JP7250426B2 - Method for synthesizing and producing alkenyl compound - Google Patents

Description

Some aspects of the present invention relate to methods of synthesizing and making alkenyl compounds. More specifically, for example, it relates to a method for producing alkenyl compounds such as styrene derivatives, which are known to be useful as raw materials for functional materials, in the presence of amino acids.

Various alkenyl compounds have long been used in the fields of electronic materials, fragrances, medicines and agricultural chemicals, and their production methods are diversified. In particular, dehydration reactions and coupling reactions are used to synthesize compounds having double bonds contained therein.

Among alkenyl compounds, styrene derivatives, for example, are important as raw materials for various polymers such as plastics, rubbers, ion exchange resins and photoresists.

In particular, polymers containing hydroxystyrene moieties with hydroxy groups on the benzene ring as structural units can impart various properties such as chemical, mechanical, and optical properties to polymers, so hydroxystyrenes are highly functional materials. is becoming increasingly important as a basic raw material for

In order to introduce hydroxystyrene as a structural unit into a polymer, it is necessary to polymerize it, and therefore a protective group is generally required. As the protecting group, for example, an organic silicon group having an acetyl group, a t-butyl group, an alkoxyalkyl group such as a methoxymethyl group and a tetrahydropyranyl group, an alkyl group, or an aryl group as a hydrogen atom of a hydroxy group is used. .

Among the protective groups described above, a particularly typical protective group for hydroxystyrene is one obtained by substituting an acetyl group for a hydrogen atom of a hydroxy group. That is, acetoxystyrenes are widely used in synthesizing polymers containing hydroxystyrene moieties as structural units.

Methods for synthesizing acetoxystyrene include, for example, a dehydration reaction of 1-(4′-acetoxyphenyl)ethanol (Patent Document 1), and a reaction between a Grignard reagent prepared from an aromatic halogen compound and a vinyl halide (Patent Document 2). and Heck reaction between 4-acetoxyhalobenzene and a vinyl compound (Patent Document 3).

JP-A-2-73076 JP-A-2000-239192 JP-A-2002-179621

However, the method described in Patent Document 1 requires multiple steps and is not sufficiently satisfactory in terms of efficiency in industrial production.
The methods described in Patent Documents 2 and 3 have problems such as the use of an expensive transition metal catalyst and the residual metal derived from the reagent or transition metal catalyst used in the product. There are concerns about using acetoxystyrenes produced using, for example, as raw materials for highly functional materials such as biomaterials and resist materials.

Several aspects of the present invention have been made to solve the above problems.

（上記式（１）中、Ｒ¹は水素原子；及び置換基を有していてもよい炭素原子数１～３０の直鎖状、分岐状若しくは環状のアルキル基；からなる群より選択されるいずれかであり、
Ｒ²は、ハメットの置換基定数σ_ｐが０より大であり、且つ、下記式（２）で示される置換基である。）

（上記式（２）中、Ｒ⁵は水素原子；及び、置換基を有していてもよい炭素原子数１～３０の直鎖状、分岐状若しくは環状のアルキル基；からなる群より選択されるいずれかである。）

（上記式（３）中、Ｒ³及びＲ⁴の各々は、独立して、水素原子；置換基を有しても良い炭素原子数１～３０の直鎖状、分岐状若しくは環状のアルキル基；置換基を有しても良い炭素原子数１～３０の直鎖状、分岐状若しくは環状のアルケニル基；置換基を有しても良い炭素原子数１～３０の直鎖状、分岐状若しくは環状のアルキニル基；及び、置換基を有しても良い炭素原子数６～３０のアリール基；からなる群より選ばれるいずれかであり、上記アルキル基、上記アルケニル基及び上記アルキニル基に含まれる少なくとも１つのメチレン基に代えてヘテロ原子含有基を含んでいても良く、上記アリール基は、環構造中に少なくとも１つの炭素原子に代えてヘテロ原子を含んでいても良い。）

（上記式（Ａ）中、Ｒ³及びＲ⁴の各々は上記式（３）のＲ³及びＲ⁴と同じ選択肢から選択される。） A method for synthesizing an alkenyl compound according to some embodiments of the present invention includes a first compound represented by the following formula (1) and a second compound represented by the following formula (3), in the presence of an amino acid, A synthetic method characterized by producing an alkenyl compound represented by the following formula (A) (hereinafter also referred to as "alkenyl compound A") by reacting at 50 to 200 ° C. in a solvent containing

