WO2022022367A1 - 一种高纯度结晶的制备方法 - Google Patents

一种高纯度结晶的制备方法 Download PDF

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WO2022022367A1
WO2022022367A1 PCT/CN2021/107742 CN2021107742W WO2022022367A1 WO 2022022367 A1 WO2022022367 A1 WO 2022022367A1 CN 2021107742 W CN2021107742 W CN 2021107742W WO 2022022367 A1 WO2022022367 A1 WO 2022022367A1
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lenvatinib
solution
lenvatinib mesylate
crystal
free base
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何训贵
张恒彬
王元
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药源药物化学（上海）有限公司
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/42—Separation; Purification; Stabilisation; Use of additives
    • C07C303/44—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/04—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

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  • the invention belongs to the field of pharmaceutical synthesis, and in particular relates to a preparation method of high-purity crystals.
  • Lenvatinib mesylate Chinese chemical name is 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide methanesulfonate , English chemical name: 4-(3-Chloro-4-(3-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxamide Mesylate, trade name Lenvanix, its structure is as follows:
  • Lenvatinib mesylate is a receptor tyrosine kinase (RTK) inhibitor that inhibits VEGFR1, VEGFR2, and VEGFR3. Lenvatinib mesylate also inhibits other RTKs associated with pathological neovascularization, tumor growth, and cancer progression, including fibroblast growth factor (FGF) receptor FGFR1,2,3,4; platelet derivatization Growth factor receptor alpha (PDGFR ⁇ ), KIT and RET.
  • RTK receptor tyrosine kinase
  • Lenvatinib combined with everolimus can increase anti-vascular and anti-tumor activities, such as reducing human endothelial cell proliferation, lumen formation, and VEGF signaling in vitro, and the increase in tumor volume in a mouse xenograft model of human renal cell carcinoma. Changes were greater than with monotherapy.
  • Lenvima (lenvatinib mesylate) was launched in the United States, the European Union and Japan for the treatment of differentiated thyroid cancer. The drug has so far treated a large number of patients with this indication.
  • the preparation technology of lenvatinib mesylate has been disclosed in Chinese patent applications CN1478078, CN101337930, CN100569753C and CN101337933A.
  • Eisai Co., Ltd. introduced the preparation of lenvatinib free base and its mesylate in CN1478078, and improved the preparation process in CN101337930.
  • the crystal form C is protected in CN100569753C, and the crystallizing method of lenvatinib mesylate is disclosed and crystal A is protected in CN101337933A. From the literature, crystal C, etc. may be used as the preparation of the crystal form of the active ingredient of the drug.
  • Lenvatinib mesylate has drug polycrystals.
  • Patent CN100569753C discloses the preparation of lenvatinib mesylate crystal A, crystal B, crystal C, acetate crystal I and hydrate crystal F. After comparing the solubility, bioavailability, hygroscopicity, solid stability and other data of crystal A and crystal C, it was found that crystal B and acetate crystal I were unstable and easily converted into crystal C. Crystalline A is also slightly less stable than Crystalline C, therefore, Crystalline C tends to be used in pharmaceutical compositions.
  • Lenvatinib mesylate crystal C its X-ray powder diffraction pattern is shown in Figure 1 (CN100569753C).
  • the diffraction angles (29 ⁇ 0.20) are 6.16°, 9.84°, 10.16°, 10.58°, 12.30°, 12.54°, 12.96°, 13.40°, 14.22°, 14.86°, 15.20°, 15.96°, 16.36°, 17.16° , 17.60°, 19.08°, 19.28°, 19.96°, 20.42°, 20.82°, 21.28°, 21.74°, 22.56°, 23.14°, 23.56°, 23.72°, 24.02°, 24.32°, 24.76°, 25.54°, 26.02 °,26.22°,26.98°,27.50°,27.98°,28.40°,28.76°,29.22°,29.50°,29.62°,29.84°,30.64°,31.28°,31.50°
  • the existing preparation methods of lenvatinib mesylate crystal C mainly include the following three types:
  • the first method is to prepare crystal C by crystallizing A.
  • Crystallized Lenvatinib mesylate A 4-[3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide methanesulfonate bis
  • n-butyl acetate was added, the mixture was heated at 115° C. for about 10 hours, and then stirred at room temperature for 1.5 hours to obtain crystal C.
  • the second method is to prepare crystal C by crystallizing I.
  • Lenvatinib mesylate crystal I was stirred in solvent methanol, ethanol or 2-propanol to obtain crystal C.
  • the free base is directly salified in acetic acid.
  • the free base 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide was mixed with acetic acid and methanesulfonic acid, dissolved and added The poor solvent 2-propanol gives crystal C.
  • Both methods 1 and 2 require the preparation of other crystalline forms from the free base, followed by transformation to form crystalline C.
  • Methods 2 and 3 use alcoholic solvents, which can potentially produce trace amounts of mesylate-type genotoxic impurities.
