WO2018054270A1 - Novel velpatasvir crystal and preparation method therefor - Google Patents

Novel velpatasvir crystal and preparation method therefor Download PDF

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WO2018054270A1
WO2018054270A1 PCT/CN2017/102062 CN2017102062W WO2018054270A1 WO 2018054270 A1 WO2018054270 A1 WO 2018054270A1 CN 2017102062 W CN2017102062 W CN 2017102062W WO 2018054270 A1 WO2018054270 A1 WO 2018054270A1
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compound
formula
crystal
saccharin
voratavivir
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PCT/CN2017/102062
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French (fr)
Chinese (zh)
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李巍
任毅
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上海众强药业有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • 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 medicinal chemistry, in particular to a new crystalline form of voratavivir, in particular to a eutectic compound of voratavivir and saccharin.
  • Vepatasvir (VLP, Formula II) is a hepatitis C treatment developed by Gilead and was approved by the FDA in June 2016. The EMA also approved the drug in July 2016. In combination with Sofosbuvir (SOF), this combination therapy can cure all known genotypes (1-6) of HCV patients in as little as 8 weeks without the need to inject interferon or ribavivir Ribavirin.
  • the compound of formula I is crystalline or amorphous.
  • the purity of the compound of formula I is ⁇ 99.0% (peak area normalization), preferably ⁇ 99.2% (peak area normalization), more preferably ⁇ 99.5, as determined by HPLC. % (peak area normalization method).
  • the molar ratio of the compound of formula II to saccharin is from 1:1.5 to 1:2.5, preferably from 1:1.8 to 1:2.2.
  • the method further comprises the step (2): subjecting the compound of the formula I obtained in the step (1) to a crystallization treatment in an inert solvent to obtain a crystal of the compound of the formula I, wherein the inert solvent Selected from the group consisting of ethanol, isopropanol, acetone, acetonitrile, tetrahydrofuran, ethyl acetate, isopropyl acetate, toluene, methyl tert-butyl ether, water, or a combination thereof.
  • the inert solvent selected from the group consisting of ethanol, isopropanol, acetone, acetonitrile, tetrahydrofuran, ethyl acetate, isopropyl acetate, toluene, methyl tert-butyl ether, water, or a combination thereof.
  • a crystalline form of a compound of formula I according to the first aspect of the invention said crystal form being crystalline form A, said X-ray powder diffraction pattern of said Form A comprising 3 or 3 More than 2 values of 2 ⁇ selected from the group consisting of: 3.5° ⁇ 0.2°, 5.3° ⁇ 0.2°, 5.8° ⁇ 0.2°, 7.2° ⁇ 0.2°, 10.7° ⁇ 0.2° or 16.3° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form A may further comprise 3 or more 2 ⁇ values selected from the group consisting of: 3.5° ⁇ 0.2°, 5.3° ⁇ 0.2°, 5.8° ⁇ 0.2°, 7.2° ⁇ 0.2°, 10.7° ⁇ 0.2°, 11.1 ° ⁇ 0.2 °, 11.7 ° ⁇ 0.2 ° or 16.3 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form A may further comprise 3 or more 2 ⁇ values selected from the group consisting of: 3.5° ⁇ 0.2°, 5.3° ⁇ 0.2°, 5.8° ⁇ 0.2°, 7.2° ⁇ 0.2°, 8.0 ⁇ 0.2°, 9.57 ⁇ 0.2°, 10.7° ⁇ 0.2°, 11.1° ⁇ 0.2°, 11.7° ⁇ 0.2° or 16.3° ⁇ 0.2°.
  • the crystalline form A has one or more characteristics selected from the group consisting of:
  • thermogravimetric analysis pattern of the crystal form A is substantially characterized as shown in FIG.
  • a fourth aspect of the invention there is provided a method of preparing a crystalline form A according to the third aspect of the invention, comprising the steps of:
  • step (b) subjecting the compound of the formula I produced in the step (a) to a crystallization treatment to form the crystal form A.
  • the compound of the formula II in the step (a), is an amorphous substance.
  • the resulting compound of formula I is amorphous.
  • the step (b) comprises the step (b-1): seeding is added, and the compound of the formula I produced in the step (a) is subjected to a crystallization treatment to form the crystal form A.
  • the seed crystal is the crystal form A according to the third aspect of the invention.
  • the step (b) comprises: optionally, crystallization treatment of the compound of the formula I produced in the step (a) in an inert solvent to form the crystalline form A, the inert solvent Selected from the following group: ethanol, Isopropanol, acetone, acetonitrile, tetrahydrofuran, ethyl acetate, isopropyl acetate, toluene, methyl tert-butyl ether, water, or a combination thereof.
  • the inert solvent selected from the following group: ethanol, Isopropanol, acetone, acetonitrile, tetrahydrofuran, ethyl acetate, isopropyl acetate, toluene, methyl tert-butyl ether, water, or a combination thereof.
  • the reaction temperature is 0 to 50 ° C, preferably 4 to 35 ° C, more preferably 10 to 25 ° C.
  • the reaction time is from 0.1 to 24 hours, preferably from 0.2 to 12 hours, more preferably from 0.5 to 3 hours.
  • Figure 1 shows an X-ray powder diffraction pattern (XRPD) of Form A of the compound of Formula I.
  • FIG. 1 shows a differential scanning calorimetry spectrum (DSC) of Form A of the compound of Formula I.
  • FIG. 3 shows the thermogravimetric analysis spectrum (TGA) of Form A of the compound of Formula I.
  • Figure 4 shows the hygroscopic curve and desorption curve of the crystalline form A of the compound of the formula I, the amorphous hygroscopic curve of the compound of the vipatavir II compound, the amorphous desorption curve of the compound of the vipavivir II compound, and the disipide diphosphate of the compound of the vapitavir II.
  • the inventors conducted extensive and intensive research to carry out a large number of optimization studies on the preparation process of voratavivir, and for the first time unexpectedly obtained a eutectic compound which is particularly suitable for the production of voratavivir and saccharin, and
  • the eutectic compound is preferably Form A.
  • the crystalline form A of the compound of the formula I of the present invention is easy to prepare, has good physical and chemical properties, is structurally stable, has excellent stability (light and high temperature and high humidity) and hygroscopicity, and contributes to reduction of impurities, thereby improving ivapar Wei's purity and quality are particularly suitable for the development and production of high quality vertapavir formulations.
  • the inventors have completed the present invention on this basis.
  • the term "about” means that the value can be recited The value of the change is no more than 1%.
  • the expression “about 100” includes all values between 99 and 101 and (eg, 99.1, 99.2, 99.3, 99.4, etc.).
  • the terms "containing” or “including” may be open, semi-closed, and closed. In other words, the terms also include “consisting essentially of,” or “consisting of.”
  • n or n or more selected from the group of 2 refers to any positive integer (eg, n, n+1, . . . ) comprising n and greater than n, wherein the upper limit Nup is all in the group The number of 2 ⁇ peaks.
  • “3 or more” includes not only 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, ...
  • the upper limit Nup is a positive integer, and includes a range of "4 or more", “5 or more", “6 or more”, and the like.
  • XRPD X-ray powder diffraction
  • X-ray powder diffraction pattern was determined under the following conditions: Cu-Ka,
  • compound of the invention refers to a compound of formula I, including amorphous, crystalline forms or mixtures thereof.
  • crystal of the invention As used herein, “crystal of the invention”, “crystal form of the invention”, “crystal form of the compound of formula I of the invention”, “crystal form of the compound of formula I", “vepacavir and saccharin” Crystalline Form A”, “Form A”, “Calclic Form A” are used interchangeably and refer to Form A of the compound of Formula I.
  • compound of formula II and “compound of formulae II” are used interchangeably and refer to a compound having the structure of formula II below, including primarily amorphous.