(In the above formula (1), R ¹ is selected from the group consisting of a hydrogen atom; and a linear, branched or cyclic alkyl group having 1 to 30 carbon atoms which may have a substituent; is either
R ² is a substituent having Hammett's substituent constant σ _p greater than 0 and represented by the following formula (2). )

(In the above formula (2), R ⁵ is a hydrogen atom; and a linear, branched or cyclic alkyl group having 1 to 30 carbon atoms which may have a substituent; selected from the group consisting of either.)

(In formula (3) above, each of R ³ and R ⁴ is independently a hydrogen atom; a linear, branched or cyclic alkyl group having 1 to 30 carbon atoms which may have a substituent; a linear, branched or cyclic alkenyl group having 1 to 30 carbon atoms which may have a substituent; a linear, branched or cyclic alkenyl group having 1 to 30 carbon atoms which may have a substituent; a cyclic alkynyl group; and an aryl group having 6 to 30 carbon atoms which may have a substituent; any one selected from the group consisting of the alkyl group, the alkenyl group and the alkynyl group A heteroatom-containing group may be included in place of at least one methylene group, and the aryl group may include a heteroatom in place of at least one carbon atom in the ring structure.)

(In formula (A) above, each of R ³ and R ⁴ is selected from the same options as R ³ and R ⁴ in formula (3) above.)

（上記式（１）中、Ｒ¹は水素原子；及び置換基を有していてもよい炭素原子数１～３０の直鎖状、分岐状若しくは環状のアルキル基；からなる群より選択されるいずれかであり、
Ｒ²は、ハメットの置換基定数σ_ｐが０より大であり、且つ、下記式（２）で示される置換基である。）

（上記式（２）中、Ｒ⁵は水素原子；及び、置換基を有していてもよい炭素原子数１～３０の直鎖状、分岐状若しくは環状のアルキル基；からなる群より選択されるいずれかである。）

（上記式（３）中、Ｒ³及びＲ⁴の各々は、独立して、水素原子；置換基を有しても良い炭素原子数１～３０の直鎖状、分岐状若しくは環状のアルキル基；置換基を有しても良い炭素原子数１～３０の直鎖状、分岐状若しくは環状のアルケニル基；置換基を有しても良い炭素原子数１～３０の直鎖状、分岐状若しくは環状のアルキニル基；及び、置換基を有しても良い炭素原子数６～３０のアリール基；からなる群より選ばれるいずれかであり、
上記アルキル基、上記アルケニル基及び上記アルキニル基は、上記アルキル基、上記アルケニル基及び上記アルキニル基に含まれる少なくとも１つのメチレン基に代えてヘテロ原子含有基を含んでいても良く、上記アリール基は環構造中に少なくとも１つの炭素原子に代えてヘテロ原子を含んでいても良い。）

（上記式（Ｂ）中、Ｒ²は上記式（１）のＲ²と同じ選択肢から選択され、Ｒ³及びＲ⁴の各々は上記式（３）のＲ³及びＲ⁴と同じ選択肢から選択される。）
（第２の工程）上記第１の工程の後に、上記第２の化合物を上記第１の温度よりも高い第２の温度で加熱して下記式（Ａ）で示されるアルケニル化合物を得る工程。

（上記式（Ａ）中、Ｒ³及びＲ⁴の各々は上記式（３）のＲ³及びＲ⁴と同じ選択肢から選択される。） A method for producing an alkenyl compound according to some embodiments of the present invention is a method for producing an alkenyl compound A including the following two steps.
(First step) A first compound represented by the following formula (1) and a second compound represented by the following formula (3) are mixed in a solvent containing an amine in the presence of an amino acid at a temperature ranging from 50 to 200°C. to obtain an alkenyl compound represented by the following formula (B) (hereinafter also referred to as “alkenyl compound B”);

(In the above formula (1), R ¹ is selected from the group consisting of a hydrogen atom; and a linear, branched or cyclic alkyl group having 1 to 30 carbon atoms which may have a substituent; is either
R ² is a substituent having Hammett's substituent constant σ _p greater than 0 and represented by the following formula (2). )

(In the above formula (2), R ⁵ is a hydrogen atom; and a linear, branched or cyclic alkyl group having 1 to 30 carbon atoms which may have a substituent; selected from the group consisting of either.)