  • Method three uses acetic acid as a solvent, and lenvatinib mesylate is easily decomposed in the process of preparing crystal C, resulting in impurity A and impurity B (the structural formulas are as follows), which are difficult to remove by conventional purification means, resulting in methanesulfonic acid
  • the level of impurities in the finished product of lenvatinib is relatively high, and the purity of related substances is relatively low.
  • the technical purpose of the present invention is to provide a preparation method of high-purity lenvatinib mesylate crystal C, which is easy to operate, environmentally friendly, can effectively reduce the generation of impurities, and is suitable for industrialized large-scale production.
  • the present invention provides a preparation method of lenvatinib mesylate crystal C, which comprises the following steps:
  • step 2) adding methanesulfonic acid and poor solvent I or the solution of methanesulfonic acid in poor solvent I after the solution of step 1) is clarified and filtered, and carries out salification reaction as following reaction formula to obtain lenvatinib mesylate crude product;
  • the purity of the obtained lenvatinib mesylate crystal C is not less than 99.5%, the content of any single impurity is not more than 0.10%, and the total impurity content is not more than 0.5%.
  • the good solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, One or a combination of acetone and acetic acid.
  • the concentration of the solution of lenvatinib free base is 0.1-0.2 g/ml.
  • step 1) the obtained solution of lenvatinib free base is heated to 50°C to 90°C to dissolve it.
  • the poor solvents I and II are each independently selected from ethyl acetate, isopropyl acetate, n-butyl acetate, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran , methyl tertiary butyl ether, n-heptane, one or a combination of several.
  • step 2) the solution of lenvatinib free base is cooled to -20°C to 20°C before adding methanesulfonic acid and poor solvent I or a solution of methanesulfonic acid in poor solvent I .
  • the concentration of the solution of the methanesulfonic acid in the poor solvent I is 0.02-0.1 g/ml.
  • the molar ratio of lenvatinib free base to methanesulfonic acid is 1:0.9-1.5, preferably 1:0.9-1.1, more preferably 1:0.9-1.0. If the methanesulfonic acid molar ratio is lower than 0.9, the methanesulfonic acid salt of this product can also be obtained, but it is a waste of free base, so it is not recommended.
  • the temperature of the salt-forming reaction is -50°C to 35°C, preferably 0-20°C.
  • the beating temperature is -50°C to 35°C, preferably 0-20°C.
  • the beating time may be 1-48 hours, especially 24 hours.
  • the lenvatinib mesylate obtained according to the above method has high purity, and the residues of various solvents are lower than the ICH limit of the raw material drug.
  • the preparation method of lenvatinib mesylate crystal C provided by the invention has the following advantages:
  • this process can effectively reduce the self-decomposition of free base, reduce the generation of impurity A and impurity B to the greatest extent, and can obtain high-purity leon mesylate vatinib.
  • Fig. 1 is the XRPD pattern of lenvatinib mesylate crystal C in patent CN100569753C.
  • FIG. 2 is an XRPD pattern of Lenvatinib mesylate crystal A prepared in Comparative Example 1.
  • FIG. 3 is an XRPD pattern of Lenvatinib mesylate crystal C prepared in Comparative Example 3.
  • FIG. 4 is the XRPD pattern of lenvatinib mesylate crystal C prepared in Example 6.
  • X-ray powder diffraction was measured on a Rigaku D/max 2550 VB-pc diffractometer using Radiation, power: 40kV ⁇ 100mA to collect relevant diffraction data in the range of 2 ⁇ 0°-60°, step width 0.02°, scanning speed 6°/min.
  • the lenvatinib free base used in the examples of the present invention is prepared with reference to Example 368 in patent CN1478078. Impurities A and B were both analyzed by LC-MS.
  • Lenvatinib free base (1 g, 2.34 mmol) was added to N,N-dimethylformamide (10 mL), and the mixture was heated to 90° C. to dissolve. After cooling to -20°C, a solution of methanesulfonic acid (0.23 g, 2.34 mmol) in methyl tert-butyl ether (10 mL) was added dropwise. After adding, keep stirring for 2 hours.
  • Lenvatinib (1 g, 2.34 mmol) was added to dimethyl sulfoxide (10 mL), and the mixture was heated to 70° C. to dissolve. After cooling to 20°C, a solution of methanesulfonic acid (0.21 g, 2.22 mmol) in ethyl acetate (10 mL) was added dropwise. After adding, keep stirring for 2 hours. Filtration, the filter cake was washed with ethyl acetate, and dried to obtain crude lenvatinib mesylate (1.10 g) with a yield of 90.1%, a purity of 99.9%, impurity A: 0.05%, and impurity B: 0.05%.
  • Lenvatinib (1 g, 2.34 mmol) was added to N-methylpyrrolidone (10 mL), and the mixture was heated to 80° C. to dissolve. After cooling to 0°C, a solution of methanesulfonic acid (0.21 g, 2.22 mmol) in n-butyl acetate (10 mL) was added dropwise. After adding, keep stirring for 2 hours. Filtration, the filter cake was washed with ethyl acetate, and dried to obtain crude lenvatinib mesylate (1.14 g) with a yield of 93.0%, a purity of 99.8%, impurity A: 0.05%, and impurity B: 0.04%.
