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WO2020199081A1 - 一种制备2-芳基丙二酸衍生物的方法、中间体及其应用 - Google Patents

一种制备2-芳基丙二酸衍生物的方法、中间体及其应用 Download PDF

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WO2020199081A1
WO2020199081A1 PCT/CN2019/080827 CN2019080827W WO2020199081A1 WO 2020199081 A1 WO2020199081 A1 WO 2020199081A1 CN 2019080827 W CN2019080827 W CN 2019080827W WO 2020199081 A1 WO2020199081 A1 WO 2020199081A1
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reaction
aryl
alkyl
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amino
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French (fr)
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陈邦池
孙殷卫
王忠元
金涛
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Oriental Luzhou Agrochemicals Co Ltd
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Oriental Luzhou Agrochemicals Co Ltd
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Priority to EP19923349.5A priority Critical patent/EP3950659B1/en
Priority to PCT/CN2019/080827 priority patent/WO2020199081A1/zh
Priority to CN201980003951.5A priority patent/CN111372913B/zh
Priority to ES19923349T priority patent/ES3047864T3/es
Priority to PL19923349.5T priority patent/PL3950659T3/pl
Priority to CA3135512A priority patent/CA3135512C/en
Priority to AU2019439692A priority patent/AU2019439692B2/en
Publication of WO2020199081A1 publication Critical patent/WO2020199081A1/zh
Priority to US17/489,630 priority patent/US11970507B2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/31—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing rings other than six-membered aromatic 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/06—Preparation of carboxylic acid amides from nitriles by transformation of cyano groups into carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
    • C07C255/41—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by carboxyl groups, other than cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the invention belongs to the field of organic synthesis, and specifically relates to a method, intermediates and applications for preparing 2-arylmalonic acid derivatives.
  • 2-Arylmalonic acid derivatives are an important class of organic compounds, which are widely used in materials, medicine, pesticides and other fields.
  • 2-phenylmalonate is an important raw material for the preparation of polymer stabilizers (CN102617450B), 2-(2,6-diethyl-4-methylphenyl)malonate diester and 2- (2,6-Diethyl-4-methylphenyl)malononitrile is an important intermediate for the preparation of the highly effective herbicide pinoxaden (WO 00/78881).
  • the first type of strategy is characterized by the CC coupling of halogenated aromatic hydrocarbons and malonic acid derivatives under the action of a catalyst to construct the framework of the target compound (Chem. Commun. 1984, 932, WO 00/78712 and WO 2004/050607 ).
  • This method often requires the use of expensive organometallic catalysts, and the catalysts are difficult to recycle and apply, and the cost is high.
  • this strategy usually uses active halogenated aromatics such as brominated or iodo aromatics as raw materials.
  • Halogenated aromatic hydrocarbons, especially halogenated aromatic hydrocarbons with different substituents at specific positions are difficult to synthesize, and are usually prepared from the corresponding aniline by diazo-halogenation reaction. During the diazo-halogenation reaction process, not only a large amount of pollution from the three wastes is produced, but also there are hidden safety hazards and halogen corrosion problems.
  • the second type of strategy is to use phenylacetic acid derivatives as raw materials to construct the target compound skeleton through condensation reaction with carbonic acid diester under the action of a strong base such as sodium hydride (Angew.Chem.,Int.Ed.2015,54(48) , 14447-14451).
  • a strong base such as sodium hydride
  • the raw material phenylacetic acid derivatives used in this method, especially the polysubstituted phenylacetic acid derivatives, are difficult to prepare.
  • strong bases such as sodium hydride (needing anhydrous and oxygen-free operation) and the hydrogen generated by the reaction are major safety hazards and are not suitable for industrial production.
  • the third strategy is based on 2-(cyclohexenylene)malonic acid derivatives as raw materials, and the products are obtained by dehydrogenation reaction at 180-200°C and the presence of a metal catalyst (WO 2018/120094).
  • the catalyst used in this method is usually a precious metal such as palladium, etc.
  • the cost of the catalyst is high, and the reaction temperature is high, which is not conducive to industrial production.
