WO2018028508A1 - 一种羟尼酮的制备方法 - Google Patents

一种羟尼酮的制备方法 Download PDF

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WO2018028508A1
WO2018028508A1 PCT/CN2017/095882 CN2017095882W WO2018028508A1 WO 2018028508 A1 WO2018028508 A1 WO 2018028508A1 CN 2017095882 W CN2017095882 W CN 2017095882W WO 2018028508 A1 WO2018028508 A1 WO 2018028508A1
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formula
compound
ethyl acetate
methylpyridine
hydroxy
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PCT/CN2017/095882
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English (en)
French (fr)
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罗楹
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罗楹
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Priority to CN201780048603.0A priority Critical patent/CN109563039A/zh
Priority to JP2019507241A priority patent/JP6764999B2/ja
Publication of WO2018028508A1 publication Critical patent/WO2018028508A1/zh

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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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6

Definitions

  • the invention belongs to the field of medicine, in particular to the copper-catalyzed carbon-coupling reaction and its application, in particular to a method for preparing hydroxynisolone.
  • Hepatic fibrosis is the common pathological basis in the progression of chronic liver disease.
  • Various chronic injuries cause degeneration and necrosis of hepatocytes, abnormal proliferation and excessive deposition of fibrous connective tissue, and the regeneration of hepatocytes, forming "false leaflets" to destroy the original tissues of the liver.
  • the structure eventually causes the liver to form nodular and hard, and the liver function is damaged, or even completely disappeared, forming cirrhosis.
  • liver fibrosis can cause liver fibrosis, such as chronic viral hepatitis, chronic alcoholism, cholestasis, metabolic disorders of congenital enzyme deficiency, long-term exposure to poisons and drugs.
  • Liver fibrosis and cirrhosis are one of the main reasons that affect the quality of life and medical expenses of patients with liver diseases.
  • the market demand for liver and liver protection drugs has increased year by year.
  • a synthesis method of a compound of formula I is disclosed in the prior art, starting from 2-amino-5-methylpyridine, which uses Me as a phenolic hydroxyl protecting group, and the reagent used for deprotection is expensive, and the reaction process It is easy to form highly toxic gas, and the waste water treatment is cumbersome, the operation is cumbersome, and the yield is low (40%).
  • the methods for preparing hydroxynisolone in the prior art mostly involve the protection of the hydroxy group of bromophenol, and it is necessary to increase the cumbersome reaction process in the industrial process.
  • the molar ratio of 2-hydroxy-5-methylpyridine to p-bromoanisole is 1:1 to 1:2 (preferably 1:1 to 1:1.8, more preferably It is 1:1-1:1.5, optimally 1:1-1:1.3).
  • the method further comprises the step (4):
  • the compound of the formula I obtained in the step (3) is mixed with a mixed solvent of ethanol and ethyl acetate, cooled, and filtered to give a white crystalline solid of the compound of formula I.
  • the mass ratio of the compound of the formula I to a mixed solvent of ethanol and ethyl acetate is from 1.5 to 7.5, preferably from 2.5 to 6.5, more preferably 3 -4.5.
  • the mass ratio of the ethanol to the ethyl acetate is (0.8-1.2): (5.8-6.2).
  • the solvent is selected from the group consisting of DMAC, DMF, or a combination thereof.
  • the catalyst in the step (1), is selected from the group consisting of CuI, CuSO 4 ⁇ 5H 2 O, K 2 CO 3 , or a combination thereof, preferably CuI and K 2 . a mixture of CO 3 or a mixture of CuSO 4 ⁇ 5H 2 O and K 2 CO 3 .
  • the solvent is DMF
  • the catalyst is a mixture of CuSO 4 ⁇ 5H 2 O and K 2 CO 3 .
  • the molar ratio of the CuI to the K 2 CO 3 is 1:50 to 1:80, preferably 1:55 to 1:70.
  • the solvent is DMAC
  • the catalyst is a mixture of CuI and K 2 CO 3 .
  • the heating reflux temperature is 130 to 150 ° C, preferably 135 to 145 ° C.
  • the aqueous ammonia concentration is 15-28% by weight, preferably 16-25% by weight, more preferably 17-20% by weight.
