WO2013020461A1 - 一种吉非替尼中间体的制备方法 - Google Patents

一种吉非替尼中间体的制备方法 Download PDF

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WO2013020461A1
WO2013020461A1 PCT/CN2012/079256 CN2012079256W WO2013020461A1 WO 2013020461 A1 WO2013020461 A1 WO 2013020461A1 CN 2012079256 W CN2012079256 W CN 2012079256W WO 2013020461 A1 WO2013020461 A1 WO 2013020461A1
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hydroxypropoxy
formula
compound
preparation
methoxy
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PCT/CN2012/079256
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French (fr)
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徐建康
赵宗敏
吴昊
蒋志强
李桂民
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浙江九洲药业股份有限公司
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D239/00Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72Quinazolines; Hydrogenated quinazolines
    • C07D239/86Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D239/00Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72Quinazolines; Hydrogenated quinazolines
    • C07D239/86Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88Oxygen atoms

Definitions

  • the invention belongs to the field of medicine and chemical industry, and particularly relates to a gefitinib intermediate and a preparation method thereof. Background technique
  • NSCLC locally advanced or metastatic non-small cell lung cancer
  • Gefitinib was originally produced by AstraZeneca and was first listed in the US on May 5, 2003. According to IMS Health data, the product has been on sale in more than 30 countries including China, with sales exceeding US$200 million in 2009.
  • PCT patent application WO2008125867 discloses a route for the preparation of gefitinib from 4-chloro-6-(3-chloropropoxy)-7-nonyloxazoline, as shown in the figure below.
  • Gefstinib Fo mula I Chinese Patent Application 200710025643.1 discloses a preparation method of 4-chloro-6-(3-chloropropoxy)-7-fluorenyl quinazoline, as shown in the following figure.
  • the purity of the product is lowered; in the cyclization reaction for preparing the compound 4, by-products are relatively easily formed due to the presence of the chlorinated group.
  • the route due to the presence of the chlorination group, the route has a by-product formed in multiple steps, so that the purity of the final product is reduced.
  • the purity of the product is only about 90% after reviewing the preparation process in the patent. .
  • the invention overcomes the defects existing in the prior art, introduces a hydroxyl group instead of chlorine, and develops a 4-chloro-6-(3-chloropropoxy group) which has less environmental pollution, less by-products, high product quality and is suitable for industrial production.
  • the present invention first provides an intermediate compound 6-(3-hydroxypropoxy group) for preparing 4-chloro-6-(3-chloropropoxy)-7-decyloxyquinazoline.
  • a -7-methoxy quinazolin-4(3H)-one having the structural formula shown in Formula II,
  • 6-(3-Hydroxypropoxy)-7-methoxy quinazolin-4(3H)-one can be used to prepare 4-chloro-6-(3-chloropropoxy)-7-decyloxyquine
  • An oxazoline having the following formula:
  • the compound of formula I 4-chloro-6-(3-chloropropoxy)-7-methoxy quinazoline, is prepared by the action of a compound of formula II under the action of thionyl chloride. Further, the preparation method comprises the following steps: mixing the compound of the formula II with an organic solvent, adding thionyl chloride, and heating and maintaining the compound of the formula I. After the reaction is completed, the obtained compound of the formula I can be obtained by the following steps: adding the reaction liquid to the low-temperature water, adding the liquid alkali to adjust the pH value, standing to separate the layers, and concentrating the organic layer under reduced pressure to obtain a white solid, and then dissolving and cooling the weight. Crystallization of the compound of formula I.
  • the organic solvent may be dichlorosilane, DMF, trichloromethane or the like; the recrystallization solvent is selected from ethyl acetate, ethanol or isopropanol; preferably, the pH is adjusted to a pH of 7 ⁇ 8.
  • the compound of formula II is a compound of formula III 2-amino-5-(3-hydroxypropoxy)-4-decyloxybenzoate
  • the ester is obtained by reacting an organic solvent with cerium acetate.