  • Lenvatinib free base (1 g, 2.34 mmol) was added to N,N-dimethylacetamide (10 mL), and heated to 60° C. to dissolve. After cooling to -20°C, a solution of methanesulfonic acid (0.24 g, 2.46 mmol) in isopropyl acetate (10 mL) was added dropwise. After adding, keep stirring for 2 hours. Filtration, the filter cake was washed with isopropyl acetate, and dried to obtain crude lenvatinib mesylate (1.16 g) with a yield of 91.6%, a purity of 99.8%, impurity A: 0.08%, and impurity B: 0.08%.
  • Lenvatinib free base (1 g, 2.34 mmol) was added to a mixed solution of acetone (10 mL) and acetic acid (1 mL), and heated to 50° C. to dissolve. After cooling to -20°C, a solution of methanesulfonic acid (0.23 g, 2.34 mmol) in tetrahydrofuran (10 mL) was added dropwise. After adding, keep stirring for 2 hours. Filtration, the filter cake was washed with tetrahydrofuran, and dried to obtain crude lenvatinib mesylate (1.16 g) with a yield of 85.6%, a purity of 99.7%, impurity A: 0.09%, and impurity B: 0.07%.
  • Example 2 The crude lenvatinib mesylate (1 g, 1.91 mmol) obtained in Example 1 was added to methyl tert-butyl ether (10 mL), and the mixture was stirred at 20° C. for 24 hours. Filtration, the filter cake was washed with methyl tert-butyl ether, and dried to obtain lenvatinib mesylate (0.92g), the yield was 92.0%, the purity was 99.8%, the largest single impurity was impurity A: 0.08%, impurity B: 0.05%.
  • Example 3 The crude lenvatinib mesylate (1 g, 1.91 mmol) obtained in Example 3 was added to n-butyl acetate (10 mL), and the mixture was stirred at 0° C. for 24 hours. Filtration, the filter cake was washed with n-butyl acetate, and dried to obtain lenvatinib mesylate (0.90g), the yield was 90.0%, the purity was 99.8%, and the largest single impurity was impurity A: 0.06%, impurity B: 0.05%.
  • Example 2 The crude lenvatinib mesylate (1 g, 1.91 mmol) obtained in Example 2 was added to ethyl acetate (10 mL), and the mixture was stirred at 0° C. for 24 hours. Filtration, the filter cake was washed with ethyl acetate, and dried to obtain lenvatinib mesylate (0.90 g) with a yield of 90.0% and a purity of 99.8%. The largest single impurity was impurity A: 0.06% and impurity B: 0.05 %.
  • Example 4 The crude lenvatinib mesylate (1 g, 1.91 mmol) obtained in Example 4 was added to acetonitrile (10 mL), and the mixture was stirred at 10° C. for 24 hours. After filtering, the filter cake was washed with acetonitrile and dried to obtain lenvatinib mesylate (0.89g) with a yield of 89.0% and a purity of 99.8%. The largest single impurity was impurity A: 0.07% and impurity B: 0.07%.
  • Example 5 The crude lenvatinib mesylate (1 g, 1.91 mmol) obtained in Example 5 was added to 2-methyltetrahydrofuran (10 mL), and the mixture was kept at 5° C. with stirring and beating for 24 hours. Filtration, the filter cake was washed with 2-methyltetrahydrofuran, and dried to obtain lenvatinib mesylate (0.89g) with a yield of 89.0% and a purity of 99.9%. The largest single impurity was impurity A: 0.08% and impurity B. : 0.07%.
  • Example 2 The crude lenvatinib mesylate (1 g, 1.91 mmol) obtained in Example 2 was added to n-heptane (10 mL), and the mixture was stirred at 0° C. for 24 hours. After filtering, the filter cake was washed with acetonitrile and dried to obtain lenvatinib mesylate (0.94g) with a yield of 94.0% and a purity of 99.9%. The largest single impurity was impurity A: 0.05% and impurity B: 0.05%.
  • Lenvatinib (1 g, 2.34 mmol) was dissolved in a mixed solution of methanol (10 ml) and methanesulfonic acid (1.2 eq) at 70°C. After dissolving, the solution was cooled to room temperature over 5.5 hours. It was then stirred at room temperature for 18.5 hours, and the crystals were filtered. Dry at below 60°C to obtain solid (0.85g, 1.63mmol), yield 69.7%, purity 96.86%, impurity A 0.49%, impurity B 0.27%.
  • the lenvatinib mesylate crystal C prepared according to the preparation method of the lenvatinib mesylate crystal C of the present application has a higher purity, and the impurities A and The content of B was greatly reduced.
  • the preparation method of lenvatinib mesylate crystal C of the present application does not use alcohol solvents, which avoids the generation of mesylate genotoxic impurities.

