Preparation method of 2-arylmalonic acid derivative or intermediate thereof

Abstract

The invention provides a preparation method of a 2-aryl malonic acid derivative or an intermediate thereof, and belongs to the field of organic synthesis. The preparation method provided by the invention comprises the following steps: mixing a compound 1, a solvent, high-valence inorganic metal salt and a polymerization inhibitor, and performing aromatization reaction to obtain a 2-aryl malonic acid derivative intermediate or a 2-aryl malonic acid derivative, the solvent comprises halogenated hydrocarbon and / or an amide solvent; the structural formula of the compound 1 is shown as a formula I; in the formula I, Y1 and Y2 are independently cyano groups or-COR6; when Y1 and Y2 are not-COR6, the 2-aryl malonic acid derivative intermediate is prepared; when both Y1 and Y2 are-COR6, the 2-aryl malonic acid derivative is prepared. In the preparation process, a large amount of three wastes are not generated, the yield of the prepared 2-aryl malonic acid derivative or the intermediate thereof is 75.7-87.8%, and the yield is good.

Description

Technical Field

[0001] The invention relates to the field of organic synthesis, and in particular to a method for preparing a 2-arylmalonic acid derivative or an intermediate thereof. Background Art

[0002] 2-Arylmalonic acid derivatives and their intermediates are an important class of organic compounds, which are widely used in materials, medicine, pesticides and other fields.

[0003] At present, the relevant method for preparing 2-arylmalonic acid derivatives and intermediates thereof is to use cyclohexadiene compounds as raw materials, and sequentially undergo isomerization reaction, halogenation reaction in the presence of a halogenating agent, and dehydrohalogenation aromatization reaction at a certain temperature to obtain 2-arylmalonic acid derivatives and intermediates thereof. This method undergoes isomerization and aromatization, and the preparation method is complicated. The halogenating agent used is a halogen element, an acyl chloride or a halogenated sulfoxide agent, and a large amount of three wastes will be generated in the preparation process, resulting in high pollution. In addition, a large amount of tar will be generated during the dehydrohalogenation aromatization reaction, which is not suitable for industrial production. Summary of the invention

[0004] The object of the present invention is to provide a method for preparing a 2-arylmalonic acid derivative or an intermediate thereof. The preparation method provided by the present invention is simple and does not generate a large amount of three wastes.

[0005] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0006] The present invention provides a method for preparing a 2-arylmalonic acid derivative or an intermediate thereof, comprising: mixing a compound 1, a solvent, a high-valent inorganic metal salt and a polymerization inhibitor, and then performing an aromatization reaction to obtain a 2-arylmalonic acid derivative intermediate or a 2-arylmalonic acid derivative; the solvent comprises a halogenated hydrocarbon and / or an amide solvent;

[0007] The structural formula of the compound 1 is shown in Formula I:

[0008]

[0009] In the formula I, R 1 , R 2 , R 3 , R 4 , R 5 Y is independently hydrogen, C1-C10 alkyl, C6-C12 aryl or a heteroaryl containing 1 or 2 atoms selected from nitrogen, oxygen and sulfur atoms; 1 and Y 2 are independently cyano or -COR 6 ; said R 6is hydrogen, C1-C10 alkyl, C1-C10 alkoxy, C6-C12 aryloxy, amino, C1-C10 alkoxyamino, C6-C12 arylamino, di(C1-C10 alkyl)amino, (C1-C10 alkyl)(C6-C12 aryl)amino, di(C6-C12 aryl)amino, C6-C12 aryl, or a heteroaryl group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur;

[0010] When the Y 1 and Y 2 Not all -COR 6 When the intermediate of the 2-arylmalonic acid derivative is prepared;

[0011] When the Y 1 and Y 2 All are -COR 6 When the reaction mixture is reacted with 2-arylmalonic acid derivatives, the obtained product is 2-arylmalonic acid derivatives.

[0012] Preferably, the R 6 It is methoxy, ethoxy or amino.

[0013] Preferably, the molar ratio of the high-valent inorganic metal salt to compound 1 is (0.5-3.0):1.

[0014] Preferably, the high-valent inorganic metal salt includes one or more of a high-valent inorganic iron salt and a high-valent inorganic copper salt.

[0015] Preferably, the molar ratio of the polymerization inhibitor to compound 1 is (0.005-2.0):1.

[0016] Preferably, the polymerization inhibitor includes one or more of phenol polymerization inhibitors and aniline polymerization inhibitors; the phenol polymerization inhibitor includes one or more of p-methoxyphenol, tert-butylhydroquinone and hydroquinone; the aniline polymerization inhibitor includes one or more of diphenylamine and phenothiazine.