  • a method for preparing 2-arylmalonic acid derivative 3 is characterized in that: in the first step, compound 1 is used as a raw material, and intermediate 2 is obtained through an isomerization reaction, which is expressed by the following equation:
  • the intermediate 2 undergoes a halogenation reaction in the presence of a halogenating reagent and a dehydrohalogenation aromatization reaction at a certain temperature to obtain a 2-arylmalonic acid derivative 3, which is expressed as follows:
  • R 1 , R 2 , R 3 , R 4 , R 5 are independently hydrogen, C1-C10 alkyl, C6-C12 aryl, or heteroaromatic containing 1 or 2 selected from nitrogen, oxygen, and sulfur atoms base;
  • Y 1 and Y 2 are independently cyano, -COR 6 , and R 6 is hydrogen, C1-C10 alkyl, C1-C10 alkoxy, C6-C12 aryloxy, amino, C1-C10 Alkylamino, C6-C12 arylamino, bis(C1-C10 alkyl)amino, (C1-C10 alkyl)(C6-C12 aryl)amino, bis(C6-C12 aryl)amino, C6-C12 Aryl or heteroaryl groups containing one or two atoms selected from nitrogen, oxygen, and sulfur.
  • R 1 , R 2 , R 3 , R 4 , and R 5 are independently hydrogen, C1-C4 alkyl, or C6-C12 aryl.
  • Y 1 and Y 2 independently of each other are cyano, -COOMe, -COOEt or -CONH 2 .
  • the isomerization reaction described in the first step can occur in the presence of one or more of alkali such as alkali metal hydroxides, alkali metal alcoholates, alkaline earth metal hydroxides, and alkaline earth metal alcoholates, preferably It is sodium hydroxide or sodium methoxide;
  • alkali such as alkali metal hydroxides, alkali metal alcoholates, alkaline earth metal hydroxides, and alkaline earth metal alcoholates, preferably It is sodium hydroxide or sodium methoxide;
  • the molar ratio of base to compound 1 is 0.8-2.4:1, preferably 1.0-1.2:1.
  • the halogenating reagent described in the second step is one or more of halogen element such as chlorine gas or liquid bromine, hypohalous acid such as hypochlorous acid or hypobromous acid, sulfonyl halide such as sulfonyl chloride or halogenated sulfoxide such as thionyl chloride.
  • halogen element such as chlorine gas or liquid bromine
  • hypohalous acid such as hypochlorous acid or hypobromous acid
  • sulfonyl halide such as sulfonyl chloride or halogenated sulfoxide such as thionyl chloride.
  • sulfonyl halide such as sulfonyl chloride or halogenated sulfoxide such as thionyl chloride.
  • One is preferably chlorine gas, sulfuryl chloride or liquid bromine.
  • the dehydrohalogenation aromatization reaction in the second step can be carried out under the action of a catalyst, and the catalyst is one or more of alkali metal halides or alkaline earth metal halides, preferably lithium chloride or sodium chloride.
  • the molar ratio of catalyst to compound 2 is 0.005-2.4:1, preferably 0.02-0.1:1.
  • the reaction temperature of dehydrohalogenation aromatization in the second step is 0-150°C, preferably 110-150°C.
  • the first and second steps can be carried out using the "one-pot method".
  • compound 3 such as 2-(2,6-diethyl-4-methylphenyl)malononitrile can be further transformed and reacted to prepare 8-(2,6-diethyl-4) -Methylphenyl)-7-oxo-1,2,4,5-tetrahydro-7H-pyrazole[1,2-d][1,4,5]oxadiazepine -9-Pivalate (Palfentrazone).
  • the present invention has the following remarkable features:
  • reaction is safe, the conditions are mild, the yield is high, and the cost is low, which is beneficial to industrial production.
