WO2021254445A1 - Forme cristalline d'inhibiteur gaba et son procédé de préparation - Google Patents

Forme cristalline d'inhibiteur gaba et son procédé de préparation Download PDF

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WO2021254445A1
WO2021254445A1 PCT/CN2021/100649 CN2021100649W WO2021254445A1 WO 2021254445 A1 WO2021254445 A1 WO 2021254445A1 CN 2021100649 W CN2021100649 W CN 2021100649W WO 2021254445 A1 WO2021254445 A1 WO 2021254445A1
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crystal form
aforana
ray powder
present
powder diffraction
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PCT/CN2021/100649
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English (en)
Chinese (zh)
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徐巾超
黄河
张�杰
叶辉青
李东明
陈勇
黄芳芳
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东莞市东阳光仿制药研发有限公司
广东东阳光药业有限公司
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Priority to CN202180040410.7A priority Critical patent/CN115768753B/zh
Publication of WO2021254445A1 publication Critical patent/WO2021254445A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member

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  • the invention belongs to the technical field of medicine and chemical engineering, and specifically relates to a new crystal form of a GABA inhibitor and a preparation method thereof.
  • Aforana is a GABA ( ⁇ -aminobutyric acid) inhibitor that inhibits the GABA chloride ion channel and makes arthropod nerves highly excited and leads to death. It is a powerful insecticide.
  • NexGard a new generation of oral in vitro anthelmintic for dogs (NexGard, common name: Aphrana Chewable Tablets), is the first domestic oral anthelmintic for dogs that kills both tick and flea parasites.
  • Aforana is 4-(5-(3-chloro-5-(trifluoromethyl)-phenyl)-4,5-dihydro-5-(trifluoromethyl)-3-iso Oxazolyl)-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl-1-naphthylcarboxamide, the structural formula is as follows:
  • Patent CN102947278B discloses multiple crystal forms of Aforana: crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F, crystal form G, crystal form H and toluene solvate , Most of the crystal forms are solvates, such as crystal form C is ethyl acetate solvate, crystal form D is dioxane cyclohexane solvate, crystal form F is n-propanol solvate, crystal Form G is acetonitrile solvate, crystal form H is isopropanol solvate, while crystal form A, crystal form B, and crystal form E have poor crystallinity, high amorphous content, and easy to crystallize, so this patent is developed The new crystal form of Aforana and the preparation method thereof have greatly improved the stability and purity of the crystal form, and the operation is simple, the yield is high, and the industrial production is easy.
  • the present invention provides multiple crystal forms of Aforana.
  • the Aforana crystal form XXI and the crystal form XXII provided by the present invention have the advantages of good product stability and high crystallinity.
  • the X-ray powder diffraction pattern of the Aforana crystal form XXI contains diffraction peaks with 2 ⁇ angles of 15.8, 18.0, 18.4, 19.6 and 21.8 degrees.
  • the aforana crystal form XXI has better stability under high temperature conditions, which is beneficial to the preparation of pharmaceutical preparations.
  • the X-ray powder diffraction pattern of the Aforana crystal form XXII contains diffraction peaks with 2 ⁇ angles of 4.4, 10.7, 13.2, 17.5, 19.3 and 25.2 degrees.
  • the first aspect of the present invention provides a crystal form of Aforana.
  • the crystal forms of Aforana are named as the crystal form XXI and the crystal form XXII, and the crystal form I, the crystal form II, the crystal form III, the crystal form IV, the crystal form V, and the crystal form respectively.
  • VI Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XVI, Form XVII, Form XVIII, Form XIX and Crystal Form XX.
  • the Aforana crystal form XXI and the crystal form XXII provided by the present invention have the advantages of good product stability and high crystallinity.
  • the X-ray powder diffraction pattern of Aforana Form I of the present invention contains 2 ⁇ angles of 3.9, 7.7, 9.8, 11.5, 13.0, 15.4, 16.6, 19.3, 20.2, 23.2, 24.0, 26.3, 27.1, 27.8, 31.7, 35.1, 35.7 degree diffraction peaks.
  • the X-ray powder diffraction pattern of the Aforana crystal form I is substantially as shown in FIG. 1.
  • the differential scanning calorimetry curve of Aforana crystal form I of the present invention has an endothermic peak at 105°C.
  • the X-ray powder diffraction pattern of Aforana Form II of the present invention contains 2 ⁇ angles of 11.1, 11.8, 13.5, 15.8, 16.8, 17.6, 18.0, 19.1, 19.6, 20.5, 21.8, 22.6, 23.5, 24.4, 27.2, 27.7 degree diffraction peaks.
  • the X-ray powder diffraction pattern of the Aforana Form II is substantially as shown in FIG. 2.
  • the differential scanning calorimetry curve of the crystal form II of Aforana of the present invention has an endothermic peak at 73°C.
  • the X-ray powder diffraction pattern of Aforana Form III of the present invention contains 2 ⁇ angles of 3.8, 11.5, 12.9, 13.5, 15.0, 16.1, 16.4, 17.4, 18.9, 19.7, 19.9, 20.6, 21.2, 21.7, 22.0, 22.3, 22.8, 23.6, 24.7, 25.4, 26.0, 26.4, 27.1, 29.6, 30.3, 30.8, 31.1, 34.8, 36.2, 37.6 degree diffraction peaks.
  • the X-ray powder diffraction pattern of the Aforana Form III is substantially as shown in FIG. 3.
  • the differential scanning calorimetry curve of Aforana Form III of the present invention has an endothermic peak at 135°C.
  • the X-ray powder diffraction pattern of Aforana Form IV of the present invention contains 2 ⁇ angles of 3.9, 11.2, 12.4, 13.5, 15.6, 16.6, 17.0, 17.4, 19.3, 19.9, 20.3, 20.8, 21.0, 21.7, 21.9, 22.3, 22.6, 23.0, 23.3, 24.0, 25.0, 26.2, 26.8, 27.2, 27.6, 29.4, 29.7, 30.0, 31.1, 31.8, 33.2, 34.5, 37.4 degree diffraction peaks.