(In formula (3) above, each of R ³ and R ⁴ is independently a hydrogen atom; a linear, branched or cyclic alkyl group having 1 to 30 carbon atoms which may have a substituent; a linear, branched or cyclic alkenyl group having 1 to 30 carbon atoms which may have a substituent; a linear, branched or cyclic alkenyl group having 1 to 30 carbon atoms which may have a substituent; any one selected from the group consisting of a cyclic alkynyl group; and an aryl group having 6 to 30 carbon atoms which may have a substituent;
The alkyl group, the alkenyl group and the alkynyl group may contain a heteroatom-containing group in place of at least one methylene group contained in the alkyl group, the alkenyl group and the alkynyl group, and the aryl group is A heteroatom may be included in place of at least one carbon atom in the ring structure. )

(In formula (B) above, R ² is selected from the same options as R ² in formula (1) above, and each of R ³ and R ⁴ is selected from the same options as R ³ and R ⁴ in formula (3) above. is done.)
(Second step) After the first step, a step of heating the second compound at a second temperature higher than the first temperature to obtain an alkenyl compound represented by the following formula (A).

(In formula (A) above, each of R ³ and R ⁴ is selected from the same options as R ³ and R ⁴ in formula (3) above.)

（上記式（１ｂ）中、Ｒ¹は水素原子；及び置換基を有していてもよい炭素原子数１～３０の直鎖状、分岐状若しくは環状のアルキル基；からなる群より選択されるいずれかであり、
Ｒ^2ｂはハメットの置換基定数σ_ｐが０より大である置換基であり、且つ、下記式（２）で示される置換基を除く。）

（上記式（２）中、Ｒ⁵は水素原子；及び、置換基を有していてもよい炭素原子数１～３０の直鎖状、分岐状若しくは環状のアルキル基；からなる群より選択されるいずれかである。）

（上記式（３）中、Ｒ³及びＲ⁴の各々は、独立して、水素原子；置換基を有しても良い炭素原子数１～３０の直鎖状、分岐状若しくは環状のアルキル基；置換基を有しても良い炭素原子数１～３０の直鎖状、分岐状若しくは環状のアルケニル基；置換基を有しても良い炭素原子数１～３０の直鎖状、分岐状若しくは環状のアルキニル基；及び、置換基を有しても良い炭素原子数６～３０のアリール基；からなる群より選ばれるいずれかであり、上記アルキル基、上記アルケニル基及び上記アルキニル基に含まれる少なくとも１つのメチレン基に代えてヘテロ原子含有基を含んでいても良く、上記アリール基は、環構造中に少なくとも１つの炭素原子に代えてヘテロ原子を含んでいても良い。）

A method for synthesizing an alkenyl compound according to one aspect of the present invention comprises a first compound represented by the following formula (1b) and a second compound represented by the following formula (3) in the presence of an amino acid, A method for synthesizing an alkenyl compound B, in which an alkenyl compound represented by the following formula (B) is produced by reacting in a solvent containing the compound at a temperature in the range of 50 to 200°C.

(In the above formula (1b), R ¹ is selected from the group consisting of a hydrogen atom; and a linear, branched or cyclic alkyl group having 1 to 30 carbon atoms which may have a substituent; is either
R ^2b is a substituent having Hammett's substituent constant σ _p greater than 0, and excludes the substituent represented by the following formula (2). )

(In the above formula (2), R ⁵ is a hydrogen atom; and a linear, branched or cyclic alkyl group having 1 to 30 carbon atoms which may have a substituent; selected from the group consisting of either.)

(In formula (3) above, each of R ³ and R ⁴ is independently a hydrogen atom; a linear, branched or cyclic alkyl group having 1 to 30 carbon atoms which may have a substituent; a linear, branched or cyclic alkenyl group having 1 to 30 carbon atoms which may have a substituent; a linear, branched or cyclic alkenyl group having 1 to 30 carbon atoms which may have a substituent; a cyclic alkynyl group; and an aryl group having 6 to 30 carbon atoms which may have a substituent; any one selected from the group consisting of the alkyl group, the alkenyl group and the alkynyl group A heteroatom-containing group may be included in place of at least one methylene group, and the aryl group may include a heteroatom in place of at least one carbon atom in the ring structure.)