  • the raw material olefin 1 is prepared by a method known in the art (for example, WO2018/120094).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

本发明提供了一种制备2-芳基丙二酸衍生物的方法、中间体及其应用。该方法以环己二烯类化合物为原料，依次经过异构化反应和卤化试剂存在下的卤化反应和一定温度下的脱卤化氢芳构化反应得到2-芳基丙二酸衍生物3。与现有技术相比具有以下显著特征和优点：(1)反应不需要昂贵的金属催化剂；(2)反应不需要使用具有安全隐患的强碱；(3)反应安全、条件温和、收率高、成本低，有利于工业化生产。

Description

一种制备2-芳基丙二酸衍生物的方法、中间体及其应用 技术领域
本发明属于有机合成领域，具体涉及一种制备2-芳基丙二酸衍生物的方法、中间体及其应用。
背景技术
2-芳基丙二酸衍生物是一类重要的有机化合物，广泛应用于材料、医药、农药等领域。例如，2-苯基丙二酸酯是制备高分子材料稳定剂的重要原料(CN102617450B)，2-(2,6-二乙基-4-甲基苯基)丙二酸二酯和2-(2,6-二乙基-4-甲基苯基)丙二腈是制备高效除草剂唑啉草酯的重要中间体(WO 00/78881)。
目前，文献报道制备2-芳基丙二酸衍生物的策略，根据C-C的建立方式可分为三大类。
第一类策略是以卤代芳烃与丙二酸衍生物在催化剂的作用下进行C-C偶联构建目标化合物骨架的手段为特征(Chem.Commun.1984，932、WO 00/78712和WO 2004/050607)。该方法常常需要使用昂贵的有机金属催化剂，且催化剂难以回收套用，成本高。另外，该策略通常使用活泼的卤代芳烃如溴代或碘代芳烃为原料。卤代芳烃，特别是在特定位置上有不同取代基的卤代芳烃，合成困难，通常是以相应的苯胺经重氮-卤代反应制备得到。在重氮-卤代反应过程中不仅产生大量的三废污染，而且存在安全隐患和卤素腐蚀问题。
第二类策略是以苯乙酸衍生物为原料，通过与碳酸二酯在强碱如氢化钠的作用下进行缩合反应构建目标化合物骨架(Angew.Chem.,Int.Ed.2015,54(48),14447-14451)。该方法所使用的原料苯乙酸衍生物尤其是多取代苯乙酸衍生物制备困难。除此之外，该策略所使用强碱如氢化钠在使用上(需无水无氧操作)及其反应所产生的氢气都是重大的安全隐患，不适合工业化生产。
第三类策略是以2-(亚环己烯基)丙二酸衍生物为原料，通过在180-200℃和金属催化剂的存在下进行脱氢反应得到产物(WO 2018/120094)。该方法所使用的催化剂通常为贵金属例如钯等，催化剂成本高，且反应温度高，不利于工业化生产。
发明内容
针对现有技术的不足，本发明技术人员开发出了一种新的制备2-芳基丙二酸衍生物的方法，该方法安全、成本低，适合工业化生产。
一种制备2-芳基丙二酸衍生物3的方法，其特征在于：第一步，以化合物1为原料，经过异构化反应得到中间体2，用方程式表示如下：
Figure PCTCN2019080827-appb-000001
第二步，中间体2经过卤化试剂存在下的卤化反应和一定温度下的脱卤化氢芳构化反应得到2-芳基丙二酸衍生物3，用方程式表示如下：
Figure PCTCN2019080827-appb-000002
其中R 1、R 2、R 3、R 4、R 5彼此独立地为氢、C1-C10烷基、C6-C12芳基或含有1个或2个选自氮、氧、硫原子的杂芳基；
Y 1和Y 2彼此独立地为氰基、-COR 6，所述的R 6为氢、C1-C10烷基、C1-C10烷氧基、C6-C12芳基氧基、氨基、C1-C10烷基氨基、C6-C12芳基氨基、二(C1-C10烷基)氨基、(C1-C10烷基)(C6-C12芳基)氨基、二(C6-C12芳基)氨基、C6-C12芳基或含有1个或2个选自氮、氧、硫原子的杂芳基。
作为优选，R 1、R 2、R 3、R 4、R 5彼此独立地为氢、C1-C4烷基、C6-C12芳基。
