WO2016034150A1 - 博舒替尼及其结晶的制备方法 - Google Patents

博舒替尼及其结晶的制备方法 Download PDF

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WO2016034150A1
WO2016034150A1 PCT/CN2015/088989 CN2015088989W WO2016034150A1 WO 2016034150 A1 WO2016034150 A1 WO 2016034150A1 CN 2015088989 W CN2015088989 W CN 2015088989W WO 2016034150 A1 WO2016034150 A1 WO 2016034150A1
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methoxy
polar solvent
aprotic polar
quinolinecarbonitrile
bosutinib
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PCT/CN2015/088989
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English (en)
French (fr)
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陈程
李阳
孟庆义
赵锐
张喜全
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正大天晴药业集团股份有限公司
连云港润众制药有限公司
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Priority claimed from CN201410450202.6A external-priority patent/CN105384686B/zh
Priority claimed from CN201410546745.8A external-priority patent/CN105503719B/zh
Application filed by 正大天晴药业集团股份有限公司, 连云港润众制药有限公司 filed Critical 正大天晴药业集团股份有限公司
Publication of WO2016034150A1 publication Critical patent/WO2016034150A1/zh

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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
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3

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  • the application belongs to the field of pharmaceutical and chemical industry, and specifically relates to a preparation method of bosutinib and its crystal.
  • Bosutinib is a potent protein kinase (Src/Abl) inhibitor. The drug was developed by Wyeth Pharmaceuticals, a Pfizer company, and was first launched in the United States on September 4, 2012. It is approved for use in chronic, accelerated, or blast-positive Philadelphia chromosome-positive chronic granulocytes. Treatment of adult patients with leukemia (CML) who have previously been treated with one or more tyrosine kinase inhibitors and are not suitable for imatinib, nilotinib and dasatinib. The chemical structure of bosutinib is shown in Formula I.
  • CML leukemia
  • Chinese patent application CN101792416A discloses a preparation method of bosutinib. The method has a low yield.
  • Chinese patent application CN101248047A discloses a bosutinib monohydrate type I crystal, and discloses a method of crystallizing bosutinib from other crystal forms to obtain bosutinib monohydrate type I crystal.
  • the present application provides a process for preparing bosutinib which is simple in process, which improves the yield by improving the reaction conditions, and is more suitable for industrial production than the prior art.
  • the preparation method of the present application of bosutinib includes:
  • the aprotic polar solvent in step 1) and step 2) above is independently selected from the group consisting of 1-methyl-2-pyrrolidone, dimethylacetamide, dimethylformamide, or any of the foregoing solvents.
  • a mixed solvent is preferably 1-methyl-2-pyrrolidone.
  • the aprotic polar solvent in step 1) and step 2) is the same aprotic polar solvent.
  • the aprotic polar solvent in step 1) and step 2) is 1-methyl-2-pyrrolidone.
  • step 1) the molar ratio of 4-chloro-6-methoxy-7-(3-chloropropoxy)-3-quinolinecarbonitrile to 2,4-dichloro-5-methoxyaniline is preferred. It is from 1:4 to 1:1, more preferably from 1:3 to 1:1, most preferably 2:3.
  • the reaction temperature is preferably from 60 ° C to 120 ° C, more preferably from 70 ° C to 120 ° C, and most preferably from 80 ° C to 110 ° C.
  • the reaction in step 1) is preferably carried out under nitrogen.
  • step 1) the molar ratio of 4-chloro-6-methoxy-7-(3-chloropropoxy)-3-quinolinecarbonitrile to pyridine hydrochloride is preferably from 1:2 to 2:1. More preferably, it is from 2:3 to 3:2, and most preferably 1:1.
  • step 2 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-(3-chloropropoxy)-3-quinolinecarbonitrile in step 2)
  • the molar ratio to N-methylpiperazine is preferably from 1:2 to 1:8, more preferably from 1:3 to 1:4.
  • the reaction temperature is preferably from 60 ° C to 120 ° C, more preferably from 70 ° C to 120 ° C, and most preferably from 80 ° C to 110 ° C.
  • the reaction in step 2) is preferably carried out under nitrogen blanket.
  • the iodide is used as a catalyst selected from the group consisting of potassium iodide, sodium iodide, magnesium iodide or lithium iodide, preferably sodium iodide.
  • Molar of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-(3-chloropropoxy)-3-quinolinecarbonitrile with iodide The ratio is preferably from 1:2 to 2:1, more preferably from 2:3 to 3:2, most preferably 1:1.
  • step 1) 4-chloro-6-methoxy-7-(3-chloropropoxy)-3-quinolinecarbonitrile of formula II can be prepared by the following procedure:
  • the aprotic polar solvent is selected from the group consisting of 1-methyl-2-pyrrolidone, dimethylacetamide, dimethylformamide or a mixed solvent of any of the above solvents, preferably 1-methyl. -2-pyrrolidine.
  • the aprotic polar solvent is the same aprotic polar solvent as the aprotic polar solvent described in steps 1) and 2) above.
  • the aprotic polar solvent is the 1-methyl-2-pyrrolidone described above in step 1) and step 2).
  • the molar ratio of 4-chloro-6-methoxy-7-hydroxy-3-quinolinecarbonitrile to 1-bromo-3-chloropropane is preferably from 1:4 to 1:1. More preferably, it is 1:4 to 1:2, most preferably 1:3.
  • the reaction temperature is preferably from 20 ° C to 60 ° C, more preferably from 20 ° C to 50 ° C, most preferably from 30 ° C to 40 ° C.
  • the above reaction in the step of preparing the compound of the formula II is preferably carried out under the protection of nitrogen.
  • the crown ether catalyst is selected from the group consisting of 18-crown-6 ether, dibenzo-18-crown-6 ether or dinitro-18-crown-6 ether, preferably dibenzo-18. - Crown-6-ether.
  • the molar ratio of 4-chloro-6-methoxy-7-hydroxy-3-quinolinecarbonitrile to the crown ether catalyst is preferably from 10:1 to 500:1, more preferably from 20:1 to 200:1, most It is preferably 50:1.
  • the potassium-containing acid-binding agent is preferably potassium hydroxide, potassium hydrogencarbonate or potassium carbonate, and most preferably potassium carbonate.
  • the molar ratio of 4-chloro-6-methoxy-7-hydroxy-3-quinolinecarbonitrile to the potassium-containing acid-binding agent is preferably from 1:4 to 1:1, more preferably from 1:4 to 1:2, most More preferably, it is 1:3.
