WO2018120094A1 - 一种制备2-(亚环己烯基)丙二酸衍生物的方法及其应用 - Google Patents

一种制备2-(亚环己烯基)丙二酸衍生物的方法及其应用 Download PDF

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WO2018120094A1
WO2018120094A1 PCT/CN2016/113671 CN2016113671W WO2018120094A1 WO 2018120094 A1 WO2018120094 A1 WO 2018120094A1 CN 2016113671 W CN2016113671 W CN 2016113671W WO 2018120094 A1 WO2018120094 A1 WO 2018120094A1
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alkyl
aryl
compound
amino
catalyst
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French (fr)
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孙殷卫
王忠元
张盼
陈邦池
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泸州东方农化有限公司
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Priority to CA3048088A priority Critical patent/CA3048088C/en
Priority to EP16925214.5A priority patent/EP3564208B1/en
Priority to PL16925214T priority patent/PL3564208T3/pl
Priority to PCT/CN2016/113671 priority patent/WO2018120094A1/zh
Priority to CN201710005064.4A priority patent/CN108264469B/zh
Publication of WO2018120094A1 publication Critical patent/WO2018120094A1/zh
Priority to US16/439,679 priority patent/US10836777B2/en

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    • 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
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    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
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    • C07C13/02—Monocyclic hydrocarbons or acyclic hydrocarbon derivatives thereof
    • C07C13/16—Monocyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with a six-membered ring
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    • 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
    • C07C255/33—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 with cyano groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by saturated carbon chains
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    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/317—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/34—Esters of acyclic saturated polycarboxylic acids having an esterified carboxyl group bound to an acyclic carbon atom
    • C07C69/38—Malonic acid esters
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    • 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 in particular relates to a novel method for preparing a 2-(cyclohexylene)malonic acid derivative and an application thereof.
  • the 2-(cyclohexylene)malonic acid derivative is a class of organic compounds having a multifunctional group.
  • There are currently two methods for preparing such compounds J. Mol. Cata. A. Chem. 2003, 195 (1-2), 263; Organometallics 1989, 8 (10), 2474).
  • the first method for preparing a 2-(cyclohexylene)malonic acid derivative is based on a cyclohexenone derivative (J. Mol. Cata. A. Chem. 2003, 195 (1-2), 263 ).
  • the cyclohexenone derivative and the malonic acid derivative are subjected to Knoevenagel condensation reaction to obtain a 2-(cyclohexylene)malonic acid derivative.
  • This method requires a highly active cyclohexenone.
  • the Knoevenagel condensation reaction yield is extremely low (3%) due to its large steric hindrance.
  • the second method for preparing a 2-(cyclohexylene)malonic acid derivative is based on a cyclohexadienyl cobalt complex (Organometallics 1989, 8(10), 2474).
  • the cyclohexene cobalt complex is reacted with dimethyl malonate at -78 ° C under the action of a strong base LDA to obtain dimethyl 2-(cyclohexenylene)malonate.
  • the reaction can obtain the target product in a moderate yield, but requires the use of a large amount of metal reagents and ultra-low temperature operation, resulting in high cost, high pollution, and unsuitable for industrial production.
  • a first object of the present invention is to provide a process for the efficient synthesis of 2-(cyclohexylene)malonic acid derivatives, in particular 2-(2,6-disubstituted cyclohexene) having a large steric hindrance Synthesis of a malonic acid derivative.
  • a second object of the present invention is to develop the use of a 2-(cyclohexylene)malonic acid derivative, particularly a 2-(2,6-disubstituted cyclohexenylene)propane having a large steric hindrance.
  • the use of acid derivatives in organic synthesis is to develop the use of a 2-(cyclohexylene)malonic acid derivative, particularly a 2-(2,6-disubstituted cyclohexenylene)propane having a large steric hindrance.
  • the present inventors have succeeded in developing a 2-(cyclohexylene)malonic acid derivative, especially 2-(2,6-disubstituted cyclohexenylene) propane, through continuous thinking and exploration.
  • a method of acid derivatives At the same time, the inventors of the present invention have further studied and successfully applied the novel method and intermediate to the synthesis of a 2-arylmalonic acid derivative and a corresponding drug such as the herbicide oxazolin.
  • a novel process for synthesizing 2-(cyclohexylene)malonic acid derivatives provided by the first object of the present invention is based on olefin (1).
  • Compound (1) undergoes a cyclization reaction with compound (2) under the action of catalyst A.
  • Intermediate (3) gives 2-(cyclohexylene)malonic acid derivative (4).