  • the preparation method of the compound of the formula II is: the compound of the formula III is mixed with an organic solvent and cerium acetate, and the mixture is heated to reflux reaction, and the compound of the formula II is obtained by cooling.
  • the organic solvent may be selected from alcohols such as isopropanol, ethanol, n-propanol, n-butanol and the like.
  • the reflux reaction time is 6 to 18 hours. After the reaction is completed, the compound can be dried by cooling, suction filtration, rinsing and drying to obtain a dry product of the compound of the formula II.
  • the compound of the formula III is obtained by a reduction reaction of a compound of the formula IV, 5-(3-hydroxypropoxy)-4-decyloxy-2-nitrobenzoic acid decyl ester. Further, the compound of the formula III is prepared by dissolving the compound of the formula IV in an organic solvent, adding a reducing agent, replacing with hydrogen, and stirring to obtain a compound of the formula III.
  • the organic solvent may be an ester such as ethyl acetate, an alcohol such as ethanol, isopropanol or the like; the reducing agent is palladium carbon or nickel; and the stirring reaction is carried out for 5 to 18 hours.
  • the obtained compound of the formula III can be obtained by the following method: the reaction liquid is reheated, filtered, and the mother liquid is concentrated under reduced pressure, and the concentrated mother liquid is heated to reflux, and then cooled, suction filtered, and dried to obtain a dry product of the compound of formula III.
  • the compound of the formula IV is obtained by reacting a compound of the formula V with 5-hydroxy-4-nonyloxy-2-nitrobenzoate and a compound of the formula VI, the reaction formula of which is: Among them, it is preferably bromine or chlorine.
  • the compound of the formula IV is prepared by dissolving the compound of the formula V in an organic solvent, adding 3-chloro-1-propanol in the presence of potassium carbonate, and refluxing the reaction to obtain a compound of the formula IV.
  • the organic solvent is acetonitrile, DMF, hydrazine, hydrazine-dimercaptoacetamide, etc.; the incubation time is 1 to 8 hours.
  • the dry product of the compound of formula IV can be obtained by the following post-treatment operation: the reaction liquid is filtered at a high temperature, the mother liquid is concentrated under reduced pressure, and the precipitated solid is re-dissolved, and the temperature is lowered, crystallized, rinsed, and dried to obtain a dry product.
  • X is a halogen, preferably Br or Cl.
  • the 5-hydroxy-4-nonyloxy-2-nitrobenzoic acid decyl ester is dissolved in an organic solvent, and 3-chloro-1-propanol or 3-bromo-1-propanol is added in the presence of potassium carbonate. And refluxing to obtain 5-(3-hydroxypropoxy)-4-methoxy-2-nitrobenzoate decyl ester;
  • the present invention provides a gefitinib intermediate and is useful for the synthesis of 4-chloro-6-(3-chloropropoxy)-7-decyloxyquinazoline.
  • the synthesis scheme of 4-chloro-6-(3-chloropropoxy)-7-methoxy quinazoline provided reduces the formation of by-products by introducing a hydroxyl group, and reduces the production cost while reducing Environmental pollution, improved product quality, the purity of 4-chloro-6-(3-chloropropoxy)-7-methoxy quinazoline obtained is above 98%, compared to prior art processes, Great improvement and improvement. detailed description
  • the invention discloses a preparation method of a gefitinib intermediate, and those skilled in the art can learn from the contents of the paper and appropriately improve the process parameters. It is to be understood that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included in the present invention.
  • the method of the present invention has been described by the preferred embodiments, and it is obvious that the method and application described herein can be modified or appropriately modified and combined without departing from the scope of the present invention. Invention technology.
