WO2016155560A1 - 乐伐替尼的对甲苯磺酸盐、其结晶形式及制备方法 - Google Patents

乐伐替尼的对甲苯磺酸盐、其结晶形式及制备方法 Download PDF

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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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toluenesulfonate
crystal
organic solvent
lenvatinib
acetone
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高军龙
刘凯
葛文雷
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Jiangsu Hengrui Medicine Co Ltd
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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

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  • 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.

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  • Health & Medical Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
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Abstract

本发明公开了乐伐替尼的对甲苯磺酸盐、其结晶形式及制备方法。具体地，本发明公开了乐伐替尼的对甲苯磺酸盐、其I型结晶形式及制备方法，所述制备方法包括将任意晶型或无定型的乐伐替尼对甲苯磺酸盐固体在单一的有机溶剂或者它们的混合有机溶剂中结晶得到乐伐替尼对甲苯磺酸I型结晶。本发明所得到乐伐替尼对甲苯磺酸盐I型结晶具备良好的晶型稳定性和化学稳定性，并且所用结晶溶剂低毒低残留。

Description

乐伐替尼的对甲苯磺酸盐、其结晶形式及制备方法 技术领域
本发明涉及乐伐替尼的对甲苯磺酸盐、及其I型结晶及制备方法和用途。
背景技术
2014年6月，卫材在美国临床肿瘤学会(ASCO)第50届年会上公布了lenvatinib(乐伐替尼、兰伐替尼，商品名：Lenvima)III期SELECT研究的积极数据。该项研究是一项多中心、随机、双盲、安慰剂对照III期研究，调查了口服lenvatinib(24mg)治疗放射性碘131抵抗的分化型甲状腺癌(RR-DTC)的疗效，主要终点为无进展生存期(PFS)，次要终点包括总缓解率(ORR)，总生存期(OS)和安全性。数据表明，与安慰剂组相比，lenvatinib治疗组无进展生存期(PFS)显著延长(18.3个月vs 3.6个月，p＜0.0001)，达到了研究的主要终点。
乐伐替尼(兰伐替尼,Lenvatinib,商品名：Lenvima)于2015年2月13日获美国食品和药物管理局批准用于治疗具有进行性，分化型甲状腺癌(DTC)的患者，这些患者尽管接受了放射性碘治疗，但是病情依然进展(放射性碘难治性疾病)。乐伐替尼(兰伐替尼,Lenvatinib)是一种口服多受体酪氨酸激酶(RTK)抑制剂，具有新颖的结合模式，除抑制参与肿瘤增殖的其他促血管生成和致癌信号通路相关RTK外，还能够选择性抑制血管内皮生长因子(VEGF)受体的激酶活性。
乐伐替尼(4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰胺)在药用时通常以甲磺酸盐存在，但该盐存在晶型复杂，不稳定的多种问题，需要开发新形式的可药用盐及其晶型，和乐伐替尼甲磺酸盐相比，在物性方面和动力学方面具有更优异的性质。
发明内容
本发明提供了一种乐伐替尼对甲苯磺酸盐，其如式(I)所示，
Figure PCTCN2016077230-appb-000001
式(I)所示化合物可由乐伐替尼和对甲苯磺酸成盐得到。
我们考察了乐伐替尼对甲苯磺酸盐在不同结晶条件下得到的一系列结晶产物，对所得结晶产物进行了X-衍射及DSC检测，发现乐伐替尼对甲苯磺酸盐在常规的结晶条件下，可以得到一种稳定性良好的晶型，我们称其为I型结晶。本申请中的I型结晶的DSC图谱显示在254.79℃附近有熔融吸热峰，X-射线粉末衍射图谱如图1所示，使用Cu-Ka辐射，以2θ角度和晶面间距(d值)表示的X-射线粉末衍射图谱，其中在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)，12.98(6.81)，13.81(6.41)，14.60(6.06)，14.88(5.95)，16.24(5.45)，16.48(5.37)，17.04(5.20)，18.16(4.88)，19.15(4.63)，19.46(4.56)，19.73(4.50)，20.13(4.41)，20.66(4.30)，20.98(4.23)，21.76(4.08)，22.77(3.90)，23.24(3.82)，24.00(3.70)，24.85(3.58)，25.85(3.52)，26.42(3.37)，27.48(3.24)，28.24(3.16)，29.07(3.07)，29.47(3.03)，31.13(2.87)，31.44(2.84)，32.26(2.77)和33.28(2.69)有特征峰。