  • the specific reaction is as follows:
  • R 1 , R 2 , R 3 , R 4 and R 5 are each independently hydrogen, C1-C10 alkyl, C6-C12 aryl or heteroaryl containing one or two selected from nitrogen, oxygen and sulfur atoms. base;
  • X 1 and X 2 are each independently cyano, -COR 6 , and R 6 is hydrogen, C1-C10 alkyl, C1-C10 alkoxy, C6-C12 aryloxy, C1-C10 alkyl Amino, C6-C12 arylamino, bis(C1-C10 alkyl)amino, (C1-C10 alkyl)(C6-C12 aryl)amino, di(C6-C12 aryl)amino, C6-C12 aryl Or contains one or two heteroaryl groups selected from nitrogen, oxygen, and sulfur atoms.
  • the present inventors have also found that the compound (1) and the compound (2) undergo a cyclization reaction in the presence of the catalyst A, and the intermediate (3) can be isolated, and the "one-pot” reaction can be carried out more directly to obtain a 2- (a ring).
  • the hexenyl) malonic acid derivative (4) is represented by the following reaction formula:
  • R 1 , R 2 , R 3 , R 4 and R 5 are each independently hydrogen, C1-C10 alkyl, C6-C12 aryl or heteroaryl containing one or two selected from nitrogen, oxygen and sulfur atoms. base;
  • X 1 and X 2 are each independently cyano, -COR 6 , and R 6 is hydrogen, C1-C10 alkyl, C1-C10 alkoxy, C6-C12 aryloxy, C1-C10 alkyl Amino, C6-C12 arylamino, bis(C1-C10 alkyl)amino, (C1-C10 alkyl)(C6-C12 aryl)amino, di(C6-C12 aryl)amino, C6-C12 aryl Or contains one or two heteroaryl groups selected from nitrogen, oxygen, and sulfur atoms.
  • the molar ratio of the compound (1) to the compound (2) is from 0.8 to 2.0:1, preferably from 1.0 to 1.5:1.
  • the catalyst A of the cyclization reaction is an organic acid including, but not limited to, acetic acid, propionic acid, TsOH, and the organic base includes but not limited to Et 3 N, DABCO, TBU, pyrrolidine, piperidine, and the inorganic base includes but is not limited to carbonic acid. Potassium, sodium carbonate, potassium hydroxide, sodium methoxide, sodium hydrogen, and mixtures of one or more of them. It is preferably Et 3 N or DABCO.
  • the molar ratio of the catalyst A to the compound (2) is from 0.005 to 2.4:1, preferably from 0.1 to 1.0:1.
  • the solvent for the cyclization reaction is water or an organic solvent
  • the organic solvent is an aromatic hydrocarbon such as benzene, toluene, chlorobenzene, an alcohol such as methanol, ethanol, an ether such as diethyl ether, tetrahydrofuran, a nitrile such as Acetonitrile, esters such as ethyl acetate, amides such as N,N-dimethylformamide, sulfone/sulfoxides such as dimethyl sulfoxide.
  • the reaction solvent is preferably toluene.
  • the cyclization reaction can also be carried out in the absence of a solvent.
  • the temperature of the cyclization reaction is from 0 to 150 ° C, preferably from 80 to 130 ° C.
  • a second object of the present invention is to provide a process for producing a 2-arylmalonic acid derivative from a 2-(cyclohexylene)malonic acid derivative.
  • the aromatization reaction of the compound (4) under the action of the catalyst B gives the 2-arylmalonic acid derivative 5, which is represented by the following reaction formula:
  • R 1 , R 2 , R 3 , R 4 and R 5 are each independently hydrogen, C1-C10 alkyl, C6-C12 aryl or heteroaryl containing one or two selected from nitrogen, oxygen and sulfur atoms. base;
  • X 1 and X 2 are each independently cyano, -COR 6 , and R 6 is hydrogen, C1-C10 alkyl, C1-C10 alkoxy, C6-C12 aryloxy, C1-C10 alkyl Amino, C6-C12 arylamino, bis(C1-C10 alkyl)amino, (C1-C10 alkyl)(C6-C12 aryl)amino, di(C6-C12 aryl)amino, C6-C12 aryl Or contains one or two heteroaryl groups selected from nitrogen, oxygen, and sulfur atoms.
  • the catalyst B is a metal catalyst, preferably Pd/C; the aromatization reaction temperature is 100-400 ° C, preferably 180-220 ° C; the aromatization reaction is solvent-free or the alcohol or ether having a boiling point higher than 150 ° C
  • the ester, amide and aromatic hydrocarbon are solvents.
  • the present invention provides a novel process for the preparation of 2-(cyclohexylene)malonic acid derivatives and their use.
  • the method adopts a completely different synthesis strategy: the prior art uses a raw material of a cyclohexane skeleton to prepare a 2-(cyclohexylene)malonic acid derivative, and the present invention uses a non-cyclohexane.
  • the starting material of the skeleton is a 2-(cyclohexylene)malonic acid derivative.