According to one aspect of the present invention, it is possible to provide a highly efficient method for synthesizing and producing an alkenyl compound that can be produced easily and inexpensively.

Some aspects of the invention relate to methods of synthesizing alkenyl compound A.
In the above formula (1), R ¹ is a hydrogen atom; and any one selected from the group consisting of a linear, branched or cyclic alkyl group having 1 to 30 carbon atoms which may have a substituent; or When R ¹ has a substituent, the number of carbon atoms including the substituent is preferably the number of carbon atoms described above.

In the above formula (1), R ² is a substituent having Hammett's substituent constant σ _p greater than zero. Although R ² does not necessarily have a benzene ring, Hammett's substituent constant is used as an index of options for substituents. R ² will be described later.

Representative examples of R ³ and R ⁴ of the above compounds in formula (3) include alkyl groups, cycloalkyl groups, cycloalkenyl groups, alkenyl groups, allyl groups, alkynyl groups and aryl groups. .
Specific examples of the alkyl group include linear alkyl groups such as methyl group, ethyl group, n-propyl group and n-butyl group; branched alkyl groups such as isopropyl group and t-butyl group;
cyclic alkyl groups such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an adamantyl group and a norbornyl group;
Examples of the alkenyl group and the alkynyl group include those in which at least one carbon-carbon single bond in the alkyl group is replaced with a carbon-carbon double bond or a carbon-carbon triple bond.

A heteroatom-containing group may be included in place of at least one methylene group contained in the alkyl group, the alkenyl group and the alkynyl group.
Examples of the heteroatom-containing groups include -O- and -S-.

Examples of the aryl group include phenyl group, naphthyl group, anthryl group, phenanthrenyl group, pentalenyl group, indenyl group, indacenyl group, acenaphthyl group, fluorenyl group, heptalenyl group, naphthacenyl group, pyrenyl group, biphenyl group and terphenyl group. mentioned.
The aryl group may be a heteroaryl group that contains a heteroatom in place of at least one carbon atom in the ring structure. Examples of the heteroaryl group include furanyl group, thienyl group, pyranyl group, sulfanylpyranyl group, pyrrolyl group, imidazoyl group, oxazolyl group, thiazolyl group, pyrazolyl group, pyridyl group, isobenzofuranyl group, benzofuranyl group and isochromenyl group. , chromenyl, indolyl, isoindolyl, benzimidazolyl, xanthenyl, acridinyl and carbazolyl groups.

Substituents that R ³ and R ⁴ may have include alkyl groups, hydroxy groups, halogen atoms, nitro groups, amino groups, and alkyl-substituted amino groups. When R ³ and R ⁴ have substituents, the number of carbon atoms including the substituents is preferably the number of carbon atoms described above.
A fluorine atom, a chlorine atom, a bromine atom etc. are mentioned as a halogen atom. Alkyl groups as R ³ and R ⁴ can be selected from the same options as alkyl groups for R ¹ . The alkyl group possessed by the above alkyl-substituted amino group can be selected from the same options as the alkyl group for R ¹ .

In the method for synthesizing the alkenyl compound A, the reaction is performed in the presence of an amino acid, and the amino acid serves as a catalyst for forming a carbon-carbon bond between the first compound and the second compound. can play a role.

By using an amino acid as a catalyst for forming a carbon-carbon bond between the first compound and the second compound, the target alkenyl compound can be obtained in high yield and efficiency. Furthermore, as will be described later, it is possible to suppress the coloring of the object by a simple experimental operation.

Amino acids are more soluble in water than ordinary organic bases such as pyrrolidine, piperidine and triethylamine. It is possible to easily separate the object and the catalyst by extraction work using .

In addition, when alkylamines such as pyrrolidine and piperidine are used as a catalyst for the carbon-carbon bond formation reaction between the first compound and the second compound, the target product itself is not colored. However, as will be described later, the reaction solution after the carbon-carbon bond forming reaction may sometimes be observed to be colored due to impurities derived from oxidation of the alkylamines by heating. In particular, even a slight coloration may not be permitted in order to use the target product as an electronic material, an optical material, a drug, or the like. Therefore, if the reaction solution is colored, the purification process may be complicated.