  • the method before the step (3), further comprises the step (3-1): mixing the purified compound of the formula II obtained in the step (2) with ethyl acetate and activated carbon, heating under reflux, filtering and cooling to crystallize .
  • the mass ratio of the ethyl acetate to the crude compound of the formula II is from 1.0 to 10.0, preferably from 2.0 to 8.0, more preferably from 3.0 to 6.0. .
  • the mass ratio of the activated carbon to the crude compound of the formula II is from 0.01 to 0.1, preferably from 0.025 to 0.075, more preferably from 0.03 to 0.06.
  • the molar ratio of the compound of the formula II to HBr is 1:5-1:10, preferably 1:6-1:8.
  • the present inventors have for the first time unexpectedly discovered a method for preparing hydroxynisolone with high yield, mild reaction conditions, safe and high efficiency.
  • the invention adopts ammonia water to treat the crude compound of the formula II, which is beneficial to the removal of copper ions remaining in the catalyst and the precipitation of the product.
  • the present invention has been completed on this basis.
  • the term “about” means that the value can vary by no more than 1% from the recited value.
  • the expression “about 100” includes all values between 99 and 101 and (eg, 99.1, 99.2, 99.3, 99.4, etc.).
  • the term "containing” or “including (including)” may be open, semi-closed, and Closed. In other words, the terms also include “consisting essentially of,” or “consisting of.”
  • the present invention treats a crude compound of the formula II with aqueous ammonia, which is advantageous for removing residual copper ions derived from the catalyst and for facilitating product precipitation.
  • the present invention omits the step of protecting p-bromophenol in the prior art, and the operation is simpler.
  • the preparation method of the present invention is simple and easy to handle, mild in reaction conditions, short in reaction time, high in yield, safer and suitable for large-scale production.
  • DMAC 190 kg, concentration 99 wt% was heated to 50 ° C, followed by the addition of 35 kg of 2-hydroxy-5-methylpyridine, 65 kg of anhydrous potassium carbonate, 74.0 kg of p-bromoanisole and 1.22 cuprous iodide. Kg, the temperature was raised to reflux, the reaction was carried out for 12-14 hours, and the heating was stopped after the point plate (TCL) was used to control until there was no raw material. The liquid temperature was then lowered to 80 ° C and filtered.
  • the purified compound of formula II was prepared by centrifugation to a distinct flow, and the compound of formula II was weighed and dried to obtain a purified compound of formula II (purity of 99.66%, yield 80%).
  • the purified decolorization kettle was pumped with 900 kg of purified water, stirred, heated until the water boiled, and then put into the above-mentioned dried filter cake 30 kg. After the filter cake was completely dissolved, 1.25 kg of activated carbon was added, refluxed for 15 minutes, and hot-pressed. After cooling to crystallization, the temperature is lowered to about 25 ° C, stirred and kept for 2 hours, centrifuged and filtered, and the filter cake is rinsed with pure water for 2 times and then dried to obtain a white crystalline solid of the compound of formula I. The oven is oven-controlled at 60 ° C and dried. The dried product of the formula I was obtained after drying (purity: 99.92%, yield 90%).
  • the purified compound of formula II was prepared by centrifugation to a distinct flow, and the compound of formula II was weighed and dried to obtain a purified compound of formula II in an amount of 99.64%.
  • the refined decolorizer is pumped into 900kg of pure water, stirred, heated until the water boils, and then put into the above-mentioned dried filter cake 30kg. After the filter cake is completely dissolved, 1.5kg of activated carbon is added, refluxed for 15 minutes, and hot filtered to cool. The crystallizer is cooled to about 25 ° C, stirred and kept for 2 hours, centrifuged and filtered, and the filter cake is rinsed with pure water for 2 times and then dried to obtain a white crystalline solid of the compound of formula I, dried at 60 ° C in an oven, dried and dried. After the preparation of the compound of the formula I, 24 kg (purity: 99.98%, yield: 80%).
  • the concentration of Cu + was determined by UV-visible spectrophotometry to be 0.05 ⁇ g/50 ml.