  • the method has the following special advantages: (1) it is very efficient to synthesize a target product having a large steric hindrance, such as a 2-(2,6-disubstituted cyclohexenylene)malonic acid derivative; 2) The reaction yield is high, the conditions are mild, and the three wastes are small, which is beneficial to industrial production. More importantly, the present invention opens up 2-(cyclohexylene)malonic acid derivatives in organic The use of the above, in particular in the synthesis of 2-arylmalonic acid derivatives and corresponding drugs such as the herbicide oxazolin.
  • the starting olefin 1 can be conveniently purchased commercially or prepared from aldehydes and ketones by methods well known in the art (for example, J. Am. Chem. Soc. 136 (28), 2014, 9918-9921; Tetrahedron, 70 (13), 2014. , 2257-2263);
  • Starting material 2 can be conveniently prepared from ketones and malonic acid derivatives by methods well known in the art (e.g., Eur. J. Med. Chem. 85, 2014, 450-457; WO 2011098398).
  • Example 8 2-(2,6-Diethyl-5-phenyl-2-ene-1-cyclohexylene)malononitrile and 2-(2,6-diethyl-5-phenyl- Preparation of 3-ene-1-cyclohexylene)malononitrile

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Abstract

一种2-(亚环己烯基)丙二酸衍生物的制备方法及其应用，以烯烃和2-取代丙二酸衍生物为原料，二者在催化剂存在下发生环合反应得到2-(亚环己烯基)丙二酸衍生物，该方法具有以下特点：（1）能非常高效的合成2-(2,6-二取代亚环己烯基)丙二酸衍生物；(2)反应收率高，条件温和，三废少，有利于工业化生产。更重要的是，所述2-(亚环己烯基)丙二酸衍生物在有机合成上的应用，特别是在2-芳基丙二酸衍生物和相应药物如除草剂唑啉草酯的合成上的应用。

Description

一种制备2-(亚环己烯基)丙二酸衍生物的方法及其应用 技术领域
本发明属于有机合成领域，具体的涉及一种制备2-(亚环己烯基)丙二酸衍生物的新方法及其应用。
背景技术
2-(亚环己烯基)丙二酸衍生物是一类具有多功能团的有机化合物。目前制备这类化合物的方法有两种(J.Mol.Cata.A.Chem.2003,195(1-2),263；Organometallics 1989,8(10),2474)。
第一种制备2-(亚环己烯基)丙二酸衍生物的方法以环己烯酮衍生物为原料(J.Mol.Cata.A.Chem.2003,195(1-2),263)。环己烯酮衍生物与丙二酸衍生物经过Knoevenagel缩合反应得到2-(亚环己烯基)丙二酸衍生物。该方法需要活性高的环己烯酮。对于活性低6-位取代的环己烯酮原料，由于空间位阻大，其Knoevenagel缩合反应产率极低(3％)。可想而知，如果用该方法使用空间位阻更大的2,6-二取代环己烯酮原料来制备2-(2,6-二取代亚环己烯基)丙二酸衍生物将是一个极大的挑战。
第二种制备2-(亚环己烯基)丙二酸衍生物的方法以环己二烯钴络合物为原料(Organometallics 1989,8(10),2474)。环己烯钴络合物在强碱LDA作用下与丙二酸二甲酯在-78℃下反应得2-(亚环己烯基)丙二酸二甲酯。该反应能以中等的收率的得到目标产物，但是需要使用大量金属试剂和超低温操作，导致该方法成本高，污染大，不适合工业化生产。
由于有效合成这类具有多功能团的2-(亚环己烯基)丙二酸衍生物方法的缺乏，这类化合物在有机合成特别是药物合成中的应用受到极大的限制。