  • the potassium-containing acid-binding agent in the step of preparing the compound of formula II is potassium carbonate
  • the crown ether-based catalyst is dibenzo-18-crown-6-ether
  • the iodide in step 2) is The aprotic polar solvent in the steps of step 1) and step 2) and the above-mentioned preparation of the compound of formula II are all 1-methyl-2-pyrrolidone.
  • Another aspect of the present application provides a method for preparing a mildly-type bosutinib monohydrate Form I crystal comprising:
  • Bosutinib is dissolved in an aprotic polar solvent, then added with water, cooled, and crystallized.
  • the bosutinib may be bosutinib prepared according to the method of the present invention, or may be bosutinib prepared according to the prior art such as WO2005065074.
  • the aprotic polar solvent is selected from the group consisting of dimethyl sulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide (DMAC), 1-methyl-2-pyrrolidone or the above.
  • a mixed solvent of the solvent preferably 1-methyl-2-pyrrolidone.
  • the mass to volume ratio of the bosutinib to the aprotic polar solvent is from 1 g: 3 mL to 1 g: 20 mL, preferably from 1 g: 3 mL to 1 g: 15 mL, more preferably from 1 g: 4 mL to 1 g: 10 mL, further It is preferably 1 g: 4 mL to 1 g: 8 mL.
  • the volume ratio of water to the aprotic polar solvent is from 0.5:1 to 10:1, preferably from 1:1 to 5:1, still more preferably from 1:1 to 3:1.
  • the temperature at which bosutinib is dissolved in the aprotic polar solvent may be from 50 ° C to 100 ° C, preferably from 50 ° C to 80 ° C, and more preferably from 50 ° C to 65 ° C.
  • water is added to maintain the temperature of the system from 50 ° C to 100 ° C, preferably from 50 ° C to 80 ° C, more preferably from 50 ° C to 65 ° C; and stirring is carried out for 15 minutes to 1 hour, preferably 30 minutes.
  • the temperature drop may be lowered to 0 ° C to 10 ° C. Cooling can be natural cooling and cooling.
  • the above method may also include filtration and drying. Drying is preferably dried under reduced pressure, and further preferably dried at 45 ° C under vacuum.
  • the above process is preferably carried out under nitrogen.
  • the bosutinib is dissolved in the aprotic polar solvent, and the bosutinib may be mixed with the aprotic polar solvent first, and then heated; or the aprotic polar solvent may be heated first, and then with Bosch Mixini.
  • a method of carbonitrile comprising: 4-chloro-6-methoxy-7-(3-chloropropoxy)-3-quinolinecarbonitrile and 2,4-dichloro-5-methoxyaniline in a non- Reaction in a protic polar solvent.
  • the aprotic polar solvent is selected from the group consisting of 1-methyl-2-pyrrolidone, dimethylacetamide, dimethylformamide, or a mixed solvent of any of the foregoing. In some preferred embodiments, the aprotic polar solvent is 1-methyl-2-pyrrolidone.
  • the molar ratio of 4-chloro-6-methoxy-7-(3-chloropropoxy)-3-quinolinecarbonitrile to 2,4-dichloro-5-methoxyaniline is preferred. It is from 1:4 to 1:1, more preferably from 1:3 to 1:1, most preferably 2:3.
  • the reaction temperature is preferably from 60 ° C to 120 ° C, more preferably from 70 ° C to 120 ° C, and most preferably from 80 ° C to 110 ° C.
  • reaction in the above process is preferably carried out under the protection of nitrogen.
  • the reaction is preferably carried out in the presence of pyridine hydrochloride; 4-chloro-6-methoxy-7-(3-chloropropoxy)-3-quinolinecarbonitrile and pyridine hydrochloride
  • the molar ratio is preferably from 1:2 to 2:1, more preferably from 2:3 to 3:2, most preferably 1:1.
  • the step 1) is to improve the reaction conditions and then the intermediate 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-
  • the yield of 7-(3-chloropropoxy)-3-quinolinecarbonitrile (formula III) is increased from 46% of the prior art (CN101792416A specification example 4) to 90%, which greatly increases the yield of the product. .
  • CN101792416A describes the fourth embodiment of the specification
  • ethylene glycol monoethyl ether is used as a solvent, and the method for producing the impurities 4-hydroxychloropropoxyquinoline and allyl groups reach 46.61% and 0.22%, respectively; and in the present application, the 1-methyl group is used.
  • 2-pyrrolidone as a solvent, the content of the above two impurities formed was only 0.28% and 0.27%, respectively (determined by HPLC).
  • N-methylpiperazine is used as a reactant and solvent in the preparation of bosutinib by nitrile (formula III) and N-methylpiperazine (CN101792416A, N-methylpiperazine and intermediate formula III in Example 4)
  • the ratio is 52:1)
  • the preparation method of the bosutinib of the present application step 2) uses 1-methyl-2-pyrrolidone instead of N-methylpiperazine as a solvent (N-methylpiperazine and intermediate formula III)
  • the molar ratio is preferably from 1:2 to 1:8), and the amount of the expensive raw material N-methylpiperazine is reduced while keeping the yield substantially constant, and the cost is lowered.
  • step 1) preferably uses 1-methyl-2-pyrrolidone as a solvent.
  • 1-methyl-2-pyrrolidone is used as a solvent to ensure the yield while avoiding the formation of a small amount of by-product diethylamine which is difficult to remove, which is more conducive to the drug.
  • the quality standard is controlled, and 1-methyl-2-pyrrolidone is more stable under alkaline reaction conditions.
  • CN101248047A uses water as a single solvent to crystallize, the specific heat capacity of water is 4.2KJ / (Kg ⁇ °C), assuming that the water is heated from normal temperature (ie 20 ° C) to 80 ° C ⁇ 95 ° C, then during the heating process, Kilograms of water need to consume at least 252 ⁇ 273KJ of energy, and the subsequent need to maintain crystals at 80 ° C ⁇ 95 ° C for 3 hours to 24 hours, need to consume a lot of energy.
  • the method disclosed in CN101248047A is to devitrify while dissolving, which is not conducive to the complete conversion of the crystal form.
  • the crystallization method provided by the present application can completely dissolve bosutinib within 15 min when the temperature of the aprotic polar solvent is 50 ° C to 65 ° C, the dissolution temperature is low, the dissolution time is short, and the energy in the heating process can be reduced. Consumption. As the temperature of the aprotic polar solvent increases, the dissolution rate of bosutinib increases and dissolves The time is further shortened.
