WO2022057164A1 - 一种多靶点抗肿瘤药物的制备方法 - Google Patents

一种多靶点抗肿瘤药物的制备方法 Download PDF

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WO2022057164A1
WO2022057164A1 PCT/CN2021/070076 CN2021070076W WO2022057164A1 WO 2022057164 A1 WO2022057164 A1 WO 2022057164A1 CN 2021070076 W CN2021070076 W CN 2021070076W WO 2022057164 A1 WO2022057164 A1 WO 2022057164A1
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胡双华
张世喜
郑琴香
林寨伟
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广州南鑫药业有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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  • the invention relates to the field of drug synthesis, in particular to a multi-target antitumor drug 4- ⁇ 4-[3-(4-chloro-3-trifluoromethylphenyl)urea]-3-fluorophenoxy ⁇ pyridine -The preparation method of 2-carboxamide.
  • VEGF Vascular endothelial growth factor
  • Tumor blood vessels are highly sensitive to VEGF, and the VEGF mRNA concentration is significantly higher in many tumor cells, including lung cancer.
  • the Raf/MEK/ERK transduction pathway exists in all eukaryotic cells, and the specific cascade phosphorylation signals of Ras, Raf, MEK and ERK are transferred from the extracellular to the nucleus. Many tumor cells have up-regulation of this pathway. Once this pathway is over-activated, the acceleration of cell proliferation and the prolongation of cell survival will lead to the formation and development of tumors.
  • 4- ⁇ 4-[3-(4-Chloro-3-trifluoromethylphenyl)urea]-3-fluorophenoxy ⁇ pyridine-2-carboxamide the structure is as follows: English name: 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)-3-fluorophenoxy)-picolinamide, CAS number: 1343498-72-5, is an effective VEGF and RAF
  • the kinase inhibitor belongs to a multi-targeted antitumor drug.
  • reaction conditions are harsh, involving high temperature and strong alkali reaction, and especially the reaction solvent DMF is partially degraded under these conditions, which is difficult to recover and apply mechanically, resulting in environmental protection pressure.
  • the yield is low, requiring silica gel column purification, which is not suitable for large-scale production.
  • Patent CN102885814A discloses the synthesis method of anticancer active compound 4- ⁇ 4-[3-(4-chloro-3-trifluoromethylphenyl)urea]-3-fluorophenoxy ⁇ pyridine-2-carboxamide, Using raw material 4-chloropyridine-2-carboxamide as raw material, 4- ⁇ 4-[3-(4-chloro-3-trifluoromethylbenzene was prepared through two synthesis steps of metal-catalyzed coupling reaction and isocyanate addition reaction urea]-3-fluorophenoxy ⁇ pyridine-2-carboxamide. The reaction requires a metal composite catalyst, the cost is high, and the generated product has many impurities, the yield is not high, and does not meet the requirements of drug quality.
  • the present application provides a new process, which is greatly improved in terms of industrial applicability, purity and yield.
  • the object of the present invention is to provide a kind of industrialized preparation method for preparing compound 1, and the synthetic route it adopts is as follows:
  • the present invention includes a method for preparing compound 1:
  • the method is divided into two steps, including: the first step, nitrogen protection, using williamson ether synthesis method to synthesize intermediate 4: using compound 3 and compound 2 as raw materials, using dimethyl sulfoxide and tetrahydrofuran as mixed solvents, in tertiary Under the action of potassium butoxide, the reaction generates intermediate 4; in the second step, use isocyanate to form urea reaction to synthesize compound 1: react intermediate 4 and compound 5 in a dioxane solvent to obtain a crude product, and obtain compound 1 after purification .
  • the molar ratio of dimethyl sulfoxide and tetrahydrofuran in the mixed solvent of the first step is 2-4:1, preferably the molar ratio is 2.5:1.
  • the mol ratio of the mixed solvent of dimethyl sulfoxide and tetrahydrofuran to potassium tert-butoxide is 5-15:1, preferably 10:1.
  • the molar ratio of dioxane and intermediate 4 in the second step is 20-100:1, preferably the molar ratio is 50:1.