作为优选，Y 1和Y 2彼此独立地为氰基、-COOMe、-COOEt或-CONH 2。
第一步中所述的异构化反应可以在碱如：碱金属氢氧化物、碱金属醇化物、碱土金属氢氧化物、碱土金属醇化物中的一种或多种的存在下发生，优选为氢氧化钠或甲醇钠；
碱与化合物1的摩尔比为0.8-2.4：1，优选为1.0-1.2：1。
第二步中所述的卤化试剂为卤素单质如氯气或液溴、次卤酸如次氯酸或次溴酸、磺酰卤如磺酰氯或卤化亚砜如氯化亚砜的一种或多种，优选为氯气、磺酰氯或液溴。
第二步中脱卤化氢芳构化反应可以在催化剂的作用下进行，所述的催化剂为碱金属卤化物或碱土金属卤化物的一种或多种，优选为氯化锂或氯化钠。
催化剂与化合物2的摩尔比为0.005-2.4：1，优选为0.02-0.1：1。
第二步所述的脱卤化氢芳构化反应温度为0-150℃，优选为110-150℃。
第一步和第二步反应可以用“一锅法”进行。
使用本发明方法制备得到化合物3，如2-(2,6-二乙基-4-甲基苯基)丙二腈可以经进一步转化和反应制备8-(2,6-二乙基-4-甲基苯基)-7-氧代-1,2,4,5-四氢-7H-吡唑[1,2-d][1,4,5]氧二氮杂
Figure PCTCN2019080827-appb-000003
-9-基特戊酸酯(唑啉草酯)。
与现有技术相比，本发明具有如下显著的特征：
(1)反应不需要昂贵的金属催化剂；
(2)反应不需要使用具有安全隐患的强碱；
(3)反应安全、条件温和、收率高、成本低，有利于工业化生产。
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。
原料烯烃1经过本领域内已知的方法制备(例如WO2018/120094)。
实施例一：2-(2,6-二乙基-4-甲基-3-烯-1-亚环己基)丙二腈的制备
向配有磁力搅拌器、温度计的250mL三口瓶中依次加入85.0g甲醇和42.9g 2-(2,6-二乙基-4-甲基-2-烯-1-亚环己基)丙二腈，搅拌混合。将反应液加热到50℃。在该温度下，向反应体系中加入10.8g甲醇钠，搅拌反应5min。反应液经过降温、酸化、萃取、浓缩和分离后得到2-(2,6-二乙基-4-甲基-3-烯-1-亚环己基)丙二腈39.0g，收率91％。 1H NMR(CDCl 3,500MHz,TMS):δ5.41(m,1H),3.23(m,1H),3.12(q,J＝7.5Hz,1H),2.40-2.35(m,1H),2.15(d,J＝17.5Hz,1H),1.73(d,J＝1.5Hz,3H),1.68-1.59(m,4H),1.13(t,J＝7.5Hz,3H),0.95(t,J＝7.6Hz,3H)。 13C NMR(CDCl 3,125MHz):δ189.5,131.7,119.0,111.9,111.7,84.8,44.0,43.0,35.9,30.5,27.4,23.3,12.8,12.2。
实施例二：2-(2,6-二乙基-4-甲基-3-烯-1-亚环己基)丙二腈的制备
向配有磁力搅拌器、温度计的250mL三口瓶中依次加入85.0g四氢呋喃和42.9g 2-(2,6-二乙基-4-甲基-2-烯-1-亚环己基)丙二腈，搅拌混合。将反应液加热 到50℃。在该温度下，向反应体系中加入11.22g氢氧化钾，搅拌反应30min。反应液经过降温、酸化、萃取、浓缩和分离后得到2-(2,6-二乙基-4-甲基-3-烯-1-亚环己基)丙二腈36.9g，收率86％。
实施例三：2-(2,6-二乙基-4-甲基苯基)丙二腈的制备
向配有磁力搅拌器、温度计和回流冷凝管的250mL三口瓶中依次加入125g氯苯和53.5g按实施例一方法制备的2-(2,6-二乙基-4-甲基-3-烯-1-亚环己基)丙二腈，搅拌混合。将反应液降温到0℃。在该温度下，向反应体系中通氯气，直到反应完全。反应液浓缩后，依次加入200mL N,N-二甲基甲酰胺和0.42g LiCl。反应液升温回流，直到反应完全。反应液经过降温、萃取、洗涤、浓缩和分离后得到产品2-(2,6-二乙基-4-甲基苯基)丙二腈47.8g，收率为90％。
