Patent Description:
<NUM>-Arylmalonic acid derivatives, as an important class of organic compounds, are widely used in the preparation of materials, medicines and pesticides. For example, <NUM>-phenylmalonate is a significant raw material for the preparation of polymer stabilizers (<CIT>); and <NUM>-(<NUM>,<NUM>-diethyl-<NUM>-methylphenyl) malonate diester and <NUM>-(<NUM>,<NUM>-diethyl-<NUM>-methylphenyl) malononitrile are crucial intermediates for preparing highly-effective herbicide Pinoxaden (<CIT>).

Currently, the reported strategies for preparing the <NUM>-arylmalonic acid derivatives may be divided into three categories according to the construction of C-C bond.

The first type of strategy is characterized by constructing a skeleton of a target compound through the C-C coupling of a halogenated aromatic hydrocarbon and a malonic acid derivative under the action of a catalyst (<NPL> , <CIT> and <CIT>). This method usually requires an expensive organometallic catalyst, and the catalyst is difficult to recycle, leading to a high cost. In addition, active halogenated aromatic hydrocarbons such as brominated or iodized aromatic hydrocarbons are generally required as raw materials. However, the halogenated aromatic hydrocarbons, especially those with different substituents at specific positions, are difficult to synthesize, and are usually prepared from the corresponding aniline by diazo-halogenation reaction. The diazo-halogenation reaction not only involves the generation of a large quantity of wastes, but also carries problems of safety concerns and halogen corrosion.

With respect to the second type of strategy, a phenylacetic acid derivative is used as a raw material and undergoes a condensation reaction with a dialkyl carbonate in the presence of a strong base (i.e., sodium hydride) to construct the skeleton of the target compound (Zi, W. and Toste, F. Gold(I)-Catalyzed Enantioselective Desymmetrization of <NUM>,<NUM>-Diols through Intramolecular Hydroalkoxylation of Allenes. However, the phenylacetic acid derivatives, especially the multi-substituted phenylacetic acid derivatives, are difficult to prepare. In addition, the strong base such as sodium hydride (needing anhydrous and oxygen-free operation) and the hydrogen produced by the reaction will cause major safety hazards. Therefore, this method is not suitable for industrial production.

The third type of strategy is to use a <NUM>-(cyclohexenylidene)malonic acid derivative as a raw material to obtain the target product through dehydrogenation reaction at <NUM>-<NUM> in the presence of a metal catalyst (generally a noble metal, such as palladium) (<CIT>). This method has high cost and high reaction temperature, and thus is not conducive to the industrial production.

Aiming at the shortcomings of the prior art, the present disclosure provides a method for preparing a <NUM>-arylmalonic acid derivative, which is safe and economical, and thus suitable for industrial production.

A method for preparing a <NUM>-arylmalonic acid derivative of formula (<NUM>), comprising:.

In some embodiments, R<NUM>, R<NUM>, R<NUM>, R<NUM> and R<NUM> are each independently hydrogen, a C<NUM>-C<NUM> alkyl group or a C<NUM>-C<NUM> aryl.

In some embodiments, Y<NUM> and Y<NUM> are each independently cyano, -COOMe, -COOEt or -CONH<NUM>.

In some embodiments, in step (<NUM>), the isomerization reaction is carried out in the presence of a base; and the base is selected from the group consisting of an alkali metal hydroxide, an alkali metal alcoholate, an alkaline earth metal hydroxide, an alkaline earth metal alcoholate and a combination thereof, preferably sodium hydroxide or sodium methoxide;.

In some embodiments, in step (<NUM>), the dehydrohalogenation-aromatization reaction is carried out under an action of a catalyst; and the catalyst is selected from the group consisting of an alkali metal halide, an alkaline earth metal halide and a combination thereof, preferably lithium chloride or sodium chloride.

In some embodiments, a molar ratio of the catalyst to the intermediate (<NUM>) is (<NUM>-<NUM>):<NUM>, preferably (<NUM>-<NUM>):<NUM>.

In some embodiments, in step (<NUM>), the dehydrohalogenation-aromatization reaction is carried out at <NUM>-<NUM>, preferably <NUM>-<NUM>.

In some embodiments, the above preparation method of the <NUM>-arylmalonic acid derivative (<NUM>) is carried out in a one-pot manner.

The <NUM>-arylmalonic acid derivative (<NUM>) prepared by the method mentioned above, for example, <NUM>-(<NUM>,<NUM>-diethyl-<NUM>-methylphenyl)malononitrile, can be used to prepare <NUM>-(<NUM>,<NUM>-diethyl-<NUM>-methylphenyl)-<NUM>-oxo-<NUM>,<NUM>,<NUM>,<NUM>-tetrahydro-<NUM>H-pyrazole[<NUM>,<NUM>-d][<NUM>,<NUM>,<NUM>] oxadiazepine-<NUM>-pyrivalate (Pinoxaden) through further transformation and reaction.