  • the X-ray powder diffraction pattern of the Aforana Form IV is substantially as shown in FIG. 4.
  • the differential scanning calorimetry curve of the crystal form IV of Aforana of the present invention has an endothermic peak at 112°C.
  • the X-ray powder diffraction pattern of Aforana Form V of the present invention contains 2 ⁇ angles of 11.4, 12.0, 12.6, 15.4, 17.7, 18.5, 19.2, 19.9, 20.5, 20.7, 21.4, 21.9, 22.5, 23.3, 24.2, 25.4, 25.8, 27.5, 29.8, 34.1 degree diffraction peaks.
  • the X-ray powder diffraction pattern of the Aforana crystal form V is substantially as shown in FIG. 5.
  • the differential scanning calorimetry curve of the Aforana crystal form V of the present invention has an endothermic peak at 105°C.
  • the X-ray powder diffraction pattern of Aforana Form VI of the present invention contains 2 ⁇ angles of 3.9, 11.5, 12.6, 13.2, 14.8, 15.8, 16.5, 17.5, 18.1, 19.1, 19.4, 20.2, 21.3, 22.0, 22.3, 22.5, 22.8, 23.4, 23.9, 25.4, 25.7, 26.3, 26.9, 27.4, 29.2, 29.9, 30.3 degree diffraction peaks.
  • the X-ray powder diffraction pattern of the Aforana crystal form VI is substantially as shown in FIG. 6.
  • the differential scanning calorimetry curve of Aforana Form VI of the present invention has an endothermic peak at 96°C.
  • the differential scanning calorimetry curve of Aforana Form VI of the present invention has an endothermic peak at 113°C.
  • the Aforana crystal form VIII of the present invention contains a diffraction peak with a 2 ⁇ angle of 18.0 degrees in the X-ray powder diffraction pattern.
  • the X-ray powder diffraction pattern of the Aforana Form VIII is substantially as shown in FIG. 7.
  • the differential scanning calorimetry curve of the Aforana crystal form VIII of the present invention has no obvious endothermic peak.
  • the X-ray powder diffraction pattern of Aforana Form IX of the present invention contains 2 ⁇ angles of 4.0, 9.8, 11.3, 11.8, 12.4, 13.6, 15.2, 16.7, 17.0, 17.7, 19.4, 19.6, 20.2, 20.5, 21.4, 21.6, 22.4, 22.7, 23.3, 23.7, 24.4, 24.9, 25.6, 26.5, 27.8, 29.9, 31.2 degree diffraction peaks.
  • the X-ray powder diffraction pattern of the Aforana Form IX is substantially as shown in FIG. 8.
  • the differential scanning calorimetry curve of Aforana Form IX of the present invention has an endothermic peak at 106°C.
  • the differential scanning calorimetry curve of Aforana Form IX of the present invention has an endothermic peak at 138°C.
  • the X-ray powder diffraction pattern of the Aforana crystal form X of the present invention contains 2 ⁇ angles of 11.2, 15.1, 15.6, 16.3, 16.6, 18.1, 19.1, 19.5, 20.0, 20.2, 20.4, 20.9, 22.3, 22.8, 24.2, 24.9, 26.1, 26.8, 27.5 degree diffraction peaks.
  • the X-ray powder diffraction pattern of the Aforana crystal form X is substantially as shown in FIG. 9.
  • the X-ray powder diffraction pattern of the Aforana crystal form XI of the present invention contains 2 ⁇ angles of 11.2, 12.4, 12.9, 14.6, 15.5, 15.9, 16.5, 17.3, 19.0, 19.2, 20.1, 20.8, 21.6, 22.2, 22.5, 23.1, 23.4, 23.8, 24.1, 24.9, 25.5, 25.9, 26.8, 27.3, 28.3, 29.1, 29.5, 29.7, 34.1, 34.8, 39.6 degree diffraction peaks.
  • the X-ray powder diffraction pattern of the Aforana Form XI is substantially as shown in FIG. 10.
  • the differential scanning calorimetry curve of the Aforana crystal form XI of the present invention has an endothermic peak at 77°C.
  • the X-ray powder diffraction pattern of the Aforana crystal form XII of the present invention contains 2 ⁇ angles of 3.8, 11.4, 12.7, 13.2, 14.7, 15.8, 16.4, 17.4, 18.8, 19.4, 19.9, 20.5, 21.2, 21.3, 22.0, 22.6, 22.7, 23.2, 23.6, 24.1, 24.5, 25.1, 25.4, 26.1, 26.6, 26.9, 27.3, 27.8, 28.5, 28.9, 29.6, 29.8, 30.3, 31.9, 34.2, 36.2, 37.4 degree diffraction peak.
  • the X-ray powder diffraction pattern of the Aforana Form XII is substantially as shown in FIG. 11.
  • the differential scanning calorimetry curve of the Aforana crystal form XII of the present invention has an endothermic peak at 101°C.
  • the X-ray powder diffraction pattern of the Aforana crystal form XIII of the present invention contains 2 ⁇ angles of 11.3, 11.8, 12.5, 13.5, 15.3, 16.5, 17.0, 18.8, 19.5, 20.3, 21.2, 21.7, 22.0, 22.3, 22.7, 23.1, 24.0, 24.4, 25.2, 25.5, 27.2, 28.5, 29.4, 31.0, 36.3 degree diffraction peaks.
  • the X-ray powder diffraction pattern of the Aforana Form XIII is substantially as shown in FIG. 12.
  • the differential scanning calorimetry curve of the Aforana crystal form XIII of the present invention has an endothermic peak at 83°C.