  • bosutinib in the present application preferably uses the same aprotic polar solvent, which can reduce the problem of solvent residue and further reduce the content of related substances.
  • the preparation process of the present application is simple, the reaction condition is mild, the solvent property is stable, the productivity is obviously improved, the cost is reduced, and the product is suitable for industrial production;
  • the crystallization method of the present application has low energy consumption in the heating process, and does not need to maintain high temperature crystal growth for a long time,
  • the advantage of short crystallization time can reduce production energy consumption, reduce environmental pollution, save production costs, and short production cycle, which can improve production efficiency.
  • the crystallization method provided by the present application is to facilitate complete conversion of the crystal form by completely dissolving bosutinib and then cooling and crystallization, and the crystallization method of the present application can reduce the content of unnecessary substances.
  • Bosutinib monohydrate Form I crystal prepared according to an embodiment of the present application.
  • DSC differential scanning calorimetry
  • the temperature was controlled at 30 ° C to 40 ° C for about 4 h, and the TLC tracking monitored the disappearance of 4-chloro-6-methoxy-7-hydroxy-3-quinolinecarbonitrile spots.
  • the reaction solution was transferred to a 200 L glass-lined reactor, and 66 L of purified water was slowly added under stirring at a temperature of 25-40 ° C. Stir at 25-35 ° C for 30 min, and filter. The obtained solid was washed three times with 10 L of purified water, respectively. The obtained wet product was air-dried at 45-55 ° C for 12 h to give the title compound 4.
  • the reaction solution was cooled to 20-30 ° C, transferred to a 200 L glass-lined reactor, 40 L of ethyl acetate was added, 75 L of purified water was slowly added with stirring, and 1 M hydrochloric acid (400 mL of concentrated hydrochloric acid and 4.5 L of purified water) was added to adjust the pH to 2.
  • 1 M hydrochloric acid 400 mL of concentrated hydrochloric acid and 4.5 L of purified water
  • the filter cake was washed with 12 L of purified water, 12 L of purified water and 12 L of ethyl acetate.
  • the solid was added to 20 L of ethyl acetate and stirred for 30 min and then filtered. The solid was washed with ethyl acetate (4 mL).
  • the reaction solution was cooled to 20-30 ° C, transferred to a 200 L glass-lined reactor, 40 L of ethyl acetate was added, 75 L of purified water was slowly added with stirring, and 1 M hydrochloric acid (400 mL of concentrated hydrochloric acid and 4.5 L of purified water) was added to adjust the pH to 2.
  • 1 M hydrochloric acid 400 mL of concentrated hydrochloric acid and 4.5 L of purified water