Abstract

提供了一种羟尼酮的制备方法，操作简便、反应条件温和、反应时间短、产率高，更安全且适用于大生产。采用氨水处理中间化合物粗品，既有利于去除催化剂中残留的铜离子，又有利于产物析出。

Description

一种羟尼酮的制备方法 技术领域
本发明属于医药领域，具体地说，本发明涉及铜催化碳杂偶联反应及其应用，具体地涉及一种羟尼酮的制备方法。
背景技术
肝纤维化是慢性肝病进展中的共同病理基础，各种慢性损伤引起肝细胞变性、坏死，纤维结缔组织异常增生并过度沉积，包裹再生的肝细胞，形成“假小叶”破坏肝脏原有的组织结构，最终使肝脏形成结节状、变硬，肝脏功能随之受损，乃至完全消失，形成肝硬化。
多种慢性疾病均可引起肝纤维化，如慢性病毒性肝炎、慢性酒精中毒、胆汁淤积、先天性酶缺陷的代谢障碍性疾病、长期接触毒物和药物等。肝纤维化、肝硬化是影响肝病患者生活质量、医疗费用支出的主要原因之一。保肝护肝用药的市场需求量逐年增加。目前可用于肝纤维化治疗的药物较少，病人和医生对安全有效的药物需求较大。预计在中国肝纤维化药物市场份额约有24亿美元，在日本约有19亿美元。迄今国际上还没有以肝纤维化为适应症的化学药品，早期对羟尼酮(以下简称为式I化合物)的研究表明其具有良好的药理学和毒理学特性，是治疗和预防肝纤维化和肝硬化的理想口服药物。
现有技术中公开了式I化合物的一种合成方法，以2-氨基-5甲基吡啶为起始原料，该方法用Me作为酚羟基保护基，其脱保护所用的试剂价格昂贵，反应过程中容易形成剧毒气体，且污水废物处理繁琐，操作繁琐，产率低(40％)。并且，现有技术中制备羟尼酮的方法大多涉及对溴苯酚的羟基保护，工业过程中需要增加繁琐的反应工序。
因此，本领域迫切需要研发出一种羟尼酮的制备方法，要求操作简便、反应条件温和、反应时间短、产率高，更安全且适用于大生产。
发明内容
本发明的目的在于提供一种羟尼酮的制备方法及其应用。
本发明第一方面，提供一种制备式I化合物的方法，包括步骤：
Figure PCTCN2017095882-appb-000001
(1)在溶剂中，催化剂存在下，将2-羟基-5-甲基吡啶与对溴苯甲醚反应，从而制得式II化合物粗品；
Figure PCTCN2017095882-appb-000002
(2)将所述式II化合物粗品用氨水洗涤，制得精制的式II化合物；和
(3)将精制的式II化合物与HBr反应，制得所述式I化合物。
在另一优选例中，所述2-羟基-5-甲基吡啶与对溴苯甲醚摩尔比为1:1-1:2(较佳地为1:1-1:1.8，更佳地为1:1-1:1.5，最佳地为1:1-1:1.3)。
在另一优选例中，所述方法还包括步骤(4)：
将步骤(3)所得的式I化合物与乙醇和乙酸乙酯的混合溶剂相混合，降温，过滤，得到式I化合物的白色结晶固体。
在另一优选例中，所述步骤(4)中，所述式I化合物与乙醇和乙酸乙酯的混合溶剂的质量比为1.5-7.5，较佳地为2.5-6.5，更佳地为3-4.5。
在另一优选例中，所述步骤(4)中，所述乙醇和乙酸乙酯的质量比为(0.8-1.2):(5.8-6.2)。
在另一优选例中，所述步骤(1)中，所述溶剂选自下组：DMAC、DMF、或其组合。
在另一优选例中，所述步骤(1)中，所述催化剂选自下组：CuI、CuSO4·5H2O、K2CO3、或其组合，较佳地，为CuI与K2CO3的混合物或者CuSO4·5H2O与K2CO3的混合物。
在另一优选例中，所述步骤(1)中，所述溶剂为DMF，并且所述催化剂为CuSO4·5H2O与K2CO3的混合物。
在另一优选例中，所述步骤(1)中，所述CuI与K2CO3的摩尔比为1:50-1:80，较佳地为1:55-1:70。
在另一优选例中，所述步骤(1)中，所述溶剂为DMAC，并且所述催化剂为CuI与K2CO3的混合物。
在另一优选例中，所述步骤(1)中，加热回流温度为130-150℃，较佳地为135-145℃。