  • the X-ray powder diffraction pattern of the Aforana crystal form XIV of the present invention contains 2 ⁇ angles of 3.9, 9.6, 11.5, 12.1, 12.9, 16.4, 17.7, 18.9, 19.3, 20.2, 22.5, 23.1, 23.9, 24.3, 25.1, 27.1, 27.6, 29.5, 37.4 degree diffraction peaks.
  • the X-ray powder diffraction pattern of the Aforana crystal form XIV is substantially as shown in FIG. 13.
  • the differential scanning calorimetry curve of the Aforana crystal form XIV of the present invention has endothermic peaks at 77°C and 134°C.
  • the X-ray powder diffraction pattern of the Aforana crystal form XV of the present invention contains 2 ⁇ angles of 4.0, 7.8, 9.8, 11.8, 12.5, 13.2, 15.7, 16.8, 17.4, 18.0, 18.3, 18.8, 19.6, 20.5, 21.4, 21.8, 23.0, 23.6, 23.9, 24.4, 24.8, 25.2, 25.5, 25.9, 27.6, 28.2, 29.5, 29.8, 30.2, 32.3, 36.9 degree diffraction peaks.
  • the X-ray powder diffraction pattern of the Aforana crystal form XV is substantially as shown in FIG. 14.
  • the differential scanning calorimetry curve of the Aforana crystal form XV of the present invention has an endothermic peak at 104°C.
  • the X-ray powder diffraction pattern of the Aforana crystal form XVI of the present invention contains 2 ⁇ angles of 11.0, 12.1, 12.7, 14.7, 16.4, 18.8, 19.2, 20.5, 22.1, 24.4, 25.4, 26.9, 35.9 degrees.
  • the X-ray powder diffraction pattern of the Aforana crystal form XVI is basically as shown in FIG. 15.
  • the differential scanning calorimetry curve of the Aforana crystal form XVI of the present invention has an endothermic peak at 73°C.
  • the X-ray powder diffraction pattern of Aforana Form XVII of the present invention contains 2 ⁇ angles of 3.9, 7.8, 9.9, 11.2, 12.3, 12.9, 15.5, 16.7, 17.0, 17.2, 17.6, 19.4, 20.0, 20.4, 20.8, 21.9, 22.1, 22.5, 22.9, 23.1, 23.4, 24.2, 24.8, 25.9, 27.4, 27.8, 29.6, 31.4, 33.1, 37.0, 37.6 degree diffraction peaks.
  • the X-ray powder diffraction pattern of the Aforana Form XVII is substantially as shown in FIG. 16.
  • the differential scanning calorimetry curve of the Aforana crystal form XVII of the present invention has an endothermic peak at 96°C.
  • the X-ray powder diffraction pattern of the Aforana crystal form XVIII of the present invention contains 2 ⁇ angles of 3.9, 7.3, 9.9, 11.4, 12.3, 12.9, 15.6, 16.9, 18.1, 19.2, 20.1, 20.9, 21.2, 21.6, 22.0, 22.6, 24.3, 25.0, 26.5, 27.2, 29.4, 31.7, 33.4, 35.0 degree diffraction peaks.
  • the X-ray powder diffraction pattern of the Aforana crystal form XVIII is substantially as shown in FIG. 17.
  • the differential scanning calorimetry curve of the Aforana crystal form XVIII of the present invention has an endothermic peak at 89°C.
  • the X-ray powder diffraction pattern of the Aforana crystal form XIX of the present invention contains 2 ⁇ angles of 4.0, 9.9, 11.1, 11.8, 12.1, 12.7, 13.2, 15.2, 16.9, 17.5, 18.1, 19.1, 19.8, 20.6, 21.2, 21.7, 21.9, 22.6, 23.4, 23.6, 24.1, 24.4, 24.7, 26.1, 26.9, 27.1, 28.3, 29.1, 29.6, 30.7, 31.5, 32.9, 34.1, 34.6, 35.6 degree diffraction peaks.
  • the X-ray powder diffraction pattern of the Aforana crystal form XIX is basically as shown in FIG. 18.
  • the differential scanning calorimetry curve of the Aforana crystal form XIX of the present invention has an endothermic peak at 140°C.
  • the X-ray powder diffraction pattern of Aforana Form XX of the present invention contains 2 ⁇ angles of 4.4, 7.6, 8.7, 10.8, 12.6, 13.2, 14.3, 19.3, 20.0, 23.2, 25.2, 27.2 degree diffraction peak.
  • the X-ray powder diffraction pattern of the Aforana crystal form XX is substantially as shown in FIG. 19.
  • the differential scanning calorimetry curve of the Aforana crystal form XX of the present invention has an endothermic peak at 106°C.
  • the Aforana crystal form XXI of the present invention has an X-ray powder diffraction pattern containing diffraction peaks with 2 ⁇ angles of 15.8, 18.0, 18.4, 19.6 and 21.8 degrees.
  • the X-ray powder diffraction pattern of the Aforana crystal form XXI includes diffraction peaks with 2 ⁇ angles of 4.7, 15.8, 16.8, 18.0, 18.4, 19.3, 19.6 and 21.8 degrees.
  • the Aforana crystal form XXI has an X-ray powder diffraction pattern including 2 ⁇ angles of 4.7, 9.3, 11.2, 15.8, 16.8, 18.0, 18.4, 19.3, 19.6, 19.9, 20.8 , 21.2, 21.4, 21.8, 23.0, 23.6, 24.0, 26.4, 28.0 and 29.7 degree diffraction peaks.
  • the Aforana crystal form XXI has an X-ray powder diffraction pattern including 2 ⁇ angles of 4.7, 5.7, 9.3, 10.8, 11.2, 12.1, 12.8, 13.8, 14.0, 15.1, 15.8 , 16.8, 18.0, 18.4, 19.3, 19.6, 19.9, 20.8, 21.2, 21.4, 21.8, 23.0, 23.6, 24.0, 24.5, 25.3, 26.0, 26.4, 27.2, 28.0, 29.7 and 31.4 degree diffraction peaks.