[0017] Preferably, the halogenated hydrocarbon includes one or more of chlorobenzene, dichlorobenzene, tetrachloroethylene or dichloroethane.

[0018] Preferably, the amide solvent includes dimethylformamide and / or dimethylacetamide.

[0019] Preferably, the temperature of the aromatization reaction is 110-150° C., and the time of the aromatization reaction is 2-3 hours.

[0020] Preferably, the mixing process of the compound 1, the solvent, the high-valent inorganic metal salt and the polymerization inhibitor is: firstly, the solvent, part of the high-valent inorganic metal salt and the polymerization inhibitor are mixed for the first time, and then the compound 1 is added for the second mixing; the remaining part of the high-valent inorganic metal salt is added during the aromatization reaction.

[0021] The present invention provides a method for preparing a 2-arylmalonic acid derivative or an intermediate thereof, comprising: mixing a compound 1, a solvent, a high-valent inorganic metal salt and a polymerization inhibitor, and then performing an aromatization reaction to obtain a 2-arylmalonic acid derivative intermediate or a 2-arylmalonic acid derivative; the solvent comprises a halogenated hydrocarbon and / or an amide solvent; the structural formula of the compound 1 is shown in formula I; in formula I, R 1 , R 2 , R 3 , R 4 , R 5 Y is independently hydrogen, C1-C10 alkyl, C6-C12 aryl or a heteroaryl containing 1 or 2 atoms selected from nitrogen, oxygen and sulfur atoms; 1 and Y 2 are independently cyano or -COR 6 ; said R 6 is hydrogen, C1-C10 alkyl, C1-C10 alkoxy, C6-C12 aryloxy, amino, C1-C10 alkoxyamino, C6-C12 arylamino, di(C1-C10 alkyl)amino, (C1-C10 alkyl)(C6-C12 aryl)amino, di(C6-C12 aryl)amino, C6-C12 aryl, or a heteroaryl group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur; when Y 1 and Y 2 Not all -COR 6 When Y 1 and Y 2 All are -COR 6 , the prepared 2-arylmalonic acid derivatives. The present invention uses a high-valent inorganic metal salt as a metal oxidant, and the high-valent inorganic metal salt performs oxidative dehydrogenation on compound 1 to form aromatization, and the high-valent inorganic metal salt itself becomes a low-valent inorganic metal salt, and at the same time, the cost of preparing 2-arylmalonic acid derivatives or intermediates thereof can be reduced; the solvent selected in the preparation process is a halogenated hydrocarbon and / or an amide solvent, which can avoid the generation of a large amount of three wastes; by adding an inhibitor, the self-polymerization of compound 1 can be prevented, thereby increasing the yield of 2-arylmalonic acid derivatives or intermediates thereof. The results of the examples show that the preparation method of the present invention is simple, low-cost, does not generate a large amount of three wastes during the preparation process, and the yield of the prepared 2-arylmalonic acid derivatives or intermediates thereof is 75.7-87.8%, which has a good yield. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 This is the hydrogen spectrum of the 2-arylmalonic acid derivative intermediate prepared in Example 4 of the present invention. DETAILED DESCRIPTION

[0023] The present invention provides a method for preparing a 2-arylmalonic acid derivative or an intermediate thereof, comprising: mixing a compound 1, a solvent, a high-valent inorganic metal salt and a polymerization inhibitor, and then performing an aromatization reaction to obtain a 2-arylmalonic acid derivative intermediate or a 2-arylmalonic acid derivative.

[0024] In the present invention, the structural formula of the compound 1 is as shown in Formula I:

[0025]

[0026] In the formula I, R 1 , R 2 , R 3 , R 4 , R 5 are independently hydrogen, C1-C10 alkyl, C6-C12 aryl or heteroaryl containing 1 or 2 atoms selected from nitrogen, oxygen and sulfur, preferably independently hydrogen, C1-C4 alkyl or C6-C12 aryl, more preferably independently hydrogen or C1-C2 alkyl; said Y 1 and Y 2 Not all -COR 6 is cyano or -COR 6 ; said R 6 It is hydrogen, C1-C10 alkyl, C1-C10 alkoxy, C6-C12 aryloxy, amino, C1-C10 alkoxyamino, C6-C12 arylamino, di(C1-C10 alkyl)amino, (C1-C10 alkyl)(C6-C12 aryl)amino, di(C6-C12 aryl)amino, C6-C12 aryl or containing 1 or 2 heteroaryl groups selected from nitrogen, oxygen, sulfur atoms, preferably methoxy, ethoxy or amino.

