WO2016155560A1 - Sel d'acide p-toluènesulfonique de lenvatinib, forme cristalline et méthode de préparation de cette dernière - Google Patents

Sel d'acide p-toluènesulfonique de lenvatinib, forme cristalline et méthode de préparation de cette dernière Download PDF

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Publication number
WO2016155560A1
WO2016155560A1 PCT/CN2016/077230 CN2016077230W WO2016155560A1 WO 2016155560 A1 WO2016155560 A1 WO 2016155560A1 CN 2016077230 W CN2016077230 W CN 2016077230W WO 2016155560 A1 WO2016155560 A1 WO 2016155560A1
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WIPO (PCT)
Prior art keywords
toluenesulfonate
crystal
organic solvent
lenvatinib
acetone
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PCT/CN2016/077230
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English (en)
Chinese (zh)
Inventor
高军龙
刘凯
葛文雷
Original Assignee
江苏恒瑞医药股份有限公司
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Application filed by 江苏恒瑞医药股份有限公司 filed Critical 江苏恒瑞医药股份有限公司
Priority to CN201680001858.7A priority Critical patent/CN106660965A/zh
Publication of WO2016155560A1 publication Critical patent/WO2016155560A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • the present invention relates to p-toluenesulfonate of le vartinib, and its type I crystal, and a preparation method and use thereof.
  • Levantinib (Lavantinib, trade name: Lenvima) was approved by the US Food and Drug Administration on February 13, 2015 for the treatment of patients with progressive, differentiated thyroid cancer (DTC). Although the patient received radioactive iodine treatment, the condition progressed (radioactive iodine-refractory disease).
  • Levartinib (Lenvatinib) is an oral multi-receptor tyrosine kinase (RTK) inhibitor with novel binding patterns that are involved in inhibiting other pro-angiogenic and oncogenic signaling pathways involved in tumor proliferation. In addition to RTK, it is also capable of selectively inhibiting the kinase activity of the vascular endothelial growth factor (VEGF) receptor.
  • VEGF vascular endothelial growth factor
  • Levatinib (4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide) is usually used as a mesylate salt
  • the salt has many problems of complex crystal form and instability, and it is necessary to develop a new form of pharmaceutically acceptable salt and its crystal form, in terms of physical properties and kinetics compared with levabinib mesylate Has more excellent properties.
  • the present invention provides a levabinib p-toluenesulfonate, which is represented by the formula (I),
  • the compound of the formula (I) can be obtained by salt formation of lavatinib and p-toluenesulfonic acid.
  • the X-ray powder diffraction pattern is represented by 4.22 (20.91), 4.70 (18.77), 8.26 (10.70), 9.38 (9.42), 9.93 (8.90), 10.83 (8.16), 11.84 (7.47), 12.58 (7.03).
  • the form of use as a raw material is not particularly limited, and any crystal form or amorphous solid may be used.
  • the preparation method of the levacitrin p-toluenesulfonate type I crystal of the present invention is :
  • organic solvent selected from a polar solvent having a carbon number of 3 or less; preferably The polar organic solvent is selected from one or more of a ketone, an alcohol, and a nitrile.
  • the polar organic solvent described in step 1) is selected from the group consisting of methanol, ethanol, isopropanol, acetone, acetonitrile, acetone/acetonitrile, and a particularly preferred organic solvent is acetone/acetonitrile.
  • the method of recrystallization is not particularly limited and can be carried out by a usual recrystallization operation method.
  • the raw material levabinib p-toluenesulfonate can be heated and refluxed in a solvent, dissolved and stirred, and then stirred and crystallized at room temperature. After the crystallization is completed, the desired crystal is obtained by filtration and drying. The crystals thus collected are usually subjected to vacuum drying under reduced pressure at room temperature to achieve the effect of removing the recrystallization solvent.
  • the crystal form of the obtained levotinib p-toluenesulfonate crystal was examined by differential scanning calorimetry (DSC) and X-ray diffraction spectrometry, and the solvent residue of the obtained crystal was examined.
  • the crystals of levotinib p-toluenesulfonate prepared according to the method of the present invention do not contain or contain only a low content of residual solvent, which meets the requirements of the national pharmacopoeia for the residual solvent of the pharmaceutical product, so that the crystal of the present invention can be compared It is used as a pharmaceutical active ingredient.
  • Figure 1 X-ray powder diffraction pattern of type I crystals of levotonib p-toluenesulfonate.
  • Example 2 Determination of the crystal form of the sample of Example 1.
  • the X-ray powder diffraction pattern of the solid sample prepared in Example 1 is shown in Fig. 1, the DSC spectrum is 2, and the sharp melting endothermic peak is 254.79 °C.
  • the sample of the levacitrin p-toluenesulfonate Form I crystal product obtained by the method of Example 1 was placed in a double-layer plastic bag, and the outer layer was sealed with an aluminum foil bag to examine the acceleration (40 ° C ⁇ 2 ° C, RH). Sample stability under conditions of 75% ⁇ 5%) and long-term (30 ° C ⁇ 2 ° C, RH 65% ⁇ 5%). The sampling time was accelerated for 6 months and long-term for 9 months. The purity of HPLC detection is shown in Table 3.