  • reaction temperature of the first step is 70-100°C, preferably the reaction temperature is 80-90°C.
  • reaction temperature of the second step is 45-65°C, preferably the reaction temperature is 50-60°C.
  • reaction time of the first step is 1.5-2 hours.
  • reaction time of the second step is 2-4 hours.
  • the specific preparation method is as follows:
  • Step 1 Add dimethyl sulfoxide and tetrahydrofuran into the reaction kettle, introduce nitrogen protection, then add potassium tert-butoxide, and after complete dissolution, control the temperature to 10-20°C. Continue to add 4-amino-3-fluorophenol, stir at room temperature for 10 minutes, add 4-chloro-2-pyridinecarboxamide, continue to stir for 10 minutes, and raise the temperature of the reaction solution to above 80°C within 30 minutes. Timing was started when the internal temperature rose to 80°C, and the reaction was kept at 85 ⁇ 2°C for 2.0 hours.
  • Step 2 add dioxane to the reaction kettle, protect with nitrogen, then add intermediate 4, stir, and heat up to 55°C. After the intermediate 4 was completely dissolved, 4-chloro-3-(trifluoromethyl) benzene isocyanate was dissolved in dioxane and pre-cooled to 10 ° C, and added dropwise to the reaction kettle for 1 hour. Body 4 continued to react for 1 hour. After cooling, the reaction solution was crystallized at 24°C for 15 hours to obtain compound 1.
  • patent US2005245530 reports a method for preparing compounds by microwave reaction in N-methylpyrrolidone, using diisopropylethylamine as a base. The rate is low and cannot be scaled up, not suitable for process development:
  • patent WO2009111061 reports another route for synthesizing sorafenib by first preparing active compound 9 from compound 7, and then reacting with compound 6.
  • the yield of this route is low, and the reaction will become more complicated:
  • the technical solution of the present invention improves the reaction yield by improving the solvent, and uses a specific tetrahydrofuran and dimethyl sulfoxide mixed solvent as a solvent, which greatly reduces the reaction temperature, improves the yield, and reduces simultaneously. production cost.
  • the technical solution of the present invention not only improves the product yield and purity, but also reduces the quantity and content of impurities by improving the reaction conditions, meets the requirements of the pharmaceutical industry, and avoids the use of chromatographic column purification, Therefore, the technical solution of the present invention is directly changed from the laboratory-level standard in the prior art to the industrial-level standard.
  • the present application uses dioxane as the solution, avoiding the use of organic base reagents and the more toxic methylene chloride as a solvent and reducing the risk of environmental pollution.
  • the present invention does not need to use metal catalysts, reduces the risk of heavy metal pollution, reduces costs, and avoids using relatively high toxicity toluene as a reaction solvent.
  • the filter cake was rinsed twice with 6.0kg of ethyl acetate, and the weight of the filter cake was 3.8kg after drying under reduced pressure.
  • 40.0 kg of methanol was poured into a 100L reaction kettle, the above-mentioned compound 1 was added, the temperature was raised to reflux, the temperature was maintained for 3.0 hours, and the temperature was lowered to 34° C. for recrystallization.
  • the crystals were rinsed twice with 4.0 kg of methanol, and dried in vacuum for 72 hours to obtain 3.5 kg of off-white crystals, the yield was about 75%, and the HPLC purity: ⁇ 99.5%.
  • the filter cake was rinsed twice with 7.0kg of ethyl acetate, and the weight of the filter cake was 4.4kg after drying under reduced pressure.
  • Into a 100L reaction kettle 45.0 kg of methanol was poured, the above-mentioned compound 1 was added, the temperature was raised to reflux, the temperature was maintained for 3.0 hours, and the temperature was lowered to 32° C. for recrystallization.
  • the crystals were rinsed twice with 4.5 kg of methanol, and dried in vacuum for 72 hours to obtain 3.9 kg of off-white crystals with a yield of about 70% and HPLC purity: ⁇ 99.4%.
  • the filter cake was rinsed twice with 5.0kg of ethyl acetate, and the weight of the filter cake was 2.4kg after drying under reduced pressure.