The beneficial effects of the present disclosure are described as follows.

The technical solutions of the present disclosure will be further described below with reference to the embodiments, and the embodiments are not intended to limit the scope of the present disclosure.

The raw material <NUM> is prepared by a method known in the prior art (for example, <CIT>).

To a <NUM> three-necked flask equipped with a magnetic stirrer and a thermometer were sequentially added <NUM> of methanol and <NUM> of <NUM>-(<NUM>,<NUM>-diethyl-<NUM>-methyl-<NUM>-ene-<NUM>-cyclohexylidene) malononitrile. The reaction mixture was stirred and heated to <NUM>, and <NUM> of sodium methoxide was added. The reaction was stirred for <NUM>. The reaction mixture was cooled, acidificated, extracted, concentrated and separated to give <NUM> of <NUM>-(<NUM>,<NUM>-diethyl-<NUM>-methyl-<NUM>-ene -<NUM>-cyclohexylidene) malononitrile (<NUM>% yield).

<NUM>H NMR (CDCl<NUM>, <NUM>, TMS): δ <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

<NUM>C NMR (CDCl<NUM>, <NUM>): δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM><NUM>, <NUM><NUM>, <NUM>, <NUM>, <NUM>, <NUM>.

To a <NUM> three-necked flask equipped with a magnetic stirrer and a thermometer were sequentially added <NUM> of tetrahydrofuran and <NUM> of <NUM>-(<NUM>,<NUM>-diethyl-<NUM>-methyl-<NUM>-ene-<NUM>-cyclohexylidene) malononitrile. The reaction mixture was stirred and heated to <NUM>, and <NUM> of potassium hydroxide was added. The reaction was stirred for <NUM>. The reaction mixture was cooled, acidificated, extracted, concentrated and separated to give <NUM> of <NUM>-(<NUM>,<NUM>-diethyl-<NUM>-methyl-<NUM>-ene-<NUM>- cyclohexylidene) malononitrile (<NUM>% yield).

To a <NUM> three-necked flask equipped with a magnetic stirrer, a thermometer and a reflux condenser were sequentially added <NUM> of chlorobenzene and <NUM> of <NUM>-(<NUM>,<NUM>-diethyl-<NUM>-methyl-<NUM>-ene-<NUM>-cyclohexylidene) malononitrile prepared in Example <NUM>. The reaction mixture was stirred, cooled to <NUM>, and introduced with chlorine gas until the reaction was complete. The reaction mixture was then concentrated, and <NUM> of N,N-dimethylformamide and <NUM> of LiCl were sequentially added, and refluxed until the reaction was complete. After that, the reaction mixture was cooled, acidificated, extracted, concentrated and separated to give <NUM> of <NUM>-(<NUM>,<NUM>-diethyl-<NUM>-methylphenyl) malononitrile (<NUM>% yield ).

To a <NUM> three-necked flask equipped with a magnetic stirrer and a thermometer were sequentially added <NUM> of N,N-dimethylformamide and <NUM> of <NUM>-(<NUM>,<NUM>-diethyl-<NUM>-methyl-<NUM>-ene-<NUM>-cyclohexylidene) malononitrile prepared in Example <NUM>. The reaction mixture was stirred, cooled to <NUM>, and introduced with chlorine gas until the reaction was complete. The reaction mixture was then concentrated, <NUM> of N-methylpyrrolidone was added and heated to <NUM> until the reaction was complete. The reaction mixture was cooled to room temperature, and extracted, washed, concentrated and separated to give <NUM> of <NUM>-(<NUM>,<NUM>-diethyl-<NUM>-methylphenyl) malononitrile (<NUM>% yield).

To a <NUM> three-necked flask equipped with a magnetic stirrer, a thermometer and a reflux condenser were sequentially added <NUM> of acetic acid and <NUM> of <NUM>-(<NUM>,<NUM>-diethyl-<NUM>-methyl-<NUM>-ene-<NUM>-cyclohexylidene) malononitrile prepared in Example <NUM>. The reaction mixture was stirred, heated to <NUM>, <NUM> of an acetic acid solution containing <NUM> of liquid bromine were added and reacted at <NUM> for <NUM>. The reaction solution was then concentrated, <NUM> of N,N-dimethylformamide and <NUM> of LiBr sequentially were added and refluxed until the reaction was complete. After that, the reaction mixture was cooled, extracted, washed, concentrated and separated to give <NUM> of <NUM>-(<NUM>,<NUM>-diethyl-<NUM>-methylphenyl) malononitrile (<NUM>% yield).