Abstract

L'invention concerne un sel d'acide p-toluènesulfonique de lenvatinib, une forme cristalline et une méthode de préparation de cette dernière. En particulier, l'invention concerne un sel d'acide p-toluènesulfonique de lenvatinib, une forme cristalline I, et une méthode de préparation de cette dernière. La méthode de préparation comprend : la cristallisation solide de tout type de sel d'acide p-toluènesulfonique de lenvatinib, cristallin ou amorphe, dans un unique solvant organique ou un solvant organique mélangé de ce dernier pour obtenir la forme cristalline I de l'acide p-toluènesulfonique de lenvatinib. La forme cristalline I obtenue du sel d'acide p-toluènesulfonique de lenvatinib de la présente invention présente une bonne stabilité polymorphique et une bonne stabilité chimique, et le solvant utilisé pour la cristallisation présente une faible toxicité et a peu de résidu.
PCT/CN2016/077230 2015-03-27 2016-03-24 Sel d'acide p-toluènesulfonique de lenvatinib, forme cristalline et méthode de préparation de cette dernière WO2016155560A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201680001858.7A CN106660965A (zh) 2015-03-27 2016-03-24 乐伐替尼的对甲苯磺酸盐、其结晶形式及制备方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201510141820.7 2015-03-27
CN201510141820 2015-03-27

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WO2016155560A1 true WO2016155560A1 (fr) 2016-10-06

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CN (1) CN106660965A (fr)
WO (1) WO2016155560A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018122780A1 (fr) * 2016-12-29 2018-07-05 Dr. Reddy’S Laboratories Limited Formes solides de mésylate de lenvatinib

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113831283B (zh) * 2021-11-04 2024-04-19 南京科默生物医药有限公司 一种仑伐替尼盐无定形物的制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1890220A (zh) * 2003-12-25 2007-01-03 卫材株式会社 4－(3－氯－4－(环丙基氨基羰基)氨基苯氧基)－7－甲氧基－6－喹啉羧酰胺的盐或其溶剂合物的结晶及其制备方法
CN101001629A (zh) * 2004-09-17 2007-07-18 卫材R&D管理有限公司 药物组合物
CN101233111A (zh) * 2005-06-23 2008-07-30 卫材R&D管理有限公司 4-（3-氯-4-（环丙基氨基羰基）氨基苯氧基）-7-甲氧基-6-喹啉羧酸酰胺的无定形盐及其制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1890220A (zh) * 2003-12-25 2007-01-03 卫材株式会社 4－(3－氯－4－(环丙基氨基羰基)氨基苯氧基)－7－甲氧基－6－喹啉羧酰胺的盐或其溶剂合物的结晶及其制备方法
CN101001629A (zh) * 2004-09-17 2007-07-18 卫材R&D管理有限公司 药物组合物
CN101233111A (zh) * 2005-06-23 2008-07-30 卫材R&D管理有限公司 4-（3-氯-4-（环丙基氨基羰基）氨基苯氧基）-7-甲氧基-6-喹啉羧酸酰胺的无定形盐及其制备方法

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018122780A1 (fr) * 2016-12-29 2018-07-05 Dr. Reddy’S Laboratories Limited Formes solides de mésylate de lenvatinib
CN110248660A (zh) * 2016-12-29 2019-09-17 雷迪博士实验室有限公司 甲磺酸乐伐替尼的固态形式
US11084791B2 (en) 2016-12-29 2021-08-10 Dr. Reddy's Laboratories Limited Solid state forms of Lenvatinib Mesylate

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