WO2018054270A1 - Nouveau cristal de velpatasvir et son procédé de préparation - Google Patents

Nouveau cristal de velpatasvir et son procédé de préparation Download PDF

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Publication number
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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WIPO (PCT)
Prior art keywords
compound
formula
crystal
saccharin
voratavivir
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PCT/CN2017/102062
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English (en)
Chinese (zh)
Inventor
李巍
任毅
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上海众强药业有限公司
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Publication of WO2018054270A1 publication Critical patent/WO2018054270A1/fr

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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

Definitions

  • 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).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un nouveau cristal de velpatasvir et son procédé de préparation. La structure du composé de formule (I) de la présente invention est représentée ci-dessous. Le cristal A du composé de formule (I) produit par le procédé de préparation selon la présente invention présente de grands effets de purification et de propriétés physiques et chimiques.
PCT/CN2017/102062 2016-09-21 2017-09-18 Nouveau cristal de velpatasvir et son procédé de préparation WO2018054270A1 (fr)

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CN201610838077.5A CN106432253B (zh) 2016-09-21 2016-09-21 一种维帕他韦新晶型及其制备方法

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CN106432253B (zh) * 2016-09-21 2019-06-14 上海众强药业有限公司 一种维帕他韦新晶型及其制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015191431A1 (fr) * 2014-06-11 2015-12-17 Gilead Pharmasset Llc Formes solides d'un composé antiviral
CN106432253A (zh) * 2016-09-21 2017-02-22 上海众强药业有限公司 一种维帕他韦新晶型及其制备方法

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ES2792503T3 (es) * 2013-08-27 2020-11-11 Gilead Pharmasset Llc Formulación combinada de dos compuestos antivirales
SI3524234T1 (sl) * 2014-06-13 2021-05-31 Ratiopharm Gmbh Trdne oblike sofosbuvira
CN105732563B (zh) * 2016-03-23 2018-08-28 江苏苏利精细化工股份有限公司 一种合成9-溴-3-(2-溴乙酰基)-10，11-二氢-5H-二苯并[c,g]色烯-8(9h)-酮的新方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015191431A1 (fr) * 2014-06-11 2015-12-17 Gilead Pharmasset Llc Formes solides d'un composé antiviral
CN106432253A (zh) * 2016-09-21 2017-02-22 上海众强药业有限公司 一种维帕他韦新晶型及其制备方法

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