本发明的第一个目的是提供一种高效合成2-(亚环己烯基)丙二酸衍生物的方法，特别是空间位阻大的2-(2,6-二取代亚环己烯基)丙二酸衍生物的合成。
本发明的第二个目的是开拓2-(亚环己烯基)丙二酸衍生物的应用，特别是空间位阻大的2-(2,6-二取代亚环己烯基)丙二酸衍生物在有机合成中的应用。
本发明技术人员通过不断思考和探索，成功地开发了一条制备2-(亚环己烯基)丙二酸衍生物，特别是2-(2,6-二取代亚环己烯基)丙二酸衍生物的方法。同时本发明技术人员进一步深入研究，将这新方法和中间体成功地应用在2-芳基丙二酸衍生物和相应药物如除草剂唑啉草酯的合成上。
发明内容
本发明第一目的所提供的一种合成2-(亚环己烯基)丙二酸衍生物的新方法，是以烯烃(1)为原料。化合物(1)在催化剂A作用下与化合物(2)发生环合反应经中间体(3)得到2-(亚环己烯基)丙二酸衍生物(4)，具体反应如下所示：
Figure PCTCN2016113671-appb-000001
其中R1、R2、R3、R4、R5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；
X1和X2彼此独立地为氰基、-COR6，所述的R6为氢、C1-C10烷基、C1-C10烷氧基、C6-C12芳基氧基、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。
本发明技术人员同时也发现化合物(1)与化合物(2)在催化剂A存在下发生环合反应，可以不分离中间体(3)，更直接地“一锅法”反应得到2-(亚环己烯基)丙二酸衍生物(4)，用反应式表示如下：
Figure PCTCN2016113671-appb-000002
其中R1、R2、R3、R4、R5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；
X1和X2彼此独立地为氰基、-COR6，所述的R6为氢、C1-C10烷基、C1-C10烷氧基、C6-C12芳基氧基、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。
化合物(1)与化合物(2)的摩尔比为0.8-2.0：1，优选为1.0-1.5：1。
所述的环合反应的催化剂A为有机酸包括但不限于乙酸、丙酸、TsOH，有机碱包括但不限于Et3N、DABCO、TBU、吡咯烷、哌啶，无机碱包括但不限于碳酸钾、碳酸钠、氢氧化钾、甲醇钠、钠氢以及它们中一种或多种的混合物。优选为Et3N、DABCO。
所述的催化剂A与化合物(2)的摩尔比为0.005-2.4：1，优选为0.1-1.0：1。
所述的环合反应的溶剂为水或有机溶剂以及它们的混合物，所述的有机溶剂为芳烃如苯、甲苯、氯苯，醇类如甲醇、乙醇，醚类如乙醚、四氢呋喃，腈类如乙腈，酯类如乙酸乙酯，酰胺如N,N-二甲基甲酰胺，砜/亚砜类如二甲基亚砜。反应溶剂优选为甲苯。
所述的环合反应也可以在无溶剂的条件下进行。
所述的环合反应的温度为0-150℃，优选为80-130℃。
本发明第二目的是提供一种从2-(亚环己烯基)丙二酸衍生物制备2-芳基丙二酸衍生物的方法。化合物(4)在催化剂B的作用下发生芳构化反应得2-芳基丙二酸衍生物5，用反应式表示如下：
Figure PCTCN2016113671-appb-000003
其中R1、R2、R3、R4、R5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；
X1和X2彼此独立地为氰基、-COR6，所述的R6为氢、C1-C10烷基、C1-C10烷氧基、C6-C12芳基氧基、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。
所述的催化剂B为金属催化剂，优选为Pd/C；芳构化反应温度为100-400℃，优选为180-220℃；芳构化反应无溶剂或者以沸点高于150℃的醇、醚、酯、酰胺、芳烃为溶剂。
本发明提供了一种新的制备2-(亚环己烯基)丙二酸衍生物的方法及其应用。该方法与现有技术相比采取完全不同的合成策略：现有技术均采用环己烷骨架的原料制备2-(亚环己烯基)丙二酸衍生物，本发明则以非环己烷骨架的原料制备2-(亚环己烯基)丙二酸衍生物。不仅如此，该方法还具有以下特殊优点：(1)能非常高效地合成空间位阻大的目标产物，如2-(2,6-二取代亚环己烯基)丙二酸衍生物；(2)反应收率高，条件温和，三废少，有利于工业化生产。更重要的是，本发明开拓了2-(亚环己烯基)丙二酸衍生物在有机合 成上的应用，特别是在2-芳基丙二酸衍生物和相应药物如除草剂唑啉草酯的合成上的应用。
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可以方便地商业购买或者由醛和酮经过本领域内公知的方法制备(例如J.Am.Chem.Soc.136(28),2014,9918-9921；Tetrahedron,70(13),2014,2257-2263)；原料2可以方便地由酮和丙二酸衍生物经过本领域内公知的方法制备(例如Eur.J.Med.Chem.85,2014,450-457；WO 2011098398)。