To a <NUM> three-necked flask equipped with a magnetic stirrer and a thermometer were sequentially added <NUM> of acetic acid and <NUM> of <NUM>-(<NUM>,<NUM>-diethyl-<NUM>-methyl-<NUM>-ene-<NUM>-cyclohexylidene) malononitrile prepared in Example <NUM>. The reaction mixture was stirred, heated to <NUM>, <NUM> of sulfonyl chloride was dropwise added and reacted at <NUM> for <NUM>. The reaction mixture was then concentrated, <NUM> of N,N-dimethylformamide was added and heated to <NUM> until the reaction was complete. After that, the reaction mixture was cooled to room temperature, and extracted, washed, concentrated and separated to give <NUM> of <NUM>-(<NUM>,<NUM>-diethyl-<NUM>-methylphenyl) malononitrile (<NUM>% yield).

To a <NUM> three-necked flask equipped with a magnetic stirrer and a thermometer were sequentially added <NUM> of chlorobenzene and <NUM> of <NUM>-(<NUM>,<NUM>-diethyl-<NUM>-methyl-<NUM>-ene-<NUM>-cyclohexylidene) malononitrile. The reaction mixture was stirred, heated to <NUM>, <NUM> of sodium methoxide was added. The reaction was stirred for <NUM>. The reaction mixture was then cooled to <NUM>, and introduced with chlorine gas until the reaction was complete. After that, the reaction mixture was concentrated, <NUM> of N-methylpyrrolidone was added and heated to <NUM> until the reaction was complete. The reaction mixture was cooled, extracted, washed, concentrated and separated to give <NUM> of <NUM>-(<NUM>,<NUM>-diethyl-<NUM>-methylphenyl) malononitrile (<NUM>% yield).

To a <NUM> three-necked flask equipped with a magnetic stirrer, a thermometer and a reflux condenser were sequentially added <NUM> of chlorobenzene and <NUM> of <NUM>-(<NUM>,<NUM>-diethyl-<NUM>-methyl-<NUM>-ene-<NUM>-cyclohexylidene) malononitrile. The reaction mixture was stirred, heated to <NUM>, <NUM> of sodium methoxide added. The reaction was stirred for <NUM>. The reaction mixture was cooled to <NUM>, and introduced with chlorine gas until the reaction was complete. Subsequently, the reaction mixture was desolventized, <NUM> of N,N-dimethylformamide and <NUM> of LiCl were sequentially added and refluxed until the reaction was completed. After that, the reaction mixture was concentrated, washed and separated to give <NUM> of <NUM>-(<NUM>,<NUM>-diethyl-<NUM>-methylphenyl) malononitrile (<NUM>% yield).

To a <NUM> three-necked flask equipped with a magnetic stirrer, a thermometer and a reflux condenser were sequentially added <NUM> of chlorobenzene and <NUM> of <NUM>-(<NUM>,<NUM>-diethyl-<NUM>-methyl-<NUM>-ene-<NUM>-cyclohexylidene) malononitrile. The reaction mixture was stirred, heated to <NUM>, <NUM> of sodium methoxide was added. The reaction was stirred for <NUM>. The reaction mixture was cooled to <NUM>, and introduced with chlorine gas until the reaction was complete. Subsequently, the reaction mixture was desolventized, <NUM> of N,N-dimethylformamide and <NUM> of NaCl were sequentially added and refluxed until the reaction was completed. The reaction mixture was concentrated, washed and separated to give <NUM> of <NUM>-(<NUM>,<NUM>-diethyl-<NUM>-methylphenyl) malononitrile (<NUM>% yield).

To a <NUM> three-necked flask equipped with a magnetic stirrer and a thermometer were sequentially added <NUM> of tetrahydrofuran and <NUM> of <NUM>-(<NUM>,<NUM>-diethyl-<NUM>-methyl-<NUM>-ene-<NUM>-cyclohexylidene) malononitrile. The reaction mixture was stirred, heated to <NUM>, <NUM> of sodium hydroxide was added. The reaction was stirred for <NUM>. After being cooled to room temperature, the reaction mixture was added with <NUM> of a <NUM>% sodium hypochlorite solution, adjusted to pH <NUM>-<NUM> with <NUM>% hydrochloric acid, reacted at room temperature under stirring for <NUM> and added with ethyl acetate for extraction. The organic phase was collected, washed, dried and concentrated, and then <NUM> of N,N-dimethylformamide was added. The reaction mixture was refluxed until the reaction was complete, and cooled, acidificated, washed, concentrated and separated to give <NUM> of <NUM>-(<NUM>,<NUM>-diethyl-<NUM>-methylphenyl) malononitrile (<NUM>% yield).