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Abstract

提供一种高纯度结晶的制备方法，具体涉及甲磺酸仑伐替尼结晶C的制备方法，其包括以下步骤：1)将仑伐替尼游离碱溶解于良溶剂中得到仑伐替尼游离碱的溶液；2)将步骤1)的溶液澄清过滤后加入甲磺酸和不良溶剂I或甲磺酸在不良溶剂I中的溶液，进行成盐反应得到甲磺酸仑伐替尼粗品；3)将得到的甲磺酸仑伐替尼粗品置于不良溶剂II中，打浆，得到甲磺酸仑伐替尼结晶C，其中，得到的甲磺酸仑伐替尼结晶C的纯度不低于99.5％，任意单个杂质不高于0.10％，总杂质不超过0.5％。依据前述的制备方法制备的甲磺酸仑伐替尼结晶C的纯度更高，其中的杂质A和杂质B的含量得到了很大程度的降低。

Description

一种高纯度结晶的制备方法 技术领域
本发明属于药物合成领域，具体涉及高纯度结晶的制备方法。
背景技术
甲磺酸仑伐替尼，中文化学名为4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰胺甲磺酸盐，英文化学名为：4-(3-Chloro-4-(3-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxamide Mesylate，商品名乐卫玛(Lenvanix)，其结构如下：
Figure PCTCN2021107742-appb-000001
甲磺酸仑伐替尼是一种酪氨酸激酶受体(RTK)抑制剂，可以抑制VEGFR1、VEGFR2和VEGFR3。甲磺酸仑伐替尼(Lenvatinib)同样可以抑制其他与病理性新生血管、肿瘤生长及癌症进展相关的RTK，包括成纤维细胞生长因数(FGF)受体FGFR1,2,3,4；血小板衍化生长因数受体α(PDGFRα)、KIT及RET。Lenvatinib联合everolimus(依维莫司)能增加抗血管及抗肿瘤活性，如通过体外降低人内皮细胞的增殖、管腔形成、VEGF信号传导等，人肾细胞癌小鼠异种移植模型中肿瘤体积的变化大于单药治疗。
2015年，Lenvima(甲磺酸仑伐替尼)在美国、欧盟及日本上市用于治疗分化型甲状腺癌。到目前为止该药物已治疗大量该适应症患者。甲磺酸仑伐替尼的制备技术已经在中国专利申请CN1478078，CN101337930，CN100569753C和CN101337933A在公开。
卫材株式会社在CN1478078中介绍了仑伐替尼游离碱以及其甲磺酸盐的制备，在CN101337930中对制备工艺进行了改进。在CN100569753C中保护了晶型C，在CN101337933A中，对甲磺酸仑伐替尼的结晶方法进行了公开并保护了结晶A。从文献看，结晶C等可能作为药物有效成分的晶型的制备。
甲磺酸仑伐替尼存在药物多结晶，专利CN100569753C中公开了甲磺酸仑伐替尼结晶A，结晶B，结晶C，醋酸合物结晶I以及水合物结晶F的制备。在对比结晶A和结晶C的溶解度，生物利用度，吸湿性，固体稳定性等 各种数据后，发现结晶B和醋酸合物结晶I不稳定，容易转化为结晶C。结晶A稳定性也比结晶C略差，因此，倾向于将结晶C用于药物组合物。
甲磺酸仑伐替尼结晶C，其X射线粉末衍射图谱如图1(CN100569753C)。在衍射角度(29土0.20)为6.16°、9.84°、10.16°、10.58°、12.30°、12.54°、12.96°、13.40°、14.22°、14.86°、15.20°、15.96°、16.36°、17.16°、17.60°、19.08°、19.28°、19.96°、20.42°、20.82°、21.28°、21.74°、22.56°、23.14°、23.56°、23.72°、24.02°、24.32°、24.76°、25.54°、26.02°、26.22°、26.98°、27.50°、27.98°、28.40°、28.76°、29.22°、29.50°、29.62°、29.84°、30.64°、31.28°、31.50°、32.44°33.64°、34.50°、35.04°、36.10°、37.64°、38.94°及39.48°处具有衍射特征峰。
甲磺酸仑伐替尼结晶C的现有制备方法主要有以下三种：
方法一，通过结晶A制备结晶C。将甲磺酸仑伐替尼结晶A，4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰胺甲磺酸盐二甲亚砜合物的结晶中加入醋酸正丁酯，在115℃下加热约10小时，然后在室温下搅拌1.5小时，得到结晶C。