  • the X-ray powder diffraction pattern of the Aforana crystal form XXI is substantially as shown in FIG. 20.
  • the differential scanning calorimetry curve of the Aforana crystal form XXI of the present invention has an endothermic peak at 116°C-126°C. In some embodiments, the differential scanning calorimetry curve of the crystalline form XXI has an endothermic peak at 118°C-123°C. In some embodiments, the differential scanning calorimetry curve of the crystalline form XXI has an endothermic peak at 121°C. In some embodiments, the differential scanning calorimetry curve of the crystalline form XXI is substantially as shown in FIG. 21.
  • thermogravimetric analysis curve shows that the crystalline form XXI loses 0.7% in the temperature range of 30°C to 150°C.
  • the crystalline form XXI contains water.
  • the crystalline form XXI contains water, and the molar ratio of Aforana to water is about 4:1.
  • the thermogravimetric analysis curve of the crystalline form XXI is substantially as shown in FIG. 22.
  • the Aforana crystal form XXII of the present invention contains diffraction peaks with 2 ⁇ angles of 10.7, 13.2, 17.5, 19.3 and 25.2 degrees in the X-ray powder diffraction pattern.
  • the X-ray powder diffraction pattern of the Aforana Form XXII includes diffraction peaks with 2 ⁇ angles of 4.4, 10.7, 13.2, 17.5, 19.3 and 25.2 degrees.
  • the Aforana crystal form XXII has an X-ray powder diffraction pattern including 2 ⁇ angles of 4.4, 10.7, 12.6, 13.2, 15.7, 17.5, 19.3, 19.9, 23.2, 25.2, and 26.5. Degree of diffraction peaks.
  • the Aforana crystal form XXII has an X-ray powder diffraction pattern including 2 ⁇ angles of 4.4, 6.6, 7.6, 8.7, 10.7, 12.6, 13.2, 14.2, 15.7, 16.7, 17.5 , 18.1, 19.3, 19.9, 21.4, 23.2, 25.2, 26.5 and 27.4 degree diffraction peaks.
  • the X-ray powder diffraction pattern of the Aforana crystal form XXII is substantially as shown in FIG. 23.
  • the differential scanning calorimetry curve of the Aforana crystal form XXII of the present invention has an endothermic peak at 108°C-118°C. In some embodiments, the differential scanning calorimetry curve of the crystalline form XXII has an endothermic peak at 110°C-116°C. In some embodiments, the differential scanning calorimetry curve of the crystalline form XXII has an endothermic peak at 113°C. In some embodiments, the differential scanning calorimetry curve of the crystal form XXII is substantially as shown in FIG. 24.
  • thermogravimetric analysis curve shows that the crystal form XXII loses 0.1% in the temperature range of 30°C to 150°C.
  • thermogravimetric analysis curve of the Aforana crystal form XXII is substantially as shown in FIG. 25.
  • the amorphous form of Aforana of the present invention has an X-ray powder diffraction pattern, as shown in FIG. 26.
  • the second aspect of the present invention provides a method for preparing the new crystal form of Aforana.
  • the preparation method of the new crystal form is simple, has good repeatability, and is suitable for industrial production.
  • the present invention provides a method for preparing the crystal form I of Aforana.
  • the preparation method of the crystal form I of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
  • a method for preparing crystal form I of aforana comprises: dissolving solid aforana in methyl ethyl ketone, cooling to precipitate crystals, filtering and drying to obtain crystal form I product.
  • the Aforana solid is dissolved in methyl ethyl ketone, and after the solution is clear, an anti-solvent is added dropwise to precipitate crystals, filtered and dried to obtain the crystal form I product.
  • the anti-solvent is one or more of n-heptane, n-hexane, cyclohexane, and isopropyl ether; in some specific embodiments, the anti-solvent is dripped It is a positive drop; in some embodiments, the anti-solvent is added in a reverse drop.
  • Aphrana is dissolved in methyl ethyl ketone and volatilized to obtain the crystal form I product.
  • the present invention provides a method for preparing the crystal form II of Aforana.
  • the preparation method of the crystal form II of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrialized production.
  • a method for preparing crystal form II of aforana includes: dissolving aforana in a good solvent, slowly adding purified water to precipitate crystals after dissolving, filtering and drying to obtain crystal form II product.
  • the good solvent is one or more of acetone, isopropanol, and acetonitrile.
  • the present invention provides a preparation method of the Aforana crystal form III.
  • the preparation method of the crystal form III of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
  • a method for preparing crystal form III of aforana comprising: dissolving aforana in dichloromethane, dissolving and adding an anti-solvent to precipitate crystals, filtering and drying to obtain crystal form III; according to the present invention
  • the anti-solvent is dimethyl carbonate.
  • Aforana is dissolved in a mixed solvent, and after dissolving, the temperature is lowered to crystallize, filtered, and dried to obtain the crystal form III product; according to the embodiment of the present invention, the mixed solvent is dichloromethane Mixed solvent with dimethyl carbonate.
  • Aforana is dissolved in a mixed solvent to prepare a crystal form III product.
  • the organic solvent is one or more of dimethyl carbonate, methyl ethyl ketone, and isopropyl acetate.
  • the mixed solvent is a mixed solvent of dimethyl carbonate, methyl ethyl ketone, and isopropyl acetate; in some specific embodiments, the preparation method is suspension; in some specific embodiments, In an embodiment, the preparation method is volatilization.
  • the present invention provides a method for preparing the aforana crystal form IV.
  • the preparation method of the crystal form IV of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
  • a method for preparing crystal form IV of aforana includes: dissolving aforana in n-butanol and volatilizing to obtain crystal form IV product.