2-(4-亚庚基)丙二腈的制备
将4-庚酮65.0g(0.569mol)，丙二腈39.4g(0.569mol)，乙酸铵6.6g(0.086mol)，乙酸10.3g(0.171mol)，甲苯依次加入反应瓶中，回流分水反应，反应完全后，降温，水洗，浓缩、纯化得到产品2-(4-亚庚基)丙二腈84.9g，收率92％。1H NMR(CDCl3,500MHz,TMS):δ2.57-2.53(m,4H),1.64-1.60(m,4H),1.02(t,J＝7.5Hz,6H)。13C NMR(CDCl3,125MHz):δ186.08,111.88,85.91,37.47,21.44,12.81。
2-(1-(4-甲氧基苯基)-2-亚丙基)丙二腈的制备
将1-(4-甲氧基苯基)-2-丙酮82.1g(0.50mol)，丙二腈33.0g(0.50mol)，乙酸铵5.8g(0.075mol)，乙酸9.0g(0.15mol)，甲苯依次加入反应瓶中，回流分水反应，反应完全后，降温，水洗，浓缩、纯化到产品2-(1-(4-甲氧基苯基)-2-亚丙基)丙二腈100.8g，收率95％。1H NMR(CDCl3,500MHz,TMS):δ7.12(d,J＝11Hz,2H),6.88(d,J＝11Hz,2H),3.80(s,5H),2.17(s,3H)。13C NMR(CDCl3,125MHz):δ180.2,159.2,129.9,126.1,114.5,112.0,111.7,85.6,55.2,42.6,22.0。
实施例一：2-(2,6-二乙基-4-甲基-2-烯-1-亚环己基)丙二腈的制备
将2-(4-亚庚基)丙二腈24.3g(0.15mol)，2-甲基丙烯醛10.5g(0.15mol)和三乙胺15.2g(0.15mol)依次加入甲苯中，升温回流反应直到反应完全。降温，1N稀盐酸洗涤，干燥，浓缩、纯化得到产品2-(2,6-二乙基-4-甲基-2-烯-1-亚环己基)丙二腈25.7g，收率为80％。1H NMR(CDCl3,500MHz,TMS):δ6.14-6.14(m,1H),3.08-3.04(m,1H),2.82-2.75(m,1H),2.57-2.46(m,2H),2.04-2.01(m,1H),1.56-1.51(m,2H),1.48-1.41(m,1H),1.12-1.01(m,6H),1.00-0.98(m,3H)。13C NMR(CDCl3,125MHz):δ175.12,148.74,134.78,113.99,113.74,43.75,34.75,28.13,16.55,15.52,20.91,13.59,11.98。
实施例二：2-(2,6-二乙基-4-甲基-2-烯-1-亚环己基)丙二腈与2-(2,6-二乙基-4-甲基-3-烯-1-亚 环己基)丙二腈的制备
将2-(4-亚庚基)丙二腈25.0g(0.154mol)，2-甲基丙烯醛14.0g(0.200mol)和三乙胺15.6g(0.154mol)依次加入甲苯中，升温回流反应直到反应完全。降温，1N稀盐酸洗涤，干燥，浓缩溶剂得到2-(2,6-二乙基-4-甲基-2-烯-1-亚环己基)丙二腈与2-(2,6-二乙基-4-甲基-3-烯-1-亚环己基)丙二腈的混合物30.4g。GC-MS分析二者的比例为91：9。
实施例三：2-(2,6-二乙基-3-羟基-4-甲基-1-亚环己基)丙二腈的制备
将2-(4-亚庚基)丙二腈3.2g(0.02mol)，2-甲基丙烯醛1.4g(0.02mol)和三乙胺2.0g(0.02mol)依次加入甲苯中，50℃下反应5h后，将反应液降温，1N稀盐酸洗涤，干燥，浓缩、纯化得到产品2-(2,6-二乙基-3-羟基-4-甲基-1-亚环己基)丙二腈4.4g，收率为95％。1H NMR(CDCl3,500MHz,TMS):δ3.82(s,1H),3.11-3.08(m,1H),3.03-2.99(m,1H),2.06-2.05(m,1H),1.87-1.81(m,2H),1.73-1.65(m,2H),1.62-1.52(m,3H),1.08-1.02(m,9H)。13C NMR(CDCl3,125MHz):δ188.8,112.2,112.0,87.1,75.1,53.1,44.0,30.9,28.4,26.4,26.0,17.4,12.9。
实施例四：2-(2,6-二乙基-4-甲基-2-烯-1-亚环己基)丙二腈的制备
将实施例三制备的2-(2,6-二乙基-3-羟基-4-甲基-1-亚环己基)丙二腈2.3g(0.01mol)和三乙胺1.0g(0.01mol)的甲苯溶液在回流条件下反应，反应完全后，降温，1N稀盐酸洗涤，干燥，浓缩、纯化得到产品2-(2,6-二乙基-4-甲基-2-烯-1-亚环己基)丙二腈1.8g，收率为84％。
实施例五：2-(2,6-二乙基-4-甲基-2-烯-1-亚环己基)丙二腈的制备
将2-(4-亚庚基)丙二腈32.4g(0.20mol)，2-甲基丙烯醛14.0g(0.20mol)和三乙烯二胺2.2g(0.02mol)依次加入甲苯中，在130℃下反应。反应完全后，降温，1N稀盐酸洗涤，乙酸乙酯萃取，干燥，浓缩、纯化得到产品2-(2,6-二乙基-4-甲基-2-烯-1-亚环己基)丙二腈39.4g，收率为92％。