To a <NUM> three-necked flask equipped with a magnetic stirrer, a thermometer and a reflux condenser were sequentially added <NUM> of ethyl acetate and <NUM> of methyl <NUM>-cyano-<NUM>-(<NUM>,<NUM>-diethyl-<NUM>-methyl-<NUM>-ene-<NUM>-cyclohexylidene)acetate. The reaction mixture was stirred, heated to <NUM>, <NUM> of sodium methoxide was added. The reaction was stirred for <NUM>. The reaction mixture was cooled to <NUM>, and was introduced with chlorine gas until the reaction was complete. The reaction mixture was then desolventized, <NUM> of N,N-dimethylformamide and <NUM> of LiCl were sequentially added and refluxed until the reaction was complete. After that, the reaction mixture was concentrated, washed and separated to give <NUM> of methyl <NUM>-cyano-<NUM>-(<NUM>,<NUM>-diethyl-<NUM>-methylphenyl) acetate (<NUM>% yield).

<NUM>H NMR (CDCl<NUM>, <NUM>, TMS): δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

<NUM>C NMR (CDCl<NUM>, <NUM>): δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>.

To a <NUM> three-necked flask equipped with a magnetic stirrer and a thermometer were sequentially added <NUM> of water and <NUM> of concentrated sulfuric acid. The reaction mixture was stirred, heated to <NUM>, <NUM> of <NUM>-(<NUM>,<NUM>-diethyl-<NUM>-methylphenyl) malononitrile was slowly added. The reaction was stirred for <NUM> at <NUM>. Then the reaction mixture was cooled, poured into ice water, and extracted with ethyl acetate. The organic phases were combined, dried and concentrated to give <NUM> of <NUM>-(<NUM>,<NUM>-diethyl-<NUM>-methylphenyl) malonamide (<NUM>% yield).

To a <NUM> three-necked flask equipped with a magnetic stirrer, a thermometer and a reflux condenser were sequentially added <NUM> of <NUM>-(<NUM>,<NUM>-diethyl-<NUM>-methylphenyl) malonamide prepared in Example <NUM>, <NUM> of [<NUM>,<NUM>,<NUM>]-oxydiazepine dihydrochloride, <NUM> of chlorobenzene and <NUM> of triethylamine. The reaction mixture was refluxed for reaction. After the reaction was completed, the reaction mixture was cooled to room temperature, <NUM> of pivaloyl chloride was slowly added and reacted at room temperature under stirring for <NUM>. The reaction mixture was then adjusted to pH <NUM>-<NUM> with diluted hydrochloric acid, and extracted with ethyl acetate. The organic phases were combined, dried, concentrated and crystallized with hexane to give <NUM> of Pinoxaden (<NUM>% yield).

Claim 1:
A method for preparing a <NUM>-arylmalonic acid derivative of formula (<NUM>), comprising:
(<NUM>) subjecting a compound (<NUM>) to an isomerization reaction to obtain an intermediate (<NUM>), as shown in the following reaction scheme:
<CHM>
and
(<NUM>) subjecting the intermediate (<NUM>) to a halogenation reaction in the presence of a halogenating agent and a dehydrohalogenation-aromatization reaction to obtain the <NUM>-arylmalonic acid derivative (<NUM>), as shown in the following reaction scheme:
<CHM>
wherein R<NUM>, R<NUM>, R<NUM>, R<NUM> and R<NUM> are each independently hydrogen, a C<NUM>-C<NUM> alkyl group, a C<NUM>-C<NUM> aryl group or a heteroaryl group containing one or two atoms selected from nitrogen, oxygen and sulfur;
Y<NUM> and Y<NUM> are each independently cyano or -COR<NUM>where R<NUM> is hydrogen, a C<NUM>-C<NUM> alkyl group, a C<NUM>-C<NUM> alkoxy group, a C<NUM>-C<NUM> aryloxy group, amino, a C<NUM>-C<NUM> alkylamino group, a C<NUM>-C<NUM> arylamino group, a di-(C<NUM>-C<NUM> alkyl)-amino group, a (C<NUM>-C<NUM> alkyl)-(C<NUM>-C<NUM> aryl)-amino group, a di-(C<NUM>-C<NUM> aryl) amino group, a C<NUM>-C<NUM> aryl group or a heteroaryl group containing one or two atoms selected from nitrogen, oxygen and sulfur.