advantages of realizing industrial production.
  • Figure 1 is the X-ray powder diffraction pattern of the crystal form A obtained in Example 1.
  • Figure 2 is a DSC spectrum of crystal form A obtained in Example 1.
  • Figure 3 is a TGA spectrum of crystal form A obtained in Example 1.
  • Figure 4 is an X-ray powder diffraction pattern of the crystal form B obtained in Example 5.
  • Figure 5 is a DSC spectrum of crystal form B obtained in Example 5.
  • Figure 6 is a TGA spectrum of crystal form B obtained in Example 5.
  • Figure 7 is a micrograph of the crystal form A obtained in Example 1.
  • Figure 8 is a micrograph of the crystal form B obtained in Example 5.
  • Figure 9 is a micrograph of the crystal form 1 obtained in the preparation example.
  • Figure 10 is a micrograph of the crystal form 2 obtained in the preparation example.
  • Figure 11 is a micrograph of the crystal form 4 obtained in the preparation example.
  • Figure 12 is a micrograph of the crystal form 5 obtained in the preparation example.
  • the crude compound of formula (I) used in the method of the present invention can be used as the raw material for preparing crystal form A or B.
  • the crude compound of formula (I) can be obtained according to step 8, page 27 of Example 13, page 129 of patent WO2021250648A1.
  • OK prepare the eluent by vacuum concentration, including but not limited to the above sources.
  • the solvent used in the present invention is not particularly limited, and commercially available conventional solvents can be used.
  • the stirring method includes magnetic stirring and mechanical stirring, and the stirring speed is 150-300 rpm/min.
  • the X-ray powder diffraction instrument and test conditions involved in the present invention are: X-ray diffraction instrument model MiniFlex600Cu target; operating method: scanning speed 20°/min, scanning step width 0.02°.
  • the DSC test conditions involved in the present invention are: DSC detector model: NETZSCH DSC 214 Polyma; operating method: heating rate 10°C/min, temperature range: 30-250°C.
  • TGA test conditions involved in the present invention are: TGA detector model: METTLER TOLEDO TGA2; operating method: heating rate: 10°C/min, temperature range: 35-300°C.
  • the OLYMPUS microscope involved in the present invention is model CX31 (10 ⁇ 10).
  • the liquid phase test conditions involved in the present invention are: the chromatographic column is Agilent Zorbax SB-18, 150 ⁇ 4.6mm, 5 ⁇ m; mobile phase A: 0.1% phosphoric acid aqueous solution; mobile phase B: acetonitrile; detection wavelength: 205nm; flow rate: 1.0ml /min; injection volume: 5 ⁇ l; column temperature: 80°C. elution gradient
  • crystal form 2 According to Example 13 disclosed in patent WO2021250648A, step 8 on page 129, line 28, crystal form 2 was prepared using ethyl acetate and methyl tert-butyl ether.
  • step 1 to step 2 were prepared to obtain crystal form 4.
  • Crystal form 5 According to page 257, Example 96 disclosed in patent WO2021250648A, crystal form 5 was prepared by concentrating with dichloromethane.
  • the crystal particles of Form A are uniform, uniform in size, almost round, with a small specific surface area, small friction between crystals, and good fluidity of the particles.
  • the particles of crystal form B are uniform, uniform in size, massive, with a small aspect ratio, a smooth crystal surface, and good particle fluidity.
  • Crystal form 1 is needle-shaped, has a large length-to-width ratio, and has poor fluidity.
  • Crystal form 2 is cone-shaped with a large aspect ratio and poor fluidity.
  • Crystal form 4 has uniform particle size, but the particle size is small, easy to agglomerate, difficult to filter, high residual mother liquor, and difficult to bake.
  • the particles of crystal form 5 are uneven, have poor fluidity, and the particles are relatively brittle, which is not conducive to subsequent processing. Therefore, the crystal habits of crystal form A and crystal form B are better, the particles are more uniform, and they are easy to store and transport as well as subsequent processing.