[0027] In the present invention, when the Y 1 and Y 2 Not all -COR 6 When the intermediate of the 2-arylmalonic acid derivative is prepared;

[0028] In the present invention, when the Y 1 and Y 2 All are -COR 6 When the reaction mixture is reacted with 2-arylmalonic acid derivatives, the obtained product is 2-arylmalonic acid derivatives.

[0029] In the present invention, the molar ratio of the high-valent inorganic metal salt to the compound 1 is preferably (0.5-3.0): 1, more preferably (1-2.8): 1, and further preferably (2.0-2.8): 1. The present invention limits the molar ratio of the high-valent inorganic metal salt to the compound 1 to the above range so that the aromatization reaction can proceed smoothly and avoid the generation of excessive by-products.

[0030] In the present invention, the high-valent inorganic metal salt preferably includes one or more of a high-valent inorganic iron salt and a high-valent inorganic copper salt, and more preferably a high-valent inorganic iron salt; the high-valent inorganic iron salt preferably includes one or more of ferric nitrate, ferric chloride or ferric sulfate. The present invention limits the high-valent inorganic metal salt to the above range, which can be more conducive to the aromatization reaction.

[0031] In the present invention, the molar ratio of the polymerization inhibitor to the compound 1 is preferably (0.005-2.0): 1, more preferably (0.02-1.5): 1, and further preferably (0.02-1.0): 1. The present invention limits the molar ratio of the polymerization inhibitor to the compound 1 to the above range to prevent the self-polymerization of the compound 1, thereby increasing the yield of the 2-arylmalonic acid derivative intermediate.

[0032] In the present invention, the polymerization inhibitor preferably includes one or more of phenolic polymerization inhibitors and aniline polymerization inhibitors; the phenolic polymerization inhibitor includes one or more of p-methoxyphenol, tert-butylhydroquinone and hydroquinone; the aniline polymerization inhibitor includes one or more of diphenylamine and phenothiazine. The present invention limits the types of polymerization inhibitors to the above range, which is more conducive to preventing the self-polymerization of compound 1.

[0033] In the present invention, the solvent includes halogenated hydrocarbons and / or amide solvents; the halogenated hydrocarbons preferably include one or more of chlorobenzene, dichlorobenzene, tetrachloroethylene or dichloroethane, more preferably dichlorobenzene and / or tetrachloroethylene; the amide solvents preferably include dimethylformamide and / or dimethylacetamide, more preferably dimethylformamide. When the solvent is a mixed liquid, the present invention has no special restrictions on the content of each component in the solvent, and any proportion of the mixture can be used. The present invention limits the type of solvent to the above range so that the solvent has a suitable boiling point and has a certain solubility in high-valent inorganic metal salts.

[0034] As an embodiment of the present invention, the mass ratio of the solvent to the compound 1 may be (3-5): 1, or (3.5-4): 1. The present invention limits the mass ratio of the solvent to the compound 1 to the above range to facilitate the aromatization reaction.

[0035] In the present invention, the mixing is preferably carried out in a non-sealed reaction container. As an embodiment of the present invention, the reaction container can be a four-necked glass bottle with a condenser, a stirring device and a thermometer.

[0036] In the present invention, the mixing is preferably carried out under stirring conditions; the present invention has no special requirements on the stirring speed, and the stirring parameters commonly used by those skilled in the art can be used.

[0037] As an embodiment of the present invention, the mixing process of the compound 1, the solvent, the high-valent inorganic metal salt and the polymerization inhibitor can be: firstly, the solvent, the high-valent inorganic metal salt and the polymerization inhibitor are mixed for the first time, and then the compound 1 is added for the second mixing; the high-valent inorganic metal salt is added in batches; the number of batch additions can be 2 times or 3 times. The present invention can avoid overheating of the solution caused by excessive heat released by dissolving the high-valent inorganic metal salt in the solvent at one time by adding the high-valent inorganic metal salt in batches.

[0038] As another embodiment of the present invention, the mixing process of the compound 1, the solvent, the high-valent inorganic metal salt and the polymerization inhibitor can also be: firstly, the solvent, part of the high-valent inorganic metal salt and the polymerization inhibitor are mixed for the first time, and then the compound 1 is added for the second mixing; the remaining part of the high-valent inorganic metal salt is added during the aromatization reaction. The part of the high-valent inorganic metal salt can be 50-70% of the total mass of the high-valent inorganic metal salt; the part of the high-valent inorganic metal salt can be added in batches; the number of batch additions can be 1-3 times, and can also be 2 times.

[0039] As an embodiment of the present invention, the present invention has no special limitation on the time interval between each batch of the batch addition, and it is sufficient to ensure that the temperature of the mixed solution is less than 110° C. after each addition of the high-valent inorganic metal salt.

