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WO2018214686A1 - 一种制备异噁嗪酮化合物的方法及其应用 - Google Patents

一种制备异噁嗪酮化合物的方法及其应用 Download PDF

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WO2018214686A1
WO2018214686A1 PCT/CN2018/084009 CN2018084009W WO2018214686A1 WO 2018214686 A1 WO2018214686 A1 WO 2018214686A1 CN 2018084009 W CN2018084009 W CN 2018084009W WO 2018214686 A1 WO2018214686 A1 WO 2018214686A1
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compound
phosphorus
base
substituted
aryl
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PCT/CN2018/084009
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English (en)
French (fr)
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盛秋菊
关保川
张天浩
张盼
章金龙
陈邦池
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浙江省诸暨合力化学对外贸易有限公司
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Priority to BR112019024928-1A priority Critical patent/BR112019024928B1/pt
Priority to EP18805250.0A priority patent/EP3632911B1/en
Publication of WO2018214686A1 publication Critical patent/WO2018214686A1/zh
Priority to US16/695,041 priority patent/US11299499B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention belongs to the field of organic synthesis, and in particular relates to a method for preparing an isoxazinone compound and an application thereof.
  • Isoxazinone compound (I) is an important class of compounds or organic synthesis intermediates, widely used in chemical, pharmaceutical, pesticide, materials and other fields.
  • such compounds can be used as UV absorbers in various UV-blocking materials (US4446262A), as a serine hydrolase inhibitor to treat, prevent or ameliorate serine hydrolase-mediated diseases (CN101535304A),
  • anthranilamide insecticides such as chlorantraniliprole, cyanamide, etc.
  • the first one is to convert the carboxylic acid (III) into the acid chloride (IV) by the action of thionyl chloride and pyridine, and the acid chloride (IV) is reacted with the substituted anthranilic acid (II') under the action of a base.
  • the benzoxazinone (I') (US4832897A) is obtained and is represented by the reaction formula as follows:
  • the method needs to be carried out in two steps, and more by-products are produced in the reaction (US8927559B2), and the yield is low, which is not favorable for industrial production.
  • the second is to directly convert the substituted anthranilic acid (II') and the carboxylic acid (III) into a benzoxazinone (I') under the action of a sulfonyl chloride and a base (WO2003/015519).
  • the method is shorter than the first method, the "one-pot method" can be completed, but the method requires an excessive amount of sulfonyl chloride, and the sulfonyl chloride not only reacts with the raw material anthranilic acid compound to form a large amount of sulfonamide by-product. Moreover, a large amount of waste water containing sulfur organic acid is generated, which brings serious problems of three wastes, which is not conducive to industrial production.
  • the third is to activate the carboxylic acid (III) by the action of the activator N,N'-carbonyldiimidazole (CDI), and then react with the substituted anthranilic acid (II') to obtain the benzoxazinone (I). ') (CN101535304A), expressed by the following equation:
  • the method is also "one-pot", but an equivalent amount of activator N, N'-carbonyldiimidazole (CDI) is required, the activator is expensive, the industrialization cost is high, and the 2 equivalents of imidazole formed are not easily recovered. It will cause three waste problems and is not conducive to industrial production.
  • the present invention provides a method for preparing an isoxazinone compound (I) which is simple in operation, environmentally friendly, low in raw material cost, high in yield, and good in product quality.
  • Q is N or C-Z
  • Each R or Z is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic aryl, substituted heteroaryl, cyano, carbonyl, alkoxycarbonyl, halogen, alkoxy, An alkylthio group, a sulfonyl group, a sulfinyl group, an alkylamino group or a nitro group; n is 0, 1, 2 or 3; R' is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic aromatic A substituted or substituted heteroaryl group.
  • Substituted alkyl/aryl/heteroaryl means that the hydrogen on the alkyl/aryl/heteroaryl group is independently independently substituted by one or more alkyl, alkenyl, alkynyl, aryl, alkoxy, halogen Substituted by nitro, cyano, sulfonyl or sulfinyl.
  • the alkyl group includes a linear alkyl group, a branched alkyl group or a cycloalkyl group.
  • the dehydrating agent is preferably a phosphorus reagent.