  • production-scale crystallization can be accomplished by operating the solution to achieve supersaturation of the compound of interest. This can be accomplished by a variety of methods, for example, dissolving the compound at relatively high temperatures and then cooling the solution below saturation solubility. Alternatively, the volume of liquid can be reduced by boiling, atmospheric evaporation, vacuum drying, or by other methods. The solubility of the compound of interest can be reduced by the addition of an anti-solvent. Another alternative is to adjust the pH to reduce solubility. A detailed description of crystallization can be found in Crystallization, Third Edition, J W Mullens, Butterworth-Heineman Ltd., 1993, ISBN 0750611294.
  • optimization of crystallization can include seeding the crystal in a desired form with the crystal as a seed.
  • many crystallization methods use a combination of the above strategies.
  • One embodiment is to dissolve the compound of interest in a solvent at elevated temperatures, followed by controlled addition of an appropriate volume of anti-solvent to bring the system just below the level of saturation. At this point, seed crystals of the desired form can be added (and the integrity of the seed crystals maintained) and the system cooled to complete crystallization.
  • the drug eutectic is formed by the combination of a non-covalent bond and a eutectic formation in a crystal lattice. At least one of the drug eutectic components is a molecular or ionic drug, and all components are solid at room temperature. It is a new drug solid form that can improve the physical and chemical properties of drugs, such as improving solubility, increasing stability, and improving bioavailability.
  • the compound of the formula I according to the present invention (including a crystalline form or an amorphous form) is structurally stable, and the preparation method thereof is simple and rapid, and is convenient for large-scale production.
  • the compound of the formula I according to the invention has a particularly low solubility in certain solvents (e.g. methyl tert-butyl ether, ethyl acetate, etc.), so that precipitation or crystallization is formed in a short time, thus purification and separation Very convenient and fast.
  • solvents e.g. methyl tert-butyl ether, ethyl acetate, etc.
  • the crystalline form A of the compound of the formula I according to the invention has a very high purity (e.g. ⁇ 99%), contributes to the reduction of impurities, and is particularly suitable for the production of high quality vertapavir.
  • the crystalline form A of the compound of the formula I according to the invention has excellent stability (light and high temperature and high humidity) and hygroscopicity, and is particularly suitable for the development and production of high quality voratavivir preparations.
  • Normal temperature or room temperature means 4 ° C to 30 ° C, preferably 15 to 25 ° C.
  • XRPD Bruker D8 Advance X-ray powder diffractometer, Cu target, Ka wavelength, tube voltage 40 KV, tube current 40 mA. Scanning range: 3-40° 2-Theta; Stepping: 0.02°; Scanning speed: 1 step / 0.1 second.
  • DSC TA Q2000 Differential Scanning Calorimeter; temperature range: 40-200 ° C; heating rate: 10 ° C / min.
  • TGA NETZSCH TG 209F3 thermogravimetric analyzer; temperature range: 30-400 ° C; heating rate: 10 ° C / min.
  • the supernatant was centrifuged and removed, and dried in an oven at 60 ° C for 12 hours to obtain a yellow solid which was determined to be an amorphous material of the compound of formula I by a polarizing microscope.
  • the centrifuge tube was placed in a centrifuge (Eppendorf minispin) and centrifuged at 12,000 rpm for 5 minutes, the supernatant was removed, and the separated solid was dried at room temperature for 1 hour to obtain a eutectic crystal form A of voratavivir and saccharin. .
  • Example 2 The crystal form A obtained in Example 2 was subjected to XRD, DSC, TGA, HPLC and the like.
  • the XRD pattern of the crystalline form A of the compound of the formula I in Example 2 of the present invention is shown in Fig. 1, wherein the main diffraction peaks and relative intensities of the crystalline form A are shown in Table 1.
  • FIG. 2 A DSC chart of Form A of the compound of Formula I of Example 2 is shown in FIG. As can be seen from Fig. 2, between 45 and 200 ° C, the heat flow curve of Form A contains a melting endothermic peak: the starting temperature and the peak temperature are 165.8 ° C and 174.1 ° C, respectively.
  • thermogravimetric curve of Form A has a slow weight loss of 3.52% due to the slow evaporation of residual solvent. After 200 ° C, the compound began to decompose, causing further weight loss.
  • HPLC crude purity of 96% of the vitamins of the compound of Verapitavir II was crystallized to the form A after the method described in Example 2, and the HPLC purity was greatly improved to 98.6%.
  • the HPLC purity of the obtained crystal form A can be further improved. 99.4%.
  • Example 2 crystallizes the amorphous crude product of the voratavivir compound II into the crystalline form A, which can efficiently remove impurities in the voratavivir and significantly improve the purity of the product.
  • the centrifuge tube was placed in a centrifuge (Eppendorf minispin) and centrifuged at 12,000 rpm for 5 minutes. The supernatant was removed, and the separated solid was dried at room temperature for 1 hour, and confirmed to be co-crystal of voratavivir and saccharin by XRPD. Form A.
  • the amorphous compound of formula I (purity 99%) and the different eutectic ligands listed in Table 2 were weighed into a 1.5 ml centrifuge tube according to the molar ratio shown in Table 2, and a suitable solvent was added to form a clear solution, and then according to the table.
  • the crystallization method shown in 2 was carried out and it was judged by a polarizing microscope whether or not a crystalline solid was formed.
  • eutectic crystal form A of voratavivir and saccharin eutectic crystal form A of voratavivir and saccharin
  • voratavivir bisphosphonate eutectic crystal form A of voratavivir and saccharin
  • voratavivir dihydrochloride eutectic crystal form A of voratavivir and saccharin
  • voratavivir dihydrochloride eutectic crystal form A of voratavivir and saccharin
  • voratavivir dihydrochloride voratavivir dihydrobromide
  • vertapavir II compound eutectic crystal form A of voratavivir and saccharin
  • voratavivir bisphosphonate eutectic crystal form A of voratavivir and saccharin
  • voratavivir dihydrochloride eutectic crystal form A of voratavivir dihydrochloride
  • voratavivir dihydrobromide vertapavir II compound
  • the photostability of eutectic crystal form A of vipavir and saccharin is significantly better than that of vapapavir II compound, vertapavir bisphosphate, voratavivir dihydrochloride and voratavivir dihydrogen. Bromate.
  • eutectic crystal form A of voratavivir and saccharin eutectic crystal form A of voratavivir and saccharin
  • voratavivir bisphosphonate eutectic crystal form A of voratavivir and saccharin
  • voratavivir dihydrochloride eutectic crystal form A of voratavivir and saccharin
  • voratavivir dihydrochloride eutectic crystal form A of voratavivir and saccharin
  • voratavivir bisphosphonate voratavivir dihydrochloride
  • voratavivir dihydrobromide vertapavir II compound
  • eutectic crystal form A of voratavivir and saccharin is significantly better than that of vapapavir II compound, vertapavir bisphosphate, vertapavir dihydrochloride and vertapavir dihydrobromide. Acid salt.
  • Hygroscopicity is one of the key physicochemical properties of drugs, and has a significant impact on drug stability, powder properties and subsequent processing.
  • the hygroscopicity results of Form A are shown in Figure 4 and Table 5, while comparing the amorphous form of the voratavivir II compound, vorapavivir bisphosphonate (Form XIV, see patent US20150361085A1) and voratavivir.
  • the hygroscopicity of the dihydrochloride salt (Form VI, see patent US20150361085A1).

Abstract

Provided in the present invention are a novel velpatasvir crystal and a preparation method therefor. The structure of formula (I) compound of the present invention is a represented below. Crystal A of formula (I) compound produced per the preparation method provided in the present invention has great purification effects and physical and chemical properties.

Description

一种维帕他韦新晶型及其制备方法Novel vertapavir form and preparation method thereof 技术领域Technical field
本发明涉及药物化学领域，尤其涉及一种维帕他韦新晶型，具体地涉及一种维帕他韦与糖精的共晶化合物。The invention relates to the field of medicinal chemistry, in particular to a new crystalline form of voratavivir, in particular to a eutectic compound of voratavivir and saccharin.