  • Aforana is dissolved in n-butanol, and after the solution is clear, an anti-solvent is added dropwise to precipitate crystals, filtered, and dried to obtain a crystal form IV product.
  • the anti-solvent is one or more of n-heptane, n-hexane, cyclohexane, and isopropyl ether; in some specific embodiments, the dropping method is normal drop ; In some specific embodiments, the dripping method is reverse dripping.
  • Aforana is dissolved in an organic solvent, the crystals are precipitated by cooling, filtered, and dried to obtain the crystal form IV product.
  • the organic solvent is one or more of n-butanol, ethylene glycol monomethyl ether, and isopropyl ether.
  • the present invention provides a preparation method of the Aforana crystal form V.
  • the preparation method of the crystal form V of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
  • a method for preparing crystal form V of Aforana includes: dissolving Aforana in 1,4-dioxane, back-dripping water to precipitate solids, filtering and drying to obtain crystal form V products.
  • the present invention provides a preparation method of the Aforana crystal form VI.
  • the preparation method of the crystal form VI of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
  • a method for preparing crystal form VI of aforana includes: dissolving aforana in butyl formate and volatilizing to obtain crystal form VI product.
  • aforana is dissolved in butyl formate, after dissolving, n-heptane or isopropyl ether is added to precipitate crystals, filtered and dried to obtain the crystal form VI product.
  • the addition method is positive drop; in some embodiments, the addition method is reverse drop.
  • the present invention provides a method for preparing the aforana crystal form VIII.
  • the preparation method of the crystal form VIII of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
  • a method for preparing crystal form VIII of Aforana includes: dissolving Aforana in an organic solvent and volatilizing to obtain crystal form VIII product.
  • the organic solvent is one or more of acetonitrile, methyl tert-butyl ether, methanol, and isopropyl ether.
  • the organic solvent is a mixed solvent of methanol and isopropyl ether.
  • the present invention provides a preparation method of the Aforana crystal form IX.
  • the preparation method of the crystal form IX of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
  • a method for preparing crystal form IX of Aforana includes: suspending Aforana in water and an organic solvent, filtering and drying to obtain crystal form IX product.
  • the organic solvent is one or more of isopropanol, N-methylpyrrolidone, and sec-butanol.
  • Aforana is dissolved in an organic solvent such as isopropanol and cooled to precipitate a solid, filtered, and dried to obtain the crystal form IX product.
  • the present invention provides a method for preparing the Aforana crystal form X.
  • the preparation method of the crystal form X of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
  • a method for preparing crystal form X of aforana comprising: suspending aforana in a mixed solvent of water and ethylene glycol dimethyl ether for 2h-20h at room temperature, filtering and drying to obtain crystal form X product.
  • the present invention provides a method for preparing the crystal form XI of Aforana.
  • the preparation method of the crystal form XI of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
  • a method for preparing crystal form IX of Aforana includes: dissolving Aforana in an organic solvent, cooling to precipitate a solid, filtering and drying to obtain crystal form XI product.
  • the organic solvent is one or more of isopropyl acetate and n-heptane.
  • the organic solvent is a mixed solvent of isopropyl acetate and n-heptane.
  • Aforana is dissolved in isopropyl acetate, the solution is slowly added dropwise to n-heptane until crystals are precipitated, filtered and dried to obtain the crystalline form XI product.
  • the present invention provides a method for preparing the Aforana crystal form XII.
  • the preparation method of the crystal form XII of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
  • a method for preparing the crystal form XII of aforana includes: dissolving the aforana in ethyl acetate, slowly dripping the clear solution into toluene until the crystals are precipitated, filtering and drying to obtain the crystal form XII product.
  • the present invention provides a preparation method of the Aforana crystal form XIII.
  • the preparation method of the crystal form XIII of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
  • a method for preparing Aforana crystal form XIII including: dissolving Aforana in ethylene glycol dimethyl ether, slowly adding the dissolved clear liquid to purified water until crystals are precipitated, filtering and drying to obtain crystals Type XIII products.
  • aforana is suspended in a binary solvent of ethylene glycol dimethyl ether and purified water for 2-24 hours at room temperature, filtered and dried to obtain the crystal form XIII product.
  • the present invention provides a method for preparing the Aforana crystal form XIV.
  • the preparation method of the crystal form XIV of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
  • a method for preparing crystal form XIV of aforana includes: dissolving aforana in toluene, cooling to precipitate a solid, and filtering to obtain crystal form XIV product.
  • the ratio of the aforana to the volume of toluene used is 10 mg/mL to 200 mg/mL; according to the embodiment of the present invention, the dissolution temperature is 40° C. to 80° C.; according to the present invention
  • the cooling temperature is -20°C to 10°C.
  • the present invention provides a method for preparing the Aforana crystal form XV.
  • the preparation method of the crystal form XV of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
  • a method for preparing the crystal form XV of Aforana includes: dissolving Aforana in a methanol organic solvent to precipitate a solid, filtering and drying to obtain the crystal form XV product.
  • the organic solvent is one or more of methanol and 1,4-dioxane.
  • the organic solvent is a mixed solvent of 1,4-dioxane and water; in some specific embodiments, the solid precipitation operation step is volatilization; in some specific embodiments, the The operation step for the precipitation of solids is cooling.
  • Aforana is dissolved in 1,4-dioxane, and purified water is slowly added dropwise to precipitate a solid after the solution is cleared, filtered and dried to obtain the crystalline form XV product.
  • the present invention provides a preparation method of the Aforana crystal form XVI.
  • the preparation method of the crystal form XVI of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrialized production.
  • a method for preparing crystal form XVI of Aforana includes: dissolving Aforana in 1-hexanol, cooling to precipitate a solid, filtering and drying to obtain crystal form XVI product.
  • the present invention provides a method for preparing the Aforana crystal form XVII.