  • the phosphorus reagent refers to a compound containing a phosphorus element, preferably phosphorus pentoxide, phosphorus oxychloride, phosphorus oxybromide, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus pentabromide, and more preferably Phosphorus oxychloride or phosphorus oxybromide.
  • the base may be an inorganic base or an organic base, preferably an organic base, more preferably a tertiary amine base such as pyridine, triethylamine, 3-methylpyridine or N,N-dimethylaminopyridine.
  • a tertiary amine base such as pyridine, triethylamine, 3-methylpyridine or N,N-dimethylaminopyridine.
  • the molar ratio of the compound II to the compound III is 1:0.5 to 1.5; the molar ratio of the compound II to the dehydrating agent is 1:1 to 2; and the molar ratio of the compound II to the base is 1:2 to 5.
  • the bisamide compound (V) is obtained and expressed by the following formula:
  • R 1 and R 2 are each independently hydrogen, alkyl or substituted alkyl, aryl or substituted aryl, heterocyclic aryl or substituted heteroaryl, However, R 1 and R 2 may not be hydrogen at the same time, and the alkyl group includes a linear alkyl group, a branched alkyl group or a cycloalkyl group; and HY is a hydrohalic acid, sulfuric acid, phosphoric acid or a carboxylic acid, preferably hydrochloric acid or sulfuric acid.
  • the base to be subjected to the ring opening reaction may be an organic base or an inorganic base, preferably an organic base, more preferably triethylamine, pyridine, 3-methylpyridine or N,N-dimethylaminopyridine.
  • R 3 is alkyl, substituted alkyl, alkene, alkynyl, aryl or substituted aryl, heterocyclic aryl or substituted heteroaryl.
  • the base to be subjected to the ring opening reaction may be an inorganic base or an organic base such as an alkali metal carbonate, an alkali metal hydroxide, an alkali metal alkoxide, triethylamine, pyridine or the like, preferably an alkali metal alkoxide.
  • the alcohol R 3 OH forms a salt with an alkali metal such as R 3 ONa, R 3 OK or the like.