在另一优选例中，所述步骤(2)中，所述氨水浓度为15-28wt％，较佳地为16-25wt％，更佳地为17-20wt％。
在另一优选例中，所述步骤(3)之前，还包括步骤(3-1)：将步骤(2)得到的精制式II化合物与乙酸乙酯和活性炭混合，加热回流，过滤降温析晶。
在另一优选例中，所述步骤(3-1)中，所述乙酸乙酯与式II化合物粗品的质量比为1.0-10.0，较佳地为2.0-8.0，更佳地为3.0-6.0。
在另一优选例中，所述步骤(3-1)中，所述活性炭与式II化合物粗品的质量比为0.01-0.1，较佳地为0.025-0.075，更佳地为0.03-0.06。
在另一优选例中，所述步骤(3)中，所述式II化合物与HBr的摩尔比为1:5-1:10，较佳地为1:6-1:8。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人通过广泛而深入的研究，首次意外地发现一种产率高、反应条件温和、安全高效的制备羟尼酮的方法。本发明采用氨水处理式II化合物粗品，既有利于去除催化剂中残留的铜离子，又有利于产物析出。在此基础上完成了本发明。
术语说明
除非另外定义，否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。
如本文所用，在提到具体列举的数值中使用时，术语“约”意指该值可以从列举的值变动不多于1％。例如，如本文所用，表述“约100”包括99和101和之间的全部值(例如，99.1、99.2、99.3、99.4等)。
如本文所用，术语“含有”或“包括(包含)”可以是开放式、半封闭式和 封闭式的。换言之，所述术语也包括“基本上由…构成”、或“由…构成”。
本发明的主要优点在于：
(1)本发明采用氨水处理式II化合物粗品，既有利于去除来源于催化剂中的残留铜离子，又有利于产物析出。
(2)本发明的工艺脱甲基过程中采用HBr替代了现有技术中常用的价格昂贵、毒性很大的BBr3。
(3)本发明省略了现有技术中用对溴苯酚进行保护这一步骤，操作更为简便。
(4)本发明的制备方法简便易于操作，反应条件温和，反应时间短，产率高，更安全且适于大生产。
原料
本发明所采用的原料列表如下表1所示：
物料名称 物理参数
2-羟基-5-甲基吡啶 黄色或微黄色结晶固体
对溴苯甲醚 无色透明液体
DMAC 无色透明液体
DMF 无色透明液体
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。
以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
实施例1-生产路线1：
1.式II化合物：N-(4-甲氧基苯基)-5-甲基-2-吡啶酮的合成
Figure PCTCN2017095882-appb-000003
上述原料投料量及投料比如表2所示：
表2
物料名称 摩尔比例 摩尔量(mol) 投料量(kg)
2-羟基-5-甲基吡啶 1.00 390 35.0
对溴苯甲醚 1.20 468 74.0
碘化亚铜 0.02 7.8 1.22
无水碳酸钾 1.20 468 65.0
DMAC - - 190.0
(1)将DMAC(190kg，浓度为99wt％)加热到50℃，依次加入2-羟基-5-甲基吡啶35kg、无水碳酸钾65kg、对溴苯甲醚74.0kg和碘化亚铜1.22kg，升温至回流，反应12-14h，采用点板(TCL)控制至没有原料点后，停止加热。随后液温降至80℃甩滤。
(2)将上述滤液返回缩合釜减压蒸馏至没有馏分流出，放入水洗水析釜中，加入55kg氨水(18wt％)和156kg水，搅拌洗涤降温，甩滤，用清水淋洗至母液无色泽。滤饼取出，放入盘中晾干，制得式II化合物粗品55.4kg(收率为72％，以2-羟基-5-甲基吡啶计)。
结果：用紫外可见分光光度法检测，未见Cu+。
2.式II化合物粗品溶解脱色