背景技术Background technique
维帕他韦(Velpatasvir，VLP，式II)是Gilead开发的丙肝治疗药物，已于2016年6月被FDA批准上市，EMA也已于2016年7月批准该药。通过和索非布韦(Sofosbuvir，SOF)联用，该组合疗法可以在短至8周的时间里治愈所有已知基因型(1-6)HCV患者，同时无需注射干扰素或联合利巴韦林(Ribavirin)。Vepatasvir (VLP, Formula II) is a hepatitis C treatment developed by Gilead and was approved by the FDA in June 2016. The EMA also approved the drug in July 2016. In combination with Sofosbuvir (SOF), this combination therapy can cure all known genotypes (1-6) of HCV patients in as little as 8 weeks without the need to inject interferon or ribavivir Ribavirin.
Figure PCTCN2017102062-appb-000001
Figure PCTCN2017102062-appb-000001
由于分子结构的特点，维帕他韦的结晶性较差。目前，Gilead公司的专利US20150361085A1申请保护了维帕他韦的通道溶剂化物、盐酸盐、磷酸盐、氢溴酸盐、和酒石酸盐。但是这些晶型的稳定性、纯化效果、吸湿性和工艺稳定性不够完善，不能很好地满足实际应用需求。Due to the characteristics of the molecular structure, the crystallinity of vertapavir is poor. Currently, Gilead's patent US20150361085A1 claims to protect the channel solvates, hydrochlorides, phosphates, hydrobromides, and tartrates of voratavivir. However, the stability, purification effect, hygroscopicity and process stability of these crystal forms are not perfect enough to meet the practical application requirements.
因此，本领域急需开发一种新的维帕他韦晶型，以进一步改善维帕他韦的结晶性、稳定性、吸湿性和工艺稳定性，从而推进其生产和应用。Therefore, there is an urgent need in the art to develop a new crystalline form of voratavivir to further improve the crystallinity, stability, hygroscopicity and process stability of voratavivir, thereby promoting its production and application.
发明内容Summary of the invention
本发明的目的在于提供一种新的维帕他韦和糖精的共晶，以进一步改善维帕他韦的结晶性、稳定性和理化性质，从而推进其生产和应用。It is an object of the present invention to provide a novel co-crystal of voratavivir and saccharin to further improve the crystallinity, stability and physicochemical properties of voratavivir, thereby promoting its production and application.
本发明第一方面，提供一种式I所示化合物，所述化合物由维帕他韦与糖精形成， In a first aspect of the invention, there is provided a compound of formula I, which is formed from versavir and saccharin,
Figure PCTCN2017102062-appb-000002
Figure PCTCN2017102062-appb-000002
在另一优选例中，所述式I化合物为晶型或无定形物。In another preferred embodiment, the compound of formula I is crystalline or amorphous.
在另一优选例中，采用HPLC测定，所述式I化合物的纯度≥99.0％(峰面积归一化法)，较佳地≥99.2％(峰面积归一化法)，更佳地≥99.5％(峰面积归一化法)。In another preferred embodiment, the purity of the compound of formula I is ≥99.0% (peak area normalization), preferably ≥99.2% (peak area normalization), more preferably ≥99.5, as determined by HPLC. % (peak area normalization method).
本发明第二方面，提供一种制备如本发明第一方面所述的式I化合物的方法，包括步骤：According to a second aspect of the invention, there is provided a method of preparing a compound of formula I according to the first aspect of the invention, comprising the steps of:
(1)将式II化合物与糖精反应，生成式I化合物：(1) reacting a compound of formula II with saccharin to form a compound of formula I:
Figure PCTCN2017102062-appb-000003
Figure PCTCN2017102062-appb-000003
在另一优选例中，所述式II化合物与糖精的摩尔比为1:1.5-1:2.5，较佳地为1：1.8-1：2.2。In another preferred embodiment, the molar ratio of the compound of formula II to saccharin is from 1:1.5 to 1:2.5, preferably from 1:1.8 to 1:2.2.
在另一优选例中，所述方法还包括步骤(2)：在惰性溶剂中，对步骤(1)得到的式I化合物进行析晶处理，得到式I化合物的晶体，其中，所述惰性溶剂选自下组：乙醇、异丙醇、丙酮、乙腈、四氢呋喃、乙酸乙酯、乙酸异丙酯、甲苯、甲基叔丁基醚、水、或其组合。In another preferred embodiment, the method further comprises the step (2): subjecting the compound of the formula I obtained in the step (1) to a crystallization treatment in an inert solvent to obtain a crystal of the compound of the formula I, wherein the inert solvent Selected from the group consisting of ethanol, isopropanol, acetone, acetonitrile, tetrahydrofuran, ethyl acetate, isopropyl acetate, toluene, methyl tert-butyl ether, water, or a combination thereof.
本发明第三方面，提供一种如本发明第一方面所述的式I化合物的晶型，所述晶型为晶型A，所述晶型A的X射线粉末衍射图谱包括3个或3个以上选自下组的2θ值：3.5°±0.2°、5.3°±0.2°、5.8°±0.2°、7.2°±0.2°、10.7°±0.2°或16.3°±0.2°。According to a third aspect of the invention, there is provided a crystalline form of a compound of formula I according to the first aspect of the invention, said crystal form being crystalline form A, said X-ray powder diffraction pattern of said Form A comprising 3 or 3 More than 2 values of 2θ selected from the group consisting of: 3.5°±0.2°, 5.3°±0.2°, 5.8°±0.2°, 7.2°±0.2°, 10.7°±0.2° or 16.3°±0.2°.
在另一优选例中，所述晶型A的X射线粉末衍射图谱可进一步包括3个或3个以上选自下组的2θ值：3.5°±0.2°、5.3°±0.2°、5.8°±0.2°、7.2°±0.2°、10.7°±0.2°、 11.1°±0.2°、11.7°±0.2°或16.3°±0.2°。In another preferred embodiment, the X-ray powder diffraction pattern of Form A may further comprise 3 or more 2θ values selected from the group consisting of: 3.5°±0.2°, 5.3°±0.2°, 5.8°± 0.2°, 7.2°±0.2°, 10.7°±0.2°, 11.1 ° ± 0.2 °, 11.7 ° ± 0.2 ° or 16.3 ° ± 0.2 °.
在另一优选例中，所述晶型A的X射线粉末衍射图谱可进一步包括3个或3个以上选自下组的2θ值：3.5°±0.2°、5.3°±0.2°、5.8°±0.2°、7.2°±0.2°、8.0±0.2°、9.57±0.2°、10.7°±0.2°、11.1°±0.2°、11.7°±0.2°或16.3°±0.2°。In another preferred embodiment, the X-ray powder diffraction pattern of Form A may further comprise 3 or more 2θ values selected from the group consisting of: 3.5°±0.2°, 5.3°±0.2°, 5.8°± 0.2°, 7.2°±0.2°, 8.0±0.2°, 9.57±0.2°, 10.7°±0.2°, 11.1°±0.2°, 11.7°±0.2° or 16.3°±0.2°.
在另一优选例中，所述晶型A具有选自下组的一个或多个特征：In another preferred embodiment, the crystalline form A has one or more characteristics selected from the group consisting of:
(1)所述晶型A的X射线粉末衍射图谱基本如图1所表征；(1) The X-ray powder diffraction pattern of the Form A is substantially characterized by Figure 1;
(2)所述晶型A的差示扫描量热法分析图谱的起始温度(onset)为165.8±3℃，和/或峰值温度(peak)为174.1±3℃；(2) The onset of the differential scanning calorimetry analysis pattern of the crystal form A is 165.8 ± 3 ° C, and / or the peak temperature (peak) is 174.1 ± 3 ° C;
(3)所述晶型A的差示扫描量热法分析图谱基本如图2所表征；和/或(3) the differential scanning calorimetry analysis pattern of the crystal form A is substantially characterized as shown in FIG. 2; and/or
(4)所述晶型A的热重分析图谱基本如图3所表征。(4) The thermogravimetric analysis pattern of the crystal form A is substantially characterized as shown in FIG.