  • the preparation method of the crystal form XVII of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
  • a method for preparing crystal form XVII of Aforana includes: dissolving Aforana in an organic solvent, cooling to precipitate a solid, filtering and drying to obtain crystal form XVII product.
  • the organic solvent is one or more of n-propanol, trifluoroethanol, and ethanol; according to the embodiment of the present invention, the organic solvent is n-propanol, trifluoroethanol , A mixed solvent of ethanol and water.
  • Aforana is dissolved in trifluoroethanol, and purified water is slowly added dropwise until the solid precipitates out, filtered and dried to obtain the crystal form XVII product.
  • the dripping method may also be reverse dripping.
  • the present invention provides a preparation method of the Aforana crystal form XVIII.
  • the preparation method of the crystal form XVIII of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
  • a method for preparing crystal form XVIII of aforana comprises: dissolving aforana in a mixed solvent of acetone and water, cooling to precipitate a solid, filtering, and drying to obtain a product of crystal form XVIII.
  • the present invention provides a method for preparing the Aforana crystal form XIX.
  • the preparation method of the crystal form XIX of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
  • a method for preparing the crystal form XIX of aforana includes: dissolving aforana in methanol, cooling to precipitate a solid, filtering, and drying to obtain the crystal form XIX product.
  • Aforana is dissolved in N-methylpyrrolidone, the solution is slowly added dropwise to purified water until a solid precipitates, filtered, and dried to obtain the crystal form XIX product.
  • the present invention provides a preparation method of the Aforana crystal form XX.
  • the preparation method of the crystal form XX of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrialized production.
  • a method for preparing Aforana crystal form XX includes: vacuum drying Aforana crystal form XIV product at 50° C. for 20 hours to obtain crystal form XX product.
  • the present invention provides a preparation method of the Aforana crystal form XXI.
  • the preparation method of the crystal form XXI of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
  • a method for preparing Aforana crystal form XXI includes: dissolving Aforana in an organic alcohol solvent under certain temperature conditions, then mixing with water, stirring to precipitate solids, filtering, and heating at 55°C-65°C. Vacuum drying at °C to obtain crystal form XXI.
  • a method for preparing Aforana Form XXI includes: dissolving Aforana in an organic alcohol solvent at a certain temperature, adding water, stirring to precipitate solids, filtering, and heating at 60°C. Under vacuum drying conditions, the crystal form XXI was obtained.
  • the water includes purified water. In some embodiments, the water is purified water.
  • the organic alcohol solvent includes methanol or ethanol.
  • the organic alcohol solvent includes methanol; in some embodiments, the organic alcohol solvent includes ethanol. In some embodiments, the organic alcohol solvent is ethanol and/or methanol.
  • the amount of water is 1-10 times that of the alcohol solvent.
  • the amount of water used is 2-10 times that of alcoholic solvents; in some embodiments, the amount of water used is 3-10 times that of alcoholic solvents; in some embodiments, the amount of water used is alcoholic solvents.
  • the amount of water is 5-10 times that of alcohol solvents; in some embodiments, the amount of water is 6-10 times that of alcohol solvents; in some embodiments , The amount of water is 7-10 times that of alcohol solvents; in some embodiments, the amount of water is 8-10 times that of alcohol solvents; in some embodiments, the amount of water is 9-10 times that of alcohol solvents Times; In some embodiments, the amount of water is 1 times that of alcohol solvents; in some embodiments, the amount of water is twice that of alcohol solvents; in some embodiments, the amount of water is that of alcohol solvents 3 times; in some embodiments, the amount of water used is 4 times that of alcohol solvents; in some embodiments, the amount of water used is 5 times that of alcohol solvents; in some embodiments, the amount of water used is alcohol solvents In some embodiments, the amount of water is 7 times that of alcohol solvents; in some embodiments, the amount of water is 8 times that of alcohol solvents; in some embodiments, the amount of water is alcohol solvents In some embodiments, the amount of
  • the stirring time is 4h-24h.
  • the stirring time is 4h-20h; in some embodiments, the stirring time is 4h-16h; in some embodiments, the stirring time is 4h-12h; in some embodiments ,
  • the stirring time is 4h-8h; in some embodiments, the stirring time is 4h; in some embodiments, the stirring time is 8h; in some embodiments, the stirring time is 12h; In some embodiments, the stirring time is 16h; in some embodiments, the stirring time is 24h.
  • the vacuum drying time is 16h-40h.
  • the vacuum drying time is 16h-36h; in some embodiments, the vacuum drying time is 16h-30h; in some embodiments, the vacuum drying time is 16h-24h; in some embodiments, the vacuum drying time is 16h-24h; In an embodiment, the vacuum drying time is 16h; in some embodiments, the vacuum drying time is 24h; in some embodiments, the vacuum drying time is 30h; in some embodiments, the vacuum drying The time is 36h; in some embodiments, the vacuum drying time is 40h.
  • the temperature is room temperature to 80°C. In some embodiments, the temperature is between room temperature and 80°C. In some embodiments, the temperature is 20°C-80°C. In some embodiments, the temperature is from room temperature to 70°C; in some embodiments, the temperature is from room temperature to 60°C; in some embodiments, the temperature is from room temperature to 50°C; in some embodiments , The temperature is room temperature-40°C; in some embodiments, the temperature is 80°C; in some embodiments, the temperature is 75°C; in some embodiments, the temperature is 70°C; In some embodiments, the temperature is 65°C; in some embodiments, the temperature is 60°C; in some embodiments, the temperature is 55°C; in some embodiments, the temperature is 50°C In some embodiments, the temperature is 45°C; in some embodiments, the temperature is 40°C; in some embodiments, the temperature is room temperature.
  • a method for preparing the crystal form XXI of aforana includes: dissolving aforana in ethanol at 60° C., adding purified water, and stirring to obtain the crystal form XXI.