向脱溶精制釜中投入乙酸乙酯(浓度≥99.0％)130㎏、药用活性炭(样品液的吸收度不得大于重铬酸钾色度标准液的吸收度)1.95㎏以及式II化合物粗品39㎏，搅拌加热回流脱色1小时，趁热过滤，滤液抽入结晶反应釜中，滤渣用8㎏乙酸乙酯洗涤，弃去滤渣，合并滤液，脱溶冷却析晶。滤液脱溶70％后，搅拌下缓慢析晶，冷却到0℃-5℃，搅拌3-5小时，放入离心分离机。离心甩滤到明显断流，制得精制的式II化合物，称重装盘，晾干，得到精制的式II化合物，(纯度为99.66％，收率80％)。
3.制备式I化合物：
Figure PCTCN2017095882-appb-000004
(3-1)制备式I化合物粗品：
将N-(4-甲氧基苯基)-5-甲基-2-吡啶酮(30kg)投入反应釜中，搅拌缓慢滴加40wt％的氢溴酸158kg，滴加完成后，升温至回流，采用点板(TCL)控制至没有原料点。冷却中和至PH＝5-6，甩滤，滤饼放入盘中晾干，制得式I化合物粗品(收率：98％)。
(3-2)打浆精制：
取上述步骤(3-1)所得的式I化合物粗品30kg，加入乙醇(浓度95％，15kg)、乙酸乙酯(浓度99％，90kg)打浆回流1h，降温至10℃，甩滤，母液回收，滤饼晾干。
向精制脱色釜中抽入纯净水900kg，搅拌，加热至水沸腾，然后投入上述晾干后的滤饼30kg，待滤饼完全溶解后，再加入活性炭1.25kg，回流15分钟，乘热压滤至冷却结晶，降温至25℃左右，搅拌保温2小时，离心甩滤，滤饼用纯净水淋洗2次后甩干，得到式I化合物的白色结晶固体，60℃下烘箱控温干燥，烘干后制得式I化合物成品(纯度：99.92％，收率90％)。
实施例2-生产路线2
1.式II化合物：N-(4-甲氧基苯基)-5-甲基-2-吡啶酮的合成
Figure PCTCN2017095882-appb-000005
上述原料投料量及投料比如表3所示：
表3
物料名称 摩尔比例 摩尔量(mol) 投料量(kg)
2-羟基-5-甲基吡啶 1.00 367 40.0
对溴苯甲醚 1.10 403.7 75.0
五水硫酸铜 0.12 43.26 10.8
无水碳酸钾 2.13 781.42 108.0
DMF - - 230.0
(1)如表2所示，依次加入对溴苯甲醚、DMF、2-羟基-5-甲基吡啶、无水碳酸钾和五水硫酸铜，升温至回流，反应12-14h，采用点板(TCL)控制至没有原料点后，停止加热。
(2)将上述混合液降温至室温甩滤，滤液减压蒸馏至没有馏分馏出，降温至120℃，放入含有156kg水的水洗水析釜中，滴加56kg氨水(18wt％)，搅拌洗涤降温，甩滤，用清水淋洗至滤液无色泽。滤饼取出，放入盘中晾干，制得式 II化合物粗品。
以2-羟基-5-甲基吡啶计的收率为80％。
2.式II化合物粗品溶解脱色
向脱溶精制釜中投入乙酸乙酯(浓度≥99.0％)170㎏、药用活性炭(样品液的吸收度不得大于重铬酸钾色度标准液的吸收度)2.75㎏以及式II化合物粗品55㎏搅拌加热回流脱色1小时，趁热过滤，滤液抽入结晶反应釜中，滤渣用乙酸乙酯20㎏洗涤，弃去滤渣，合并滤液，脱溶冷却析晶。滤液脱溶70％后，搅拌下缓慢析晶，冷却到0℃-5℃，搅拌3-5小时，放入离心分离机。离心甩滤到明显断流，制得精制的式II化合物，称重装盘，晾干，得到精制的式II化合物，含量为99.64％。
3.制备式I化合物：
Figure PCTCN2017095882-appb-000006
(3-1)制备式I化合物粗品：
将N-(4-甲氧基苯基)-5-甲基-2-吡啶酮(44kg)投入反应釜中，搅拌缓慢滴加40wt％的氢溴酸267kg，滴加完成后，升温至回流，采用点板(TCL)控制至没有原料点。冷却中和至PH＝6，甩滤，滤饼放入盘中晾干，制得式I化合物粗品。
(3-2)打浆精制：
取上述步骤(3-1)所得的式I化合物粗品44kg，加入0.5倍量的乙醇(浓度95％，22kg)、三倍量的乙酸乙酯(浓度99％，132kg)打浆回流1h，降温至10℃，甩滤，母液回收，滤饼晾干。