本发明第四方面，提供一种制备如本发明第三方面所述的晶型A的方法，包括步骤：According to a fourth aspect of the invention, there is provided a method of preparing a crystalline form A according to the third aspect of the invention, comprising the steps of:
(a)在溶剂中，将式II化合物与糖精反应，生成式I化合物，并且，所述溶剂选自下组：乙醇、异丙醇、丙酮、乙腈、四氢呋喃、乙酸乙酯、乙酸异丙酯、甲苯、甲基叔丁基醚、水、或其组合；(a) reacting a compound of formula II with a saccharin in a solvent to form a compound of formula I, and the solvent is selected from the group consisting of ethanol, isopropanol, acetone, acetonitrile, tetrahydrofuran, ethyl acetate, isopropyl acetate , toluene, methyl tert-butyl ether, water, or a combination thereof;
Figure PCTCN2017102062-appb-000004
Figure PCTCN2017102062-appb-000004
(b)对步骤(a)生成的式I化合物进行结晶处理，从而形成所述晶型A。(b) subjecting the compound of the formula I produced in the step (a) to a crystallization treatment to form the crystal form A.
在另一优选例中，所述步骤(a)中，所述式II化合物为无定形物。In another preferred embodiment, in the step (a), the compound of the formula II is an amorphous substance.
在另一优选例中，所述步骤(a)中，生成的式I化合物为无定形物。In another preferred embodiment, in the step (a), the resulting compound of formula I is amorphous.
在另一优选例中，所述步骤(b)包括步骤(b-1)：加入晶种，对步骤(a)生成的式I化合物进行结晶处理，从而形成所述晶型A。In another preferred embodiment, the step (b) comprises the step (b-1): seeding is added, and the compound of the formula I produced in the step (a) is subjected to a crystallization treatment to form the crystal form A.
在另一优选例中，所述步骤(b-1)中，所述晶种为本发明第三方面所述的晶型A。In another preferred embodiment, in the step (b-1), the seed crystal is the crystal form A according to the third aspect of the invention.
在另一优选例中，所述步骤(b)包括：任选地，在惰性溶剂中，对步骤(a)生成的式I化合物进行结晶处理，从而形成所述晶型A，所述惰性溶剂选自下组：乙醇、 异丙醇、丙酮、乙腈、四氢呋喃、乙酸乙酯、乙酸异丙酯、甲苯、甲基叔丁基醚、水、或其组合。In another preferred embodiment, the step (b) comprises: optionally, crystallization treatment of the compound of the formula I produced in the step (a) in an inert solvent to form the crystalline form A, the inert solvent Selected from the following group: ethanol, Isopropanol, acetone, acetonitrile, tetrahydrofuran, ethyl acetate, isopropyl acetate, toluene, methyl tert-butyl ether, water, or a combination thereof.
在另一优选例中，所述步骤(a)中，反应温度为0-50℃，较佳地为4-35℃，更佳地为10-25℃。In another preferred embodiment, in the step (a), the reaction temperature is 0 to 50 ° C, preferably 4 to 35 ° C, more preferably 10 to 25 ° C.
在另一优选例中，所述步骤(a)中，反应时间为0.1-24小时，较佳地为0.2-12小时，更佳地为0.5-3小时。In another preferred embodiment, in the step (a), the reaction time is from 0.1 to 24 hours, preferably from 0.2 to 12 hours, more preferably from 0.5 to 3 hours.
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。It is to be understood that within the scope of the present invention, the various technical features of the present invention and the various technical features specifically described hereinafter (as in the embodiments) may be combined with each other to constitute a new or preferred technical solution. Due to space limitations, we will not repeat them here.
附图说明DRAWINGS
图1显示了式I化合物晶型A的X-射线粉末衍射谱图(XRPD)。Figure 1 shows an X-ray powder diffraction pattern (XRPD) of Form A of the compound of Formula I.
图2显示了式I化合物晶型A的差示扫描量热分析谱图(DSC)。Figure 2 shows a differential scanning calorimetry spectrum (DSC) of Form A of the compound of Formula I.
图3显示了式I化合物晶型A的热失重分析谱图(TGA)。Figure 3 shows the thermogravimetric analysis spectrum (TGA) of Form A of the compound of Formula I.
图4显示了式I化合物晶型A的吸湿曲线和解吸附曲线、维帕他韦式II化合物无定形的吸湿曲线、维帕他韦式II化合物无定形的解吸附曲线、维帕他韦双磷酸盐的吸湿曲线、维帕他韦双磷酸盐的解吸附曲线、维帕他韦双盐酸盐的吸湿曲线和维帕他韦双盐酸盐的解吸附曲线。Figure 4 shows the hygroscopic curve and desorption curve of the crystalline form A of the compound of the formula I, the amorphous hygroscopic curve of the compound of the vipatavir II compound, the amorphous desorption curve of the compound of the vipavivir II compound, and the disipide diphosphate of the compound of the vapitavir II. The hygroscopic curve of the salt, the desorption curve of voratavivir bisphosphonate, the hygroscopic curve of voratavivir dihydrochloride and the desorption curve of voratavivir dihydrochloride.
具体实施方式detailed description
本发明人经过广泛而深入的研究，对维帕他韦的制备工艺进行了大量优化研究，首次意外地获得了一种特别适合于生产的维帕他韦和糖精的共晶化合物，并且所述共晶化合物优选为晶型A。本发明的式I化合物的晶型A易于制备，有良好的理化性质，结构稳定，具有优异的稳定性(光照和高温高湿)和吸湿性，并且有助于减少杂质，进而提高维帕他韦的纯度和质量，特别适合用于开发和生产高质量的维帕他韦制剂。发明人在此基础上完成了本发明。The inventors conducted extensive and intensive research to carry out a large number of optimization studies on the preparation process of voratavivir, and for the first time unexpectedly obtained a eutectic compound which is particularly suitable for the production of voratavivir and saccharin, and The eutectic compound is preferably Form A. The crystalline form A of the compound of the formula I of the present invention is easy to prepare, has good physical and chemical properties, is structurally stable, has excellent stability (light and high temperature and high humidity) and hygroscopicity, and contributes to reduction of impurities, thereby improving ivapar Wei's purity and quality are particularly suitable for the development and production of high quality vertapavir formulations. The inventors have completed the present invention on this basis.
术语the term
除非另外定义，否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。All technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs, unless otherwise defined.
如本文所用，在提到具体列举的数值中使用时，术语“约”意指该值可以从列举 的值变动不多于1％。例如，如本文所用，表述“约100”包括99和101和之间的全部值(例如，99.1、99.2、99.3、99.4等)。As used herein, when used in reference to a specifically recited value, the term "about" means that the value can be recited The value of the change is no more than 1%. For example, as used herein, the expression "about 100" includes all values between 99 and 101 and (eg, 99.1, 99.2, 99.3, 99.4, etc.).
如本文所用，术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之，所述术语也包括“基本上由…构成”、或“由…构成”。As used herein, the terms "containing" or "including" may be open, semi-closed, and closed. In other words, the terms also include "consisting essentially of," or "consisting of."
如本文所用，术语“n个或n个以上选自下组的2θ值”指包括n以及大于n的任意正整数(例如n、n+1、….)，其中上限Nup为该组中所有2θ峰值的个数。例如“3个或3个以上”不仅包括3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、…上限Nup各个正整数，还包括“4个或4个以上”、“5个或5个以上”、“6个或6个以上”等范围。As used herein, the term "n or n or more selected from the group of 2" refers to any positive integer (eg, n, n+1, . . . ) comprising n and greater than n, wherein the upper limit Nup is all in the group The number of 2θ peaks. For example, "3 or more" includes not only 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, ... The upper limit Nup is a positive integer, and includes a range of "4 or more", "5 or more", "6 or more", and the like.