  • the mixture was filtered at a high temperature, and the mother liquor was concentrated under reduced pressure to stop at 90 °C. After steaming, add 400 ml of ethyl acetate and wash three times with 250 ml of saline. Dry and decolorize for half an hour, filter. The mother liquid was concentrated to dryness under reduced pressure, and a pale-brown solid was precipitated, and concentrated, and then 50 ml of ethyl acetate was added and the mixture was warmed. Back The solution was dissolved, cooled slightly, and 100 ml of n-hexane was added dropwise to separate the material.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

一种吉非替尼关键中间体的制备方法,具体为4-氯-6-(3-氯丙氧基)-7-甲氧基喹唑啉的制备方法,由式(II)化合物6-(3-羟基丙氧基)-7-甲氧基喹唑啉-4(3H)-酮与氯化亚砜反应制得。式(II)化合物以5-羟基-4-甲氧基-2-硝基苯甲酸甲酯为原料经与式(VI)所示卤代醇的缩合,还原硝基,醋酸甲脒环合制备得到。

Description

种吉非替尼中间体的制备方法 本申请要求于 2011年 8月 5 日提交中国专利局、 申请号为
201110223971.9、 发明名称为"一种吉非替尼中间体的制备方法"的中国专 利申请的优先权, 其全部内容通过引用结合在本申请中。 技术领域
本发明属于医药化工领域, 具体涉及一种吉非替尼中间体及其制备方 法。 背景技术
4-氯 -6-(3-氯丙氧基) -7-曱氧基喹唑啉, 英文名
4-chloro-6-(3-chloropropoxy)-7-methoxy -quinazoline, CAS号 692059-41-9 , 是一种制备吉非替尼的重要中间体, 结构如下式 I所示,
Figure imgf000002_0001
吉非替尼, 英文 gefitinib, 化学名 N-(3-氯 -4-氟苯基 )-7-曱氧基 -6-(3-吗 啉—4-丙氧基)喹唑啉 -4-胺,是一种选择性表皮生长因子受体 (EGFR)酪氨酸 激酶抑制剂, 它竟争 EGFR-TK催化区域上 Mg-ATP结合位点, 阻断其信号 传递, 抑制有丝分裂原活化蛋白激酶的活化,促进细胞凋亡, 抑制肿瘤血 管生成,适用于治疗既往接受过化学治疗或不适于化疗的局部晚期或转移 性非小细胞肺癌 (NSCLC)。 吉非替尼由阿斯利康公司原创, 于 2003年 5月 5 曰在美国首次上市。 据 IMS Health数据报道, 该产品已在中国在内的 30多 个国家上市销售, 2009年销售额已超过 2亿美元。 PCT专利申请 WO2008125867公开了由 4-氯 -6-(3-氯丙氧基) -7-曱氧 基 唑啉制备吉非替尼的路线, 路线如下图所示,