实施例四：2-(2,6-二乙基-4-甲基苯基)丙二腈的制备
向配有磁力搅拌器、温度计的500mL三口瓶中依次加入125.0g N,N-二甲基甲酰胺和64.4g按实施例一方法制备的2-(2,6-二乙基-4-甲基-3-烯-1-亚环己基)丙二腈，搅拌混合。将反应液降温到0℃。在该温度下，向反应体系中通氯气，直到反应完全。反应液浓缩后加入N-甲基吡咯烷酮300mL，升温到130℃直到反应完全。将反应液降低到室温后，经过萃取、洗涤、浓缩和分离得到2-(2,6-二乙基-4-甲基苯基)丙二腈51.0g，收率为80％。
实施例五：2-(2,6-二乙基-4-甲基苯基)丙二腈的制备
向配有磁力搅拌器、温度计和回流冷凝管的250mL三口瓶中依次加入85.0g乙酸和21.5g按实施例一方法制备的2-(2,6-二乙基-4-甲基-3-烯-1-亚环己基)丙二腈，搅拌混合。将反应液升温到45℃。在该温度下，滴加17.6g液溴的60g乙酸溶液，滴完在该温度下反应2h。反应液浓缩后依次加入100mL N,N-二甲基甲酰胺和0.95gLiBr。反应液升温回流，直到反应完全。反应液经过降温、萃取、洗涤、浓缩和分离后得到产品2-(2,6-二乙基-4-甲基苯基)丙二腈10.6g，收率为50％。
实施例六：2-(2,6-二乙基-4-甲基苯基)丙二腈的制备
向配有磁力搅拌器、温度计的500mL三口瓶中依次加入170.0g乙酸和42.9g按实施例一方法制备的2-(2,6-二乙基-4-甲基-3-烯-1-亚环己基)丙二腈，搅拌混合。将反应液升温到45℃。在该温度下，滴加29.8g磺酰氯，滴完在该温度下 继续反应1h。反应液浓缩后加入N,N-二甲基甲酰胺200mL，升温到130℃，直到反应完全。将反应液降低到室温，经过萃取、洗涤、浓缩和分离得到2-(2,6-二乙基-4-甲基苯基)丙二腈30.0g，收率为70％。
实施例七：2-(2,6-二乙基-4-甲基苯基)丙二腈的制备
向配有磁力搅拌器、温度计的250mL三口瓶中依次加入125.0g氯苯和64.4g2-(2,6-二乙基-4-甲基-2-烯-1-亚环己基)丙二腈，搅拌混合。将反应液升温到50℃。在该温度下，向反应体系中加入16.2g甲醇钠，搅拌反应5min。将反应液降温到0℃。在该温度下，向反应体系中通氯气，直到反应完全。反应液浓缩后加入N-甲基吡咯烷酮300mL，升温到110℃直到反应完全。将反应液经过降温、萃取、洗涤、浓缩和分离得到2-(2,6-二乙基-4-甲基苯基)丙二腈49.0g，收率为77％。
实施例八：2-(2,6-二乙基-4-甲基苯基)丙二腈的制备
向配有磁力搅拌器、温度计和回流冷凝管的500mL三口瓶中依次加入125.0g氯苯和53.5g 2-(2,6-二乙基-4-甲基-2-烯-1-亚环己基)丙二腈，搅拌混合。将反应液升温到50℃。在该温度下，向反应体系中加入13.4g甲醇钠，搅拌反应5min。将反应液降温到0℃。在该温度下，向反应体系中通氯气，直到反应完全。将反应液经过脱溶后，依次加入200g N,N-二甲基甲酰胺和0.85g LiCl。将反应混合液升温回流，直到反应完全。反应液经过浓缩、洗涤、分离后得到产品2-(2,6-二乙基-4-甲基苯基)丙二腈47.2g，收率为89％。
实施例九：2-(2,6-二乙基-4-甲基苯基)丙二腈的制备
向配有磁力搅拌器、温度计和回流冷凝管的500mL三口瓶中依次加入125.0g氯苯和53.5g 2-(2,6-二乙基-4-甲基-2-烯-1-亚环己基)丙二腈，搅拌混合。将反应液升温到50℃。在该温度下，向反应体系中加入13.4g甲醇钠，搅拌反应5min。将反应混合液降温到0℃。在该温度下，向反应体系中通氯气，直到反应完全。反应液经过脱溶后依次加入200g N,N-二甲基甲酰胺和1.17g NaCl。反应液升温回流，直到反应完全。反应液经浓缩、洗涤、分离后得到产品2-(2,6-二乙基-4-甲基苯基)丙二腈45.6g，收率为86％。
实施例十：2-(2,6-二乙基-4-甲基苯基)丙二腈的制备