本发明制备I型结晶的方法中，可作为原料使用的存在形态没有特别限定，可以使用任意晶型或无定型固体，本发明的乐伐替尼对甲苯磺酸盐I型结晶的制备方法为：
1)将任意晶型或无定型的乐伐替尼对甲苯磺酸盐固体溶解于有机溶剂或其水溶液中，析晶，所述有机溶剂选自碳原子数小于等于3的极性溶剂；优选所述的极性有机溶剂选自酮类、醇类、腈类的一种或几种
2)过滤结晶并洗涤，干燥。
在本发明优选的实施方案中，步骤1)中所述的极性有机溶剂选自甲醇，乙醇，异丙醇、丙酮、乙腈、丙酮/乙腈，特别优选的有机溶剂为丙酮/乙腈。
重结晶的方法没有特别限定，可以用通常的重结晶操作方法进行。例如，可以将原料乐伐替尼对甲苯磺酸盐在溶剂中加热回流溶解搅拌溶解后，常温搅拌析晶，结晶完成后，经过滤干燥，即可得到所需要的结晶。所滤取的结晶体通常在减压下，常温条件下进行真空干燥，就能达到去除重结晶溶剂的效果。
通过差示扫描热分析(DSC)、X－衍射图谱测定，对得到的乐伐替尼对甲苯磺酸盐结晶体进行了晶型研究，同时对所得结晶的溶剂残留进行了检测。
按照本发明的方法制备的乐伐替尼对甲苯磺酸盐结晶不含有或仅含有较低含量的残留溶剂，符合国家药典规定的有关医药产品残留溶剂的限量要求，因而本发明的结晶可以较好地作为医药活性成分使用。
经研究表明，本发明制备乐伐替尼对甲苯磺酸盐I型结晶在研磨、压力和受热等条件下，晶型稳定性良好，能够满足生产运输储存的药用要求，生产工艺稳定可重复可控，能够适应于工业化生产。
附图说明
图1乐伐替尼对甲苯磺酸盐的I型结晶的X-射线粉末衍射图谱。
图2乐伐替尼对甲苯磺酸盐的I型结晶的DSC图谱。
具体实施方式
以下将结合实施例更详细地解释本发明，本发明的实施例仅用于说明本发明的技术方案，并非限定本发明的实质和范围。
实验所用的测试仪器
1、DSC谱
仪器型号：Mettler Toledo DSC 1 Staree System
吹扫气：氮气
升温速率：10.0℃/min
温度范围：40-350℃
2、X-射线衍射谱
仪器型号：Bruker D8Focus X-射线粉末衍射仪
射线：单色Cu-Kα射线(λ＝1.5406)
扫描方式：θ/2θ，扫描范围：2－40°
电压：40KV，电流：40mA
实施例1：乐伐替尼对甲苯磺酸盐的制备
向10L反应瓶中加入448.92g(2.83mol)对甲苯磺酸一水合物和8.0L丙酮，然后加入840g(1.97mol)乐伐替尼(依专利CN1478078A制备)，加热回流15min，停止加热，搅拌析晶16h，过滤，真空45～55℃干燥5h，得粉色固体1062.1～1121.3g，收率90.0～95.0％。
将34.0L丙酮/乙腈/水(2:2:1；V/V)对甲苯磺酸乐伐替尼加入到50L反应釜中，搅拌下加入800g(1.34mol)对甲苯磺酸乐伐替尼，加热回流溶解，趁热压滤至另一个50L反应釜中，15～25℃搅拌析晶20-21h。过滤，得湿品。将25L丙酮/乙腈/水(2:2:1；V/V)加入到50L反应釜中，并加入所得湿品和30g活性炭，加热回流溶解，趁热压滤至50L反应釜中，搅拌析晶16h，过滤，真空45～55℃干燥20h，得类白色固体440～520g，收率55～65％。(HPLC>98％)1H-NMR(400MHz,DMSO):0.44(m,2H),0.65-0.70(m,3H),2.23(s,3H),2.56-2.62(m,1H),4.08(s,3H),6.97(d,1H),7.11(d,2H),7.28(d,1H),7.37(dd,1H),7.48(d,2H),7.64(d,1H)，7.51(d,1H),7.,94(brs,1H),8.00(brs,1H),8.09(s,1H),8.38(d,1H),8.73(s,1H),9.00(d,1H).13C-NMR(400MHz,DMSO):166.24,162.02,158.52,155.95,153.80,152.11,148.02,135.07,125.49,125.22,122.55,122.32,120.84,114.90,108.38,103.50,56.65,22.83,6.73.ESI/MS:[M+H]＝427.11
实施例2：测定实施例1样品的晶型
实施例1中制得的固体样品X-射线粉末衍射图谱见图1，DSC图谱见2，有尖锐熔融吸热峰254.79℃
实施例3
将按实施例1方法制得的乐伐替尼对甲苯磺酸盐I型结晶进行研磨、压力和受热等特殊稳定性研究，结果表明晶型稳定，详细的实验数据参见下表2：
表2、乐伐替尼对甲苯磺酸盐I型结晶特殊稳定性研究
Figure PCTCN2016077230-appb-000002
实施例4
将按实施例1方法制得的乐伐替尼对甲苯磺酸盐I型结晶产物样品放置在双层塑料袋中，外层再用铝箔袋密封，考察在加速(40℃±2℃，RH 75％±5％)条件下和长期(30℃±2℃，RH 65％±5％)条件下样品的稳定性。考察取样时间为加速6个月，长期9个月，HPLC检测纯度见表3。
表3、乐伐替尼对甲苯磺酸盐I型结晶样品的稳定性
Figure PCTCN2016077230-appb-000003
稳定性考察结果表明，乐伐替尼对甲苯磺酸盐I型结晶样品，经高温和高湿条件下的稳定性比较发现，高湿、高温对产品的质量影响不大，说明其具有较好的稳定性。