Figure imgf000003_0001
Ό N mep f
W3爾
Figure imgf000003_0002
Gefstinib Fo mula I 中国专利申请 200710025643.1公开了一种 4-氯 -6-(3-氯丙氧基) -7-曱氧 基喹唑啉的制备方法, 路线如下图所示,
Figure imgf000003_0003
4 该路线中,化合物 1的制备中会产生式 (1)所示的溴代副产物 3-(3-溴丙 氧基 )-4-曱氧基苯曱酸曱酯,
Figure imgf000004_0001
且溴代副产物在后续的硝基还原反应中容易脱溴而进一步生成其他副产 物; 化合物 2的制备中会有式 (2)所示的二聚副产物生成,
Figure imgf000004_0002
化合物 2制备化合物 3的硝基还原反应中, 使用铁粉做还原剂, 环境 污染较大, 而若采用钯碳或镍等还原剂, 则容易发生脱氯反应, 生成式 ( 所示的化合物 2-氨基 -4-曱氧基 -5-丙氧基苯曱酸曱酯,
Figure imgf000004_0003
(3)
使得产物纯度降低; 制备化合物 4的环合反应中, 因氯代基团的存在, 也 比较容易形成副产物。 总之, 该路线因氯代基团的存在, 在多个步骤中均 会有副产物生成,使得最终产物的纯度质量降低,经对该专利中制备工艺 的复核, 其产物纯度仅在 90%左右。
因此, 需要进一步开发一种环境污染少、 副产物少、 产物质量高、 适 合工业化生产的 4-氯 -6-(3-氯丙氧基) -7-曱氧基喹唑啉的制备方法。 发明内容
本发明克服了现有技术中存在的缺陷, 引入羟基代替氯, 开发了一种 环境污染少、 副产物少、 产物质量高、 适合工业化生产的 4-氯 -6-(3-氯丙 氧基) -7-曱氧基喹唑啉的制备方法。
为了达到上述技术目的, 本发明首先提供了一种制备 4-氯 -6-(3-氯丙 氧基 )-7—曱氧基喹唑啉的中间体化合物 6-(3-羟基丙氧基) -7-曱氧基喹唑啉 -4(3H)-酮, 其结构式如式 II所示,
Figure imgf000005_0001
6-(3-羟基丙氧基) -7-曱氧基喹唑啉 -4(3H)-酮可用于制备 4-氯 -6-(3-氯 丙氧基 )-7-曱氧基喹唑啉, 其反应式如下式所示,
Figure imgf000005_0002
所述式 I化合物 4-氯 -6-(3-氯丙氧基) -7-曱氧基喹唑啉的制备法为由式 II 化合物在氯化亚砜的作用下制得。 进一步地, 所述制备方法为: 将式 II化 合物与有机溶剂混合, 加入氯化亚砜, 加热保温反应得式 I化合物。反应 完全后,可以依照如下方式处理得到式 I化合物成品:将反应液加入到低 温水中, 滴加液碱调节 PH值,静置分层, 减压浓缩有机层,得白色固体, 再溶解降温重结晶得式 I化合物精品。
所述有机溶剂可以为二氯曱烷、 DMF、 三氯曱烷等; 所述重结晶溶 剂选自乙酸乙酯、 乙醇或异丙醇;较佳地,所述 PH值调节至 PH为 7 ~ 8。
式 II化合物由式 III化合物 2-氨基 -5-(3-羟基丙氧基) -4-曱氧基苯曱酸曱 酯与有机溶剂和醋酸曱脒反应制得。进一步地,所述式 II化合物的制备方 法为: 式 III化合物与有机溶剂、 醋酸曱脒混合, 升温至回流反应, 降温结 晶得式 II化合物。 所述有机溶剂可选自醇类, 如异丙醇、 乙醇、 正丙醇、 正丁醇等。 所述回流反应的时间为 6 ~ 18小时。反应完成后可经降温,抽 滤, 淋洗, 烘干处理得到式 II化合物干品。