  • a method for preparing the crystal form XXI of Aforana includes: dissolving Aforana in methanol at room temperature, adding purified water, and stirring to obtain the crystal form XXI.
  • the present invention provides a preparation method of the Aforana crystal form XXII.
  • the preparation method of the crystal form XXII of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
  • a method for preparing crystal form XXII of Aforana includes: drying crystal form VI of Aforana in vacuum at 50°C-70°C for 16h-48h to obtain crystal form XXII.
  • a method for preparing the crystal form of Aforana XXII includes: drying the crystal form of Aforana VI under vacuum at 60° C. for 24 hours to obtain the crystal form XXII.
  • the invention provides a preparation method of the amorphous Aforana.
  • the amorphous preparation method of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
  • a method for preparing amorphous afrana comprising: dissolving afrana in a good solvent, adding purified water dropwise after dissolving, separating solids, filtering and drying to obtain an amorphous product; according to the present invention
  • the good solvent is one or more of methanol, ethanol, dimethylformamide, and dimethyl sulfoxide.
  • the dripping method is forward dripping; in some specific embodiments, the dripping method is reverse dripping.
  • Aforana is dissolved in dichloromethane, the temperature is lowered, and an amorphous form is precipitated.
  • Aforana is dissolved in an organic solvent and evaporated to dryness to obtain an amorphous product.
  • the organic solvent is methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, acetone, butanone, ethyl acetate, butyl formate, One or more of ethyl formate, isopropyl acetate, tetrahydrofuran, acetonitrile, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, dichloromethane, methyl isobutyl ketone cyclohexane, and toluene.
  • the volatilization process is rotary evaporation; in some specific embodiments, the volatilization process is volatilization.
  • Crystal form or amorphous form can be identified by a variety of technical means, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point method, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) ), nuclear magnetic resonance, Raman spectroscopy, X-ray single crystal diffraction, dissolution calorimetry, scanning electron microscope (SEM), quantitative analysis, solubility and dissolution rate, etc.
  • XRPD X-ray powder diffraction
  • IR infrared absorption spectroscopy
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • Raman spectroscopy X-ray single crystal diffraction
  • dissolution calorimetry scanning electron microscope (SEM), quantitative analysis, solubility and dissolution rate, etc.
  • X-ray powder diffraction can detect the change of crystal form, crystallinity, crystal structure state and other information, and it is a common method to identify crystal form.
  • the peak position of the XRPD spectrum mainly depends on the structure of the crystal form and is relatively insensitive to experimental details, while its relative peak height depends on many factors related to sample preparation and instrument geometry. Therefore, in some embodiments, the crystalline form of the present invention is characterized by an XRPD pattern with certain peak positions, which is substantially as shown in the XRPD pattern provided in the drawings of the present invention.
  • the 2 ⁇ measurement of the XRPD pattern may have experimental errors.
  • the 2 ⁇ measurement of the XRPD pattern may be slightly different between different instruments and different samples, so the 2 ⁇ value cannot be regarded as absolute. According to the condition of the instrument used in this experiment, the diffraction peak has an error tolerance of ⁇ 0.2°.
  • Differential scanning calorimetry is a technique that measures the energy difference between a sample and an inert reference material (commonly used ⁇ -Al 2 O 3) with temperature changes under program control through continuous heating or cooling.
  • the melting peak height of the DSC curve depends on many factors related to sample preparation and instrument geometry, and the peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the crystalline form of the present invention is characterized by a DSC chart with characteristic peak positions, which is substantially as shown in the DSC chart provided in the accompanying drawings of the present invention.
  • the DSC spectrum may have experimental errors.
  • the peak position and peak value of the DSC spectrum may be slightly different between different instruments and different samples. Therefore, the peak position or the value of the peak value of the DSC endothermic peak cannot be regarded as absolute. According to the condition of the instrument used in this experiment, the melting peak has an error tolerance of ⁇ 3°C.
  • Thermogravimetric analysis is a technique for measuring the quality of a substance with temperature changes under program control. It is suitable for checking the loss of solvent in the crystal or the process of sample sublimation and decomposition. It can be inferred that the crystal contains crystal water or crystal solvent. Case.
  • the quality change displayed by the TGA curve depends on many factors such as sample preparation and instrument; the quality change of TGA detection varies slightly between different instruments and different samples. According to the condition of the instrument used in this experiment, there is an error tolerance of ⁇ 0.1% for the mass change.
  • substantially as shown in the figure refers to a certain "crystal form” that is substantially pure and has at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least in the X-ray powder diffraction pattern. 90%, or at least 95%, or at least 99% of the peaks appear in the X-ray powder diffraction pattern given.
  • the content of a certain crystal form in the sample gradually decreases, some diffraction peaks attributable to the crystal form in the X-ray powder diffraction pattern may be reduced due to the detection sensitivity of the instrument.
  • the diffraction angle 2 ⁇ also called 2theta or diffraction peak
  • the diffraction angle 2 ⁇ also called 2theta or diffraction peak
  • the term "diffraction peak" refers to a feature that is not attributed to background noise by those skilled in the art.
  • room temperature refers to a temperature of about 20°C to 35°C or about 23°C to 28°C or about 25°C.
  • mg/mL means milligram/ml
  • h means hour
  • g means gram
  • ml means milliliter
  • °C means degrees Celsius
  • mL/min means milliliters/minute.
  • Figure 1 shows the XRPD spectrum of Form I.
  • Figure 2 shows the XRPD spectrum of Form II.
  • Figure 3 shows the XRPD spectrum of Form III.
  • Figure 4 shows the XRPD spectrum of Form IV.
  • Figure 5 shows the XRPD spectrum of Form V.
  • Figure 6 shows the XRPD spectrum of Form VI.
  • Figure 7 shows the XRPD spectrum of Form VIII.
  • Figure 8 shows the XRPD spectrum of Form IX.
  • Figure 9 shows the XRPD spectrum of Form X.