  • 30.0kg of methanol was injected into a 100L reaction kettle, the above-mentioned compound 1 was added, the temperature was raised to reflux, the temperature was maintained for 3.0 hours, cooled, and the internal temperature was lowered to 32° C. for recrystallization.
  • the crystals were rinsed twice with 3.0 kg of methanol, and dried in vacuum for 72 hours to obtain 2.2 kg of off-white crystals with a yield of about 71% and HPLC purity: ⁇ 99.3%.
  • Embodiment 7 Compound 1 quality standard and detection method
  • Purity determination method (HPLC, area normalization method.)
  • the injection volume is 10 ⁇ l
  • Mobile phase A 10mmol/L ammonium formate
  • the impurities are as follows:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Pyridine Compounds (AREA)

Abstract

本发明公开了一种多靶点抗肿瘤药物的制备方法，其包括以下步骤：第一步，氮气保护，使用Williamson醚合成法，以4-氨基-3-氟苯酚和4-氯-2-吡啶甲酰胺为原料，以二甲基亚砜和四氢呋喃为混合溶剂，在叔丁醇钾的作用下，反应生成2-氨基甲酰基-4-((3-氟-4-氨基)苯氧基)吡啶；第二步，以2-氨基甲酰基-4-((3-氟-4-氨基)苯氧基)吡啶和4-氯-3-(三氟甲基)苯异氰酸酯在二氧六环溶剂中反应得粗产品，精制后得终产物4-{4-[3-(4-氯-3-三氟甲基苯基)脲]-3-氟苯氧基}吡啶-2-甲酰胺。

Description

一种多靶点抗肿瘤药物的制备方法 技术领域
本发明涉及药物合成领域，特别涉及一种多靶点抗肿瘤药物4-{4-[3-(4-氯-3-三氟甲基苯基)脲]-3-氟苯氧基}吡啶-2-甲酰胺的制备方法。
背景技术
血管内皮生长因子(VEGF)是肿瘤血管生成过程中最重要的细胞生长因子之一，肿瘤血管对VEGF高度敏感，在很多肿瘤细胞中VEGF mRNA浓度显著地高于正常细胞，这些肿瘤包括肺癌。另外，所有真核细胞中均存在Raf/MEK/ERK这一转导通路，其通过Ras、Raf、MEK及ERK的特异性级联磷酸化信号由细胞外传入细胞核内。许多肿瘤细胞存在这一通路的上调，一旦该通路发生过度激活，细胞增殖的加速与细胞生存期的延长会导致肿瘤的形成及发展。4-{4-[3-(4-氯-3-三氟甲基苯基)脲]-3-氟苯氧基}吡啶-2-甲酰胺，结构如下式：
Figure PCTCN2021070076-appb-000001
英文名称：4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)-3-fluorophenoxy)-picolinamide，CAS号：1343498-72-5，是一种有效的VEGF及RAF激酶抑制剂，属于一种多靶点抗肿瘤药物。