式 III化合物由式 IV化合物 5-(3-羟基丙氧基) -4-曱氧基 -2-硝基苯曱酸 曱酯经还原反应得到。 进一步地, 所述式 III化合物的制备方法为: 式 IV化 合物溶于有机溶剂, 加入还原剂, 氢气置换, 搅拌反应得式 III化合物。 所 述有机溶剂可以为酯类如乙酸乙酯, 醇类如乙醇、异丙醇等; 所述还原剂 为钯碳或镍; 所述搅拌反应的时间为 5 ~ 18小时。反应完成后, 可以依照 如下方式处理得到式 III化合物成品: 将反应液重新升温, 过滤, 减压浓缩 母液, 将浓缩母液升温至回流后降温, 抽滤, 干燥得式 III化合物干品。
式 IV化合物由式 V化合物 5-羟基 -4-曱氧基 -2-硝基苯曱酸曱酯与式 VI 所示的化合物反应制得, 其反应式为:
Figure imgf000006_0001
其中 为 素, 优选为溴或氯。
进一步地,所述式 IV化合物的制备方法为:式 V化合物溶于有机溶剂, 在碳酸钾存在下, 加入 3-氯 -1-丙醇, 回流保温反应得式 IV化合物。 所述 有机溶剂为乙腈、 DMF、 Ν,Ν-二曱基乙酰胺等; 保温反应时间为 1 ~ 8小 时。反应完成后, 可经如下后处理操作得到式 IV化合物干品: 高温过滤反 应液,将母液减压浓缩,再将析出固体重新溶解,升温后降温析晶,淋洗, 烘干得干品。
本发明所采用的 4-氯 -6-(3-氯丙氧基) -7-曱氧基喹唑啉的合成技术方 案为: 以 5-羟基 -4-曱氧基 -2-硝基苯曱酸曱酯为原料, 经过卤代醇缩合、 还原硝基、醋酸曱脒环合和氯化亚砜氯代反应制备得到,以反应式表示如 下图所示,
Figure imgf000007_0001
其中 X为卤素, 优选为 Br或 Cl。
进一步地, 4-氯 -6-(3-氯丙氧基) -7-曱氧基喹唑啉的制备方法为:
) 将 5-羟基 -4-曱氧基 -2-硝基苯曱酸曱酯溶于有机溶剂, 在碳酸钾存在下, 加入 3-氯 -1-丙醇或 3-溴 -1-丙醇, 回流保温反应得 5-(3-羟基丙氧基) -4-曱 氧基 -2-硝基苯曱酸曱酯;
) 将 5-(3-羟基丙氧基) -4-曱氧基 -2-硝基苯曱酸曱酯溶于有机溶剂,加入还原 剂,氢气置换,搅拌反应得 2-氨基 -5-(3-羟基丙氧基) -4-曱氧基苯曱酸曱酯;) 将 2-氨基 -5-(3-羟基丙氧基) -4-曱氧基苯曱酸曱酯与有机溶剂和醋酸曱脒 混合, 回流保温反应得 6-(3-羟基丙氧基) -7-曱氧基喹唑啉 -4(3H)-酮;
) 将 6-(3-羟基丙氧基) -7-曱氧基喹唑啉 -4(3H)-酮与有机溶剂混合,加入氯化 亚砜, 加热保温反应得 4-氯 -6-(3-氯丙氧基) -7-曱氧基喹唑啉。 本发明提供了一种吉非替尼中间体, 并用于 4-氯 -6-(3-氯丙氧基) -7-曱 氧基喹唑啉的合成。所提供的 4-氯 -6-(3-氯丙氧基) -7-曱氧基喹唑啉的合成 方案通过羟基的引入, 减少了副产物的生成, 在降低了生产成本的同时, 降低了环境污染,提高了产物质量,制得的 4-氯 -6-(3-氯丙氧基) -7-曱氧基 喹唑啉的纯度在 98%以上, 相对于现有技术工艺, 有很大的提高和改善。 具体实施方式
本发明公开了一种吉非替尼中间体的制备方法,本领域技术人员可以 借鉴本文内容, 适当改进工艺参数实现。 特别需要指出的是, 所有类似的 替换和改动对本领域技术人员来说是显而易见的,它们都被视为包括在本 发明。本发明的方法已经通过较佳实施例进行了描述,相关人员明显能在 不脱离本发明内容、精神和范围内对本文所述的方法和应用进行改动或适 当变更与组合, 来实现和应用本发明技术。