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  • Proteomics, Peptides & Aminoacids (AREA)
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Abstract

本发明涉及式(I)化合物(HS378)的晶型A和B及它们的制备方法。所述晶型A及晶型B物理化学稳定良好、晶习规则、粒度均一性好、流动性良好，所述晶型A及晶型B的制备方法简单，且除杂效果较好，容易过滤，收率高，可获得杂质少，纯度高的样品，很好的解决了难除杂质的纯化问题。

Description

HS378晶型及其制备方法 技术领域
本发明涉及化学制药领域。更具体地说，本发明涉及(1R,2S,5S)-N-{(1S)-1-氰基-2-[(3S)-2-氧代吡咯烷-3-基]-乙基}-6,6-二甲基-3-[3-甲基-N-(三氟乙酰基)-L-缬氨酰]-3-氮杂双环[3.1.0]己烷-2-甲酰胺(HS378)的晶型A和B以及所述晶型的制备方法及它们的医药用途。
技术背景
2019年全球冠状病毒病爆发，新冠肺炎已成为全球疫情。新型冠状病毒是一种高度传染性的核糖核酸冠状病毒，在最严重的情况下会导致威胁生命的病毒性肺炎。与疫苗一样，抗病毒疗法也是应对新冠肺炎的医疗对策的重要组成部分。HS378是一种口服生物可利用的SARSCoV-2主要蛋白酶抑制剂，具有体外冠状病毒抗病毒活性和优异的靶外选择性和体内安全性。在小鼠适应的新型冠状病毒模型中证明了口服活性，并在健康人体参与者的一期临床试验中实现了超过体外抗病毒细胞效力的口服血浆浓度。
式(I)化合物的化学名为(1R,2S,5S)-N-{(1S)-1-氰基-2-[(3S)-2-氧代吡咯烷-3-基]-乙基}-6,6-二甲基-3-[3-甲基-N-(三氟乙酰基)-L-缬氨酰]-3-氮杂双环[3.1.0]己烷-2-甲酰胺(本申请中将其命名为HS378)，其结构式如下所示:
目前，辉瑞公司的专利WO2021250648A公开了HS378晶型1、晶型2、晶型4、晶型5。晶型2为甲基叔丁基醚溶剂化物，晶型5为无定形。晶型1、晶型4与晶型5的制备均以晶型2作为底物，工艺过程中存在两个难以除去的杂质，这两个杂质的相对保留时间 RRT＝0.96、RRT＝1.04，晶型1、2、4、5的结晶工艺均不能有效去除，因此有必要开发新的晶型及其新工艺。
发明内容
因此，针对上述现有技术中存在的问题，本发明提供了HS378晶型A和晶型B，它们的结晶方法具有较优除杂效果。
本发明所述的HS378的晶型A(以下称为晶型A)的X-射线粉末衍射图谱在以下衍射角2θ处具有特征峰:6.2±0.2°、6.9±0.2°、7.9±0.2°、10.5±0.2°、11.5±0.2°、11.9±0.2°、12.5±0.2°、13.9±0.2°、14.3±0.2°、15.8±0.2°、18.7±0.2°、19.4±0.2°、20.7±0.2°和23.3±0.2°。
更进一步地，本发明的晶型A的X-射线粉末衍射图谱具有如下表1所示的2θ值、晶面间距d值和相对强度数据:
表1