[0040] As an embodiment of the present invention, the remaining part of the high-valent inorganic metal salt can be added when the aromatization reaction is 1 to 1.5 hours. The present invention adopts the above-mentioned method of adding the high-valent inorganic metal salt to enable the high-valent inorganic metal salt to fully exert its effect and further improve the conversion efficiency of the 2-arylmalonic acid derivative intermediate.

[0041] In the present invention, the compound 1 is preferably added dropwise; as an embodiment of the present invention, the rate of the addition can be 1-2 mL / min, or 1.5 mL / min. The present invention adopts the method of addition dropwise and limits the rate of addition dropwise to the above range to ensure that the reaction is fully carried out.

[0042] As an embodiment of the present invention, the mixing is preferably carried out at room temperature; after the first mixing is completed, the mixed solution obtained by the first mixing can be cooled to below 50° C., and then compound 1 is added.

[0043] The present invention has no particular limitation on the time of the first mixing and the second mixing, as long as the raw materials can be mixed uniformly.

[0044] After the second mixing is completed, the present invention preferably uses nitrogen to replace the gas in the reaction container; as an embodiment of the present invention, the number of replacements can be 3 times. The present invention uses nitrogen to replace the gas in the reaction container to prevent compound 1 from being oxidized by oxygen during the reaction process.

[0045] In the present invention, the temperature of the aromatization reaction is preferably 110-150°C, more preferably 125-130°C; the time of the aromatization reaction is preferably 2-3h, more preferably 2.5h-3h. In the present invention, limiting the temperature and time of the aromatization reaction to the above ranges can make the reaction proceed smoothly and improve the yield of the 2-arylmalonic acid derivative intermediate.

[0046] In the present invention, the aromatization reaction is preferably carried out under reflux conditions. The present invention can make the reaction more complete and improve the yield of the 2-arylmalonic acid derivative intermediate by reflux.

[0047] As an embodiment of the present invention, taking the high-valent inorganic metal salt as ferric chloride as an example, the chemical equation of the aromatization reaction is shown in Formula 1:

[0048]

[0049] After the aromatization reaction time reaches 2 to 3 hours, in the present invention, the aromatization reaction product is preferably cooled, quenched, extracted and precipitated in sequence to obtain a 2-arylmalonic acid derivative intermediate.

[0050] In the present invention, the cooling is preferably water cooling to room temperature; the temperature of the water used in the water cooling is room temperature. In the present invention, the aromatization reaction can be terminated by cooling to room temperature.

[0051] In the present invention, the quenching agent used for quenching is preferably dilute hydrochloric acid; as an embodiment of the present invention, the concentration of the dilute hydrochloric acid can be 6wt%. The present invention can quench the activity of the high-valent inorganic metal salt by using dilute hydrochloric acid, and at the same time extract the high-valent inorganic metal salt into the aqueous phase (dilute hydrochloric acid) and wash it away.

[0052] After quenching, the reaction solution is preferably washed in the present invention; the solvent used for washing is preferably water; the number of washings is preferably 2. In the present invention, inorganic salts in the reaction system can be washed away by using water as the washing liquid.

[0053] In the present invention, the solvent used for the extraction is preferably an alkaline solution; the alkaline solution is preferably a sodium hydroxide solution; the present invention has no special requirements on the concentration and dosage of the sodium hydroxide solution, and the concentration and dosage commonly used as an extractant by those skilled in the art can be used. As an embodiment of the present invention, the mass concentration of the sodium hydroxide solution can be 5-10%. The present invention can extract the target product (2-arylmalonic acid derivative intermediate or 2-arylmalonic acid derivative) through extraction.

[0054] In the present invention, the precipitation agent used for the precipitation is preferably industrial hydrochloric acid or acetic acid, more preferably industrial hydrochloric acid. The pH value of the precipitation of the present invention is preferably 6 to 7. The present invention has no particular limitation on the amount of the precipitation agent added, and the pH of the reaction solution obtained after the extraction can be adjusted to 6 to 7.

[0055] After the precipitation is completed, the precipitated product is preferably filtered to obtain a 2-arylmalonic acid derivative intermediate or a 2-arylmalonic acid derivative.

[0056] The present invention has no special limitation on the operation of the suction filtration, and the operation can be performed by the suction filtration commonly used by those skilled in the art.

[0057] The present invention adopts a high-valent inorganic metal salt as a metal oxidant, and the high-valent inorganic metal salt performs oxidative dehydrogenation on compound 1 to form aromatization, and the high-valent inorganic metal salt itself becomes a low-valent inorganic metal salt, and at the same time, the cost of preparing 2-arylmalonic acid derivatives or intermediates thereof can be reduced; the solvent selected in the preparation process is a halogenated hydrocarbon and / or an amide solvent, which can avoid generating a large amount of three wastes; and the addition of an inhibitor can prevent the self-polymerization of compound 1, thereby improving the yield of the 2-arylmalonic acid derivatives or intermediates thereof.