实施例六：2-(2,6-二乙基-4-甲基-2-烯-1-亚环己基)丙二腈的制备
在0～5℃下，将2-(4-亚庚基)丙二腈48.7g(0.30mol)的THF溶液滴加到NaH 12.4g(0.31mol)的THF溶液中，滴完升到室温反应20min，然后滴加2-甲基丙烯醛27.3g(0.39mol)的THF溶液，滴完回流反应。反应完全后，降温，1N稀盐酸淬灭反应，乙酸乙酯萃取，干燥，浓缩、纯化得到产品2-(2,6-二乙基-4-甲基-2-烯-1-亚环己基)丙二腈13.5g。
实施例七：2-(2,6-二乙基-4-甲基-2-烯-1-亚环己基)丙二腈的制备
将2-(4-亚庚基)丙二腈25.0g(0.154mol)，2-甲基丙烯醛14.0g(0.20mol)和三乙烯二胺3.4g(0.031mol)依次加入反应瓶中，在80℃下反应。反应完全后，降温，加入乙酸乙酯溶解，1N稀盐酸洗涤，干燥，浓缩蒸馏得到产品21.4g。
实施例八：2-(2,6-二乙基-5-苯基-2-烯-1-亚环己基)丙二腈和2-(2,6-二乙基-5-苯基-3-烯-1-亚环己基)丙二腈的制备
将2-(4-亚庚基)丙二腈64.9g(0.40mol)，肉桂醛68.7g(0.52mol)和三乙胺40.5g(0.40mol)依次加入甲苯中，升温回流反应直到反应完全。降温，1N稀盐酸洗涤，干燥，浓缩得到2-(2,6-二乙基-5-苯基-2-烯-1-亚环己基)丙二腈和2-(2,6-二乙基-5-苯基-3-烯-1-亚环己基)丙二腈的混合物83.4g。GC-MS分析二者的比例为94：6。纯化得到产品2-(2,6-二乙基-5-苯基-2-烯-1-亚环己基)丙二腈77.4g，收率为70％。1H NMR(CDCl3,500MHz,TMS):δ7.31-7.28(m,2H),7.26-7.23(m,1H),7.08-7.06(m,2H),6.36-6.25(m,1H),3.31(d,1H,J＝5.0Hz),3.21-3.18(m,1H),2.86-2.77(m,2H),2.67(dd,1H,J1＝20.5Hz,J2＝4.0Hz),2.59-2.51(m,1H),1.77-1.70(m,1H),1.65-1.59(m,1H),1.12(t,3H,J＝7.5Hz),1.05(t,3H,J＝7.5Hz)。13C NMR(CDCl3,125MHz):δ173.0,142.4,139.7,136.7,128.7,127.0,126.5,113.3,81.0,51.5,41.7,28.0,27.6,26.7,13.5,12.1。
实施例九：2-(6-(4-甲氧基苯基)-4-甲基-2-烯-1-亚环己基)丙二腈的制备
将2-(1-(4-甲氧基苯基)-2-亚丙基)丙二腈31.8g(0.15mol)，2-甲基丙烯醛14.0g(0.20mol)和三乙胺15.2g(0.15mol)依次加入甲苯中，升温回流反应直到反应完全。降温，1N稀盐酸洗涤，干燥，浓缩、纯化到产品2-(6-(4-甲氧基苯基)-4-甲基-2-烯-1-亚环己基)丙二腈34.9g，收率为93％。1H NMR(CDCl3,500MHz,TMS):δ9.02-7.00(m,2H),6.94(dd,J1＝10.0Hz,J2＝2.5Hz,1H),6.85-6.84(m,2H),6.67(d,J＝10.0Hz,1H),4.27-4.25(m,1H),3.78(s,3H),2.39-2.31(m,1H),2.08-2.04(m,1H),1.76-1.71(m,1H),1.10(d,J＝7.5Hz,3H)。13C NMR(CDCl3,125MHz):δ170.7,158.8,155.3,130.4,130.3,128.1,124.5,114.3,114.1,112.2,111.9,82.1,55.2,43.4,37.7,27.5,19.9。
实施例十：2-(2,6-二苯基-4-甲基-2-烯-1-亚环己基)丙二腈的制备
将2-(2,6-二苯基亚丙基)丙二腈77.5g(0.30mol)，2-甲基丙烯醛23.1g(0.33mol)和三乙胺30.3g(0.30mol)依次加入甲苯中，升温回流反应直到反应完全。降温，1N稀盐酸洗涤，干燥，浓缩、纯化得到产品2-(2,6-二苯基-4-甲基-2-烯-1-亚环己基)丙二腈91.2g，收率为98％。1H NMR(CDCl3,500MHz,TMS):δ7.46-7.24(m,1H),6.38-6.37(m,1H),4.54-4.52(m,1H),2.57-2.51(m,1H),2.36-2.30(m,1H),1.95-1.88(m,1H),1.17(d,J＝9.0Hz,3H)。13C NMR(CDCl3,125MHz):δ169.9,153.1,138.4,137.8,137.4,129.1,129.0,128.8,127.6,127.0,113.6,110.9,83.9,45.9,37.2,28.5,20.4
实施例十一：2-(3-甲基-2-烯-1-亚环己基)丙二腈的制备