非限制性地，本发明的晶型A的X-射线粉末衍射图谱基本上如图1所示。
本发明所述晶型A的差示扫描量热(DSC)图谱存在一个吸热峰Peak值为105.2℃。
非限制性地，本发明的晶型A具有如图2所示的DSC图谱。
本发明所述晶型A的热重分析仪(TGA)图谱存在失重。
非限制性地，本发明的晶型A具有如图3所示的TGA图谱。
结合DSC及TGA数据，表明本发明的晶型A为乙酸异丁酯溶剂化物。
非限制性地，本发明的晶型A具有如图7所示的显微镜照片，晶体晶习为块状，接近于球形，颗粒间摩擦力小，流动性良好。
本发明的另一目的还在于提供制备所述晶型A的方法，该方法包括以下步骤:
(1)将式(I)化合物粗品与醇和乙酸异丁酯的混合溶剂混合；
(2)搅拌结晶1-24h；
(3)过滤，得晶型A。
优选地，其中，上述步骤(1)中式(I)化合物粗品与混合溶剂的质量体积比为1:5～40，其单位为g/ml；所述醇和乙酸异丁酯的体积比(ml/ml)为1:7-1:100；所述醇为C1-C2醇；所述混合的温度为25-80℃。
优选地，步骤(2)中的中搅拌结晶的温度为5-25℃。
本发明的式(I)化合物的晶型B(以下称为晶型B)的X-射线粉末衍射图谱在以下衍射角2θ处具有特征峰:6.7±0.2°、7.4±0.2°、9.3±0.2°、10.0±0.2°、10.9±0.2°、11.2±0.2°、15.8±0.2°、16.4±0.2°、17.4±0.2°、18.4±0.2°、19.4±0.2°、20.3±0.2°和20.8±0.2°。
更进一步地，本发明的晶型B的X-射线粉末衍射图谱具有如下表2所示的2θ值、晶面间距d值和相对强度数据:
表2
非限制性地，本发明的晶型B的X-射线粉末衍射图谱基本上如图4所示。
本发明所述晶型B的差示扫描量热(DSC)图谱存在一个吸热峰Peak值为94.4℃。
非限制性地，本发明的晶型B具有如图5所示的DSC图谱。
本发明所述晶型B的热重分析仪(TGA)图谱存在失重台阶。
非限制性地，本发明的晶型B具有如图6所示的TGA图谱。
结合DSC及TGA数据，表明本发明的晶型B为异丙醇溶剂化物。
非限制性地，本发明的晶型B具有如图8所示的显微镜照片，晶型B晶习为柱状，晶习表面光滑，流动性良好。
本发明的另一目的还在于提供制备所述晶型B的方法，该方法包括以下步骤:
(1)将式(I)化合物粗品与异丙醇混合；
(2)搅拌结晶1-24h；
(3)过滤，得晶型B。
优选地，其中，上述步骤(1)中中粗品与异丙醇的质量体积比为1:5～30，其单位为g/ml；所述混合的温度为25-80℃。
优选地，步骤(2)中的中搅拌结晶的温度为5-25℃。
本发明还涉及含式(I)化合物晶型A和/或晶型B的药物组合物，所述药物组合物包含治疗有效量的式(I)化合物晶型A和/或晶型B，以及一种或多种药学上可接受的载体。
本发明还涉及式(I)化合物晶型A、晶型B或它们的药物组合物在制备用于治疗新型冠状病毒的药物中的用途。
采用本发明的制备方法制备得到的晶型A和晶型B两种新晶型，物理化学稳定良好、晶习规则、粒度均一性好，流动性好，很好的解决了现有专利技术中结晶过程繁琐、颗粒小、颗粒不均匀等不足，在加工适应性方面均具有优异的性质。且新晶型的制备方法可有效去除难除杂质，获得杂质少，纯度高的样品，也可作为中间体，使成品的结晶工艺更简单。本发明的结晶工艺简单、便于操作、污染小、具有可实现工业化生产的优点。
附图说明：
图1为实施例1所得的晶型A的X-射线粉末衍射图谱。
图2为实施例1所得的晶型A的DSC图谱。
图3为实施例1所得的晶型A的TGA图谱。
图4为实施例5所得的晶型B的X-射线粉末衍射图谱。
图5为实施例5所得的晶型B的DSC图谱。
图6为实施例5所得的晶型B的TGA图谱。
图7为实施例1所得的晶型A的显微镜照片。
图8为实施例5所得的晶型B的显微镜照片。
图9为制备例所得的晶型1的显微镜照片。
图10为制备例所得的晶型2的显微镜照片。
图11为制备例所得的晶型4的显微镜照片。
图12为制备例所得的晶型5的显微镜照片。
具体实施例
下列实施例是为了进一步解释说明本发明，而不是构成对本发明范围的限制或限定。
本发明方法中所使用的作为制备晶型A或B的原料可使用式(I)化合物粗品，式(I)化合物粗品可按照专利WO2021250648A1公开的实施例13，第129页的步骤8，第27行，将洗脱液真空浓缩制备，包括但不限于上述来源。
本发明所使用的溶剂没有特别的限制，可采用商购的常规溶剂。
除非另有说明，本发明方法中所述的“搅拌”可以采用本领域的常规方法，例如搅拌方式包括磁力搅拌、机械搅拌，搅拌速度为150-300rpm/min。
本发明所涉及的X-射线粉末衍射仪器及测试条件为:X-衍射仪器型号MiniFlex600Cu靶；操作方法:扫描速度20°/min，扫描步宽0.02°。
本发明涉及的DSC测试条件为:DSC检测仪型号为:NETZSCH DSC 214Polyma；；操作方法:升温速率10℃/min，温度范围:30-250℃。
本发明涉及的TGA测试条件为:TGA检测仪型号为:METTLER TOLEDO TGA2；操作方法:升温速率10℃/min，温度范围:35-300℃。
本发明涉及的OLYMPUS显微镜，型号为CX31(10×10)。
本发明涉及的液相测试条件为：色谱柱为Agilent Zorbax SB-18，150×4.6mm，5μm；流动相A：0.1％磷酸水溶液；流动相B：乙腈；检测波长：205nm；流速：1.0ml/min；进样量：5μl；柱温：80℃。洗脱梯度