向配有磁力搅拌器、温度计的250mL三口瓶中依次加入85.0g四氢呋喃和42.9g 2-(2,6-二乙基-4-甲基-2-烯-1-亚环己基)丙二腈，搅拌混合。将反应液升温 到50℃。在该温度下，向反应体系中加入8.0g氢氧化钠，搅拌反应5min。将反应液冷却到室温，向反应体系中加入32.7g 5％次氯酸钠溶液，再向反应体系中缓慢滴加10％盐酸，调节pH为3-4。室温搅拌反应30min。反应液中加入乙酸乙酯萃取，有机相经过分液、洗涤、干燥、浓缩后加入200mL N,N-二甲基甲酰胺。升温到回流，直到反应完全。反应液经过降温、酸化、洗涤、浓缩和分离后得到2-(2,6-二乙基-4-甲基苯基)丙二腈29.5g，收率为70％。
实施例十一：2-氰基-2-(2,6-二乙基-4-甲基苯基)乙酸甲酯的制备
向配有磁力搅拌器、温度计和回流冷凝管的250mL三口瓶中依次加入60.0g乙酸乙酯和30.0g 2-氰基-2-(2,6-二乙基-4-甲基-2-烯-1-亚环己基)乙酸甲酯，搅拌混合。将反应液升温到50℃。在该温度下，向反应体系中加入6.8g甲醇钠，搅拌反应5min。将反应液降温到5℃。在该温度下向反应体系中通氯气，直到反应完全。反应液经脱溶后依次加入100mL N,N-二甲基甲酰胺和0.22gLiCl。升温回流，直到反应完全。反应液浓缩、洗涤、分离后得到2-氰基-2-(2,6-二乙基-4-甲基苯基)乙酸甲酯23.1g，收率为81％。 1H NMR(CDCl 3,500MHz,TMS):δ6.95(s,2H),3.80(s,3H),2.76-2.59(m,4H),2.32(s,3H),1.24(t,J＝9.5Hz,6H)。 13C NMR(CDCl 3,125MHz):δ166.5,142.8,139.2,128.2,123.9,115.9,53.7,36.8,26.3,21.1,15.0。
实施例十二：2-(2,6-二乙基-4-甲基苯基)丙二酰胺的制备
向配有磁力搅拌器、温度计的100mL三口瓶中依次加入3.6g水和50.0g浓硫酸，搅拌混合。将反应混合液升温到45℃。向得到的反应液中缓慢加入21.2g 2-(2,6-二乙基-4-甲基苯基)丙二腈。反应液在50℃搅拌反应5h。降温，将反应混合物到入冰水中，用乙酸乙酯萃取。合并的有机相干燥浓缩后得到2-(2,6-二乙基-4-甲基苯基)丙二酰胺24.1g，收率97％。
实施例十三：唑啉草酯的合成
向配有磁力搅拌器、温度计和回流冷凝管的250mL三口瓶中依次加入24.8g按实施例十一方法制备的2-(2,6-二乙基-4-甲基苯基)丙二酰胺、21.0g[1,4,5]-氧二氮杂
Figure PCTCN2019080827-appb-000004
二氢盐酸盐、125.0g氯苯和40.4g三乙胺。将反应液加热回流，待反应完全后将反应液冷却到室温，缓慢加入21.6g新戊酰氯，并在室温下继续搅拌反应2h。然后将该混合物用稀盐酸调节pH为3-4，乙酸乙酯萃取。合并的 有机相经过干燥、浓缩后用己烷重结晶得到产物唑啉草酯29.6g，收率为74％。 1H NMR(CDCl 3,500MHz,TMS):δ8.88(s,2H),4.28-4.26(m,2H),3.94-3.93(m,2H),3.89-3.83(m,4H),2.56-2.47(m,2H),2.45-2.40(m,2H),2.39(s,3H),1.12(t,J＝9.0Hz,3H),1.23(s,9H)。

Claims (10)

  1. 一种制备2-芳基丙二酸衍生物3的方法，其特征在于：第一步，以化合物1为原料，经过异构化反应得到中间体2，用方程式表示如下：
    Figure PCTCN2019080827-appb-100001
    第二步，中间体2经过卤化试剂存在下的卤化反应和一定温度下的脱卤化氢芳构化反应得到2-芳基丙二酸衍生物3，用方程式表示如下：
    Figure PCTCN2019080827-appb-100002
    其中R 1、R 2、R 3、R 4、R 5彼此独立地为氢、C1-C10烷基、C6-C12芳基或含有1个或2个选自氮、氧、硫原子的杂芳基；