  • the filter cake was washed with 12 L of purified water, 12 L of purified water and 12 L of ethyl acetate.
  • the solid was added to 20 L of ethyl acetate and stirred for 30 min.
  • the obtained product was dried under vacuum at 35 ° C to 40 ° C for 12 h to give 5.4 g of the title compound (yield: 90.0%).
  • the reaction solution was cooled to 20-30 ° C, transferred to a 200 L glass-lined reactor, 40 L of ethyl acetate was added, 75 L of purified water was slowly added with stirring, and 1 M hydrochloric acid (400 mL of concentrated hydrochloric acid and 4.5 L of purified water) was added to adjust the pH to 2.
  • 1 M hydrochloric acid 400 mL of concentrated hydrochloric acid and 4.5 L of purified water
  • the filter cake was washed with 12 L of purified water, 12 L of purified water and 12 L of ethyl acetate.
  • the solid was added to 20 L of ethyl acetate and stirred for 30 min.
  • the obtained product was dried under vacuum at 35 ° C to 40 ° C for 12 h to give 5.2 g of the title compound (yield: 86.7%).
  • the crude 5.6 kg of bosutinib was mixed with ethyl acetate and silica gel in equal portions, and concentrated under reduced pressure at 35 ° C to 40 ° C to obtain a sand.
  • DMAC dimethylacetamide
  • Mobile phase using 20 mmol/L ammonium formate solution (pH adjusted to 4.5 with formic acid) as mobile phase A, acetonitrile as mobile phase B, gradient elution according to Table 1.

Abstract

公开了博舒替尼及其结晶的制备方法。该方法包括以4-氯-6-甲氧基-7-羟基-3-喹啉甲腈和2，4-二氯-5-甲氧基苯胺为起始原料，以非质子极性溶剂为反应溶剂制备博舒替尼；以及将博舒替尼溶于非质子极性溶剂，加入水，降温，析晶，制得博舒替尼一水合物I型结晶。该方法减少了杂质生成，显著提高了产率并降低了成本；结晶方法耗能低、无需长时间维持高温转晶、产品纯度高，适用于工业化生产。

Description

博舒替尼及其结晶的制备方法
相关申请的交叉引用
本申请要求于2014年9月4日向中国国家知识产权局提交的第201410450202.6号中国专利申请以及于2014年10月15日向中国国家知识产权局提交的第201410546745.8号中国专利申请的优先权和权益，所述申请公开的内容通过引用整体并入本文中。
技术领域
本申请属于医药化工领域，具体涉及博舒替尼及其结晶的制备方法。
背景技术
博舒替尼是一种强效的蛋白激酶(Src/Abl)抑制剂。该药物由美国辉瑞(Pfizer)旗下的惠氏(Wyeth)制药公司开发，于2012年9月4日在美国初次上市，被批准用于慢性的、加速期或急变期费城染色体呈阳性的慢性粒细胞白血病(CML)成年患者的治疗，该患者以往已采用过一种或以上的酪氨酸激酶抑制剂治疗，且不适用于伊马替尼、尼罗替尼和达沙替尼。博舒替尼的化学结构如式I所示。
Figure PCTCN2015088989-appb-000001
中国专利申请CN101792416A公开了一种博舒替尼的制备方法。该方法产率较低。
中国专利申请CN101248047A公开了一种博舒替尼一水合物I型结晶，并公开了由其它晶型的博舒替尼转晶，制得博舒替尼一水合物I型结晶的方法。
发明概述
本申请一方面提供了一种工艺简单的博舒替尼的制备方法，该方法通过改进反应条件有效提高了产率，相比现有技术更适用于工业化生产。
本申请博舒替尼的制备方法包括：
1)在吡啶盐酸盐存在下，式II的4-氯-6-甲氧基-7-(3-氯丙氧基)-3-喹啉甲腈与2，4-二氯-5-甲氧基苯胺在非质子极性溶剂中反应，得到式III的4-[(2，4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-(3-氯丙氧基)-3-喹啉甲腈；
Figure PCTCN2015088989-appb-000002
以及
2)在碘化物存在下，式III的4-[(2，4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-(3-氯丙氧基)-3-喹啉甲腈与N-甲基哌嗪在非质子极性溶剂中反应，得到式I的博舒替尼。
Figure PCTCN2015088989-appb-000003
在一些实施方案中，上述步骤1)和步骤2)中所述非质子极性溶剂独立地选自1-甲基-2-吡咯烷酮、二甲基乙酰胺、二甲基甲酰胺或上述任意溶剂的混合溶剂，优选为1-甲基-2-吡咯烷酮。在一些优选实施方案中，步骤1)和步骤2)中所述非质子极性溶剂为同一种非质子极性溶剂。在一些优选实施方案中，步骤1)和步骤2)中所述非质子极性溶剂均为1-甲基-2-吡咯烷酮。
步骤1)中，4-氯-6-甲氧基-7-(3-氯丙氧基)-3-喹啉甲腈与2，4-二氯-5-甲氧基苯胺的摩尔比优选为1∶4至1∶1，更优选为1∶3至1∶1，最优选为2∶3。
步骤1)中，反应温度优选为60℃-120℃，更优选为70℃-120℃，最优选为80℃-110℃。
步骤1)中的反应优选在氮气保护下进行。