方法二，通过结晶I制备结晶C。将甲磺酸仑伐替尼结晶I在溶剂甲醇、乙醇或2-丙醇中搅拌，得到结晶C。
方法三，游离碱在醋酸中直接成盐。将游离碱4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰胺与醋酸和甲磺酸混合，使其溶解后加入不良溶剂2-丙醇，得到结晶C。
上述制备方法中，虽然都可以得到甲磺酸仑伐替尼结晶C，但是存在以下缺点：
方法一和二都需要先从游离碱制备其他晶型，然后转晶生成结晶C。
方法二和三使用了醇类溶剂，会潜在产生微量的甲磺酸酯类基因毒性杂质。
方法三采用醋酸作溶剂，在制备结晶C的过程中甲磺酸仑伐替尼容易分解，产生杂质A、杂质B(结构式分别如下)，该杂质难以通过常规的纯化手段进行去除，导致甲磺酸仑伐替尼成品中杂质水平较高，有关物质纯度较低。
Figure PCTCN2021107742-appb-000002
由于上述三种方法存在操作过于繁琐、潜在产生基因毒性杂质和降解杂质A和B的缺点，不利于商业化生产。所以，寻求能通过简单操作得到高纯度甲磺酸仑伐替尼的制备方法具有非常重要的现实意义。
发明内容
本发明的技术目的是提供一种高纯度甲磺酸仑伐替尼结晶C的制备方法，该方法操作简便、环境友好、能够有效降低杂质的生成，适用于工业化大规模生产。
一方面，本发明提供一种甲磺酸仑伐替尼结晶C的制备方法，其包括以下步骤：
1)将仑伐替尼游离碱溶解于良溶剂中得到仑伐替尼游离碱的溶液；
2)将步骤1)的溶液澄清过滤后加入甲磺酸和不良溶剂I或甲磺酸在不良溶剂I中的溶液，如以下反应式进行成盐反应得到甲磺酸仑伐替尼粗品；
Figure PCTCN2021107742-appb-000003
3)将得到的甲磺酸仑伐替尼粗品置于不良溶剂II中，打浆，得到甲磺酸仑伐替尼结晶C，
其中，得到的甲磺酸仑伐替尼结晶C的纯度不低于99.5％，任意单个杂质含量不高于0.10％，总杂质含量不超过0.5％。
在具体实施方式中，在步骤1)中，所述良溶剂选自N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、二甲基亚砜、丙酮、醋酸中的一种或几种的组合。
在具体实施方式中，在步骤1)中，所述仑伐替尼游离碱的溶液的浓度为0.1-0.2g/ml。
在具体实施方式中，在步骤1)中，将得到的仑伐替尼游离碱的溶液加热至50℃～90℃，以使其溶清。
在具体实施方式中，在步骤2)和3)中，所述不良溶剂I和II各自独立地选自乙酸乙酯、乙酸异丙酯、乙酸正丁酯、乙腈、四氢呋喃、2-甲基四氢呋喃、甲基叔丁基醚、正庚烷中的一种或几种的组合。
在具体实施方式中，在步骤2)中，在加入甲磺酸和不良溶剂I或甲磺酸在不良溶剂I中的溶液之前将仑伐替尼游离碱的溶液冷却至-20℃～20℃。
在具体实施方式中，在步骤2)中，所述甲磺酸在不良溶剂I中的溶液的浓度为0.02-0.1g/ml。
在具体实施方式中，仑伐替尼游离碱与甲磺酸的摩尔比为1:0.9-1.5，优选1:0.9-1.1，进一步优选1:0.9-1.0。如果甲磺酸摩尔比低于0.9也能得到本品的甲磺酸盐，但是比较浪费游离碱，所以不推荐。
在具体实施方式中，在步骤2)中，所述成盐反应的温度为-50℃～35℃，优选为0-20℃。
在具体实施方式中，在步骤3)中，所述打浆温度为-50℃～35℃，优选为0-20℃。
在具体实施方式中，在步骤3)中，所述打浆的时间可为1-48小时，特别是24小时。
根据上述方法得到的甲磺酸仑伐替尼，纯度高，各项溶剂残留低于原料药ICH限度。
有益效果
本发明提供的甲磺酸仑伐替尼结晶C的制备方法与现有的工艺相比，有以下优点：
(1)通过大量的实验，筛选出合适的溶剂体系，在特定的温度下成盐、打浆，即可得到结晶C，无需加晶种诱导。
(2)通过筛选合适的甲磺酸当量、成盐溶剂和成盐温度，本工艺可以有效降低游离碱自身分解，最大程度降低杂质A和杂质B的产生，能够得到高纯度的甲磺酸仑伐替尼。
(3)通过避免使用醇类溶剂，避免了甲磺酸酯类基因毒性杂质的产生。
(4)本工艺得到的成品不含溶剂，溶剂残留符合ICH要求。
(5)操作简单，使用环境友好的溶剂，适用于工业化生产。
附图说明
图1为专利CN100569753C中甲磺酸仑伐替尼结晶C的XRPD图。
图2为对比实施例1中制备的甲磺酸仑伐替尼结晶A的XRPD图。
图3为对比实施例3中制备的甲磺酸仑伐替尼结晶C的XRPD图。
图4为实施例6中制备的甲磺酸仑伐替尼结晶C的XRPD图。
具体实施方式