现有技术中已经有4-{4-[3-(4-氯-3-三氟甲基苯基)脲]-3-氟苯氧基}吡啶-2-甲酰胺的制备方法，专利CN102643229A报道的方法，将4-氯吡啶-2-甲酰胺和3-氟-4-氨基苯酚溶于DMF，然后加入t-BuOK，在165℃搅拌75分钟制备2-氨基甲酰基-4-((3-氟-4-氨基)苯氧基)吡啶。然后将2-氨基甲酰基-4-((3-氟-4-氨基)苯氧基)吡啶溶于乙酸乙酯，然后加入3-三氟甲基-4-氯苯基异氰酸酯，60℃搅拌4小时，减压蒸出溶剂，硅胶柱纯化得白色固体4-{4-[3-(4-氯-3-三氟甲基苯基)脲]-3-氟苯氧基}吡啶-2-甲酰胺。该反应条件苛刻，涉及到高温、强碱反应，尤其反应溶剂DMF在此条件下部分降解，难于回收套用，造成环保压力。同时，收率偏低，需要硅胶柱纯化，不适合规模化生产。
专利CN102885814A公开了抗癌活性化合物4-{4-[3-(4-氯-3-三氟甲基苯基)脲]-3-氟苯氧基}吡啶-2-甲酰胺的合成方法，以原料4-氯吡啶-2-甲酰胺为原料，经过金属催化偶 联反应、异氰酸酯加成反应2个合成步骤制备4-{4-[3-(4-氯-3-三氟甲基苯基)脲]-3-氟苯氧基}吡啶-2-甲酰胺。该反应需要金属复合催化剂，成本较高，并且所生成的产物杂质较多，收率不高，不符合药品质量的要求。
因此，为了满足了在生产中要求，本申请提供了新的工艺，其在工业实用性、纯度和收率方面均有较大地改善。
发明内容
本发明的目的是提供一种制备化合物1的工业化的制备方法，其采用的合成路线如下方案：
Figure PCTCN2021070076-appb-000002
本发明包含一种制备化合物1的方法：
Figure PCTCN2021070076-appb-000003
该方法分为两个步骤，包括：第一步，氮气保护，使用williamson醚合成法合成中间体4：以化合物3和化合物2为原料，以二甲基亚砜和四氢呋喃为混合溶剂，在叔丁醇钾的作用下，反应生成中间体4；第二步，使用异氰酸酯成脲反应合成化合物1：以中间体4和化合物5在二氧六环溶剂中反应得粗产品，精制后得化合物1。
其中，所述第一步混合溶剂中二甲基亚砜和四氢呋喃的摩尔比为2-4:1，优选摩尔比2.5:1。
其中，所述第一步中二甲基亚砜和四氢呋喃的混合溶剂与叔丁醇钾摩尔比为5-15:1，优选摩尔比10:1。
其中，所述第二步中二氧六环与中间体4的摩尔比为20-100:1，优选摩尔比50:1。
其中，所述第一步反应温度为70-100℃，优选反应温度为80-90℃。
其中，所述第二步反应温度为45-65℃，优选反应温度为50-60℃。
其中，所述第一步反应时间为1.5-2小时。
其中，所述第二步反应时间为2-4小时。
具体制备方法如下：
步骤一：在反应釜中加入二甲基亚砜和四氢呋喃，通入氮气保护，再加入叔丁醇钾，待完全溶解后，控温10～20℃。继续加入4-氨基-3-氟苯酚，常温搅拌10分钟，加入4-氯-2-吡啶甲酰胺，继续搅拌10分钟，在30分钟内将反应液温度升至80℃以上。从内温升至80℃开始计时，于85±2℃保温反应2.0小时。反应结束后，冷却降温至20℃以下，滴加1M氢氧化钠水溶液，滴毕后于将反应釜内温缓慢降至0～2℃。趁冷过滤浆料，滤饼用去离子水洗涤。滤饼悬浮于去离子水中打浆30分钟，过滤。滤饼用去离子水洗涤，减压干燥后得中间体4。
步骤二：在反应釜中加入二氧六环，氮气保护，再加入中间体4，搅拌，升温至55℃。待中间体4完全溶解后，将4-氯-3-(三氟甲基)苯异氰酸酯溶于二氧六环并预冷至10℃，1小时滴加至反应釜内，滴毕后与中间体4继续反应1小时。冷却，反应液24℃析晶15小时得到化合物1。
化合物1结晶纯化：离心过滤，滤饼用乙酸乙酯淋洗两次，减压干燥后得滤饼；在反应釜内打入甲醇，加入上述化合物1，升温至回流，保温3.0小时，冷却，使内温降至34℃进行重结晶；结晶用甲醇淋洗两次，真空干燥72小时得类白色晶体。