  • the preparation method of the isoxazinone compound provided by the invention has the following advantages:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

本发明公开了一种制备异噁嗪酮化合物(I)的方法及其应用。该方法及其应用包括：将化合物(II)和羧酸(III)在脱水剂和碱的作用下反应得到异噁嗪酮化合物(I)，后者再在碱作用下与氨基化合物的质子酸盐(IV)或R3OH(VII)发生开环反应得到双酰胺化合物(V)或N-酰基苯甲酸酯化合物(VI)。该方法原料廉价易得、生产成本低，操作简便、反应温和、避免了使用甲磺酰氯等有机试剂带来的含硫有机酸废水问题，三废少且易处理；适合工业化生产。

Description

一种制备异噁嗪酮化合物的方法及其应用 技术领域
本发明属于有机合成领域，具体涉及一种制备异噁嗪酮化合物的方法及其应用。
背景技术
异噁嗪酮化合物(I)是一类重要的化合物或有机合成中间体，广泛应用于化工、医药、农药、材料等领域。例如，该类化合物可以作为紫外光吸收剂用于各种防紫外的材料中(US4446262A)，可以作为丝氨酸水解酶抑制剂来治疗、预防或改善丝氨酸水解酶介导的疾病(CN101535304A)，还可以作为制备邻氨基苯甲酰胺类杀虫剂(如氯虫苯甲酰胺、溴氰虫酰胺等)的重要中间体(WO2003/015519和WO2004/067528)等。
Figure PCTCN2018084009-appb-000001
目前，关于异噁嗪酮化合物的合成方法主要有以下三种报道：
第一种是将羧酸(III)在二氯亚砜和吡啶的作用下先转化成酰氯(IV)，酰氯(IV)再在碱的作用下，与取代邻氨基苯甲酸(II’)反应得到苯并噁嗪酮(I’)(US4832897A)，用反应式表示如下：
Figure PCTCN2018084009-appb-000002
该方法需分两步进行，且在反应中有较多副产物产生(US8927559B2)，收率低，不利于工业化生产。
第二种是将取代邻氨基苯甲酸(II’)和羧酸(III)在磺酰氯和碱的作用下， 直接转化成苯并噁嗪酮(I’)(WO2003/015519)，用反应式表示如下：
Figure PCTCN2018084009-appb-000003
该方法虽然比第一种方法路线短，“一锅法”就能完成，但该方法需要使用过量的磺酰氯，磺酰氯不仅会与原料邻氨基苯甲酸化合物反应生成大量的磺酰胺副产物，而且会产生大量含硫有机酸的废水，带来严重的三废问题，不利于工业化生产。
第三种是将羧酸(III)先在活化剂N,N’-羰二咪唑(CDI)的作用下活化，再与取代邻氨基苯甲酸(II’)反应得到苯并噁嗪酮(I’)(CN101535304A)，用反应式表示如下：
Figure PCTCN2018084009-appb-000004
该方法也是“一锅法”完成的，但是需要用到等当量的活化剂N,N’-羰二咪唑(CDI)，活化剂昂贵，工业化成本高，而且生成的2当量的咪唑不容易回收，会造成三废问题，不利于工业化生产。
发明内容
为克服现有技术中的不足，本发明提供了一种操作简单、工艺环保、原料成本低、收率高、产品质量好的制备异噁嗪酮化合物(I)的方法。
一种制备异噁嗪酮化合物(I)的方法，其特征在于，该方法包括：将化合物(II)和羧酸(III)在脱水剂和碱的作用下反应得到异噁嗪酮化合物(I)，用反应式表示如下：
Figure PCTCN2018084009-appb-000005
Q是N或C-Z；
其中，Q为C-Z时，化合物(II)的结构式如下：
Figure PCTCN2018084009-appb-000006
每个R或Z独立的是氢、烷基、取代烷基、芳基、取代芳基、杂环芳基、取代杂环芳基、氰基、羰基、烷氧羰基、卤素、烷氧基、烷硫基、磺酰基、亚磺酰基、烷胺基或硝基；n是0，1，2或3；R’是氢、烷基、取代烷基、芳基、取代芳基、杂环芳基或取代杂环芳基。
取代烷基/芳基/杂芳基是指烷基/芳基/杂芳基上的氢各自独立地被1个或多个烷基、烯基、炔基、芳基、烷氧基、卤素、硝基、氰基、磺酰基或亚磺酰基取代。
所述的烷基包括直链烷基、支链烷基或环烷基。
所述的脱水剂优选为磷试剂。磷试剂是指含有磷元素的化合物，优选为五氧化二磷、三氯氧磷、三溴氧磷、三氯化磷、三溴化磷、五氯化磷、五溴化磷，更优选为三氯氧磷或三溴氧磷。
所述的碱可以为无机碱或有机碱，优选为有机碱，更优选为吡啶、三乙胺、3-甲基吡啶、N,N-二甲氨基吡啶等叔胺碱。
化合物II与化合物III的投料摩尔比是1:0.5～1.5；化合物II与脱水剂的投料摩尔比是1:1～2；化合物II与碱的投料摩尔比为1:2～5。