不需进一步详细说明，本领域技术人员借助前面的描述，可以最大程度地利用本发明。因此，下面提供的实施例仅仅是进一步阐明本发明而己，并不意味着以任何方式限制本发明的范围。
本发明的分析检测条件如下：
X-射线粉末衍射是由Rigaku D/max 2550 VB-pc衍射仪测得，采用
Figure PCTCN2021107742-appb-000004
辐射，功率：40kV×100mA在2θ0°-60°范围采集相关衍射数据，步宽0.02°，扫描速度6°/min。
本发明实施例中使用的仑伐替尼游离碱参考专利CN1478078中实施例368制备。杂质A和B均采用LC-MS分析。
实施例1：甲磺酸仑伐替尼粗品的制备
Figure PCTCN2021107742-appb-000005
N,N-二甲基甲酰胺(10mL)中加入仑伐替尼游离碱(1g，2.34mmol)，加热至90℃溶清。冷却至-20℃，滴加甲磺酸(0.23g，2.34mmol)的甲基叔丁基醚(10mL)溶液。加完后保温搅拌2小时。过滤，滤饼用甲基叔丁基醚洗涤，烘干，得到甲磺酸仑伐替尼粗品(1.16g)，收率为94.6％，纯度99.8％，杂质A:0.08％，杂质B:0.05％。
H-NMR(600MHz，DMSO-d6)：δMSO-(d，1H)，8.73(s,1H)，8.38(d，1H)，8.09(s,1H)，7.96(d，2H)，7.66(s,1H)，7.65(d，1H)，7.37(dd，1H)，7.27(m,1H)，6.96(d，1H)，4.09(s，3H)，2.69(m,1H)，2.36(s，3H)，0.68(m,2H)，0.44(s，2H)。
实施例2：甲磺酸仑伐替尼粗品的制备
二甲基亚砜(10mL)中加入仑伐替尼(1g，2.34mmol)，加热至70℃溶清。冷却至20℃，滴加甲磺酸(0.21g，2.22mmol)的乙酸乙酯(10mL)溶液。加完后保温搅拌2小时。过滤，滤饼用乙酸乙酯洗涤，烘干，得到甲磺酸仑伐替尼粗品(1.10g)，收率为90.1％，纯度99.9％，杂质A:0.05％，杂质B:0.05％。
实施例3：甲磺酸仑伐替尼粗品的制备
N-甲基吡咯烷酮(10mL)中加入仑伐替尼(1g，2.34mmol)，加热至80℃溶清。冷却至0℃，滴加甲磺酸(0.21g，2.22mmol)的乙酸正丁酯(10mL)溶液。加完后保温搅拌2小时。过滤，滤饼用乙酸乙酯洗涤，烘干，得到甲磺酸仑伐替尼粗品(1.14g)，收率为93.0％，纯度99.8％，杂质A:0.05％，杂质B:0.04％。
实施例4：甲磺酸仑伐替尼粗品的制备
N,N-二甲基乙酰胺(10mL)中加入仑伐替尼游离碱(1g，2.34mmol)，加热至60℃溶清。冷却至-20℃，滴加甲磺酸(0.24g，2.46mmol)的乙酸异丙酯(10mL)溶液。加完后保温搅拌2小时。过滤，滤饼用乙酸异丙酯洗涤，烘干，得到甲磺酸仑伐替尼粗品(1.16g)，收率为91.6％，纯度99.8％，杂质A:0.08％，杂质B:0.08％。
实施例5：甲磺酸仑伐替尼粗品的制备
丙酮(10mL)和醋酸(1mL)的混合溶液中加入仑伐替尼游离碱(1g，2.34mmol)，加热至50℃溶清。冷却至-20℃，滴加甲磺酸(0.23g，2.34mmol)的四氢呋喃(10mL)溶液。加完后保温搅拌2小时。过滤，滤饼用四氢呋喃洗涤，烘干，得到甲磺酸仑伐替尼粗品(1.16g)，收率为85.6％，纯度99.7％，杂质A:0.09％，杂质B:0.07％。
实施例6：甲磺酸仑伐替尼结晶C的制备
甲基叔丁基醚(10mL)中加入实施例1中所得甲磺酸仑伐替尼粗品(1g，1.91mmol)，20℃保温搅拌打浆24小时。过滤，滤饼用甲基叔丁基醚洗涤，烘干，得到甲磺酸仑伐替尼(0.92g)，收率为92.0％，纯度99.8％，最大单一杂质为杂质A：0.08％，杂质B:0.05％。
H-NMR(600MHz，DMSO-d6)：
δMSO-(d，1H)，8.73(s,1H)，8.38(d，1H)，8.09(s,1H)，7.96(d，2H)，7.66(s,1H)，7.65(d，1H)，7.37(dd，1H)，7.27(m,1H)，6.96(d，1H)，4.09(s，3H)，2.69(m,1H)，2.36(s，3H)，0.68(m,2H)，0.44(s，2H)。
XRPD(2RPD-d°)：