Claims (7)

  1. 式(I)所示的乐伐替尼对甲苯磺酸盐，
    Figure PCTCN2016077230-appb-100001
  2. 乐伐替尼对甲苯磺酸盐的I型结晶，其特征在于使用Cu-Ka辐射，得到以2θ角度和晶面间距表示的X-射线粉末衍射图谱，所述结晶具有如图1所示的X-射线粉末衍射图谱，其中在约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)，12.98(6.81)，13.81(6.41)，14.60(6.06)，14.88(5.95)，16.24(5.45)，16.48(5.37)，17.04(5.20)，18.16(4.88)，19.15(4.63)，19.46(4.56)，19.73(4.50)，20.13(4.41)，20.66(4.30)，20.98(4.23)，21.76(4.08)，22.77(3.90)，23.24(3.82)，24.00(3.70)，24.85(3.58)，25.85(3.52)，26.42(3.37)，27.48(3.24)，28.24(3.16)，29.07(3.07)，29.47(3.03)，31.13(2.87)，31.44(2.84)，32.26(2.77)和33.28(2.69)有特征峰。
  3. 一种制备如权利要求2所述的乐伐替尼对甲苯磺酸盐的I型结晶的方法，所述方法包括下述步骤：
    1)将任意晶型或无定型的乐伐替尼对甲苯磺酸盐固体溶解于有机溶剂或其与水的混合溶剂中，析晶，所述有机溶剂选自碳原子数小于等于3的极性溶剂；优选所述的极性有机溶剂选自酮类、醇类、腈类的一种或几种；
    2)过滤结晶并洗涤，干燥。
  4. 根据权利要求3所述的方法，其特征在于在步骤1)中所述的极性有机溶剂选自甲醇，乙醇，异丙醇、丙酮、乙腈、丙酮/乙腈。
  5. 根据权利要求3所述的方法，其步骤1)中所述的有机溶剂为丙酮/乙腈；所述有机溶剂与水的混合溶剂为丙酮/乙腈/水，其体积比优选为2：2：1。
  6. 一种药物组合物，其含有如权利要求1所述的乐伐替尼对甲苯磺酸盐或权利要求2所述的I型结晶以及药学上可接受的载体。
  7. 如权利要求1所述的乐伐替尼对甲苯磺酸盐、权利要求2所述的I型结晶或权利要求6所述的药物组合物在制备治疗癌症药物中的用途，优选所述癌症是甲状腺癌。
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018122780A1 (en) * 2016-12-29 2018-07-05 Dr. Reddy’S Laboratories Limited Solid state forms of lenvatinib mesylate

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 (en) * 2016-12-29 2018-07-05 Dr. Reddy’S Laboratories Limited Solid state forms of lenvatinib mesylate
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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