    Y 1和Y 2彼此独立地为氰基、-COR 6，所述的R 6为氢、C1-C10烷基、C1-C10烷氧基、C6-C12芳基氧基、氨基、C1-C10烷基氨基、C6-C12芳基氨基、二(C1-C10烷基)氨基、(C1-C10烷基)(C6-C12芳基)氨基、二(C6-C12芳基)氨基、C6-C12芳基或含有1个或2个选自氮、氧、硫原子的杂芳基。
  2. 根据权利要求1所述的方法，其特征在于，R 1、R 2、R 3、R 4、R 5彼此独立地为氢、C1-C4烷基、C6-C12芳基；Y 1和Y 2彼此独立地为氰基、-COOMe、-COOEt或-CONH 2。
  3. 根据权利要求1所述的方法，其特征在于，第一步中所述的异构化反应在碱的存在下进行，所述的碱为碱金属氢氧化物、碱金属醇化物、碱土金属氢氧化物、碱土金属醇化物中的一种或多种；碱与化合物1的摩尔比为0.8-2.4：1；第二步中所述的卤化试剂为卤素单质、次卤酸、磺酰卤或卤化亚砜的一种或多种；第二步中脱卤化氢芳构化反应在催化剂的作用下进行，所述的催化剂为碱金属卤化物或碱土金属卤化物的一种或多种；催化剂与化合物2的摩尔比为0.005-2.4：1；第二步所述的脱卤化氢芳构化反应温度为0-150℃。
  4. 根据权利要求3所述的方法，其特征在于，第一步中所述的碱优选为氢氧化 钠或甲醇钠；碱与化合物1的摩尔比优选为1.0-1.2：1；第二步中所述的卤化试剂优选为氯气、磺酰氯或液溴；第二步中脱卤化氢芳构化反应催化剂优选为氯化锂或氯化钠；催化剂与化合物2的摩尔比优选为0.02-0.1：1；第二步所述的脱卤化氢芳构化反应温度优选为110-150℃。
  5. 根据权利要求1-4所述的任一方法，其特征在于，第一步和第二步反应可以用“一锅法”进行。
  6. 一种中间体2，其结构式表示如下：
    Figure PCTCN2019080827-appb-100003
    其中R 1、R 2、R 3、R 4、R 5彼此独立地为氢、C1-C10烷基、C6-C12芳基或含有1个或2个选自氮、氧、硫原子的杂芳基；
    Y 1和Y 2彼此独立地为氰基、-COR 6，所述的R 6为氢、C1-C10烷基、C1-C10烷氧基、C6-C12芳基氧基、氨基、C1-C10烷基氨基、C6-C12芳基氨基、二(C1-C10烷基)氨基、(C1-C10烷基)(C6-C12芳基)氨基、二(C6-C12芳基)氨基、C6-C12芳基或含有1个或2个选自氮、氧、硫原子的杂芳基。
  7. 根据权利要求6所述的化合物，其特征在于，R 1、R 2、R 3、R 4、R 5彼此独立地是氢、C1-C4烷基、C6-C12芳基；Y 1和Y 2彼此独立地是氰基、-COOMe、-COOEt或-CONH 2。
  8. 根据权利要求7所述的化合物，其特征在于，R 1、R 3为氢，R 2为甲基，R 4、R 5为乙基；Y 1和Y 2为氰基。
  9. 根据权利要求1-4任一方法制备的2-芳基丙二酸衍生物3的应用，其特征在于化合物3进一步反应制备8-(2,6-二乙基-4-甲基苯基)-7-氧代-1,2,4,5-四氢-7H-吡唑[1,2-d][1,4,5]氧二氮杂
    Figure PCTCN2019080827-appb-100004
    -9-基特戊酸酯。
  10. 根据权利要求6-8所述的中间体2，其特征在于中间体2应用于8-(2,6-二乙基-4-甲基苯基)-7-氧代-1,2,4,5-四氢-7H-吡唑[1,2-d][1,4,5]氧二氮杂
    Figure PCTCN2019080827-appb-100005
    -9-基特戊酸酯的制备。
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CN111372913A (zh) 2020-07-03
AU2019439692A1 (en) 2021-11-04
CA3135512A1 (en) 2020-10-08
ES3047864T3 (en) 2025-12-05

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