将2-(2-亚丙基)丙二腈26.5g(0.25mol)，乙烯基甲基酮22.8g(0.32mol)和三乙胺25.2g(0.25mol)依次加入甲苯中，升温回流反应直到反应完全。降温，1N稀盐酸洗涤，干燥，浓缩、纯化得到产品2-(3-甲基-2-烯-1-亚环己基)丙二腈26.1g。1H NMR(CDCl3,500MHz,TMS):δ6.61-6.61(m,1H),2.72(t,J＝6.5Hz,2H),2.34(t,J＝7.5Hz,2H),2.07-2.07(m,3H),1.91-1.85(m,2H)。13C NMR(CDCl3,125MHz):δ170.7,162.1,121.5,113.0,112.3,31.1,28.9,25.2,21.2。
实施例十二：2-氰基-2-(2,6-二乙基-4-甲基-1-亚环己烯基)乙酸甲酯的制备
将2-氰基-3-丙基-2-烯己酸甲酯58.6g(0.300mol)，2-甲基丙烯醛27.3g(0.390mol)和三乙胺30.3g(0.300mol)依次加入甲苯中，升温回流反应直到反应完全。降温，1N稀盐酸洗涤，干燥，浓缩得到2-氰基-2-(2,6-二乙基-4-甲基-1-亚环己烯基)乙酸甲酯62.8g，收率为84％。1H NMR(CDCl3,500MHz,TMS):δ6.02-5.90(m,1H),3.83-3.82(m,3H),3.63-3.07(m,1H),2.91-2.44(m,2H),2.22-1.95(m,2H),1.58-1.42(m,3H),1.08-1.04(m,4H),1.00-0.90(m,5H)。
实施例十三：2-(3-甲基-2-烯-1-亚环己基)丙二酸二乙酯的制备
将2-(2-亚丙基)丙二酸二乙酯120.1g(0.60mol)，乙烯基甲基酮54.7g(0.78mol)和三乙胺60.6g(0.60mol)依次加入甲苯中，升温回流反应直到反应完全。降温，1N稀盐酸洗涤，干燥，浓缩蒸馏得到产品2-(3-甲基-2-烯-1-亚环己基)丙二酸二乙酯60.5g。1H NMR(CDCl3,500MHz,TMS):δ6.61-6.60(m,1H),4.28-4.18(m,4H),2.65(t,J＝8.0Hz,2H),2.15(t,J＝8.0Hz,2H),1.898(d,J＝1.5Hz,1H),1.80-1.73(m,2H),1.32-1.26(m,6H)。13C NMR(CDCl3,125MHz):δ165.8,165.8,151.9,151.6,121.4,118.7,60.6,60.4,30.6,27.1,24.8,21.8,13.9。
实施例十四：2-(2,6-二乙基-4-甲基苯基)丙二腈的制备
将2-(2,6-二乙基-4-甲基-2-烯-1-亚环己基)丙二腈214.1g(1mol)和Pd/C 2.2g在氮气气氛中加热到180℃，反应完全后，降温，加入乙酸乙酯，过滤除去催化剂，少量溶剂洗涤催化剂。有机相干燥、浓缩结晶得到2-(2,6-二乙基-4-甲基苯基)丙二腈188.9g，收率89％。
实施例十五：2-(2,6-二苯基-4-甲基苯基)丙二腈的制备
将2-(2,6-二苯基-4-甲基-2-烯-1-亚环己基)丙二腈15.5g(0.05mol)和Pd/C 0.8g加热到220℃反应，反应完全后，降温，过滤除去催化剂，少量溶剂洗涤催化剂。浓缩得到产品2-(2,6-二苯基-4-甲基苯基)丙二腈10.9g，收率71％。1H NMR(CDCl3,500MHz,TMS):δ7.54-7.46(m,10H),7.21(s,2H),5.11(s,1H),2.44(s,3H)。13C NMR(CDCl3,125MHz):δ143.4,140.2,138.8,131.6,129.4,129.0,128.7,119.7,112.2,24.4,21.0。
实施例十六：2-(3-甲基苯基)丙二酸二乙酯的制备
将2-(3-甲基-2-烯-1-亚环己基)丙二酸二乙酯20.0g(0.08mol)和Pt/C 0.04g在N,N-二甲基乙酰胺中加热到160℃反应，反应完全后，降温，过滤除去催化剂，少量溶剂洗涤催化剂。浓缩得到产品2-(3-甲基苯基)丙二酸二乙酯16.6g，收率84％。1H NMR(CDCl3,500MHz,TMS):δ7.27-7.13(m,4H),4.57(s,1H),4.20(q,J＝7.0Hz,4H),2.35(s,3H),1.26(t,J＝7.0Hz,6H)。13C NMR(CDCl3,125MHz):δ168.2,138.2,132.6,129.8,128.9,128.4,126.2,61.7,57.8,14.0,13.9。
实施例十七：2-(2,6-二乙基-4-甲基-2-烯-1-亚环己基)丙二酸二甲酯的制备
将2-(4-亚庚基)丙二酸二甲酯22.8g(0.10mol)，2-甲基丙烯醛7.0g(0.10mol)和三乙烯二胺2.2g(0.02mol)依次加入反应瓶中，加热反应。反应完全后，降温，加入乙酸乙酯溶解，1N稀盐酸洗涤，干燥，浓缩得到产品。
实施例十八：2-(2,6-二乙基-4-甲基苯基)丙二酸二甲酯的制备