6.13°，9.80°，10.18°，10.56°，12.30°，12.92°，14.25°，14.85，15.16°，17.12d，17.70d，19.04d，19.24d，19.99d，20.37d，20.88d，21.23d，21.82d，22.61d，23.16d，23.61d，23.99d，24.38d，24.86d，25.64d，26.24d，27.02d，28.37d，29.53d，30.79d，33.69d，34.47d，35.04d，36.03d，37.64d。
实施例7：甲磺酸仑伐替尼结晶C的制备
乙酸正丁酯(10mL)中加入实施例3中所得甲磺酸仑伐替尼粗品(1g，1.91mmol)，0℃保温搅拌打浆24小时。过滤，滤饼用乙酸正丁酯洗涤，烘干，得到甲磺酸仑伐替尼(0.90g)，收率为90.0％，纯度99.8％，最大单一杂质为杂质A:0.06％，杂质B:0.05％。
实施例8：甲磺酸仑伐替尼结晶C的制备
乙酸乙酯(10mL)中加入实施例2中所得甲磺酸仑伐替尼粗品(1g，1.91mmol)，0℃保温搅拌打浆24小时。过滤，滤饼用乙酸乙酯洗涤，烘干，得到甲磺酸仑伐替尼(0.90g)，收率为90.0％，纯度99.8％，最大单一杂质为杂质A:0.06％，杂质B:0.05％。
实施例9：甲磺酸仑伐替尼结晶C的制备
乙腈(10mL)中加入实施例4中所得甲磺酸仑伐替尼粗品(1g，1.91mmol)，10℃保温搅拌打浆24小时。过滤，滤饼用乙腈洗涤，烘干，得到甲磺酸仑伐替尼(0.89g)，收率为89.0％，纯度99.8％，最大单一杂质为杂质A:0.07％，杂质B:0.07％。
实施例10：甲磺酸仑伐替尼结晶C的制备
2-甲基四氢呋喃(10mL)中加入实施例5中所得甲磺酸仑伐替尼粗品(1g，1.91mmol)，5℃保温搅拌打浆24小时。过滤，滤饼用2-甲基四氢呋喃洗涤，烘干，得到甲磺酸仑伐替尼(0.89g)，收率为89.0％，纯度99.9％，最大单一杂质为杂质A:0.08％，杂质B:0.07％。
实施例11：甲磺酸仑伐替尼结晶C的制备
正庚烷(10mL)中加入实施例2中所得甲磺酸仑伐替尼粗品(1g，1.91mmol)，0℃保温搅拌打浆24小时。过滤，滤饼用乙腈洗涤，烘干，得到甲磺酸仑伐替尼(0.94g)，收率为94.0％，纯度99.9％，最大单一杂质为杂质A:0.05％，杂质B:0.05％。
对比实施例1：
甲磺酸仑伐替尼结晶A的制备(专利CN100569753C中实施例5制备方法1)
Figure PCTCN2021107742-appb-000006
于70℃下将仑伐替尼(1g，2.34mmol)溶解于甲醇(10ml)和甲磺酸(1.2eq)的混合溶液中。溶清后，经历5.5小时将溶液冷至室温。然后在室温下搅拌18.5小时，过滤结晶。在60℃以下干燥得到固体(0.85g，1.63mmol)，收率69.7％，纯度96.86％，杂质A 0.49％,杂质B 0.27％。
H-NMR(600MHz，DMSO-d6)：
δ-NMR(d，1H)，8.73(s,1H)，8.38(d，1H)，8.09(s,1H)，7.96(d，2H)，7.66(s,1H)，7.65(d，1H)，7.37(dd，1H)，7.27(m,1H)，6.96(d，1H)，4.09(s，3H)，2.69(m,1H)，2.36(s，3H)，0.68(m,2H)，0.44(s，2H)。
XRPD(2θ±0.2°)：
6.530，9.640，10.62.，11.38.，12.59.，13.11.，14.44.，15.38.，16.71.，17.00.，17.28.，17.68.，18.36.，18.86.，19.36.，19.93.，20.32.，20.81°，21.35°，22.17°，22.91°，23.15°，23.39°，24.05°，24.78°，25.46°，25.86°，26.41°，26.69°，27.66°，28.31°，28.63°，29.19°，29.65°，29.93°，30.29°，32.64°，32.83°，33.30°，35.38°，36.69°，37.31°。
对比实施例2：
甲磺酸仑伐替尼二甲基亚砜溶剂合物的制备(CN100569753C,实施例8制备方法1)
室温下，向仑伐替尼游离碱(0.50g，1.17mmol)中加入二甲基亚砜(5ml)，在80℃下使其溶解。在60℃下依次向反应液中加入甲磺酸(0.22g，1.2eq)，乙酸乙酯(1ml)和结晶A。再过45分钟滴入乙酸乙酯(4ml)。滴加完毕后搅拌15分钟，再经过1小时冷却至室温，继续搅拌18小时。过滤结晶。在60℃以下干燥得到固体(0.46g，1.15mmol)，收率98.3％，纯度97.45％。
对比实施例3：
甲磺酸仑伐替尼结晶C的制备(CN100569753C,实施例7制备方法1)