XRPD：X-射线粉末衍射，X射线粉末衍射图谱为以下条件下测定：Cu-Ka，
Figure PCTCN2017102062-appb-000005
XRPD: X-ray powder diffraction, X-ray powder diffraction pattern was determined under the following conditions: Cu-Ka,
Figure PCTCN2017102062-appb-000005
DSC：差示扫描量热DSC: Differential Scanning Calorimetry
TGA：热重分析TGA: Thermogravimetric Analysis
DVS：动态水分吸附DVS: Dynamic moisture adsorption
wt％：重量百分比Wt%: weight percentage
式I化合物及其晶型Compound of formula I and its crystal form
如本文所用，术语“本发明化合物”指式I化合物，包括其无定形、晶型或其混合物。The term "compound of the invention" as used herein refers to a compound of formula I, including amorphous, crystalline forms or mixtures thereof.
Figure PCTCN2017102062-appb-000006
Figure PCTCN2017102062-appb-000006
如本文所用，所述“本发明的晶体”、“本发明的晶型”、“本发明的式I化合物的晶型”、“式I化合物的晶型”、“维帕他韦和糖精共晶晶型A”、“晶型A”、“共晶晶型A”可互换使用，均指式I化合物的晶型A。As used herein, "crystal of the invention", "crystal form of the invention", "crystal form of the compound of formula I of the invention", "crystal form of the compound of formula I", "vepacavir and saccharin" Crystalline Form A", "Form A", "Calclic Form A" are used interchangeably and refer to Form A of the compound of Formula I.
式II化合物Compound of formula II
如本文所用，术语“式II化合物”、“维帕他韦式II化合物”可互换使用，均指具有如下式II所示结构的化合物，主要包括其无定形。 As used herein, the terms "compound of formula II" and "compound of formulae II" are used interchangeably and refer to a compound having the structure of formula II below, including primarily amorphous.
Figure PCTCN2017102062-appb-000007
Figure PCTCN2017102062-appb-000007
结晶crystallization
在本发明中，可以通过操作溶液，使得感兴趣化合物的达到过饱和，从而完成生产规模的结晶。这可以通过多种方法来完成，例如，在相对高的温度下溶解化合物，然后冷却溶液至饱和溶解度以下。或者通过沸腾、常压蒸发、真空干燥或通过其它的一些方法来减小液体体积。可通过加入反溶剂来降低感兴趣化合物的溶解度。另一种可选方法是调节pH值以降低溶解度。有关结晶方面的详细描述请见Crystallization,第三版,J W Mullens,Butterworth-Heineman Ltd.，1993,ISBN0750611294。In the present invention, production-scale crystallization can be accomplished by operating the solution to achieve supersaturation of the compound of interest. This can be accomplished by a variety of methods, for example, dissolving the compound at relatively high temperatures and then cooling the solution below saturation solubility. Alternatively, the volume of liquid can be reduced by boiling, atmospheric evaporation, vacuum drying, or by other methods. The solubility of the compound of interest can be reduced by the addition of an anti-solvent. Another alternative is to adjust the pH to reduce solubility. A detailed description of crystallization can be found in Crystallization, Third Edition, J W Mullens, Butterworth-Heineman Ltd., 1993, ISBN 0750611294.
结晶的优化可包括用所需形式的晶体作为晶种接种于结晶介质中。另外，许多结晶方法使用上述策略的组合。一个实施例是在高温下将感兴趣的化合物溶解在溶剂中，随后通过受控方式加入适当体积的抗溶剂，以使体系正好在饱和水平之下。此时，可加入所需形式的晶种(并保持晶种的完整性)，将体系冷却以完成结晶。Optimization of crystallization can include seeding the crystal in a desired form with the crystal as a seed. In addition, many crystallization methods use a combination of the above strategies. One embodiment is to dissolve the compound of interest in a solvent at elevated temperatures, followed by controlled addition of an appropriate volume of anti-solvent to bring the system just below the level of saturation. At this point, seed crystals of the desired form can be added (and the integrity of the seed crystals maintained) and the system cooled to complete crystallization.
共晶Eutectic
药物共晶是活性药物成分通过非共价键和共晶形成物结合在一个晶格中形成的。药物共晶组分中至少有一个是分子或离子型药物，同时所有组分在室温下均为固体。它是一种新的药物固体型态，可以改善药物的理化性质，比如改善溶解度、增加稳定性、提高生物利用度等。The drug eutectic is formed by the combination of a non-covalent bond and a eutectic formation in a crystal lattice. At least one of the drug eutectic components is a molecular or ionic drug, and all components are solid at room temperature. It is a new drug solid form that can improve the physical and chemical properties of drugs, such as improving solubility, increasing stability, and improving bioavailability.
本发明的主要优点包括：The main advantages of the invention include:
(1)本发明所述的式I化合物(包括晶型或无定形物)结构稳定，并且其制备方法简单、快速，便于大规模化生产。(1) The compound of the formula I according to the present invention (including a crystalline form or an amorphous form) is structurally stable, and the preparation method thereof is simple and rapid, and is convenient for large-scale production.
(2)本发明所述的式I化合物在某些溶剂(如：甲基叔丁基醚、乙酸乙酯等)中的溶解度特别低，因此在短时间内形成沉淀或结晶，因此纯化和分离非常方便和快速。(2) The compound of the formula I according to the invention has a particularly low solubility in certain solvents (e.g. methyl tert-butyl ether, ethyl acetate, etc.), so that precipitation or crystallization is formed in a short time, thus purification and separation Very convenient and fast.
(3)本发明所述的式I化合物晶型A具有非常高的纯度(如≥99％)，有助于减少杂质，特别适合用作生产高质量的维帕他韦。 (3) The crystalline form A of the compound of the formula I according to the invention has a very high purity (e.g. ≥ 99%), contributes to the reduction of impurities, and is particularly suitable for the production of high quality vertapavir.
(4)本发明所述的式I化合物晶型A具有优异的稳定性(光照和高温高湿)和吸湿性，特别适合用于开发和生产高质量的维帕他韦制剂。(4) The crystalline form A of the compound of the formula I according to the invention has excellent stability (light and high temperature and high humidity) and hygroscopicity, and is particularly suitable for the development and production of high quality voratavivir preparations.
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。The invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are not intended to limit the scope of the invention. The experimental methods in the following examples which do not specify the specific conditions are usually in accordance with conventional conditions or according to the conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.
以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。常温或室温指4℃-30℃，较佳地15-25℃。The experimental materials and reagents used in the following examples are available from commercially available sources unless otherwise specified. Normal temperature or room temperature means 4 ° C to 30 ° C, preferably 15 to 25 ° C.
仪器和通用方法Instruments and general methods
XRPD：Bruker D8Advance X-射线粉末衍射仪，Cu靶，Ka波长，管电压40KV，管电流40mA。扫描范围：3-40° 2-Theta；步进：0.02°；扫描速度：1步/0.1秒。XRPD: Bruker D8 Advance X-ray powder diffractometer, Cu target, Ka wavelength, tube voltage 40 KV, tube current 40 mA. Scanning range: 3-40° 2-Theta; Stepping: 0.02°; Scanning speed: 1 step / 0.1 second.
DSC：TA Q2000差示扫描量热仪；温度范围：40-200℃；加热速率：10℃/分钟。DSC: TA Q2000 Differential Scanning Calorimeter; temperature range: 40-200 ° C; heating rate: 10 ° C / min.
TGA：NETZSCH TG 209F3热重分析仪；温度范围：30-400℃；加热速率：10℃/分钟。TGA: NETZSCH TG 209F3 thermogravimetric analyzer; temperature range: 30-400 ° C; heating rate: 10 ° C / min.
实施例1制备式I化合物的无定形物Example 1 Preparation of an amorphous form of a compound of formula I
称取84mg式II化合物粗品至1.5ml离心管，加入1mL的乙酸乙酯，超声至溶解，加入40mg糖精并超声5分钟，有浅黄色油状沉淀形成。Weigh 84 mg of the crude compound of formula II into a 1.5 ml centrifuge tube, add 1 mL of ethyl acetate, sonicate to dissolve, add 40 mg of saccharin and sonicate for 5 minutes, and form a pale yellow oily precipitate.
离心并移去上清液，置于60℃烘箱干燥12小时，得到黄色固体，经偏光显微镜确定为式I化合物的无定形物。The supernatant was centrifuged and removed, and dried in an oven at 60 ° C for 12 hours to obtain a yellow solid which was determined to be an amorphous material of the compound of formula I by a polarizing microscope.