[0058] As an embodiment of the present invention, the 2-arylmalonic acid derivative intermediate can be further hydrolyzed to obtain a 2-arylmalonic acid derivative. The present invention has no particular limitation on the hydrolysis operation, and the technical scheme for hydrolyzing the 2-arylmalonic acid derivative intermediate well known to those skilled in the art can be used.

[0059] The technical solutions in the present invention will be described clearly and completely below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0060] Example 1

[0061] A method for preparing a 2-arylmalonic acid derivative intermediate (2-(2,6-diethyl-4-methylphenyl)malononitrile):

[0062] 180 g of dichlorobenzene and 200 g of tetrachloroethylene were added to a 1000 mL reaction container equipped with a thermometer and a stirrer, and then 386.2 g of ferric sulfate was added in two batches. After the temperature of the reaction solution was cooled to 50° C., 1 g of tert-butylhydroquinone was added and stirred for 5 minutes, and then 100 g of 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylene)malononitrile was added dropwise at a rate of 1.5 mL / min. After the addition was completed, nitrogen replacement was performed 3 times, and an aromatization reaction was performed at 120° C. for 2 h. After the reaction was completed, the reaction solution was cooled to room temperature, 300 g of dilute hydrochloric acid with a concentration of 6 wt % was added for quenching, and then washed with water 3 times, extracted with a sodium hydroxide solution with a mass concentration of 8% after washing, and adjusted the pH of the extract to 6-7 with industrial hydrochloric acid (mass concentration of 30%) after extraction for precipitation, and filtered to obtain 75 g of 2-(2,6-diethyl-4-methylphenyl)malononitrile;

[0063] The mass ratio of dichlorobenzene to tetrachloroethylene is 0.9:1;

[0064] The molar ratio of the ferric sulfate to 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene)malononitrile is 2.0:1;

[0065] The molar ratio of the tert-butylhydroquinone to 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene)malononitrile is 0.01:1;

[0066] The ratio of the total mass of the dichlorobenzene and tetrachloroethylene to the mass of 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene)malononitrile is 3.8:1.

[0067] The calculation formula of yield is:

[0068]

[0069] M 实际 is the mass of the product actually obtained, M 理论 is the theoretical mass of the product.

[0070] According to calculation, the yield of 2-(2,6-diethyl-4-methylphenyl)malononitrile obtained in Example 1 is 75.7%.

[0071] Example 2

[0072] A method for preparing a 2-arylmalonic acid derivative intermediate (2-(2,6-diethyl-4-methylphenyl)malononitrile):

[0073] In a 1000 mL reaction vessel equipped with a thermometer and a stirrer, 100 g of dimethylformamide and 200 g of tetrachloroethylene were added, and then 386.2 g of ferric sulfate was added in two batches. After the reaction solution temperature was cooled to 50 °C, 1 g of methoxyphenol was added and stirred for 5 minutes. Then, 100 g of 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene)malononitrile, after the addition is completed, nitrogen replacement is performed 3 times, and aromatization reaction is performed at 120°C for 2 hours. After the reaction is completed, the reaction solution is cooled to room temperature, 300g of dilute hydrochloric acid with a concentration of 6wt% is added for quenching, and then washed with water 3 times, extracted with a sodium hydroxide solution with a mass concentration of 8% after washing, and after extraction, the pH of the extract is adjusted to 6-7 with industrial hydrochloric acid (mass concentration of 30%) for precipitation, and after precipitation, filtration is performed to obtain 83.1g of 2-(2,6-diethyl-4-methylphenyl)malononitrile;

[0074] The mass ratio of dimethylformamide to tetrachloroethylene is 0.5:1;

[0075] The molar ratio of the ferric sulfate to 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene)malononitrile is 2.0:1;

[0076] The molar ratio of the methoxyphenol to 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene)malononitrile is 0.017:1;

[0077] The ratio of the total mass of dimethylformamide and tetrachloroethylene to the mass of 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene)malononitrile is 3:1.

[0078] The calculation formula of yield is:

[0079]

[0080] M 实际 is the mass of the product actually obtained, M 理论 is the theoretical mass of the product.

[0081] According to calculation, the yield of 2-(2,6-diethyl-4-methylphenyl)malononitrile obtained in Example 2 is 83.8%.