应当强调的是，本发明技术方案中所涉及的数值或数值端点，其含义或意欲的保护范围并不局限于该数字本身，本领域技术人员能够理解，它们包含了那些已被本领域广为接受的可允许误差范围，例如实验误差、测量误差、统计误差和随机误差等等，而这些误差范围均包含在本发明的范围之内。
实施例1
将粗品1g加入0.3ml甲醇和10ml乙酸异丁酯中混合混匀，升温至40℃，缓慢降温至25℃，搅拌结晶2h，过滤，得0.87g晶体，纯度为99.86％，经测X-射线粉末衍射图谱(XRD)，确认为晶型A。
该晶型的X-射线粉末衍射、DSC以及TGA谱图分别如图1-3所示，显微镜照片如图7所示，在本发明中将其命名为晶型A。
实施例2
将粗品1g加入0.1ml乙醇和10ml乙酸异丁酯中混合混匀，升温至80℃，缓慢降温至15℃，搅拌结晶1h，过滤，得0.89g晶体，纯度为99.78％，经测X-射线粉末衍射图谱(XRD)，确认为晶型A。
实施例3
将粗品1g加入0.2ml甲醇和4.8ml乙酸异丁酯中混合混匀，溶解至25℃，缓慢降温至5℃，搅拌结晶24h，过滤，得0.85g晶体，纯度为99.91％，经测X-射线粉末衍射图谱(XRD)，确认为晶型A。
实施例4
将粗品1g加入5ml甲醇和35ml乙酸异丁酯中混合混匀，溶解至25℃，缓慢降温至5℃，搅拌结晶2h，过滤，得0.80g晶体，纯度为100％，经测X-射线粉末衍射图谱(XRD)，确认为晶型A。
实施例5
将粗品1g加入5ml异丙醇中混合混匀，升温至80℃，缓慢降温至25℃，搅拌结晶3h，过滤，得0.87g晶体，纯度为99.57％，经测X-射线粉末衍射图谱(XRD)，确认为晶型B。
该晶型的X-射线粉末衍射、DSC以及TGA谱图分别如图4-6所示，显微镜照片如图8所示，在本发明中将其命名为晶型B。
实施例6
将粗品1g加入20ml异丙醇中混合混匀，升温至35℃，缓慢降温至15℃，搅拌结晶1h，过滤，得0.84g晶体，纯度为99.73％，经测X-射线粉末衍射图谱(XRD)，确认为晶型B。
实施例7
将粗品1g加入30ml异丙醇中混合混匀,溶解于25℃，缓慢降温至5℃，搅拌结晶24h，过滤，得0.82g晶体，纯度为99.91％，经测X-射线粉末衍射图谱(XRD)，确认为晶型B。制备例：
晶型1的制备：依照专利WO2021250648A公开的第135页，步骤2制备获得晶型1。
晶型2的制备：依照专利WO2021250648A公开的实施例13，第129页的步骤8，第28行，用乙酸乙酯与甲基叔丁基醚制备获得晶型2。
晶型4的制备：依照专利WO2021250648A公开的第151-152页，步骤1-步骤2制备获得晶型4。
晶型5的制备：依照专利WO2021250648A公开的第257页，实施例96，用二氯甲烷浓缩制备获得晶型5。
对比例1
本发明的实施例1所得晶型A、实施例5所得晶型B及制备例得到的晶型1、2、4、5的样品、粗品，进行HPLC检测，结果见表1。
表1