将实施例十七制备的2-(2,6-二乙基-4-甲基-2-烯-1-亚环己基)丙二酸二甲酯和Pd/C 1.1g在氮气气氛中加热到180℃，反应完全后，将温，加入乙酸乙酯，滤去固体，有机相干燥、浓缩得到2-(2,6-二乙基-4-甲基苯基)丙二酸二甲酯22.2g，收率80％。1H NMR(CDCl3,500MHz,TMS):δ6.93(s,2H),5.06(s,1H),3.73(s,6H),2.64(q,J＝7.0Hz,4H),2.30(s,3H),1.18(t,J＝7.0Hz,6H)。13C NMR(CDCl3,125MHz):δ15.2,21.1,26.6,51.5,52.6,126.4,127.9,137.9,143.6,169.3。
实施例十九：唑啉草酯的制备
将实施例十八制备的2-(2,6-二乙基-4-甲基苯基)丙二酸二甲酯15.3g(0.05mol)、[1,4,5]-氧二氮杂环庚烷二氢氯酸盐10.5g(0.06mol)和三乙胺20.2g(0.20mol)在二甲苯中搅拌回流反应。反应完全后，降温，加入新戊酰氯10.8g(0.09mol)，室温反应。反应完全后，将该混合物用稀盐酸调节pH为酸性，乙酸乙酯萃取。合并的有机相干燥，浓缩结晶得到产物唑啉草酯14.4g，收率为72％。1H NMR(CDCl3,500MHz,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 (9)

  1. 一种制备2-(亚环己烯基)丙二酸衍生物的方法，其特征在于，化合物(1)与化合物(2)在催化剂A存在下发生环合反应经过中间体(3)制备化合物(4)；或者化合物(1)与化合物(2)在催化剂A存在下发生环合反应直接制备化合物(4)，用方程式表示如下：
    Figure PCTCN2016113671-appb-100001
    其中R1、R2、R3、R4、R5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；
    X1和X2彼此独立地为氰基、-COR6，所述的R6为氢、C1-C10烷基、C1-C10烷氧基、C6-C12芳基氧基、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，化合物(1)与化合物(2)的摩尔比为0.8-2.0:1；所述的环合反应所用的催化剂A为有机酸、有机碱、无机碱以及它们中一种或多种的混合物；催化剂A与化合物(2)的摩尔比为0.005-2.4:1；环合反应温度为0-150℃；环合反应在无溶剂或者以水、有机溶剂或它们的混合物为溶剂下进行。
  3. 根据权利要求2所述的方法，其特征在于，化合物(1)与化合物(2)的摩尔比优选为1.0-1.5：1；所述的环合反应所用的催化剂A优选为Et3N、DABCO，催化剂A与化合物(2)的摩尔比优选为0.1-1.0：1；环合反应温度优选为80-130℃；环合反应溶剂优选为甲苯。
  4. 式(3)或(4)所示的化合物或它们的混合物，
    Figure PCTCN2016113671-appb-100002
    其中R4为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；R1、R2、R3、R5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；
    X1和X2彼此独立地为氰基、-COR6，所述的R6为氢、C1-C10烷基、C1-C10烷氧基、C6-C12芳基氧基、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。
  5. 根据权利要求4所述的化合物，其特征在于，R4是C1-C4烷基、C6-C12芳基；R1、R2、R3、R5彼此独立地是氢、C1-C4烷基、C6-C12芳基；X1和X2彼此独立地是氰基、-COOMe、-COOEt。
  6. 一种2-(亚环己烯基)丙二酸衍生物的应用，其特征在于，化合物(4)在催化剂B的作用下发生芳构化反应得到2-芳基丙二酸衍生物(5)，用方程式表示如下：
    Figure PCTCN2016113671-appb-100003
    其中R1、R2、R3、R4、R5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；
    X1和X2彼此独立地为氰基、-COR6，所述的R6为氢、C1-C10烷基、C1-C10烷氧基、C6-C12芳基氧基、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所述的应用，其特征在于，所述的催化剂B为金属催化剂，芳构化温度为100-400℃，芳构化反应无溶剂或者以沸点高于150℃的醇、醚、酯、酰胺、芳烃为溶 剂。
  8. 根据权利要求7所述的应用，其特征在于，所述的催化剂B优选为Pd/C，芳构化反应温度优选为180-220℃。
  9. 权利要求4或5所述化合物在唑啉草酯合成中的应用。
PCT/CN2016/113671 2016-12-30 2016-12-30 一种制备2-(亚环己烯基)丙二酸衍生物的方法及其应用 WO2018120094A1 (zh)

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