为了进一步理解本发明,下面结合实施例对本发明提供的中间体 6-(3- 羟基丙氧基) -7-曱氧基喹唑啉 -4(3H)-酮及其用于制备 4-氯 -6-(3-氯丙氧 基) -7-曱氧基喹唑啉的合成方法进行详细的说明。 需要理解的是, 这些实 施例描述只是为进一步详细说明本发明的特征,而不是对本发明范围或本 发明权利要求范围的限制。 实施例 1 : 5-(3-羟基丙氧基) -4-曱氧基 -2-硝基苯曱酸曱酯的制备
在 1000ml四口瓶中投入 5-羟基 -4-曱氧基 -2-硝基苯曱酸曱酯 50g , 乙腈 500ml, 搅拌溶解, 再投入碳酸钾 87.5g, 升温。 于 75°C滴加 61g3-溴 -1-丙 醇和 200ml乙腈的混合液, 约 1小时滴完。 滴毕, 升温回流保温三小时, 至反应完全。 反应毕, 高温过滤, 母液减压浓缩, 至 90°C停止。 蒸毕, 加 400ml乙酸乙酯, 250ml食盐水洗三次。 干燥脱色半小时, 过滤。 母液减 压浓缩干, 析出淡青色固体, 停止浓缩, 补加 50ml乙酸乙酯, 升温。 回 流溶清, 稍降温, 滴加 100ml正己烷, 析料。 于室温下抽滤, 少量正己烷 淋洗, 得湿品 59g, 烘干得 5-(3-羟基丙氧基) -4-曱氧基 -2-硝基苯曱酸曱酯 干品 54.3g, 收率: 86.5%。 实施例 2: 5-(3-羟基丙氧基) -4-曱氧基 -2-硝基苯曱酸曱酯的制备
在 1000ml四口瓶中投入 50g5-羟基 -4-曱氧基 -2-硝基苯曱酸曱酯, 500ml乙腈,搅拌溶解,再投入 87.5g碳酸钾,升温。 于 75°C滴加 61g3-氯 -1- 丙醇和 200ml乙腈的混合液, 约 30分钟滴完。 滴毕, 升温回流保温 5小时, 至反应完全。 反应毕, 高温过滤, 母液减压浓缩, 至 90°C停止。 蒸毕, 加 400ml乙酸乙酯, 250ml食盐水洗三次。 干燥脱色半小时, 过滤。 母液减 压浓缩干, 析出固体, 补加 50ml乙酸乙酯, 升温。 回流溶清, 稍降温, 滴加 100ml正己烷, 析料。 于室温下抽滤, 少量正己烷淋洗, 得湿品 59g, 烘干得 5-(3-羟基丙氧基) -4-曱氧基 -2-硝基苯曱酸曱酯干品, 收率: 84.2%。 实施例 3: 2-氨基 -5-(3-羟基丙氧基) -4-曱氧基苯曱酸曱酯的制备
2000ml高压釜中投 62g的 5-(3-羟基丙氧基) -4-曱氧基 -2-硝基苯曱酸 曱酯, 1000ml乙酸乙酯, 搅拌, 溶清, 再加入 5.2g钯炭, 氢气置换数次, 设置温度 30°C , 压力 0.8MPa, 搅拌 12小时。 搅拌毕, 点板至反应完全, 将反应液抽入 1000ml的四口瓶中, 有固体析出。 重新升温至 65 V保温 lOmin, 过滤。 母液减压浓缩, 至约剩 300ml体积时, 停止浓缩, 重新升 温至回流, 仍溶不清, 降温。 于室温下抽滤, 200ml正庚烷淋洗得湿品 39g, 65°C烘干得 2-氨基 -5-(3-羟基丙氧基) -4-曱氧基苯曱酸曱酯干品 37.3g, 收率: 80.2%。 实施例 4: 6-(3-羟基丙氧基) -7-曱氧基喹唑啉 -4(3H)-酮的制备
500ml四口瓶中投 2-氨基 -5-(3-羟基丙氧基) -4-曱氧基苯曱酸曱酯 25g, 异丙醇 375ml, 醋酸曱脒 16.5g, 搅拌升温。 回流下逐渐溶清, 后又有料 析出, 回流保温 12小时。 保温毕, 点板至反应完全。 降温。 于 5°C左右 抽滤, 20ml异丙醇淋洗。 得湿品 27.1g, 烘干得 6-(3-羟基丙氧基) -7-曱氧 基喹唑啉 -4(3H)-酮干品 23.7g, 收率: 96.7%。