由表1可知，晶型A及晶型B的制备方法，对难除杂质的去除效果优于晶型1、2、4、5。
对比例2
本发明的实施例1所得晶型A、实施例5所得晶型B及制备例得到的晶型1、2、4、5的样品，置于60℃，分别放置5天、10天，分别进行HPLC及XRD检测，结果见表2。
表2
由表2可知，晶型A、晶型B及晶型I在60℃放置10天，晶型及液相HPLC数据稳 定较晶型2、晶型4、晶型5稳定。
对比例3
本发明的实施例1所得晶型A、实施例5所得晶型B及制备例得到的晶型1、2、4、5的样品的显微镜照片分别如图7-12所示。
晶型A晶体颗粒均匀，大小均一，为类圆形，比表面积小，晶体间摩擦力小，颗粒的流动性较好。晶型B颗粒均匀，大小均一，为块状，长宽比小，晶体表面光滑，颗粒流动性好。晶型1为针状，长宽比较大，流动性较差。晶型2为锥状，长宽比大，流动性差。晶型4粒度均一，但颗粒度较小，容易聚团，不易过滤，母液残留高，不易烘料。晶型5颗粒不均一，流动性差，且颗粒脆性较大，不利于后续加工处理。所以晶型A及晶型B的晶习较优，颗粒较均匀，易于存储和运输以及后续加工处理。

Claims (12)

  1. 一种式(I)化合物的晶型A，其特征在于，其X-射线粉末衍射图谱在以下衍射角2θ处具有特征峰:6.2±0.2°、6.9±0.2°、7.9±0.2°、10.5±0.2°、11.5±0.2°、11.9±0.2°、12.5±0.2°、13.9±0.2°、14.3±0.2°、15.8±0.2°、18.7±0.2°、19.4±0.2°、20.7±0.2°和23.3±0.2°
  2. 根据权利要求1所述的晶型A，其特征在于，其X-射线粉末衍射图谱基本上如图1所示。
  3. 一种制备权利要求1～2任一项所述的晶型A的方法，该方法包括以下步骤:
    (1)将式(I)化合物粗品与醇和乙酸异丁酯的混合溶剂混合；
    (2)缓慢降温，搅拌结晶1-24h；
    (3)过滤，得晶型A。
  4. 根据权利要求3所述的方法，其特征在于，所述步骤(1)中式(I)化合物粗品与混合溶剂的质量体积比为1:5～40，其单位为g/ml；所述醇和乙酸异丁酯的体积比(ml/ml)为1:7-1:100；所述醇为C1-C2醇；所述混合的温度为25-80℃。
  5. 根据权利要求3所述的方法，其中所述步骤(2)中搅拌结晶的温度为5-25℃。
  6. 一种式(I)化合物的晶型B，其特征在于，其X-射线粉末衍射图谱在以下衍射角2θ处具有特征峰:6.7±0.2°、7.4±0.2°、9.3±0.2°、10.0±0.2°、10.9±0.2°、11.2±0.2°、15.8±0.2°、16.4±0.2°、17.4±0.2°、18.4±0.2°、19.4±0.2°、20.3±0.2°和20.8±0.2°

  7. 根据权利要求6所述的晶型B，其特征在于，其X-射线粉末衍射图谱基本上如图2所示。
  8. 一种制备权利要求6～7任一项所述的晶型B的方法，该方法包括以下步骤:
    (1)将式(I)化合物粗品与异丙醇混合；
    (2)搅拌结晶1-24h；
    (3)过滤，得晶型B。
  9. 根据权利要求8所述的方法，其特征在于，所述步骤(1)中粗品与异丙醇的质量体积比为1:5～30，其单位为g/ml；所述混合的温度为25-80℃。
  10. 根据权利要求8所述的方法，其中所述步骤(2)中搅拌结晶的温度为5-25℃。
  11. 一种药物组合物，其含有权利要求1-2任何一项所述的式(I)化合物晶型A和/或权利要求6-7任何一项所述的式(I)化合物晶型B。
  12. 根据权利要求1-2任何一项所述的式(I)化合物晶型A、权利要求6-7任何一项所述的式(I)化合物晶型B或权利要求11所述的药物组合物在制备用于治疗新型冠状病毒的药物中的用途。
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