  • Figure 10 shows the XRPD spectrum of Form XI.
  • Figure 11 shows the XRPD spectrum of Form XII.
  • Figure 12 shows the XRPD spectrum of Form XIII.
  • Figure 13 shows the XRPD spectrum of Form XIV.
  • Figure 14 shows the XRPD spectrum of Form XV.
  • Figure 15 shows the XRPD spectrum of Form XVI.
  • Figure 16 shows the XRPD spectrum of Form XVII.
  • Figure 17 shows the XRPD spectrum of Form XVIII.
  • Figure 18 shows the XRPD spectrum of Form XIX.
  • Figure 19 shows the XRPD spectrum of Form XX.
  • Figure 20 shows the XRD spectrum of the crystalline form XXI.
  • Figure 21 shows the DSC spectrum of the crystalline form XXI.
  • Figure 22 shows the TGA spectrum of Form XXI.
  • Figure 23 shows the XRD spectrum of Form XXII.
  • Figure 24 shows the DSC spectrum of Form XXII.
  • Figure 25 shows the TGA spectrum of Form XXII.
  • Figure 26 shows the XRPD spectrum of the amorphous form.
  • the reagents used in the present invention can be purchased from the market or can be prepared by the method described in the present invention.
  • crystal forms IX, XIX, XXI and XXII were investigated, including high temperature test, high humidity test and strong light irradiation test, to investigate the stability of the crystal form.
  • High temperature test Take appropriate amounts of the above crystal samples, lay them flat in a weighing bottle, and place them in a constant temperature and humidity box at 60°C ⁇ 5°C, RH 75 ⁇ 5%, and then take the samples in 0, 5, and 15 days. About 100 mg, the crystal form was tested by powder X-ray powder diffraction (XRPD), and the results are shown in Table 1.
  • High humidity test Take appropriate amounts of the above-mentioned crystal samples, and place them in a weighing bottle, place them in a constant temperature and humidity box at 25°C, RH 92.5 ⁇ 5%, and then take about 100mg of the above samples on 0, 5, and 15 days. , Using powder X-ray powder diffraction (XRPD) to test its crystal form, the results are shown in Table 1.
  • XRPD powder X-ray powder diffraction
  • Illumination test Take appropriate amounts of the above crystal samples and spread them in a weighing bottle. Place them in a constant temperature and humidity box (25°C, RH 60) with visible light 4500Lux ⁇ 500Lux(VIS) and ultraviolet light % ⁇ 5%), and then about 100 mg of the above sample was taken at 0, 5, and 15 days, and the crystal form was tested by powder X-ray powder diffraction (XRPD). The results are shown in Table 1.
  • Table 1 Stability test results of crystal forms IX, XIX, XXI and XXII
  • the crystal form XXI, the crystal form XXII and the crystal form A and the crystal form B disclosed in CN102947278B were mixed and stirred in water at room temperature, 37°C and 60°C for 24 hours, respectively.
  • the crystal form of the obtained solid was filtered, dried and tested, and the results are shown in Table 2 below.
  • crystal form B transforms into crystal form XXI with high crystallinity, indicating that the crystal
  • the stability of Form XXI is higher than that of Form A and Form B, that is, the order of stability is: Form XXI>Form B>Form XXII>Form A.
  • Table 3 Bulk density, tap density and Carr index of crystal form B and crystal form XXI and XXII samples
  • the DSC method parameters are as follows:
  • the TGA method parameters are as follows:

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Abstract

La présente invention concerne le domaine technique de l'industrie pharmaceutique et chimique, et plus particulièrement, une forme cristalline d'un inhibiteur GABA et son procédé de préparation. La forme cristalline GABA présente les avantages d'une bonne stabilité de produit, d'une cristallinité élevée, etc. En outre, le procédé de préparation de la forme cristalline est simple, présente une bonne répétabilité et est approprié pour une production industrielle.
PCT/CN2021/100649 2020-06-19 2021-06-17 Forme cristalline d'inhibiteur gaba et son procédé de préparation WO2021254445A1 (fr)

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Citations (4)

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Publication number Priority date Publication date Assignee Title
CN102947278A (zh) * 2010-05-27 2013-02-27 杜邦公司 4-[5-[3-氯-5-(三氟甲基)苯基]-4,5-二氢-5-(三氟甲基)-3-异*唑基]-n-[2-氧代-2-[(2,2,2-三氟乙基)氨基]乙基]-1-萘甲酰胺的晶形
CN109195955A (zh) * 2016-04-06 2019-01-11 梅里亚股份有限公司 用于制备对映异构地富集的异噁唑啉化合物-(S)-afoxolaner的结晶甲苯溶剂化物的方法
CN111032634A (zh) * 2017-04-05 2020-04-17 勃林格殷格翰动物保健美国公司 (s)-阿福拉纳的晶型
CN112457267A (zh) * 2020-11-27 2021-03-09 麦蒂辛生物医药科技成都有限公司 一种异噁唑啉杀虫剂的制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102947278A (zh) * 2010-05-27 2013-02-27 杜邦公司 4-[5-[3-氯-5-(三氟甲基)苯基]-4,5-二氢-5-(三氟甲基)-3-异*唑基]-n-[2-氧代-2-[(2,2,2-三氟乙基)氨基]乙基]-1-萘甲酰胺的晶形
CN109195955A (zh) * 2016-04-06 2019-01-11 梅里亚股份有限公司 用于制备对映异构地富集的异噁唑啉化合物-(S)-afoxolaner的结晶甲苯溶剂化物的方法
CN111032634A (zh) * 2017-04-05 2020-04-17 勃林格殷格翰动物保健美国公司 (s)-阿福拉纳的晶型
CN112457267A (zh) * 2020-11-27 2021-03-09 麦蒂辛生物医药科技成都有限公司 一种异噁唑啉杀虫剂的制备方法

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