1H NMR (400MHz, DMSO): δ= 1.900-1.963 (m, 2H, J=25.2 MHz), δ= 3.575-3.619 (m, 2H, 17.6 MHz), δ= 3.920 (s, 3H), δ= 4.122-4.153 (t, 2H, J=6.4 MHz), δ= 4.581-4.607 (t, 1H, J=5.2 MHz), δ= 7.134 (s, 1H), δ= 7.453 (s,lH), δ= 7.992 (s, 1H), δ= 12.066 (s, 1H) 实施例 5: 4-氯 -6-(3-氯丙氧基) -7-曱氧基喹唑啉的制备
250ml四口瓶中投 6-(3-羟基丙氧基) -7-曱氧基喹唑啉 -4(3H)-酮 9g,二 氯曱烷 100ml, DMF1.4g, 搅拌, 不溶。 于室温下滴加氯化亚砜, 约半小 时滴完。 滴毕, 升温至回流, 回流保温 12小时。 保温毕, 点板反应完全。 在另一 500ml瓶中投 100ml水, 降温至 10°C。将反应液滴入 500ml瓶中, 同时滴加液碱( 32g片碱和 100ml水), 控制温度小于 20 °C , 滴毕, 调至 PH=7 ~ 8。 调毕, 静置分层, 水层再用二氯曱烷 70ml提取一次。 合并有 机层, 水 80ml洗一次, 有机层脱色干燥, 过滤。 母液减压浓缩干, 析出 白色固体,再投乙酸乙酯 43ml ,搅拌升温。至约 65 °C溶清,回流保温 1 Omin , 降温。于 5°C左右抽滤, 15ml乙酸乙酯淋洗。得湿品 7.7g,烘干得 4-氯 -6-(3- 氯丙氧基) -7-曱氧基喹唑啉干品 7.7g, 收率: 74.5%。
描述,相关技术人员明显能在不脱离本发明内容、精神和范围内对本文所
明技术。特别需要指出的是,所有相类似的替换和改动对本领域技术人员 来说是显而易见的, 它们都被视为包括在本发明的精神、 范围和内容中。

Claims

权 利 要 求
1. 6-(3-羟基丙氧基) -7-曱氧基喹唑啉 -4(3H)-酮, 结构式如下式 II所示,
Figure imgf000011_0001
2. 一种 6-(3-羟基丙氧基) -7-曱氧基喹唑啉 -4(3H)-酮的制备方法, 由 2-氨基 -5-(3-羟基丙氧基) -4-曱氧基苯曱酸曱酯与醋酸曱脒反应制得。
3. 根据权利要求 2所述的制备方法, 其特征在于, 所述 2-氨基 -5-(3-羟基丙 氧基 )-4-曱氧基苯曱酸曱酯由 5-(3-羟基丙氧基) -4-曱氧基 -2-硝基苯曱酸曱 酯经还原反应制得。
4. 根据权利要求 3所述的制备方法,其特征在于,所述还原反应的还原剂为 钯碳或镍。
5. 根据权利要求 3所述的制备方法, 其特征在于, 所述 5-(3-羟基丙氧基) -4- 曱氧基 -2-硝基苯曱酸曱酯由 5-羟基 -4-曱氧基 -2-硝基苯曱酸曱酯与式 VI所 示化合物反应制得,
VI , 其中 X为卤素。
6. 根据权利要求 5所述的制备方法, 其特征在于, 所述 X为溴或氯。
7. 一种 4-氯 -6-(3-氯丙氧基) -7-曱氧基喹唑啉的制备方法, 由 6-(3-羟基丙氧 基) -7-曱氧基喹唑啉 -4(3Η)-酮与氯化亚砜反应制得。
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