步骤1)中，4-氯-6-甲氧基-7-(3-氯丙氧基)-3-喹啉甲腈与吡啶盐酸盐的摩尔比优选为1∶2至2∶1，更优选为2∶3至3∶2，最优选为1∶1。
步骤2)中，4-[(2，4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-(3-氯丙氧基)-3-喹啉甲腈与N-甲基哌嗪的摩尔比优选为1∶2至1∶8，更优选为1∶3-1∶4。
步骤2)中，反应温度优选为60℃-120℃，更优选为70℃-120℃，最优选为80℃-110℃。
步骤2)中的反应优选在氮气保护中进行。
步骤2)中，碘化物用作催化剂，选自碘化钾、碘化钠、碘化镁或碘化锂，优选为碘化钠。4-[(2，4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-(3-氯丙氧基)-3-喹啉甲腈与碘化物的摩尔比优选为1∶2至2∶1，更优选为2∶3至3∶2，最优选为1∶1。
步骤1)中，式II的4-氯-6-甲氧基-7-(3-氯丙氧基)-3-喹啉甲腈可以通过下述步骤制备得到：
在含钾缚酸剂和冠醚类催化剂存在下，4-氯-6-甲氧基-7-羟基-3-喹啉甲腈与1-溴-3-氯丙烷发生烷基化反应，得到式II的4-氯-6-甲氧基-7-(3-氯丙氧基)-3-喹啉甲腈。
Figure PCTCN2015088989-appb-000004
上述制备式II化合物的步骤中，4-氯-6-甲氧基-7-羟基-3-喹啉甲腈与1-溴-3-氯丙烷优选在非质子极性溶剂中发生反应。在一些优选实施方案中，所述非质子极性溶剂选自1-甲基-2-吡咯烷酮、二甲基乙酰胺、二甲基甲酰胺或上述任意溶剂的混合溶剂，优选为1-甲基-2-吡咯烷。在一些优选实施方案中，所述非质子极性溶剂与上述步骤1)和步骤2)中所述非质子极性溶剂为同一种非质子极性溶剂。在一些优选实施方案中，所述非质子极性溶剂与上述步骤1)和步骤2)中所述非质子极性溶剂均为1-甲基-2-吡咯烷酮。
上述制备式II化合物的步骤中，4-氯-6-甲氧基-7-羟基-3-喹啉甲腈与1-溴-3-氯丙烷的摩尔比优选为1∶4至1∶1，更优选为1∶4至1∶2，最优选为 1∶3。
上述制备式II化合物的步骤中，反应温度优选为20℃-60℃，更优选为20℃-50℃，最优选为30℃-40℃。
上述制备式II化合物的步骤中的反应优选在氮气保护下进行。
上述制备式II化合物的步骤中，冠醚类催化剂选自18-冠-6醚、二苯并-18-冠-6醚或二氮-18-冠-6醚，优选为二苯并-18-冠-6-醚。4-氯-6-甲氧基-7-羟基-3-喹啉甲腈与冠醚类催化剂的摩尔比优选为10∶1至500∶1，更优选为20∶1至200∶1，最优选为50∶1。
上述制备式II化合物的步骤中，含钾缚酸剂优选为氢氧化钾、碳酸氢钾或碳酸钾，最优选为碳酸钾。4-氯-6-甲氧基-7-羟基-3喹啉甲腈与含钾缚酸剂的摩尔比优选为1∶4至1∶1，更优选为1∶4至1∶2，最更优选为1∶3。
在一些优选实施方案中，上述制备式II化合物的步骤中的含钾缚酸剂为碳酸钾，冠醚类催化剂为二苯并-18-冠-6-醚；步骤2)中的碘化物为碘化钠；和/或步骤1)和步骤2)以及上述制备式II化合物的步骤中的非质子极性溶剂均为1-甲基-2-吡咯烷酮。
本申请的另一方面提供了一种条件温和的博舒替尼一水合物I型结晶的制备方法，其包括：
将博舒替尼溶于非质子极性溶剂，再加入水，降温，析晶。
其中博舒替尼可以是按照本发明前述方法制得的博舒替尼，也可以是参照WO2005065074等现有技术制得的博舒替尼。
上述方法中，所述非质子极性溶剂选自二甲基亚砜(DMSO)、二甲基甲酰胺(DMF)、二甲基乙酰胺(DMAC)、1-甲基-2-吡咯烷酮或上述溶剂的混合溶剂，优选1-甲基-2-吡咯烷酮。
上述方法中，所述博舒替尼与非质子极性溶剂的质量体积比为1g∶3mL～1g∶20mL，优选1g∶3mL～1g∶15mL，进一步优选1g∶4mL～1g∶10mL，更进一步优选1g∶4mL～1g∶8mL。
上述方法中，水与非质子极性溶剂的体积比为0.5∶1～10∶1，优选1∶1～5∶1，更进一步优选1∶1～3∶1。
上述方法中，博舒替尼溶于非质子极性溶剂的温度可以是50℃～100℃，优选50℃～80℃，进一步优选50℃～65℃。
优选地，上述方法中，加入水，保持体系温度为50℃-100℃，优选为50℃-80℃，更优选为50℃-65℃；搅拌15分钟至1小时，优选30分钟。
上述方法中，降温可以是降温到0℃～10℃。降温可以是自然冷却降温。
上述方法还可以包括过滤和干燥。干燥优选减压干燥，进一步优选45℃下真空干燥。
上述方法优选在氮气下进行。
上述方法中，将博舒替尼溶于非质子极性溶剂，可以是将博舒替尼与非质子极性溶剂先混合，再加热；或将非质子极性溶剂先加热，再与博舒替尼混合。
本申请再一方面提供制备4-[(2，4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-(3-氯丙氧基)-3-喹啉甲腈的方法，包括：4-氯-6-甲氧基-7-(3-氯丙氧基)-3-喹啉甲腈与2，4-二氯-5-甲氧基苯胺在非质子极性溶剂中反应。
在一些实施方案中，所述非质子极性溶剂选自1-甲基-2-吡咯烷酮、二甲基乙酰胺、二甲基甲酰胺或上述任意溶剂的混合溶剂。在一些优选实施方案中，所述非质子极性溶剂为1-甲基-2-吡咯烷酮。
在上述方法中，4-氯-6-甲氧基-7-(3-氯丙氧基)-3-喹啉甲腈与2，4-二氯-5-甲氧基苯胺的摩尔比优选为1∶4至1∶1，更优选为1∶3至1∶1，最优选为2∶3。
在上述方法中，反应温度优选为60℃-120℃，更优选为70℃-120℃，最优选为80℃-110℃。
上述方法中的反应优选在氮气保护下进行。
在上述方法中，所述反应优选在吡啶盐酸盐存在下进行；4-氯-6-甲氧基-7-(3-氯丙氧基)-3-喹啉甲腈与吡啶盐酸盐的摩尔比优选为1∶2至2∶1，更优选为2∶3至3∶2，最优选为1∶1。
本申请的博舒替尼及其结晶的制备方法中所用的原料及试剂均已工业化生产。
本申请的博舒替尼的制备方法中，步骤1)改进反应条件后将中间体4-[(2，4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-(3-氯丙氧基)-3-喹啉甲腈(式III)的收率从现有技术的46％(CN101792416A说明书实施例4)提高到90％，大幅提高了产品的收率。例如，CN101792416A说明书实施例4的 制备方法中采用乙二醇单乙醚作为溶剂，该方法生成杂质4-羟基氯丙氧喹啉和烯丙基物分别达到46.61％和0.22％；而本申请实施例3中采用1-甲基-2-吡咯烷酮作为溶剂，所生成的上述两种杂质的含量仅分别为0.28％和0.27％(经HPLC测定)。