向甲磺酸仑伐替尼的二甲基亚砜合物(0.40g，0.76mmol)中加入醋酸正丁酯(8ml)，将反应液在115℃下搅拌10小时，然后在室温下搅拌1.5小时。过滤结晶。在60℃以下干燥得到固体(0.28g，0.54mmol)，收率71.1％，纯度97.20％，杂质A:1.11％，杂质B:0.46％。
实验批号：YMY-30-14
H-NMR(600MHz，DMSO-d6)：
δMSO-(d，1H)，8.73(s,1H)，8.38(d，1H)，8.098(s,1H)，7.95(d，2H)，7.67(s,1H)，7.65(d，1H)，7.38(dd，1H)，7.28(m,1H)，6.96(d，1H)，4.10(s，3H)，2.69(m,1H)，2.37(s，3H)，0.68(m,2H)，0.44(s，2H)。
XRPD(2RPD8d°)：
6.138，9.66°，10.18d，10.54°，12.28°，12.92d，14.23°，15.20°，
17.06°，17.71°，19.249，19.99d，20.36°，20.83°，21.331，21.81°，
23.66°，24.41°，24.77°，25.66°，26.39°，27.00°，27.65d，28.31°，
29.599，29.91d，30.76°，32.62d，33.69°，35.00°，36.03°，37.67°。
从上述实施例和对比实施例可以看出，根据本申请的甲磺酸仑伐替尼结晶C的制备方法制备的甲磺酸仑伐替尼结晶C的纯度更高，其中的杂质A 和杂质B的含量得到了很大程度的降低。而且，本申请的甲磺酸仑伐替尼结晶C的制备方法没有使用醇类溶剂，避免了甲磺酸酯类基因毒性杂质的产生。
以上所述，仅为本发明的具体实施方式，但本发明的保护范围并不局限于此，任何熟悉本领域的技术人员在本发明所揭示的技术范围内，可不经过创造性劳动想到的变化或替换，都应涵盖在本发明的保护范围之内。

Claims (10)

  1. 一种甲磺酸仑伐替尼结晶C的制备方法，其包括以下步骤：
    1)将仑伐替尼游离碱溶解于良溶剂中得到仑伐替尼游离碱的溶液；
    2)将步骤1)的溶液澄清过滤后加入甲磺酸和不良溶剂I或甲磺酸在不良溶剂I中的溶液，如以下反应式进行成盐反应得到甲磺酸仑伐替尼粗品；
    Figure PCTCN2021107742-appb-100001
    3)将得到的甲磺酸仑伐替尼粗品置于不良溶剂II中，打浆，得到甲磺酸仑伐替尼结晶C，
    其中，得到的甲磺酸仑伐替尼结晶C的纯度不低于99.5％，任意单个杂质含量不高于0.10％，总杂质含量不超过0.5％。
  2. 根据权利要求1所述的方法，其中，在步骤1)中，所述良溶剂选自N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、二甲基亚砜、丙酮、醋酸中的一种或几种的组合。
  3. 根据权利要求1所述的方法，其中，在步骤1)中，所述仑伐替尼游离碱的溶液的浓度为0.1-0.2g/ml。
  4. 根据权利要求1所述的方法，其中，在步骤1)中，将得到的仑伐替尼游离碱的溶液加热至50℃～90℃，以使其溶清。
  5. 根据权利要求1所述的方法，其中，在步骤2)和3)中，所述不良溶剂I和II各自独立地选自乙酸乙酯、乙酸异丙酯、乙酸正丁酯、乙腈、四氢呋喃、2-甲基四氢呋喃、甲基叔丁基醚、正庚烷中的一种或几种的组合。
  6. 根据权利要求1所述的方法，其中，在步骤2)中，在加入甲磺酸在不良溶剂I中的溶液之前将仑伐替尼游离碱的溶液冷却至-20℃～20℃。
  7. 根据权利要求1所述的方法，其中，在步骤2)中，所述甲磺酸在不良溶剂I中的溶液的浓度为0.02-0.1g/ml。
  8. 根据权利要求1所述的方法，其中，仑伐替尼游离碱与甲磺酸的摩尔比为1:0.9-1.5，优选1:0.9-1.1，更优选1:0.9-1.0。
  9. 根据权利要求1所述的方法，其中，在步骤2)中，所述成盐反应的温度为-50℃～35℃，优选为0-20℃。
  10. 根据权利要求1所述的方法，其中，在步骤3)中，所述打浆温度为-50℃～35℃，优选为0-20℃，以及
    在步骤3)中，所述打浆的时间为1-48小时，优选为24小时。
PCT/CN2021/107742 2020-07-28 2021-07-22 一种高纯度结晶的制备方法 WO2022022367A1 (zh)

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