Even when the obtained target product is used in a reaction such as polymerization, the reaction may be inhibited by impurities that cause coloration. Therefore, once colored, a complicated purification step may be required, especially when the above target product is used as a raw material for electronic materials, optical materials, pharmaceuticals, and the like.

Specific examples of amino acids used as catalysts include glycine, alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, β - such as alanine, sarcosine and proline.

In the method for synthesizing the alkenyl compound A, one or more of the above amino acids may be used. Since amino acids are generally highly water-soluble, when the alkenyl compound has fat solubility, the alkenyl compound A can be easily isolated by performing an extraction operation using water and an organic solvent after the reaction. Sometimes. Glycine, alanine, sarcosine, and the like, which are particularly highly water-soluble, are sometimes preferred as amino acids used as catalysts.

When an amino acid is used as a catalyst, the amount used is preferably 0.01 to 1 equivalent (molar ratio) relative to the second compound, and from the viewpoint of economy, it is about 0.01 to 0.2 equivalent. It is more preferable to have However, when the first compound or the second compound is more expensive than the amino acid, it is possible to increase the amount of the amino acid used and reduce the amount of the first compound or the second compound used. . For example, it may be possible to reduce the production cost by using 1 or more molar equivalents of an amino acid with respect to the first compound or the second compound.

In the method for synthesizing the alkenyl compound A, the amine used as a solvent includes, for example, straight-chain, straight-chain and branched alkylamines (methyl, ethyl, alkyl groups having 3 carbon atoms (n- propyl, iso-propyl), alkyl groups with 4 carbon atoms (alkylamines with up to 20 carbon atoms such as n-butyl, iso-butyl, sec-butyl, tert-butyl); cyclic amines such as piperidine and pyrrolidine aromatic amines such as pyridine and aniline; and the like.

Amines containing heteroatoms such as morpholine and N-hydroxylamine can also be used as solvents. Amines that function as polymerization inhibitors, such as N-hydroxylamine, can also be used as solvents.

Among the above amines, pyridine is particularly desirable from the viewpoint of reaction efficiency and economy. When synthesizing an unsaturated carboxylic acid as the alkenyl compound A, etc., the inclusion of an amine in the solvent improves the solubility of the target substance, thereby suppressing the adhesion of the target substance to the reaction vessel, etc., and after the reaction processing becomes easier.

As described above, when heating is performed in the presence of amines, a coloring phenomenon may be observed due to impurities generated by oxidation of the amines due to heating. , By using an amino acid as a catalyst for the carbon-carbon bond formation reaction between the first compound and the second compound, the reaction proceeds quickly, so that the heating time is shortened and coloring due to oxidation of amines is prevented. Minimized.

By using an amine as a solvent, particularly when the target product is an unsaturated carboxylic acid or when the unsaturated carboxylic acid is passed through during the reaction, the unsaturated carboxylic acid is easily dissolved in the solvent, and the reaction progresses. can be accelerated, the adhesion of unsaturated carboxylic acid to the reaction vessel is suppressed, and post-treatment after the reaction is simplified.

In the method for synthesizing the alkenyl compound A, the solvent may include, in addition to the amine, hydrocarbon solvents, ethers, esters, amides, sulfur-containing solvents, halogen solvents and solvents having a nitrile group. In addition, it is preferable that the amine content in the solvent is 30% by mass or more, and the content of the solvent other than the amine is preferably 70% by mass or less. Examples of the hydrocarbon solvent include saturated or unsaturated hydrocarbon compounds such as pentane, hexane, cyclohexane, heptane, octane, hexene, octene, and cyclooctene; and aromatic compounds such as toluene, benzene, xylene, and mesitylene. Hydrocarbon compounds can be used.

As the ethers, for example, ethers having a hydrocarbon group such as diethyl ether, diisopropyl ether and dibutyl ether can be used. It may also be possible to use ethers with multiple oxygen atoms such as 1,2-dimethoxyethane. As the esters, for example, esters synthesized from carboxylic acids and alcohols such as ethyl acetate and butyl acetate can be used. Examples of amides that can be used include dimethylformamide and dimethylacetamide. Examples of the sulfur-containing solvent include carbon disulfide and dimethylsulfoxide. Examples of the organic halogen solvent include methylene chloride, chloroform and carbon tetrachloride. Solvents having a nitrile group include, for example, acetonitrile, propionitrile and butyronitrile. Solvents having multiple types of functional groups such as ether groups and ester groups such as propylene glycol 1-monomethyl ether 2-acetate may also be used.