[0082] Example 3

[0083] A method for preparing a 2-arylmalonic acid derivative intermediate (2-(2,6-diethyl-4-methylphenyl)malononitrile):

[0084] In a 1000mL reaction vessel equipped with a thermometer and a stirrer, 100g of dimethylformamide and 200g of tetrachloroethylene were added, and then 151.4g of ferric chloride was added in two batches. After the reaction solution temperature was cooled to 50°C, 1g of methoxyphenol was added and stirred for 5 minutes. Then, 100g of 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene)malononitrile, after the addition is completed, nitrogen replacement is performed 3 times, and aromatization reaction is performed at 120°C for 2 hours. After the reaction is completed, the reaction solution is cooled to room temperature, 300g of dilute hydrochloric acid with a concentration of 6wt% is added for quenching, and then washed with water 3 times, extracted with a sodium hydroxide solution with a mass concentration of 8% after washing, and after extraction, the pH of the extract is adjusted to 6-7 with industrial hydrochloric acid (mass concentration of 30%) for precipitation, and after precipitation, filtration is performed to obtain 87.0g of 2-(2,6-diethyl-4-methylphenyl)malononitrile;

[0085] The mass ratio of dimethylformamide to tetrachloroethylene is 0.5:1;

[0086] The molar ratio of the ferric chloride to 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene)malononitrile is 2:1;

[0087] The molar ratio of p-methoxyphenol to 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene)malononitrile is 0.017:1;

[0088] The ratio of the total mass of dimethylformamide and tetrachloroethylene to the mass of 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene)malononitrile is 3:1.

[0089] The calculation formula of yield is:

[0090]

[0091] M 实际 is the mass of the product actually obtained, M 理论 is the theoretical mass of the product.

[0092] According to calculation, the yield of 2-(2,6-diethyl-4-methylphenyl)malononitrile obtained in Example 3 is 87.8%.

[0093] Example 4

[0094] A method for preparing a 2-arylmalonic acid derivative intermediate (2-(2,6-diethyl-4-methylphenyl)malononitrile):

[0095] 100 g of dimethylformamide and 200 g of dichlorobenzene were added to a 1000 mL reaction container equipped with a thermometer and a stirrer, and then 151.4 g of ferric chloride was added in two batches. After the temperature of the reaction solution was cooled to 50° C., 1 g of hydroquinone was added and stirred for 5 minutes, and then 100 g of 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylene)malononitrile was added dropwise at a rate of 1.5 mL / min. After the addition was completed, nitrogen replacement was performed 3 times, and an aromatization reaction was performed at 120° C. for 2 h. After the reaction was completed, the reaction solution was cooled to room temperature, 300 g of dilute hydrochloric acid with a concentration of 6 wt % was added for quenching, and then washed with water 3 times, extracted with a sodium hydroxide solution with a mass concentration of 8% after washing, and adjusted the pH of the extract to 6-7 with industrial hydrochloric acid (mass concentration of 30%) after extraction for precipitation. After precipitation, suction filtration was performed to obtain 77.6 g of 2-(2,6-diethyl-4-methylphenyl)malononitrile;

[0096] The mass ratio of dimethylformamide to dichlorobenzene is 0.5:1;

[0097] The molar ratio of the ferric chloride to 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene)malononitrile is 2:1;

[0098] The molar ratio of the hydroquinone to 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene)malononitrile is 0.02:1;

[0099] The ratio of the total mass of dimethylformamide and tetrachloroethylene to the mass of 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene)malononitrile is 3:1.

[0100] The calculation formula of yield is:

[0101]

[0102] M 实际 is the mass of the product actually obtained, M 理论 is the theoretical mass of the product.

[0103] According to calculation, the yield of 2-(2,6-diethyl-4-methylphenyl)malononitrile obtained in Example 4 is 78.3%.

[0104] The 2-(2,6-diethyl-4-methylphenyl)malononitrile obtained in Example 4 was measured by a nuclear magnetic resonance instrument. The obtained hydrogen spectrum is as follows: Figure 1 As shown, the hydrogen spectrum data is:

[0105] 1 HNMR (500MHz, Chloroform-d) δ7.02 (s, 2H), 5.31 (s, 1H), 2.83 (d, J=7.5Hz, 4H), 2.36 (s, 3H), 1.34 (t, J=7.5Hz, 6H).