一种制备双酰胺化合物(V)的方法，其特征在于，按照上述方法制备得到的异噁嗪酮化合物(I)与氨基化合物的质子酸盐(IV)在碱的作用下发生开环反应，得到双酰胺化合物(V)，用反应式表示如下：
Figure PCTCN2018084009-appb-000007
其中，Q、n、R、R’的定义同上；R 1、R 2分别独立的是氢、烷基或取代烷基、芳基或取代芳基、杂环芳基或取代杂环芳基，但R 1、R 2不能同时是氢，所述的烷基包括直链烷基、支链烷基或环烷基；HY是氢卤酸、硫酸、磷酸或羧酸，优选为盐酸或硫酸。开环反应所述的碱可以是有机碱或无机碱，优选是有机碱，更优选为三乙胺、吡啶、3-甲基吡啶或N,N-二甲氨基吡啶。
一种N-酰基苯甲酸酯化合物(VI)的制备方法，其特征在于，按照上述方法制备得到的异噁嗪酮化合物(I)与R 3OH(VII)在碱的作用下发生开环反应，得到N-酰基苯甲酸酯化合物(VI)，用方程式表示如下：
Figure PCTCN2018084009-appb-000008
其中，Q、n、R、R’的定义同上；R 3是烷基、取代烷基、烯烃基、炔烃基、芳基或取代芳基、杂环芳基或取代杂环芳基。开环反应所述的碱可以是无机碱或有机碱，如碱金属的碳酸盐、碱金属的氢氧化物、碱金属的醇盐、三乙胺、吡啶等，优选为碱金属的醇盐，最优选为醇R 3OH与碱金属形成盐，如R 3ONa、R 3OK等。
与现有技术相比，本发明提供的异噁嗪酮化合物的制备方法具有以下优点：
(1)原材料便宜易得，生产成本低；
(2)避免了使用甲磺酰氯等有机试剂带来的含硫有机酸废水问题，三废少且易处理；
(3)采用“一锅法”工艺，操作简单，反应条件温和，收率高，适合工业化生产。
具体实施方式
下面的实施例进一步举例说明了本发明的一些特征，但本发明所申请保护的内容和范围并不受下述实施例的限制。
实施例1：2-[3-溴-1-(3-氯-2-吡啶基)-1H-吡唑-5-基]-6-氯-8-甲基-4H-3,1-苯并噁嗪-4-酮制备
在100mL的三口瓶中，加入3-溴-1-(3-氯-2-吡啶基)-1H-吡唑-5-甲酸3.02g、3-甲基吡啶1.95g和乙腈15mL，-5℃条件下滴加POBr 35.73g，滴毕保温搅拌半小时，再加入2-氨基-3-甲基-5-氯苯甲酸1.86g，室温反应1小时。加入20mL水搅拌0.5小时，过滤，滤饼用3:2的乙腈-水洗涤，干燥得产品4.16g，收率92％。
实施例2：2-[3-溴-1-(3-氯-2-吡啶基)-1H-吡唑-5-基]-6-氰基-8-甲基-4H-3,1-苯并噁嗪-4-酮制备
在100mL的三口瓶中，加入3-溴-1-(3-氯-2-吡啶基)-1H-吡唑-5-甲酸3.02g、3-甲基吡啶1.95g和乙腈15mL，-5℃条件下滴加POCl 33.23g，滴毕保温搅拌半小时，再加入2-氨基-3-甲基-5-氰基苯甲酸1.94g，室温反应1小时。加入20mL水搅拌0.5小时，过滤，滤饼用3:2的乙腈-水洗涤，干燥得产品3.82g，收率86％。 1H NMR(500MHz,DMSO)δ8.63(dd,1H),8.40–8.33(m,2H),8.10(s,1H),7.77(dd,1H),7.60(s,1H),1.73(s,3H).4.16g。
实施例3：2-[3-溴-1-(3-氯-2-吡啶基)-1H-吡唑-5-基]-8-甲基-4H-3,1-苯并噁嗪-4-酮制备
在100mL的三口瓶中，加入3-溴-1-(3-氯-2-吡啶基)-1H-吡唑-5-甲酸3.02g、三乙胺2.02g和乙腈15mL，-5℃条件下滴加POCl 33.23g，滴毕保温搅拌半小时，再加入2-氨基-3-甲基苯甲酸3.02g，室温反应2小时。加入20mL水搅拌0.5小时，过滤，滤饼用3:2的乙腈-水洗涤，干燥得产品3.76g，收率90％。 1H NMR(500MHz,DMSO)δ8.63(dd,1H),8.35(dd,1H),7.93(d,1H),7.76(dd,1H),7.68(d,1H),7.49(dd,2H),1.74(s,3H).
实施例4：2-[3,4-二溴-1-(3-氯-2-吡啶基)-1H-吡唑-5-基]-6-氰基-8-甲基-4H-3,1-苯并噁嗪-4-酮制备
在100mL的三口瓶中，加入3,4-二溴-1-(3-氯-2-吡啶基)-1H-吡唑-5-甲酸3.81g、N,N-二甲氨基吡啶2.46g和乙腈15mL，-5℃条件下滴加POCl 33.23g，滴毕保温搅拌半小时，再加入2-氨基-3-甲基-5-氯苯甲酸1.86g，滴加完毕后，室温反应3小时。加入20mL水搅拌0.5小时，过滤，滤饼用3:2的乙腈-水洗涤，干燥得产品5.04g，收率95％。 1H NMR(400MHz,DMSO)δ8.60(d,1H),8.36(d,1H),7.97–7.88(m,1H),7.83(s,1H),7.76(dd,,1H),1.88(S,3H).