对于本发明所述技术方案的第一步成醚反应，专利US2005245530报道了一种在N-甲基吡咯烷酮中，以二异丙基乙胺为碱，通过微波反应制备化合物的方法，该方法收率低且无法放大，不适合作为工艺开发：
Figure PCTCN2021070076-appb-000004
对于本发明所述技术方案第二步成脲反应，专利WO2009111061报道了另一条通过先由化合物7制备活性化合物9，再与化合物6反应合成索拉非尼的路线。但是实验证明，该路线收率较低，且反应会变得比较复杂：
Figure PCTCN2021070076-appb-000005
经过摸索和反复试验，本发明最终摸索出一种制备化合物1的工业化的方法。
与现有技术相比，本发明的有益技术效果体现在：
1)与现有技术比较，本发明技术方案通过改进溶剂，提高了反应产率，以特定的四氢呋喃和二甲基亚砜混合溶剂作为溶媒，大大降低了反应温度，提高了产率，同时降低了生产成本。
2)与现有技术比较，本发明技术方案通过改进反应条件，不仅提高了产物产率和纯度，同时又减少了杂质的数量和含量，符合医药工业的要求，并且避免了使用色谱柱纯化，从而使本发明技术方案从现有技术中的实验室级标准直接变为工业级标准。
3)与现有技术比较，本申请以用二氧六环作溶液，避免了使用有机碱类试剂和毒性较大的二氯甲烷做溶媒降低了环境污染的风险。
4)与现有技术比较,本发明无需使用金属催化剂，降低了重金属污染的风险，降低了成本，并避免了使用毒性相对较高的甲苯做反应溶媒。
具体实施方式
实施例1 2-氨基甲酰基-4-((3-氟-4-氨基)苯氧基)吡啶(化合物4)的制备
在100L反应釜中加入19.36kg二甲基亚砜和7.2kg四氢呋喃，通入氮气保护，再加入4.88kg叔丁醇钾，待完全溶解后，控温10～20℃。继续加入4.54kg 4-氨基-3-氟苯酚(化合物3)，常温搅拌10分钟，加入5.57kg 4-氯-2-吡啶甲酰胺(化合物2)，继续搅拌10分钟，在30分钟内将反应液温度升至80℃以上。从内温升至80℃开始计时，于85±2℃保温反应2.0小时。反应结束后，冷却降温至20℃以下，滴加1M氢氧化钠水溶液70kg，滴毕后于将反应釜内温缓慢降至0～2℃。趁冷过滤浆料，滤饼用120kg去离子水洗涤。滤饼悬浮于80kg去离子水中打浆30分钟，过滤。滤饼用20kg去离子水洗涤，减压干燥后得中间体4，称重为6.5kg(收率约为82.3％)。
实施例2 4-{4-[3-(4-氯-3-三氟甲基苯基)脲]-3-氟苯氧基}吡啶-2-甲酰胺(化合物1)的制备
在100L反应釜中加入37.3kg二氧六环，氮气保护，再加入2.5kg中间体4，搅拌，升温至55℃。待中间体4完全溶解后，将2.2kg 4-氯-3-(三氟甲基)苯异氰酸酯(化合物5)溶于6.7kg二氧六环并预冷至10℃，1小时滴加至100L反应釜内，滴毕后与中间体4继续反应1小时。冷却，反应液24℃析晶15小时得到化合物1。离心过滤，滤饼用6.0kg乙酸乙酯淋洗两次，减压干燥后滤饼重量为3.8kg。在100L反应釜内打入40.0kg甲醇，加入上述化合物1，升温至回流，保温3.0小时，冷却，使内温降至34℃进行重结晶。结晶用4.0kg甲醇淋洗两次，真空干燥72小时得类白色晶体3.5kg，收率约为75％，HPLC纯度：≥99.5％。 1H NMR(500MHz,DMSO-d 6)：δ7.17(d，1H),7.21(m,1H),7.32(m,1H),7.41(d,1H),7.62(d,2H),7.73(s,1H),8.17(m,3H),8.54(d,1H),8.72(s,1H),9.51(s,1H)；MS(ESI)m/z:469.1(M+H) +。
实施例3 2-氨基甲酰基-4-((3-氟-4-氨基)苯氧基)吡啶(化合物4)的制备