In the method for synthesizing the alkenyl compound A, R ² is a substituent having Hammett's substituent constant σ _p greater than zero. The substituent having Hammett's substituent constant σ _p greater than 0 includes an electron-withdrawing group. As a result, the negative charge on the carbon atom connecting the R ¹ OCO— group and the R ² group in the first compound represented by the above formula (1) is stabilized, and the hydrogen atom on the carbon atom becomes a proton. A reaction that desorbs as occurs easily. Here, the Hammett substituent constant σ in the present invention is obtained by the empirical rule proposed by LP Hammett in 1935 in order to quantitatively discuss the influence of substituents on the reaction or equilibrium of benzene derivatives (σp value and the sum of the σm value and the σo value).
Of the substituent constants determined by Hammett's rule, the σp value and σm value are, for example, JA Dean ed., "Lange's Handbook of Chemistry" 12th edition, 1979 (McGraw-Hill) and "Kagaku no Ryori" extra edition, No. 122. , 96-103, 1979 (Nankodo). Furthermore, the σo value considered for the effect of steric hindrance is, for example, Nuclear magnetic resonance studies of ortho-substituted phenols in dimethyl sulfoxide solutions. Electronic effects of ortho substituents. J. Am. Chem. SoC., 1969, 91 (2), pp379 -388, by M. Thomas and James G. Traynham.

Particularly preferred as R ² are electron-withdrawing groups other than halogen atoms. This is because when R ² is a halogen atom, a reaction in which the halogen atom is eliminated may also occur, and a hydrogen atom on the carbon atom connecting between the carboxyl group or ester group containing R ¹ and R ² This is because the selectivity of the elimination reaction of is lowered.

Typical examples of R ² are, for example, cyano group, nitro group, perfluoroalkyl group, alkylcarbonyl group, alkyloxycarbonyl group and the like. The above ester group may have a substituent such as an alkyl group, alkenyl group, carboxyl group, alkynyl group or aryl group.

In any of the above methods for synthesizing an alkenyl compound ^, in the following reaction formula, the methylene group (the ^methylene group) is particularly activated because both R ² and R ¹ OCO-- are electron withdrawing groups.

By setting the reaction temperature in the range of 50 to 200° C. in the method for synthesizing the alkenyl compound A, R ¹ OCO— can be easily eliminated. Especially when R ¹ is a hydrogen atom, a decarboxylation reaction easily occurs.

In the method for producing the alkenyl compound A, R ² is preferably a substituent represented by the following formula (2). In addition, in the following formula (2), R ⁵ is selected from the same options as R ¹ above. By using such a substituent, for example, when R ⁵ is a hydrogen atom, an unsaturated carboxylic acid is produced. When R ⁵ is an optionally substituted alkyl group, an unsaturated ester is produced.

A method for producing the alkenyl compound A according to one embodiment of the present invention includes the following two steps.
(First step) the first compound represented by the above formula (1) and the second compound represented by the above formula (3) in the presence of an amino acid in a solvent containing an amine in the range of 50 to 200 ° C. to obtain an alkenyl compound represented by the following formula (B).

In formula (B) above, R ² is selected from the same options as R ² in formula (1) above, and each of R ³ and R ⁴ is selected from the same options as R ³ and R ⁴ in formula (3) above. be.

(Second step) After the first step, a step of heating the second compound at a second temperature higher than the first temperature to obtain the upper alkenyl compound A.

A reaction diagram of the method for producing the alkenyl compound A is illustrated below.

In the method for producing alkenyl compound A, the first temperature is preferably 50 to 200° C., and the second temperature is more preferably higher than the first temperature. More preferably, the first temperature is 50-100°C. By setting the first temperature in the range of 50 to 100° C., for example, the decarboxylation reaction of only one molecule as shown in the above reaction formula occurs, and the alkenyl compound B may be obtained with high selectivity. be. Further, in the method for synthesizing the alkenyl compound A, by setting the first temperature in the range of 50 to 100° C., the thermal decomposition of the second compound is particularly suppressed, and the material balance may be improved. . Furthermore, by setting the first temperature in the range of 60 to 80° C., the decomposition of the first compound and the like and the coloring after the reaction are further suppressed.
The alkenyl compound B can be selectively obtained in the above reaction when the substituent of R ² is other than the substituent represented by the above formula (2).