实施例5：2-[3-溴-1-(3-氯-2-吡啶基)-1H-吡唑-5-基]-6-溴-8-甲基-4H-3,1-苯并噁嗪-4-酮制备
在100mL的三口瓶中，加入3-溴-1-(3-氯-2-吡啶基)-1H-吡唑-5-甲酸3.02g、吡啶3.95g和乙腈15mL，-5℃条件下滴加PCl 32.74g，滴毕保温搅拌半小时，再加入2-氨基-3-甲基-5-溴苯甲酸2.3g，室温反应1小时。加入20mL水搅拌0.5小时，过滤，滤饼用3:2的乙腈-水洗涤，干燥得产品4.42g，收率89％。 1H NMR(500MHz,DMSO)δ8.63(dd,1H),8.35(dd,1H),8.02(d,1H),7.95–7.87(m,1H),7.77(dd,1H),7.54(s,1H),1.71(s,3H).
实施例6：2-[吡啶-4-基]-6-氯-8-甲基-4H-3,1-苯并噁嗪-4-酮的制备
在100mL的三口瓶中，加入异烟酸1.84g、三乙胺2.02g和乙腈15mL，-5℃条件下滴加POCl 34.59g，滴毕保温搅拌半小时，再加入2-氨基-3-甲基-5-氯苯甲酸1.86g，室温反应2.5小时。加入20mL水搅拌0.5小时，过滤，滤饼用3:2的乙腈-水洗涤，干燥得产品2.5g，收率92％。 1H NMR(400MHz,DMSO)δ8.86(d,2H),8.09(dd,2H),8.01–7.92(m,2H),2.62(s,3H).
实施例7：2-[3-溴-1-(3-氯-2-吡啶基)-1H-吡唑-5-基]-4H-吡啶并[2,3-d][3,1]噁嗪-4-酮的制备
在100mL的三口瓶中，加入3-溴-1-(3-氯-2-吡啶基)-1H-吡唑-5-甲酸3.02g、三乙胺2.02g和乙腈15mL，-5℃条件下滴加POCl 34.59g，滴毕保温搅拌半小时，再加入2-氨基-3吡啶甲酸1.86g，室温反应2小时。加入20mL水搅拌0.5小时，过滤，滤饼用3:2的乙腈-水洗涤，干燥得产品3.67g，收率91％。 1H NMR(400MHz,DMSO)δ8.88(dd,1H),8.63–8.56(m,1H),8.52–8.43(m,1H),8.33(dd,1H),7.77(dd,1H),7.65–7.56(m,2H)。
实施例8：3-溴-N-(2-甲基-4-氰基-6-(甲氨酰基)苯基)-1-(3-氯-2-吡啶基)-1H-吡唑-5-甲酰胺的制备
将2-[3-溴-1-(3-氯-2-吡啶基)-1H-吡唑-5-基]-6-氰基-8-甲基-4H-3,1-苯并噁嗪-4-酮4.17g溶于20ml乙腈，然后加入三乙胺1.78g、甲胺硫酸盐2.82g，室温搅拌2.5小时，减压脱除溶剂，加水洗涤，烘干，得3-溴-N-(2-甲基-4-氰基-6-(甲氨 酰基)苯基)-1-(3-氯-2-吡啶基)-1H-吡唑-5-甲酰胺4.08g，收率98％。
实施例9：3-溴-N-(2-甲基-4-氯-6-(甲氨酰基)苯基)-1-(3-氯-2-吡啶基)-1H-吡唑-5-甲酰胺的制备
将2-[3-溴-1-(3-氯-2-吡啶基)-1H-吡唑-5-基]-6-氯-8-甲基-4H-3,1-苯并噁嗪-4-酮4.2g溶于20ml乙腈，然后加入4-二甲氨基吡啶1.23g、甲胺硫酸盐2.18g，室温搅拌2.5小时，减压脱除溶剂，加水洗涤，烘干，得3-溴-N-(2-甲基-4-氯-6-(甲氨酰基)苯基)-1-(3-氯-2-吡啶基)-1H-吡唑-5-甲酰胺4.27g，收率95％。
实施例10：3-溴-N-(2-甲基-4-氯-6-(甲氧酰基)苯基)-1-(3-氯-2-吡啶基)-1H-吡唑-5-甲酰胺的制备