在100L反应釜中加入23.23kg二甲基亚砜和6.0kg四氢呋喃，通入氮气保护，再加入5.37kg叔丁醇钾，待完全溶解后，控温10～20℃。继续加入4.99kg 4-氨基-3-氟苯酚(化合物3)，常温搅拌10分钟，加入6.13kg 4-氯-2-吡啶甲酰胺(化合物2)，继续搅拌10分钟，在30分钟内将反应液温度升至80℃以上。从内温升至80℃开始计时，于85±2℃保温反应2.0小时。反应结束后，冷却降温至20℃以下，滴加1M氢氧化钠水溶液80kg，滴毕后于将反应釜内温缓慢降至0～2℃。趁冷过滤浆料，滤饼用140kg去离子水洗涤。滤饼悬浮于90kg去离子水中打浆30分钟，过滤。滤饼用25kg去离子水洗涤，减压干燥后得中间体4，称重为6.9kg(收率约为81.4％)。
实施例4 4-{4-[3-(4-氯-3-三氟甲基苯基)脲]-3-氟苯氧基}吡啶-2-甲酰胺(化合物1)的制备
在100L反应釜中加入41.0kg二氧六环，氮气保护，再加入3.0kg中间体4，搅拌，升温至60℃。待中间体4完全溶解后，将2.6kg 4-氯-3-(三氟甲基)苯异氰酸酯(化合物5)溶于7.4kg二氧六环并预冷至10℃，1小时滴加至100L反应釜内，滴毕后与中间体4继续反应1小时。冷却，反应液25℃析晶12小时得到化合物1。离心过滤，滤饼用7.0kg 乙酸乙酯淋洗两次，减压干燥后滤饼重量为4.4kg。在100L反应釜内打入45.0kg甲醇，加入上述化合物1，升温至回流，保温3.0小时，冷却，使内温降至32℃进行重结晶。结晶用4.5kg甲醇淋洗两次，真空干燥72小时得类白色晶体3.9kg，收率约为70％，HPLC纯度：≥99.4％。
实施例5 2-氨基甲酰基-4-((3-氟-4-氨基)苯氧基)吡啶(化合物4)的制备
在100L反应釜中加入12.90kg二甲基亚砜和4.3kg四氢呋喃，通入氮气保护，再加入4.0kg叔丁醇钾，待完全溶解后，控温10～20℃。继续加入3.78kg 4-氨基-3-氟苯酚(化合物3)，常温搅拌15分钟，加入4.64kg 4-氯-2-吡啶甲酰胺(化合物2)，继续搅拌15分钟，在40分钟内将反应液温度升至80℃以上。从内温升至80℃开始计时，于80±2℃保温反应2.5小时。反应结束后，冷却降温至20℃以下，滴加1M氢氧化钠水溶液50kg，滴毕后于将反应釜内温缓慢降至0～2℃。趁冷过滤浆料，滤饼用100kg去离子水洗涤。滤饼悬浮于60kg去离子水中打浆30分钟，过滤。滤饼用15kg去离子水洗涤，减压干燥后得中间体4，称重为5.2kg(收率约为78.4％)。
实施例6 4-{4-[3-(4-氯-3-三氟甲基苯基)脲]-3-氟苯氧基}吡啶-2-甲酰胺(化合物1)的制备
在100L反应釜中加入25.0kg二氧六环，氮气保护，再加入1.7kg中间体4，搅拌，升温至50℃。待中间体4完全溶解后，将1.5kg 4-氯-3-(三氟甲基)苯异氰酸酯(化合物5)溶于4.5kg二氧六环并预冷至10℃，1小时滴加至100L反应釜内，滴毕后与中间体4继续反应1小时。冷却，反应液24℃析晶15小时得到化合物1。离心过滤，滤饼用5.0kg乙酸乙酯淋洗两次，减压干燥后滤饼重量为2.4kg。在100L反应釜内打入30.0kg甲醇，加入上述化合物1，升温至回流，保温3.0小时，冷却，使内温降至32℃进行重结晶。结晶用3.0kg甲醇淋洗两次，真空干燥72小时得类白色晶体2.2kg，收率约为71％，HPLC纯度：≥99.3％。
实施例7化合物1质量标准及检测方法
纯度测定方法：(HPLC，面积归一法。)
色谱柱：Waters Symmetry C18 4.6×50mm，3.5um检测器：紫外检测器；
流速：1.0mL/分钟；
检测波长262nm；
浓度0.3mg/mL；
进样量10μl；