As the first compound, a compound having two carboxyl groups with one methylene group sandwiched therebetween, such as malonic acid, or a compound having two ester groups with one methylene group sandwiched therebetween, such as an ester of malonic acid, can be used. When used, a thermal decomposition reaction such as decarboxylation is likely to occur, so by appropriately setting the first temperature, the thermal decomposition reaction can be controlled before the reaction with the second compound. can. If it decomposes, it is preferable to add the first compound in the decomposed amount. In the method A for synthesizing the alkenyl compound, setting the first temperature in the range of 50 to 100° C. may suppress thermal decomposition of the first compound and improve the material balance.

In the method for synthesizing the alkenyl compound A, the second compound is preferably a compound represented by the following formula (4).

In the above formula (4), each of R ⁶ to R ⁹ is, independently of each other, a hydrogen atom; a hydroxy group; a cyclic alkyl group; and a linear, branched or cyclic alkoxy group having 1 to 30 carbon atoms which may have a substituent; The alkoxy group may contain a divalent heteroatom-containing group in place of at least one methylene group contained in the alkyl group and the alkoxy group.
When R ⁶ to R ⁹ have substituents, the number of carbon atoms including the substituents is preferably the number of carbon atoms described above.
The heteroatom-containing groups that R ⁶ to R ⁹ may have include the same heteroatom-containing groups as the above heteroatom-containing groups for R ³ and R ⁴ .

In the method for synthesizing the alkenyl compound A, the R ¹ OCO- group is preferably eliminated by decarboxylation in the reaction at 50 to 200°C.

In the method for producing the alkenyl compound A, after the first step, the first compound and the second compound are further heated in the solvent at a second temperature higher than the first temperature. a second step of allowing Preferably, the first temperature is set in the range of 50 to 100.degree. C., and the second temperature is set in the range of 100 to 200.degree.

In this method for producing alkenyl compound A, by setting the first temperature in the range of 50 to 100° C., for example, when compound (1a) shown in the following reaction formula is used as the first compound, compound ( 1a) is a reaction in which one molecule of carbon dioxide is eliminated after suppressing the thermal decomposition of a compound that is normally easily thermally decomposed because it has an R ¹ OCO-- group and an R ⁵ OCO-- group with one methylene group interposed therebetween. A carbon-carbon bond forming reaction can occur with Furthermore, by setting the second temperature higher than the first temperature after the carbon-carbon bond formation reaction, the elimination reaction of the second molecule of carbon dioxide proceeds, and two An alkenyl compound A having two hydrogen atoms on the carbon atom on the side of the two carbon atoms of the heavy bond that is not the carbon atom to which R ³ and R ⁴ are bonded is produced.

In any of the methods for producing alkenyl compound A described above, it is preferable that the second compound is a compound represented by the following formula (4), and the alkenyl compound is a hydroxystyrene derivative. By having at least one hydroxy group on the benzene ring of the second compound, a carbon-carbon bond forming reaction accompanied by elimination of carbon dioxide in the first molecule between the first compound and the second compound The elimination reaction of the second molecule of carbon dioxide after is likely to occur, and the yield of the corresponding hydroxystyrene derivative may be improved.

One aspect of the present invention is a production method of obtaining an alkenyl derivative using the alkenyl compound A obtained by the production method of the alkenyl compound A described above. In the method for producing the alkenyl derivative, when a hydroxy group-containing alkenyl compound is used as the second compound, the hydrogen atom of at least one hydroxy group is substituted with a protecting group to obtain the alkenyl derivative. It is characterized by having a step.
The hydroxy group-containing alkenyl compound is the second compound represented by the formula (3), in which at least one of R ³ and R ⁴ has at least one hydroxy group as a substituent.
Examples of the protecting group include an acetyl group, a t-butyl group, an alkoxyalkyl group such as a methoxymethyl group and a tetrahydropyranyl group, an alkyl group, or an organic silicon group having an aryl group as the hydrogen atom of the hydroxy group. is mentioned.
In one aspect of the method for producing an alkenyl derivative of the present invention, it is preferable to use a hydroxystyrene derivative as the hydroxy group-containing alkenyl compound. By substituting the hydrogen atom of at least one hydroxy group of the hydroxystyrene derivative with a protective group, the polymerizability of the hydroxystyrene derivative is suppressed, and the isolation or purification of the hydroxystyrene derivative by distillation or the like is facilitated.