实施例2制备式I化合物的晶型AExample 2 Preparation of Form A of the Compound of Formula I
称取84mg式II化合物粗品至1.5ml离心管，加入0.4ml丙酮，超声至溶解，然后加入38mg糖精，超声至溶解。将此溶液于置于室温放置。7天后观察到有固体沉淀析出，经偏光显微镜确认为晶体。Weigh 84 mg of the crude compound of formula II into a 1.5 ml centrifuge tube, add 0.4 ml of acetone, sonicate to dissolve, then add 38 mg of saccharin and sonicate to dissolve. This solution was placed at room temperature. After 7 days, a solid precipitate was observed and confirmed to be a crystal by a polarizing microscope.
将该离心管置于离心机(Eppendorf minispin)在12000转离心5分钟，移去上清液，将分离到的固体于室温下干燥1小时，得到维帕他韦和糖精的共晶晶型A。The centrifuge tube was placed in a centrifuge (Eppendorf minispin) and centrifuged at 12,000 rpm for 5 minutes, the supernatant was removed, and the separated solid was dried at room temperature for 1 hour to obtain a eutectic crystal form A of voratavivir and saccharin. .
结果result
对实施例2所得晶型A进行XRD、DSC、TGA和HPLC等检测。 The crystal form A obtained in Example 2 was subjected to XRD, DSC, TGA, HPLC and the like.
本发明实施例2的式I化合物晶型A的XRD图如图1所示，其中，晶型A的主要衍射峰以及相对强度如表1所示。The XRD pattern of the crystalline form A of the compound of the formula I in Example 2 of the present invention is shown in Fig. 1, wherein the main diffraction peaks and relative intensities of the crystalline form A are shown in Table 1.
表1.维帕他韦和糖精的共晶晶型A的XRD数据Table 1. XRD data for eutectic crystal form A of voratavivir and saccharin
2θ位置[°]2θ position [°] 相对强度[％]Relative Strength[%]
3.53.5 19.419.4
5.35.3 46.446.4
5.85.8 100.0100.0
7.27.2 45.645.6
10.710.7 33.433.4
11.111.1 11.711.7
11.711.7 12.512.5
16.316.3 49.849.8
实施例2的式I化合物晶型A的DSC图如图2所示。从图2中可知，在45-200℃之间，晶型A的热流曲线包含有一个熔融吸热峰：起始温度和峰值温度分别为165.8℃和174.1℃。A DSC chart of Form A of the compound of Formula I of Example 2 is shown in FIG. As can be seen from Fig. 2, between 45 and 200 ° C, the heat flow curve of Form A contains a melting endothermic peak: the starting temperature and the peak temperature are 165.8 ° C and 174.1 ° C, respectively.
实施例2的式I化合物晶型A的TGA图如图3所示。从图3中可知，在30-190℃之间，晶型A的热重曲线有3.52％的缓慢失重，是由于残留溶剂缓慢挥发造成。200℃之后，化合物开始分解，造成进一步的失重。The TGA pattern of Form A of the compound of Formula I of Example 2 is shown in FIG. As can be seen from Fig. 3, between 30 and 190 ° C, the thermogravimetric curve of Form A has a slow weight loss of 3.52% due to the slow evaporation of residual solvent. After 200 ° C, the compound began to decompose, causing further weight loss.
HPLC分析结果表明，晶型A中糖精的含量为29.8wt％，证明晶型A中维帕他韦和糖精的摩尔比例为1:2(理论糖精含量为30.3wt％)。The results of HPLC analysis showed that the content of saccharin in Form A was 29.8 wt%, demonstrating that the molar ratio of voratavivir to saccharin in Form A was 1:2 (the theoretical saccharin content was 30.3 wt%).
HPLC纯度为96％的维帕他韦式II化合物无定形粗品在经实施例2所述方法结晶为晶型A后，其HPLC纯度可以大幅度提高至98.6％。HPLC crude purity of 96% of the vitamins of the compound of Verapitavir II was crystallized to the form A after the method described in Example 2, and the HPLC purity was greatly improved to 98.6%.
进一步地，将HPLC纯度已经为99.0％的维帕他韦式II化合物无定形粗品进行实施例2所述操作结晶为晶型A后，所得晶型A的HPLC纯度还可以得到进一步的提高，达到99.4％。Further, after the amorphous crude product of the compound having the HPLC purity of 99.0% of the vipavir II compound is crystallized into the crystal form A as described in Example 2, the HPLC purity of the obtained crystal form A can be further improved. 99.4%.
这表明，经实施例2所述结晶方法将维帕他韦式II化合物无定形粗品结晶为晶型A可高效去除维帕他韦中的杂质，显著提高产品的纯度。This indicates that the crystallization method described in Example 2 crystallizes the amorphous crude product of the voratavivir compound II into the crystalline form A, which can efficiently remove impurities in the voratavivir and significantly improve the purity of the product.
实施例3经由式I化合物的无定形制备式I化合物的晶型AExample 3 Preparation of Form A of a Compound of Formula I via Amorphous Formulation of a Compound of Formula I
称取100mg式I化合物无定形(纯度99％)至1.5ml离心管，加入1ml丙酮，超声至溶解，然后加入晶型A的晶种，将此溶液于置于室温放置。4小时后观察到有固体沉淀析出。100 mg of the compound of formula I was weighed (purity 99%) into a 1.5 ml centrifuge tube, 1 ml of acetone was added, sonicated until dissolved, then seed crystals of Form A were added and the solution was placed at room temperature. A solid precipitate was observed after 4 hours.
将该离心管置于离心机(Eppendorf minispin)在12000转离心5分钟，移去上清液，将分离到的固体于室温下干燥1小时，经XRPD确认为维帕他韦和糖精的共晶 晶型A。The centrifuge tube was placed in a centrifuge (Eppendorf minispin) and centrifuged at 12,000 rpm for 5 minutes. The supernatant was removed, and the separated solid was dried at room temperature for 1 hour, and confirmed to be co-crystal of voratavivir and saccharin by XRPD. Form A.
实施例4维帕他韦共晶的制备与筛选Example 4 Preparation and Screening of Vipavir Co-crystals
将式I化合物无定形(纯度99％)和如表2所列出的不同共晶配体按表2所示摩尔比称取至1.5ml离心管，加入适当的溶剂形成澄清溶液，然后按表2所示结晶方法处理并通过偏光显微镜判断是否有结晶性固体形成。The amorphous compound of formula I (purity 99%) and the different eutectic ligands listed in Table 2 were weighed into a 1.5 ml centrifuge tube according to the molar ratio shown in Table 2, and a suitable solvent was added to form a clear solution, and then according to the table. The crystallization method shown in 2 was carried out and it was judged by a polarizing microscope whether or not a crystalline solid was formed.
表2.维帕他韦共晶的制备与筛选Table 2. Preparation and screening of vorpacavir eutectic
Figure PCTCN2017102062-appb-000008
Figure PCTCN2017102062-appb-000008
Figure PCTCN2017102062-appb-000009
Figure PCTCN2017102062-appb-000009
对常用共晶配体进行了***筛选，意外的发现所有筛选的共晶配体中只有糖精可以和维帕他韦形成结晶性共晶，且此共晶中维帕他韦和糖精的摩尔比固定的为约1:2，不随制备过程中二者加入的摩尔比变化而变化。Systematic screening of commonly used eutectic ligands, it was unexpectedly found that only saccharin in the selected eutectic ligands can form crystalline eutectic with voratavivir, and the molar ratio of vertapavir to saccharin in the eutectic It is fixed at about 1:2 and does not vary with the molar ratio of the two added during the preparation.