另外，现有技术以4-氯-6-甲氧基-7-(3-氯丙氧基)-3-喹啉甲腈(式II)与2，4-二氯-5-甲氧基苯胺制备中间体4-[(2，4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-(3-氯丙氧基)-3-喹啉甲腈(式III)时，使用乙二醇单乙醚作为溶剂，该溶剂闪点、沸点较低，且接触空气或在光照条件下可生成具有潜在爆炸危险性的过氧化物，而本申请的博舒替尼的制备方法步骤1)使用的1-甲基-2-吡咯烷酮在使用、运输和存储时均更为安全环保。
另外，现有技术以4-[(2，4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-(3-氯丙氧基)-3-喹啉甲腈(式III)和N-甲基哌嗪制备博舒替尼时，使用N-甲基哌嗪作为反应物兼溶剂(CN101792416A实施例4中N-甲基哌嗪与中间体式III投料量摩尔比为52∶1)，而本申请的博舒替尼的制备方法步骤2)使用1-甲基-2-吡咯烷酮代替N-甲基哌嗪作为溶剂(N-甲基哌嗪与中间体式III摩尔比优选为1∶2-1∶8)，在保持收率基本不变的同时减少了昂贵原料N-甲基哌嗪的投料量，降低了成本。
另外，本申请的博舒替尼的制备方法步骤1)优选使用1-甲基-2-吡咯烷酮作为溶剂。相对于非优选的二甲基乙酰胺和二甲基甲酰胺，使用1-甲基-2-吡咯烷酮作为溶剂在保证收率的同时可避免难以除去的少量副产物二乙胺生成，更利于药品质量标准的控制，且1-甲基-2-吡咯烷酮在碱性反应条件下性质更为稳定。
另外，CN101248047A采用水作为单一溶剂转晶时，水的比热容为4.2KJ/(Kg·℃)，假设将水从常温(即20℃)开始加热至80℃～95℃，则加热过程中，每千克水至少需消耗252～273KJ能量，且后续还需在80℃～95℃下维持3小时～24小时转晶，需进一步消耗大量能量。且CN101248047A所公开的方法是边溶解边析晶，不利于晶型的彻底转化。本申请所提供的结晶方法在非质子极性溶剂的温度为50℃～65℃时就已经可以在15min以内完全溶解博舒替尼，溶解温度低，溶解时间短，能够降低升温过程中的能耗。随着非质子极性溶剂的温度升高，博舒替尼的溶解速率加快，溶解 时间进一步缩短。
最后，本申请博舒替尼的制备和结晶过程优选使用相同的非质子极性溶剂，可减少溶剂残留问题，进一步降低有关物质含量。
本申请的制备工艺步骤简单，反应条件温和，溶剂性质稳定，显著提高了产率并降低了成本，适用于工业化生产；本申请结晶方法具有升温过程耗能低、无需长时间维持高温转晶、结晶时间短的优点，能够降低生产能耗，减少环境污染，节约生产成本，同时生产周期短，可以提高生产效率。本申请所提供的结晶方法是通过完全溶解博舒替尼，再降温析晶的方法，有利于晶型的彻底转化，且本申请的结晶方法能够降低不需要物质的含量。
附图说明
图1为本申请一实施例制备得到的博舒替尼一水合物I型结晶的X-射线粉末衍射光谱。
图2为本申请一实施例制备得到的博舒替尼一水合物I型结晶的差示扫描量热(DSC)测量图。
具体实施方式
以下结合实施例对本发明技术方案做进一步非限制的详细说明。
实施例1：4-氯-6-甲氧基-7-(3-氯丙氧基)-3-喹啉甲腈的制备
氮气保护下，在50L搪瓷反应釜中加入33L 1-甲基-2-吡咯烷酮，搅拌下依次加入3.30kg 4-氯-6-甲氧基-7-羟基-3-喹啉甲腈、6.65kg 1-溴-3-氯丙烷、5.83kg无水碳酸钾、99g二苯并-18-冠-6-醚(4-氯-6-甲氧基-7-羟基-3-喹啉甲腈与1-溴-3-氯丙烷的摩尔比为1∶3)。氮气保护下控温30℃-40℃搅拌反应约4h以上，TLC跟踪监测至4-氯-6-甲氧基-7-羟基-3-喹啉甲腈斑点消失。反应液转移至200L搪玻璃反应釜中，控温25-40℃搅拌下缓慢加入66L纯化水。加毕控温25-35℃搅拌30min，过滤。所得固体分别用10L纯化水洗涤3次。所得湿品45-55℃鼓风干燥12h，得到黄色粉末状的标题化合物4.00kg，收率91.4％。
实施例2：4-[(2，4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-(3-氯丙氧基)-3-喹啉甲腈的制备
在氮气保护下，在30L玻璃反应釜中加入20L二甲基乙酰胺，搅拌下依次加入3.70kg 2，4-二氯-5-甲氧基苯胺、1.48kg吡啶盐酸盐、4.00kg实施例1制得的4-氯-6-甲氧基-7-(3-氯丙氧基)-3-喹啉甲腈(4-氯-6-甲氧基-7-(3-氯丙氧基)-3-喹啉甲腈与2，4-二氯-5-甲氧基苯胺的摩尔比为2∶3)，搅拌加热控温90-100℃反应3h以上，TLC跟踪监控至中间体1斑点消失。反应液降温至20-30℃，转移至200L搪玻璃反应釜，加入40L乙酸乙酯，搅拌下缓慢加入75L纯化水，加入1M盐酸(400mL浓盐酸与4.5L纯化水配制)调节pH值至2，搅拌30min，过滤，滤饼分别用12L纯化水、12L纯化水、12L乙酸乙酯洗涤。固体加入20L乙酸乙酯中，搅拌打浆30min后过滤。固体用4L乙酸乙酯洗涤，所得产品在35℃-40℃真空干燥12h，得到黄色粉末状的标题化合物5.3kg，收率为88.3％。
实施例3：4-[(2，4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-(3-氯丙氧基)-3-喹啉甲腈的制备
在氮气保护下，在30L玻璃反应釜中加入20L 1-甲基-2-吡咯烷酮，搅拌下依次加入3.70kg 2，4-二氯-5-甲氧基苯胺、1.48kg吡啶盐酸盐、4.00kg实施例1制得的4-氯-6-甲氧基-7-(3-氯丙氧基)-3-喹啉甲腈(4-氯-6-甲氧基-7-(3-氯丙氧基)-3-喹啉甲腈与2，4-二氯-5-甲氧基苯胺的摩尔比为2∶3)，搅拌加热控温90-100℃反应3h以上，TLC跟踪监控至中间体1斑点消失。反应液降温至20-30℃，转移至200L搪玻璃反应釜，加入40L乙酸乙酯，搅拌下缓慢加入75L纯化水，加入1M盐酸(400mL浓盐酸与4.5L纯化水配制)调节pH值至2，搅拌30min，过滤，滤饼分别用12L纯化水、12L纯化水、12L乙酸乙酯洗涤。固体加入20L乙酸乙酯中，搅拌打浆30min后过滤，固体用4L乙酸乙酯洗涤。所得产品在35℃-40℃真空干燥12h，得到黄色粉末状的标题化合物5.4kg，收率为90.0％。
实施例4：4-[(2，4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-(3-氯丙氧 基)-3-喹啉甲腈的制备