[0106] Example 5

[0107] A method for preparing a 2-arylmalonic acid derivative intermediate (2-(2,6-diethyl-4-methylphenyl)malononitrile):

[0108] 100 g of dimethylformamide and 200 g of tetrachloroethylene were added to a 1000 mL reaction container equipped with a thermometer and a stirrer, and then 226.0 g of ferric nitrate was added in two batches. After the temperature of the reaction solution was cooled to 50° C., 1 g of hydroquinone was added and stirred for 5 minutes, and then 100 g of 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylene)malononitrile was added dropwise at a rate of 1.5 mL / min. After the addition was completed, nitrogen replacement was performed 3 times, and an aromatization reaction was performed at 120° C. for 2 h. After the reaction was completed, the reaction solution was cooled to room temperature, 300 g of dilute hydrochloric acid with a concentration of 6 wt % was added for quenching, and then washed with water 3 times, extracted with a sodium hydroxide solution with a mass concentration of 8% after washing, and adjusted the pH of the extract to 6-7 with industrial hydrochloric acid (mass concentration of 30%) after extraction for precipitation. After precipitation, suction filtration was performed to obtain 85.3 g of 2-(2,6-diethyl-4-methylphenyl)malononitrile;

[0109] The mass ratio of dimethylformamide to tetrachloroethylene is 0.5:1;

[0110] The molar ratio of the ferric nitrate to 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene)malononitrile is 2:1;

[0111] The molar ratio of the hydroquinone to 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene)malononitrile is 0.02:1;

[0112] The ratio of the total mass of the dimethylformamide and tetrachloroethylene to the mass of 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene)malononitrile is 3:1.

[0113] The calculation formula of yield is:

[0114]

[0115] M 实际 is the mass of the product actually obtained, M 理论 is the theoretical mass of the product.

[0116] According to calculation, the yield of 2-(2,6-diethyl-4-methylphenyl)malononitrile obtained in Example 5 was 86.1%.

[0117] Example 6

[0118] A method for preparing a 2-arylmalonic acid derivative intermediate (2-(2,6-diethyl-4-methylphenyl)malononitrile):

[0119] In a 1000mL reaction vessel equipped with a thermometer and a stirrer, 100g of dimethylformamide and 200g of tetrachloroethylene were added, and then 226.0g of ferric nitrate was added in two batches. After the reaction solution temperature was cooled to 50°C, 1g of p-methoxyphenol was added and stirred for 5 minutes. Then, 100g of 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene)malononitrile, after the addition is completed, nitrogen replacement is performed 3 times, and aromatization reaction is performed at 120°C for 2 hours. After the reaction is completed, the reaction solution is cooled to room temperature, 300g of dilute hydrochloric acid with a concentration of 6wt% is added for quenching, and then washed with water 3 times, extracted with a sodium hydroxide solution with a mass concentration of 8% after washing, and after extraction, the pH of the extract is adjusted to 6-7 with industrial hydrochloric acid (mass concentration of 30%) for precipitation, and after precipitation, filtration is performed to obtain 79.3g of 2-(2,6-diethyl-4-methylphenyl)malononitrile;

[0120] The mass ratio of dimethylformamide to tetrachloroethylene is 0.5:1;

[0121] The molar ratio of the ferric nitrate to 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene)malononitrile is 2:1;

[0122] The molar ratio of p-methoxyphenol to 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene)malononitrile is 0.017:1;

[0123] The ratio of the total mass of the dimethylformamide and tetrachloroethylene to the mass of 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene)malononitrile is 3:1.

[0124] The calculation formula of yield is:

[0125]

[0126] M 实际is the mass of the product actually obtained, M 理论 is the theoretical mass of the product.

[0127] According to calculation, the yield of 2-(2,6-diethyl-4-methylphenyl)malononitrile obtained in Example 6 is 80.0%.

[0128] Example 7

[0129] A preparation method of a 2-arylmalonic acid derivative (2-cyano-2-(2,6-diethyl-4-methylphenyl)acetic acid methyl ester):

[0130] In a 500mL reaction vessel equipped with a thermometer and a stirrer, 50g of dimethylformamide and 100g of tetrachloroethylene were added, and then 104.3g of ferric nitrate was added in two batches. After the reaction solution temperature was cooled to 50°C, 0.5g of hydroquinone was added and stirred for 5 minutes. Then, 50g of 2-cyano-2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylene)acetic acid methyl ester, after the addition is completed, nitrogen replacement is performed 3 times, and aromatization reaction is performed at 120°C for 2 hours. After the reaction is completed, the reaction solution is cooled to room temperature, and dilute hydrochloric acid with a concentration of 6wt% is added for quenching, and then washed with water 3 times, and then extracted with a sodium hydroxide solution with a mass concentration of 8% after washing, and after extraction, industrial hydrochloric acid (mass concentration of 30%) is used to adjust the pH of the extract to 6-7 for precipitation, and after precipitation, suction filtration is performed to obtain 43.7g of 2-cyano-2-(2,6-diethyl-4-methylphenyl)acetic acid methyl ester;

[0131] The mass ratio of dimethylformamide to tetrachloroethylene is 0.5:1;

[0132] The molar ratio of the ferric sulfate to methyl 2-cyano-2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene)acetate is 2:1;

[0133] The molar ratio of hydroquinone to methyl 2-cyano-2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene)acetate is 0.02:1;

[0134] The ratio of the total mass of the dimethylformamide and tetrachloroethylene to the mass of methyl 2-cyano-2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene)acetate is 3:1.