实施例5光照稳定性评估Example 5 Light Stability Evaluation
(1)对维帕他韦和糖精的共晶晶型A、维帕他韦双磷酸盐(晶型XIV，参见专利US20150361085A1)、维帕他韦双盐酸盐(晶型VI，参见专利US20150361085A1)、维帕他韦双氢溴酸盐(晶型XVIII，参见专利US20150361085A1)和维帕他韦式II化合物无定形的光照稳定性进行了考察。(1) eutectic crystal form A of voratavivir and saccharin, vorapavivir bisphosphonate (Form XIV, see patent US20150361085A1), vertapavir bishydrochloride (Form VI, see patent US20150361085A1) ), the amorphous light stability of the voratavivir dihydrobromide (Form XVIII, see patent US20150361085A1) and the Verapitavir II compound was investigated.
将下述样品：维帕他韦和糖精的共晶晶型A、维帕他韦双磷酸盐、维帕他韦双盐酸盐、维帕他韦双氢溴酸盐和维帕他韦式II化合物无定形分别置于表面皿中，摊成厚度不超过1mm的薄层，放置于光照强度为4400lux的LS-3000光照试验箱中，持续12天光照。The following samples were obtained: eutectic crystal form A of voratavivir and saccharin, voratavivir bisphosphonate, voratavivir dihydrochloride, voratavivir dihydrobromide and vertapavir II compound The amorphous sheets were placed in a watch glass and spread into a thin layer having a thickness of not more than 1 mm, and placed in an LS-3000 light test chamber with an illumination intensity of 4,400 lux for 12 days.
(2)应用HPLC对光照后样品纯度进行检查并与初始纯度进行对比。结果如表3所示，经过120万lux·小时的光照后，维帕他韦式II化合物无定形的HPLC纯度下降了6.5％，维帕他韦双磷酸盐的HPLC纯度下降了28.5％，维帕他韦双盐酸盐的HPLC纯度下降了11.2％，维帕他韦双氢溴酸盐的HPLC纯度下降了70.2％，维帕他韦和糖精的共晶晶型A的HPLC纯度仅下降了3.9％。维帕他韦和糖精的共晶晶型A的光稳定性明显优于维帕他韦式II化合物无定形、维帕他韦双磷酸盐、维帕他韦双盐酸盐和维帕他韦双氢溴酸盐。(2) The purity of the sample after illumination was examined by HPLC and compared with the initial purity. The results are shown in Table 3. After 1.2 million lux·hr of light, the amorphous HPLC purity of the vipavir II compound decreased by 6.5%, and the HPLC purity of the vipavivir diphosphate decreased by 28.5%. The HPLC purity of patavivir dihydrochloride decreased by 11.2%, the HPLC purity of voratavix dihydrobromide decreased by 70.2%, and the HPLC purity of copavivir and saccharin eutectic crystal A decreased by only 3.9%. . The photostability of eutectic crystal form A of vipavir and saccharin is significantly better than that of vapapavir II compound, vertapavir bisphosphate, voratavivir dihydrochloride and voratavivir dihydrogen. Bromate.
表3.维帕他韦不同晶型光照稳定性对比Table 3. Comparison of light stability of different crystal forms of voratavivir
晶型Crystal form HPLC纯度下降(％)HPLC purity decreased (%)
维帕他韦式II化合物无定形Vipathavir II compound amorphous 6.56.5
维帕他韦双磷酸盐Vipavir diphosphate 28.528.5
维帕他韦双盐酸盐Vipavir dihydrochloride 11.211.2
维帕他韦双氢溴酸盐Vipavir dihydrobromide 70.270.2
维帕他韦和糖精的共晶晶型AEutectic Form A of Vipavir and Saccharin 3.93.9
实施例6加速稳定性评估 Example 6 Accelerated Stability Evaluation
(1)对维帕他韦和糖精的共晶晶型A、维帕他韦双磷酸盐(晶型XIV，参见专利US20150361085A1)、维帕他韦双盐酸盐(晶型VI，参见专利US20150361085A1)、维帕他韦双氢溴酸盐(晶型XVIII，参见专利US20150361085A1)和维帕他韦式II化合物无定形的加速稳定性进行了考察。(1) eutectic crystal form A of voratavivir and saccharin, vorapavivir bisphosphonate (Form XIV, see patent US20150361085A1), vertapavir bishydrochloride (Form VI, see patent US20150361085A1) The amorphous accelerated stability of the voratavivir dihydrobromide (Form XVIII, see patent US20150361085A1) and the voratavivir II compound was investigated.
将下述样品：维帕他韦和糖精的共晶晶型A、维帕他韦双磷酸盐、维帕他韦双盐酸盐、维帕他韦双氢溴酸盐和维帕他韦式II化合物无定形分别置于表面皿中，摊成厚度不超过1mm的薄层，放置于温度为40 2℃和湿度为75 5％的稳定性试验箱中，持续4周。The following samples were obtained: eutectic crystal form A of voratavivir and saccharin, voratavivir bisphosphonate, voratavivir dihydrochloride, voratavivir dihydrobromide and vertapavir II compound The amorphous sheets were placed in a watch glass and spread into a thin layer having a thickness of not more than 1 mm, and placed in a stability test chamber at a temperature of 40 2 ° C and a humidity of 75 5% for 4 weeks.
(2)应用HPLC对稳定性试验后样品纯度进行检查并与初始纯度进行对比。(2) The purity of the sample after the stability test was checked by HPLC and compared with the initial purity.
结果如表4所示，经过4周加速稳定性试验后，维帕他韦式II化合物无定形的HPLC纯度下降了0.5％，维帕他韦双磷酸盐的HPLC纯度下降了0.8％，维帕他韦双盐酸盐的HPLC纯度下降了0.7％，维帕他韦双氢溴酸盐的HPLC纯度下降了4.1％，维帕他韦和糖精的共晶晶型A的HPLC纯度在4周加速稳定性试验后没有下降。维帕他韦和糖精的共晶晶型A的稳定性明显优于维帕他韦式II化合物无定形、维帕他韦双磷酸盐、维帕他韦双盐酸盐和维帕他韦双氢溴酸盐。The results are shown in Table 4. After a 4-week accelerated stability test, the amorphous HPLC purity of the vipavir II compound decreased by 0.5%, and the HPLC purity of the vipavivir diphosphate decreased by 0.8%. The HPLC purity of the dihydrochloride salt was reduced by 0.7%, the HPLC purity of the vipavir dihydrobromide was decreased by 4.1%, and the HPLC purity of the eutectic crystal form of the vipavir and saccharin was accelerated at 4 weeks. There was no decline after the test. The stability of eutectic crystal form A of voratavivir and saccharin is significantly better than that of vapapavir II compound, vertapavir bisphosphate, vertapavir dihydrochloride and vertapavir dihydrobromide. Acid salt.
表4.维帕他韦加速稳定性对比Table 4. Comparison of accelerated stability of voratavivir
晶型Crystal form HPLC纯度下降(％)HPLC purity decreased (%)
维帕他韦式II化合物无定形Vipathavir II compound amorphous 0.50.5
维帕他韦双磷酸盐Vipavir diphosphate 0.80.8
维帕他韦双盐酸盐Vipavir dihydrochloride 0.70.7
维帕他韦双氢溴酸盐Vipavir dihydrobromide 4.14.1
维帕他韦和糖精的共晶晶型AEutectic Form A of Vipavir and Saccharin 0.00.0
实施例7晶型A吸湿性评估Example 7 Crystal Form A Hygroscopicity Evaluation
吸湿性通过动态水分吸附(DVS)进行了评估，具体测试方法如下：Hygroscopicity was evaluated by dynamic moisture adsorption (DVS). The specific test methods are as follows:
仪器：SMS DVS AdvantageInstrument: SMS DVS Advantage
方法：相对湿度0-90％，step:10％Method: relative humidity 0-90%, step: 10%
吸湿性是药物关键理化性质之一，对药物稳定性、粉体学性质和后继加工工艺有显著影响。晶型A的吸湿性结果如图4和表5所示，同时对比了维帕他韦式II化合物无定形、维帕他韦双磷酸盐(晶型XIV，参见专利US20150361085A1)和维帕他韦双盐酸盐(晶型VI，参见专利US20150361085A1)的吸湿性。Hygroscopicity is one of the key physicochemical properties of drugs, and has a significant impact on drug stability, powder properties and subsequent processing. The hygroscopicity results of Form A are shown in Figure 4 and Table 5, while comparing the amorphous form of the voratavivir II compound, vorapavivir bisphosphonate (Form XIV, see patent US20150361085A1) and voratavivir. The hygroscopicity of the dihydrochloride salt (Form VI, see patent US20150361085A1).