在氮气保护下，在30L玻璃反应釜中加入20L二甲基甲酰胺，搅拌下依次加入3.70kg 2，4-二氯-5-甲氧基苯胺、1.48kg吡啶盐酸盐、4.00kg实施例1制得的4-氯-6-甲氧基-7-(3-氯丙氧基)-3-喹啉甲腈(4-氯-6-甲氧基-7-(3-氯丙氧基)-3-喹啉甲腈与2，4-二氯-5-甲氧基苯胺的摩尔比为2∶3)，搅拌加热控温90-100℃反应3h以上，TLC跟踪监控至中间体1斑点消失。反应液降温至20-30℃，转移至200L搪玻璃反应釜，加入40L乙酸乙酯，搅拌下缓慢加入75L纯化水，加入1M盐酸(400mL浓盐酸与4.5L纯化水配制)调节pH值至2，搅拌30min，过滤，滤饼分别用12L纯化水、12L纯化水、12L乙酸乙酯洗涤。固体加入20L乙酸乙酯中，搅拌打浆30min后过滤，固体用4L乙酸乙酯洗涤。所得产品在35℃-40℃真空干燥12h，得到黄色粉末状的标题化合物5.2kg，收率为86.7％。
实施例5：博舒替尼的制备
在氮气保护下，在30L玻璃反应釜中加入16.2L 1-甲基-2-吡咯烷酮，搅拌下依次加入1.62kg碘化钠、4.77L N-甲基哌嗪、5.4kg实施例3制得的4-[(2，4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-(3-氯丙氧基)-3-喹啉甲腈(4-[(2，4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-(3-氯丙氧基)-3-喹啉甲腈与N-甲基哌嗪摩尔比为1∶4)，搅拌加热控温90℃-100℃搅拌反应3h以上，TLC跟踪监测至中间体2斑点消失。反应液降温至20-30℃，转移至200L搪玻璃反应釜中，搅拌下缓慢加入135L纯化水，搅拌1h，过滤。固体分别用10.8L纯化水洗涤3次，过滤，产品在40℃-50℃真空干燥12h，得到博舒替尼粗品为类白色固体5.6kg。
分批次等比例将5.6kg博舒替尼粗品与乙酸乙酯、硅胶混合，35℃-40℃减压浓缩得砂状物。
28kg 100-200目硅胶作为固定相装柱，再依次加入砂状物、2.8kg石英砂。以乙酸乙酯/甲醇/氨水＝300/100/1(体积比，由1080kg乙酸乙酯、320kg甲醇与4L氨水混合配制)为流动相洗脱，TLC监测。收集博舒替尼纯品洗脱液，40～45℃减压浓缩，得到淡黄色固体状的标题化合物4.5kg，收率73.3％。
实施例6：博舒替尼一水合物I型结晶的制备
在三口瓶中加入280mL 1-甲基-2-吡咯烷酮，搅拌下加入35.0g实施例5制得的博舒替尼，加热至55℃～60℃，搅拌15min溶清，缓慢加入560mL纯化水，加毕控温55℃～60℃搅拌30min。降温至0℃～10℃搅拌2h，过滤。滤饼用100mL纯化水洗涤，45℃真空干燥12h，得到白色固体25.5g。经X-射线粉末衍射鉴定为博舒替尼一水合物I型结晶，谱图如图1所示，其差示扫描量热(DSC)测量图如图2所示。
实施例7：博舒替尼一水合物I型结晶的制备
在三口瓶中加入140mL 1-甲基-2-吡咯烷酮，搅拌下加入35.0g实施例5制得的博舒替尼，加热至50℃～55℃，搅拌15min溶清，缓慢加入420mL纯化水，加毕控温50℃～55℃搅拌30min。降温至0℃～10℃搅拌1h，过滤。滤饼用100mL纯化水洗涤，45℃真空干燥12h，得到白色固体28.1g。经X-射线粉末衍射鉴定为博舒替尼一水合物I型结晶，谱图与图1类似。
实施例8：博舒替尼一水合物I型结晶的制备
在三口瓶中加入350mL 1-甲基-2-吡咯烷酮，搅拌下加入35.0g实施例5制得的博舒替尼，加热至75℃～80℃，搅拌10min溶清，缓慢加入560mL纯化水，加毕控温75℃～80℃搅拌30min。降温至0℃～10℃搅拌2h，过滤。滤饼用100mL纯化水洗涤，45℃真空干燥12h，得到白色固体22.5g。经X-射线粉末衍射鉴定为博舒替尼一水合物I型结晶，谱图与图1类似。
实施例9：博舒替尼一水合物I型结晶的制备
在三口瓶中加入700mL二甲基甲酰胺(DMF)，搅拌下加入35.0g实施例5制得的博舒替尼，加热至50℃～55℃，搅拌15min溶清，缓慢加入350mL纯化水，加毕控温50℃～55℃搅拌30min。降温至0℃～10℃搅拌2h，过滤。滤饼用100mL纯化水洗涤，45℃真空干燥12h，得到白色固体21.8g。经X-射线粉末衍射鉴定为博舒替尼一水合物I型结晶，谱图与图1类似。
实施例10：博舒替尼一水合物I型结晶的制备
在三口瓶中加入525mL二甲基亚砜(DMSO)，搅拌下加入35.0g实施例5制得的博舒替尼，加热至60℃～65℃，搅拌12min溶清，缓慢加入525mL纯化水，加毕控温60℃～65℃搅拌30min。降温至0℃～10℃搅拌2h，过滤。滤饼用100mL纯化水洗涤，45℃真空干燥12h，得到白色固体27.6g。经X-射线粉末衍射鉴定为博舒替尼一水合物I型结晶，谱图与图1类似。
实施例11：博舒替尼一水合物I型结晶的制备
在三口瓶中加入105mL 1-甲基-2-吡咯烷酮，搅拌下加入35.0g实施例5制得的博舒替尼，加热至75℃～80℃，搅拌10min溶清，缓慢加入1050mL纯化水，加毕控温75℃～80℃搅拌30min。降温至0℃～10℃搅拌0.5h，过滤。滤饼用100mL纯化水洗涤，45℃真空干燥12h，得到白色固体27.5g。经X-射线粉末衍射鉴定为博舒替尼一水合物I型结晶，谱图与图1类似。
实施例12：博舒替尼一水合物I型结晶的制备
在三口瓶中加入105mL二甲基乙酰胺(DMAC)，搅拌下加入35.0g实施例5制得的博舒替尼，加热至95℃～100℃，搅拌6min溶清。缓慢加入525mL纯化水，加毕控温95℃～100℃搅拌30min。降温至0℃～10℃搅拌2h，过滤。滤饼用100mL纯化水洗涤，45℃真空干燥12h，得到白色固体29.2g。经X-射线粉末衍射鉴定为博舒替尼一水合物I型结晶，谱图与图1类似。
实施例13：有关物质测定
方法：
仪器：Waters e2695
检测器：Waters 2489紫外检测器；
工作站：Empower 2
色谱柱：用十八烷基硅烷键合硅胶为填充剂
流动相：以20mmol/L甲酸铵溶液(用甲酸调节pH值至4.5)为流动相A，以乙腈为流动相B，按表1进行梯度洗脱
表1
时间(min) 流动相A(％) 流动相B(％)
0 75 25
5 75 25
25 40 60
40 40 60
45 75 25
55 75 25
柱温：35℃
流速：1.0ml/min
检测波长：269nm
进样量：10μl
其结果如表2所示。
表2
Figure PCTCN2015088989-appb-000005
本说明书中所引用的所有专利、专利申请公开、专利申请及非专利出版物，均通过引用以其全文并入本申请中。
上述对本申请中涉及的发明的一般性描述和对其具体实施方式的描述不应理解为是对该发明技术方案构成的限制。本领域所属技术人员根据本申请的公开，可以在不违背所涉及的发明构成要素的前提下，对上述一般性描述或/和具体实施方式(包括实施例)中的公开技术特征进行增加、减少或组合， 形成属于所述发明的其它的技术方案。本申请中所公开的发明的保护范围应该以权利要求书所限定的保护范围为准。

Claims (21)

  1. 式I的博舒替尼的制备方法，包括以下步骤：