[0135] The calculation formula of yield is:

[0136]

[0137] M 实际 is the mass of the product actually obtained, M 理论is the theoretical mass of the product.

[0138] According to calculation, the yield of methyl 2-cyano-2-(2,6-diethyl-4-methylphenyl)acetate obtained in Example 7 was 81.1%.

[0139] The hydrogen spectrum and carbon spectrum of 2-cyano-2-(2,6-diethyl-4-methylphenyl)acetic acid methyl ester obtained in Example 7 were measured by nuclear magnetic resonance, and the hydrogen spectrum data obtained were: 1 HNMR (CDCl3, 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);

[0140] The carbon spectrum data are: 13 C NMR (CDCl3, 500MHz): 166.5, 142.8, 139.2, 128.2, 123.9, 115.9, 53.7, 36.8, 26.3, 21.1, 15.0.

[0141] The preparation method of the invention is simple and low in cost, and does not generate a large amount of three wastes during the preparation process. The yield of the prepared 2-arylmalonic acid derivative or its intermediate is 75.7-87.8%, which has a good yield.

[0142] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing a 2-arylmalonic acid derivative or an intermediate thereof, comprising: Compound 1, a solvent, a high-valent inorganic metal salt and a polymerization inhibitor are mixed and then subjected to aromatization reaction to obtain a 2-arylmalonic acid derivative intermediate or a 2-arylmalonic acid derivative; the solvent includes a halogenated hydrocarbon and / or an amide solvent; The structural formula of the compound 1 is shown in Formula I: In the formula I, R 1 , R 2 , R 3 , R 4 , R 5 Y is independently hydrogen, C1-C10 alkyl, C6-C12 aryl or a heteroaryl containing 1 or 2 atoms selected from nitrogen, oxygen and sulfur atoms; 1 and Y 2 are independently cyano or -COR 6 ; said R 6 is hydrogen, C1-C10 alkyl, C1-C10 alkoxy, C6-C12 aryloxy, amino, C1-C10 alkoxyamino, C6-C12 arylamino, di(C1-C10 alkyl)amino, (C1-C10 alkyl)(C6-C12 aryl)amino, di(C6-C12 aryl)amino, C6-C12 aryl, or a heteroaryl group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur; When the Y 1 and Y 2 Not all -COR 6 When the intermediate of the 2-arylmalonic acid derivative is prepared; When the Y 1 and Y 2 All are -COR 6 When the reaction mixture is reacted with 2-arylmalonic acid derivatives, the obtained product is 2-arylmalonic acid derivatives.

2. The preparation method according to claim 1, characterized in that: The R 6 It is methoxy, ethoxy or amino.

3. The preparation method according to claim 1, characterized in that: The molar ratio of the high-valent inorganic metal salt to compound 1 is (0.5-3.0):

1.

4. The preparation method according to claim 1 or 3, characterized in that: The high-valent inorganic metal salt includes one or more of a high-valent inorganic iron salt and a high-valent inorganic copper salt.

5. The preparation method according to claim 1, characterized in that: The molar ratio of the polymerization inhibitor to the compound 1 is (0.005-2.0):

1.

6. The preparation method according to claim 1 or 5, characterized in that: The polymerization inhibitor includes one or more of phenol polymerization inhibitors and aniline polymerization inhibitors; the phenol polymerization inhibitor includes one or more of p-methoxyphenol, tert-butylhydroquinone and hydroquinone; the aniline polymerization inhibitor includes one or more of diphenylamine and phenothiazine.

7. The preparation method according to claim 1, characterized in that: The halogenated hydrocarbons include one or more of chlorobenzene, dichlorobenzene, tetrachloroethylene or dichloroethane.

8. The preparation method according to claim 1, characterized in that: The amide solvent includes dimethylformamide and / or dimethylacetamide.

9. The preparation method according to claim 1, characterized in that: The temperature of the aromatization reaction is 110-150° C., and the time of the aromatization reaction is 2-3 hours.

10. The preparation method according to claim 1, characterized in that: The mixing process of the compound 1, the solvent, the high-valent inorganic metal salt and the polymerization inhibitor is as follows: the solvent, part of the high-valent inorganic metal salt and the polymerization inhibitor are first mixed, and then the compound 1 is added for a second mixing; the remaining part of the high-valent inorganic metal salt is added during the aromatization reaction.

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