将2-[3-溴-1-(3-氯-2-吡啶基)-1H-吡唑-5-基]-6-氯-8-甲基-4H-3,1-苯并噁嗪-4-酮10g溶于100mL甲醇中，室温下加入10g甲醇钠，搅拌反应1小时。减压脱除溶剂，加水洗涤，烘干，得3-溴-N-(2-甲基-4-氯-6-(甲氧酰基)苯基)-1-(3-氯-2-吡啶基)-1H-吡唑-5-甲酰胺9.74g，收率91％。

Claims (10)

  1. 一种制备异噁嗪酮化合物(I)的方法，其特征在于，该方法包括：将化合物(II)和羧酸(III)在脱水剂和碱的作用下反应得到异噁嗪酮化合物(I)，用反应式表示如下：
    Figure PCTCN2018084009-appb-100001
    其中，
    Q是N或C-Z；每个R或Z独立的是氢、烷基、取代烷基、芳基、取代芳基、杂环芳基、取代杂环芳基、氰基、羰基、烷氧羰基、卤素、烷氧基、烷硫基、磺酰基、亚磺酰基、烷胺基或硝基；
    n是0，1，2或3；
    R’是氢、烷基、取代烷基、芳基、取代芳基、杂环芳基或取代杂环芳基。
  2. 根据权利要求1所述的方法，其特征在于，所述的脱水剂为磷试剂，所述的碱为有机碱。
  3. 根据权利要求2所述的方法，其特征在于，所述的磷试剂优选为五氧化二磷、三氯氧磷、三溴氧磷、三氯化磷、三溴化磷、五氯化磷或五溴化磷。
  4. 根据权利要求3所述的方法，其特征在于，所述的磷试剂进一步优选为三氯氧磷或三溴氧磷。
  5. 根据权利要求2所述的方法，其特征在于，所述的有机碱优选为吡啶、3-甲基吡啶、N,N-二甲氨基吡啶、三乙胺。
  6. 根据权利要求1所述的方法，其特征在于，化合物II与化合物III的投料摩尔比是1:0.5～1.5；化合物II与脱水剂的投料摩尔比是1:1～2；化合物II与碱的投料摩尔比为1:2～5。
  7. 一种双酰胺化合物(V)的制备方法，其特征在于，如权利要求1-6任一项方法制备得到的异噁嗪酮化合物(I)与氨基化合物的质子酸盐(IV)在碱的作用下发生开环反应，得到双酰胺化合物(V)，用反应式表示如下：
    Figure PCTCN2018084009-appb-100002
    其中，
    Q、n、R、R’的定义如权利要求1所述；
    R 1、R 2分别独立的是氢、烷基或取代烷基、芳基或取代芳基、杂环芳基或取代杂环芳基，但R 1、R 2不能同时是氢；
    HY是氢卤酸、硫酸、磷酸或羧酸。
  8. 根据权利要求7所述的方法，其特征在于，所述的HY优选为盐酸或硫酸；开环反应中的碱优选为三乙胺、吡啶、3-甲基吡啶、N,N-二甲氨基吡啶。
  9. 一种N-酰基苯甲酸酯化合物(VI)的制备方法，其特征在于，如权利要求1-6任一项方法制备得到的化合物(I)与R 3OH(VII)在碱的作用下发生开环反应，得到N-酰基苯甲酸酯化合物(VI)，用方程式表示如下：
    Figure PCTCN2018084009-appb-100003
    其中，
    Q、n、R、R’的定义如权利要求1所述；
    R 3是烷基、取代烷基、烯烃基、炔烃基、芳基或取代芳基、杂环芳基或取代杂环芳基。
  10. 根据权利要求9所述的方法，其特征在于，开环反应中的碱优选为碱金属的醇盐。
PCT/CN2018/084009 2017-05-26 2018-04-23 一种制备异噁嗪酮化合物的方法及其应用 WO2018214686A1 (zh)

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