    1)在吡啶盐酸盐存在下，式II的4-氯-6-甲氧基-7-(3-氯丙氧基)-3-喹啉甲腈与2，4-二氯-5-甲氧基苯胺在非质子极性溶剂中反应，得到式III的4-[(2，4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-(3-氯丙氧基)-3-喹啉甲腈；
    Figure PCTCN2015088989-appb-100001
    2)在碘化物存在下，式III的4-[(2，4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-(3-氯丙氧基)-3-喹啉甲腈与N-甲基哌嗪在非质子极性溶剂中反应，得到式I的博舒替尼，
    Figure PCTCN2015088989-appb-100002
  2. 权利要求1所述的方法，其中步骤1)和步骤2)中所述非质子极性溶剂独立地选自1-甲基-2-吡咯烷酮、二甲基乙酰胺、二甲基甲酰胺或上述任意溶剂的混合溶剂；优选步骤1)和步骤2)中所述非质子极性溶剂为同一种非质子极性溶剂；更优选步骤1)和步骤2)中所述非质子极性溶剂均为1-甲基-2-吡咯烷酮。
  3. 权利要求1或2所述的方法，其中步骤1)中，4-氯-6-甲氧基-7-(3-氯丙氧基)-3-喹啉甲腈与2，4-二氯-5-甲氧基苯胺的摩尔比为1∶4至1∶1，优选为1∶3至1∶1，更优选为2∶3；和/或反应温度为60℃-120℃，优选为70℃-120℃，更优选为80℃-110℃；和/或4-氯-6-甲氧基-7-(3-氯丙氧基)-3-喹啉甲腈与吡啶盐酸盐的摩尔比为1∶2至2∶1，优选为2∶3至3∶2，更优选为1∶1。
  4. 权利要求1-3中任一项所述的方法，其中步骤2)中，4-[(2，4-二氯 -5-甲氧基苯基)氨基]-6-甲氧基-7-(3-氯丙氧基)-3-喹啉甲腈与N-甲基哌嗪的摩尔比为1∶2至1∶8，优选为1∶3-1∶4；和/或所述碘化物选自碘化钾、碘化钠、碘化镁或碘化锂，优选碘化钠；和/或4-[(2，4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-(3-氯丙氧基)-3-喹啉甲腈与碘化物的摩尔比为1∶2至2∶1，优选为2∶3至3∶2，更优选为1∶1；和/或反应温度为60℃-120℃，优选为70℃-120℃，更优选为80℃-110℃。
  5. 权利要求1-4中任一项所述的方法，其中在含钾缚酸剂和冠醚类催化剂存在下，4-氯-6-甲氧基-7-羟基-3-喹啉甲腈与1-溴-3-氯丙烷发生反应，得到式II的4-氯-6-甲氧基-7-(3-氯丙氧基)-3-喹啉甲腈，
    Figure PCTCN2015088989-appb-100003
  6. 权利要求5所述的方法，其中4-氯-6-甲氧基-7-羟基-3-喹啉甲腈与1-溴-3-氯丙烷在非质子极性溶剂中发生反应，优选所述非质子极性溶剂选自1-甲基-2-吡咯烷酮、二甲基乙酰胺、二甲基甲酰胺或上述任意溶剂的混合溶剂，更优选所述非质子极性溶剂与步骤1)和步骤2)中所述非质子极性溶剂为同一种非质子极性溶剂，最优选均为1-甲基-2-吡咯烷酮。
  7. 权利要求5或6所述的方法，其中4-氯-6-甲氧基-7-羟基-3-喹啉甲腈与1-溴-3-氯丙烷的摩尔比为1∶4至1∶1，优选为1∶4至1∶2，更优选1∶3；和/或反应温度为20℃-60℃，优选为20℃-50℃，更优选为30℃-40℃。
  8. 权利要求5-7中任一项所述的方法，其中所述含钾缚酸剂为氢氧化钾、碳酸氢钾或碳酸钾，优选为碳酸钾；和/或4-氯-6-甲氧基-7-羟基-3喹啉甲腈与所述含钾缚酸剂的摩尔比为1∶4至1∶1，优选为1∶4至1∶2，更优选为1∶3；和/或所述冠醚类催化剂为18-冠-6醚、二苯并-18-冠-6醚或二氮-18-冠-6醚，优选为二苯并-18-冠-6-醚；和/或4-氯-6-甲氧基-7-羟基-3-喹啉甲腈与所述冠醚类催化剂的摩尔比为10∶1至500∶1，优选为20∶1至200∶1，最优选为50∶1。
  9. 权利要求5-8中任一项所述的方法，其中步骤1)和步骤2)中的所述反应以及4-氯-6-甲氧基-7-羟基-3-喹啉甲腈与1-溴-3-氯丙烷发生的反应 均在氮气保护下进行。
  10. 博舒替尼一水合物I型结晶的制备方法，其包括将博舒替尼溶于非质子极性溶剂，再加入水，降温，析晶。
  11. 权利要求10所述的方法，其中所述的非质子极性溶剂选自1-甲基-2-吡咯烷酮、二甲基乙酰胺、二甲基亚砜、二甲基甲酰胺或上述任意溶剂的混合溶剂，所述非质子极性溶剂优选为1-甲基-2-吡咯烷酮。
  12. 权利要求10或11所述的方法，其中所述博舒替尼与所述非质子极性溶剂的质量体积比为1g∶3ml-1g∶20ml，优选为1g∶4ml-1g∶10ml，更优选为1g∶4ml-1g∶8ml。
  13. 权利要求10-12中任一项所述的方法，其中所述水与所述非质子极性溶剂的体积比为0.5∶1～10∶1，优选为1∶1-5∶1，更优选为1∶1-3∶1。
  14. 权利要求10-13中任一项所述的方法，其中所述博舒替尼溶于所述非质子极性溶剂的温度是50℃-100℃，优选为50℃-80℃，更优选为50℃-65℃。
  15. 权利要求10-14中任一项所述的方法，其中所述降温为降温至0℃-10℃。
  16. 权利要求10-15中任一项所述的方法，其中所述方法还包括过滤和干燥。
  17. 权利要求10-16中任一项所述的方法，其中所述方法在氮气保护下进行。
  18. 权利要求10-17中任一项所述的方法，其中所述博舒替尼由权利要求1-9中任一项所述的方法制备得到。
  19. 4-[(2，4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-(3-氯丙氧基)-3-喹啉甲腈的制备方法，包括：将4-氯-6-甲氧基-7-(3-氯丙氧基)-3-喹啉甲腈与2，4-二氯-5-甲氧基苯胺在非质子极性溶剂中反应。
  20. 权利要求19所述的方法，其中所述非质子极性溶剂选自1-甲基-2-吡咯烷酮、二甲基乙酰胺、二甲基甲酰胺或上述任意溶剂的混合溶剂，所述非质子极性溶剂优选为1-甲基-2-吡咯烷酮。
  21. 权利要求19或20所述的方法，其中4-氯-6-甲氧基-7-(3-氯丙氧基)-3-喹啉甲腈与2，4-二氯-5-甲氧基苯胺的摩尔比为1∶4至1∶1，优选为1∶3 至1∶1，更优选为2∶3；和/或反应温度为60℃-120℃，优选为70℃-120℃，更优选为80℃-110℃；和/或所述反应在吡啶盐酸盐存在下进行，4-氯-6-甲氧基-7-(3-氯丙氧基)-3-喹啉甲腈与吡啶盐酸盐的摩尔比为1∶2至2∶1，优选为2∶3至3∶2，更优选为1∶1；和/或所述反应在氮气保护下进行。
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