精制脱色釜抽入纯净水900kg，搅拌，加热至水沸腾，然后投入上述晾干后的滤饼30kg，待滤饼完全溶解后，再加入活性炭1.5kg，回流15分钟，趁热压滤至冷却结晶釜，降温至25℃左右，搅拌保温2小时，离心甩滤，滤饼用纯净水淋洗2次后甩干，得到式I化合物的白色结晶固体，60℃下烘箱控温干燥，烘干后制得式I化合物成品24kg(纯度：99.98％，收率：80％)。
对比例1
同实施例1，不同之处在于，在式II化合物：N-(4-甲氧基苯基)-5-甲基-2-吡啶酮的合成步骤中，使用水代替氨水洗涤，结果制得的式II化合物粗品收率仅为42％。
结果：紫外可见分光光度法检测Cu+浓度为0.05μg/50ml。
可以看出，使用氨水洗涤之后，能够有效去除铜离子，同时，得到的中间体式II化合物的收率更高，更有利于产物的析出。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种制备式I化合物的方法，包括步骤：
    Figure PCTCN2017095882-appb-100001
    (1)在溶剂中，催化剂存在下，将2-羟基-5-甲基吡啶与对溴苯甲醚反应，从而制得式II化合物粗品；
    Figure PCTCN2017095882-appb-100002
    (2)将所述式II化合物粗品用氨水洗涤，制得精制的式II化合物；和
    (3)将精制的式II化合物与HBr反应，制得所述式I化合物。
  2. 如权利要求1所述的方法，其特征在于，所述2-羟基-5-甲基吡啶与对溴苯甲醚摩尔比为1:1-1:2。
  3. 如权利要求1所述的方法，其特征在于，所述方法还包括步骤(4)：
    将步骤(3)所得的式I化合物与乙醇和乙酸乙酯的混合溶剂相混合，降温，过滤，得到式I化合物的白色结晶固体。
  4. 如权利要求1所述的方法，其特征在于，所述步骤(4)中，所述式I化合物与乙醇和乙酸乙酯的混合溶剂的质量比为1.5-7.5。
  5. 如权利要求1所述的方法，其特征在于，所述步骤(4)中，所述乙醇和乙酸乙酯的质量比为(0.8-1.2):(5.8-6.2)。
  6. 如权利要求1所述的方法，其特征在于，所述步骤(1)中，所述溶剂选自下组：DMAC、DMF、或其组合。
  7. 如权利要求1所述的方法，其特征在于，所述步骤(1)中，所述催化剂选自下组：CuI、CuSO4·5H2O、K2CO3、或其组合。
  8. 如权利要求1所述的方法，其特征在于，所述步骤(2)中，所述氨水浓度为15-28wt％。
  9. 如权利要求1所述的方法，其特征在于，所述步骤(3)之前，还包括步骤(3-1)：将步骤(2)得到的精制式II化合物与乙酸乙酯和活性炭混合，加热回流，过滤降温析晶。
  10. 如权利要求1所述的方法，其特征在于，所述步骤(3)中，所述式II化合物与HBr的摩尔比为1:5-1:10。
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Publication number Priority date Publication date Assignee Title
WO2005047256A1 (fr) * 2003-11-14 2005-05-26 Shanghai Genomics, Inc. Derives de pyridone, et utilisation correspondante
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005047256A1 (fr) * 2003-11-14 2005-05-26 Shanghai Genomics, Inc. Derives de pyridone, et utilisation correspondante
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