结果表明，晶型A的吸湿性明显低于维帕他韦式II化合物无定形、维帕他韦双 磷酸盐和维帕他韦双盐酸盐，且其解吸附滞后现象微弱，这些结果直接证明了晶型A具有优异的吸湿性、更优的理化性质和良好的可加工性。The results showed that the hygroscopicity of crystal form A was significantly lower than that of the compound of vipatavir II, vertapavir Phosphate and voratavivir dihydrochloride, and its desorption hysteresis is weak, these results directly prove that Form A has excellent hygroscopicity, better physical and chemical properties and good processability.
表5.维帕他韦各晶型吸湿性对比Table 5. Comparison of hygroscopicity of each form of voratavivir
Figure PCTCN2017102062-appb-000010
Figure PCTCN2017102062-appb-000010
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。 All documents mentioned in the present application are hereby incorporated by reference in their entirety in their entireties in the the the the the the the the In addition, it should be understood that various modifications and changes may be made by those skilled in the art in the form of the appended claims.

Claims (11)

  1. 一种式I所示化合物，其特征在于，所述化合物由维帕他韦与糖精形成，A compound of formula I, characterized in that said compound is formed by voratavivir and saccharin,
    Figure PCTCN2017102062-appb-100001
    Figure PCTCN2017102062-appb-100001
  2. 如权利要求1所述的式I化合物，其特征在于，所述式I化合物为晶型或无定形物。A compound of formula I according to claim 1 wherein the compound of formula I is crystalline or amorphous.
  3. 一种制备如权利要求1所述的式I化合物的方法，其特征在于，包括步骤：A method of preparing a compound of formula I according to claim 1 comprising the steps of:
    (1)将式II化合物与糖精反应，生成式I化合物：(1) reacting a compound of formula II with saccharin to form a compound of formula I:
    Figure PCTCN2017102062-appb-100002
    Figure PCTCN2017102062-appb-100002
  4. 如权利要求3所述的方法，其特征在于，所述式II化合物与糖精的摩尔比为1:1.5-1:2.5。The method of claim 3 wherein the molar ratio of the compound of formula II to saccharin is from 1:1.5 to 1:2.5.
  5. 如权利要求3所述的方法，其特征在于，所述方法还包括步骤(2)：在惰性溶剂中，对步骤(1)得到的式I化合物进行析晶处理，得到式I化合物的晶体，其中，所述惰性溶剂选自下组：乙醇、异丙醇、丙酮、乙腈、四氢呋喃、乙酸乙酯、乙酸异丙酯、甲苯、甲基叔丁基醚、水、或其组合。The method according to claim 3, further comprising the step (2): subjecting the compound of the formula I obtained in the step (1) to a crystallization treatment in an inert solvent to obtain a crystal of the compound of the formula I, Wherein the inert solvent is selected from the group consisting of ethanol, isopropanol, acetone, acetonitrile, tetrahydrofuran, ethyl acetate, isopropyl acetate, toluene, methyl tert-butyl ether, water, or a combination thereof.
  6. 一种如权利要求1所述的式I化合物的晶型，其特征在于，所述晶型为晶型A，所述晶型A的X射线粉末衍射图谱包括3个或3个以上选自下组的2θ值：3.5°±0.2°、5.3°±0.2°、5.8°±0.2°、7.2°±0.2°、10.7°±0.2°或16.3°±0.2°。A crystalline form of a compound of formula I according to claim 1, wherein said crystalline form is crystalline form A, and said X-ray powder diffraction pattern of said crystalline form A comprises 3 or more selected from the group consisting of The 2θ values of the group are: 3.5 ° ± 0.2 °, 5.3 ° ± 0.2 °, 5.8 ° ± 0.2 °, 7.2 ° ± 0.2 °, 10.7 ° ± 0.2 ° or 16.3 ° ± 0.2 °.
  7. 如权利要求6所述的晶型，其特征在于，所述晶型A的X射线粉末衍射图谱包括3个或3个以上选自下组的2θ值：3.5°±0.2°、5.3°±0.2°、5.8°±0.2°、7.2°±0.2°、8.0±0.2°、9.57±0.2°、10.7°±0.2°、11.1°±0.2°、11.7°±0.2°或16.3°±0.2°。 The crystal form according to claim 6, wherein the X-ray powder diffraction pattern of the Form A comprises 3 or more 2θ values selected from the group consisting of: 3.5 ° ± 0.2 °, 5.3 ° ± 0.2 °, 5.8 ° ± 0.2 °, 7.2 ° ± 0.2 °, 8.0 ± 0.2 °, 9.57 ± 0.2 °, 10.7 ° ± 0.2 °, 11.1 ° ± 0.2 °, 11.7 ° ± 0.2 ° or 16.3 ° ± 0.2 °.
  8. 如权利要求6所述的晶型，其特征在于，所述晶型A具有选自下组的一个或多个特征：The crystalline form of claim 6 wherein said Form A has one or more characteristics selected from the group consisting of:
    (1)所述晶型A的X射线粉末衍射图谱基本如图1所表征；(1) The X-ray powder diffraction pattern of the Form A is substantially characterized by Figure 1;
    (2)所述晶型A的差示扫描量热法分析图谱的起始温度(onset)为165.8±3℃，和/或峰值温度(peak)为174.1±3℃；(2) The onset of the differential scanning calorimetry analysis pattern of the crystal form A is 165.8 ± 3 ° C, and / or the peak temperature (peak) is 174.1 ± 3 ° C;
    (3)所述晶型A的差示扫描量热法分析图谱基本如图2所表征；和/或(3) the differential scanning calorimetry analysis pattern of the crystal form A is substantially characterized as shown in FIG. 2; and/or
    (4)所述晶型A的热重分析图谱基本如图3所表征。(4) The thermogravimetric analysis pattern of the crystal form A is substantially characterized as shown in FIG.
  9. 一种制备如权利要求6所述的晶型A的方法，其特征在于，包括步骤：A method of preparing Form A according to claim 6, comprising the steps of:
    (a)在溶剂中，将式II化合物与糖精反应，生成式I化合物，并且，所述溶剂选自下组：乙醇、异丙醇、丙酮、乙腈、四氢呋喃、乙酸乙酯、乙酸异丙酯、甲苯、甲基叔丁基醚、水、或其组合；(a) reacting a compound of formula II with a saccharin in a solvent to form a compound of formula I, and the solvent is selected from the group consisting of ethanol, isopropanol, acetone, acetonitrile, tetrahydrofuran, ethyl acetate, isopropyl acetate , toluene, methyl tert-butyl ether, water, or a combination thereof;
    Figure PCTCN2017102062-appb-100003
    Figure PCTCN2017102062-appb-100003
    (b)对步骤(a)生成的式I化合物进行结晶处理，从而形成所述晶型A。(b) subjecting the compound of the formula I produced in the step (a) to a crystallization treatment to form the crystal form A.
  10. 如权利要求9所述的方法，其特征在于，所述步骤(a)中，所述式II化合物为无定形物，和/或，所述步骤(a)中，生成的式I化合物为无定形物。The method according to claim 9, wherein in the step (a), the compound of the formula II is an amorphous substance, and/or, in the step (a), the produced compound of the formula I is Shaped object.
  11. 如权利要求9所述的方法，其特征在于，所述步骤(b)包括步骤(b-1)：加入晶种，对步骤(a)生成的式I化合物进行结晶处理，从而形成所述晶型A。 The method according to claim 9, wherein said step (b) comprises the step (b-1) of: adding a seed crystal, crystallization treatment of the compound of the formula I produced in the step (a), thereby forming the crystal Type A.
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