稀释剂：乙腈/甲醇＝1/1(v/v)；
流动相A：10mmol/L甲酸铵；
流动相B：乙腈/甲醇＝1/1(v/v)；
测定结果：
将实施例2所得到的化合物1进行测定，结果如下：
Figure PCTCN2021070076-appb-000006
其中杂质情况下如下所示：
Figure PCTCN2021070076-appb-000007
以上所述仅为本发明的较佳实施例，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (9)

  1. 一种多靶点抗肿瘤药物化合物1的制备方法，其特征在于包括如下步骤:
    第一步，使用williamson醚合成法合成中间体4：以化合物3和化合物2为原料，以四氢呋喃和二甲基亚砜为混合溶剂，在叔丁醇钾的作用下，反应生成中间体4；
    第二步，使用异氰酸酯成脲反应合成化合物1：以中间体4和化合物5在二氧六环溶剂中反应得粗产品，精制后得化合物1；
    具体化学反应式如下：
    Figure PCTCN2021070076-appb-100001
  2. 按照权利要求1所述的制备方法，其特征在于所述第一步混合溶剂中二甲基亚砜和四氢呋喃的摩尔比为2-4:1，优选摩尔比2.5:1。
  3. 按照权利要求1所述的制备方法，其特征在于所述第一步中二甲基亚砜和四氢呋喃的混合溶剂与叔丁醇钾摩尔比为5-15:1，优选摩尔比10:1。
  4. 按照权利要求1所述的制备方法，其特征在于所述第二步中二氧六环与中间体4的摩尔比为20-100:1，优选摩尔比50:1。
  5. 按照权利要求1所述的制备方法，其特征在于所述第一步反应温度为70-100℃，优选反应温度为80-90℃。
  6. 按照权利要求1所述的制备方法，其特征在于所述第二步反应温度为45-65℃，优选反应温度为50-60℃。
  7. 按照权利要求1所述的制备方法，其特征在于所述第一步反应时间为1.5-2小时。
  8. 按照权利要求1所述的制备方法，其特征在于所述第二步反应时间为2-4小时。
  9. 一种多靶点抗肿瘤药物化合物1的制备方法，其特征在于包括如下步骤：
    步骤一：在反应釜中加入二甲基亚砜和四氢呋喃，通入氮气保护，再加入叔丁醇钾，待完全溶解后，控温10～20℃。继续加入4-氨基-3-氟苯酚，常温搅拌10分钟，加入4-氯-2-吡啶甲酰胺，继续搅拌10分钟，在30分钟内将反应液温度升至80℃以上。从内温升至80℃开始计时，于85±2℃保温反应2.0小时。反应结束后，冷却降温至20℃以下，滴 加1M氢氧化钠水溶液，滴毕后于将反应釜内温缓慢降至0～2℃。趁冷过滤浆料，滤饼用去离子水洗涤。滤饼悬浮于去离子水中打浆30分钟，过滤。滤饼用去离子水洗涤，减压干燥后得中间体4；
    步骤二：在反应釜中加入二氧六环，氮气保护，再加入中间体4，搅拌，升温至55℃。待中间体4完全溶解后，将4-氯-3-(三氟甲基)苯异氰酸酯溶于二氧六环并预冷至10℃，1小时滴加至反应釜内，滴毕后与中间体4继续反应1小时。冷却，反应液24℃析晶15小时得到化合物1；
    化合物1结晶纯化：离心过滤，滤饼用乙酸乙酯淋洗两次，减压干燥后得滤饼；在反应釜内打入甲醇，加入上述化合物1，升温至回流，保温3.0小时，冷却，使内温降至34℃进行重结晶；结晶用甲醇淋洗两次，真空干燥72小时得类白色晶体；
    具体化学反应式如下：
    Figure PCTCN2021070076-appb-100002
PCT/CN2021/070076 2020-09-21 2021-01-04 一种多靶点抗肿瘤药物的制备方法 WO2022057164A1 (zh)

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