It is preferable that the method for producing the alkenyl compound A described above further includes a step of substituting a hydrogen atom of at least one hydroxy group of the hydroxystyrene derivative to convert it to a protective group. Examples of the protective group include an acetyl group, a t-butyl group, an alkoxyalkyl group such as a methoxymethyl group and a tetrahydropyranyl group, an alkyl group, or an organosilicon group having an aryl group for the hydrogen atom of the hydroxy group. mentioned. By substituting the hydrogen atom of at least one hydroxy group of the hydroxystyrene derivative with a protective group in this manner, the polymerizability of the hydroxystyrene derivative is suppressed, and the isolation or purification of the hydroxystyrene derivative by distillation or the like is facilitated. becomes.

Among the protecting groups described above, an acetyl group is particularly preferably used, for example. That is, by using an acetoxystyrene derivative as the hydroxystyrene derivative, the polymerizability during isolation or purification is suppressed, and deprotection after polymerization is facilitated.

In the method for producing the alkenyl compound A, the first step and the second step are preferably performed continuously in the same reaction vessel. Here, "continuously" means that after the first step, the second step is performed in the same reaction vessel without transferring the reaction solution in the reaction vessel to another reaction vessel. means. By continuously carrying out the first step and the second step in the same reaction vessel in this way, the production time of the alkenyl compound can be shortened, and the manpower required for production can be reduced. It becomes possible and leads to the reduction of manufacturing cost.

It is preferable that the first and second steps in the method for producing the alkenyl compound A and the third step in the method for producing the alkenyl derivative are performed continuously in the same reaction vessel. Here, "continuously" means that after the first step, the second step is performed in the same reaction vessel without transferring the reaction solution in the reaction vessel to another reaction vessel, and It means that the third step is also carried out in the same reaction vessel as it is without being transferred to another reaction vessel. By continuously performing the first step to the third step in the same reaction vessel in this way, the time for producing the alkenyl compound can be shortened, and the manpower required for production can be reduced. This leads to a reduction in manufacturing costs. By performing the third step in the same container as the first step and the second step, for example, as in the example shown in Example 7, the hydrogen atom of the hydroxy group can be replaced by an acetyl group or the like. When converting to a protective group, the amino acid that functioned as a catalyst in the first step or the second step or the amine-based solvent used as a solvent can be used as a catalyst, so the material balance is high and there is little waste. Process construction becomes possible.

In the above method for producing an alkenyl derivative, an unsaturated carboxylic acid such as compound G may be passed through in the course of the reaction, as shown in the reaction formula below. In the reaction formula below, each of R ¹⁸ to R ²¹ may be independently a hydrogen atom or a substituent other than a hydrogen atom, and R ²² is, for example, a methyl group, a t-butyl group, an acetyl group, or a pivaloyl group. , a protecting group such as a benzoyl group.

As shown in the above reaction formula, compound H is produced from compound G by decarboxylation, and then the hydrogen atom of the hydroxy group on the benzene ring of compound H is substituted with a protecting group. Here, the decarboxylation reaction from compound G to compound H proceeds rapidly by heating to a temperature set in the range of 100°C to 250°C. is preferably heated at about 120°C to 140°C

In one aspect of the present invention, the first compound represented by the above formula (1b) and the second compound represented by the above formula (3) are combined in the presence of an amino acid in a solvent containing an amine at 50 to 200 A method for synthesizing an alkenyl compound B in which an alkenyl compound represented by the following formula (B) is produced by reacting in the range of °C.

The following are non-limiting examples of synthesizing compounds according to some aspects of the present invention.

<Synthetic production of α,β-unsaturated carboxylic acid>
A first compound comprising one methylene group and two electron-withdrawing groups bonded to the one methylene group, which is representative of the first compound above, and a representative of the second compound above A compound having a carbonyl group, which is a typical example, is stirred with an amino acid as a catalyst in a solvent containing an amine at an appropriate temperature for a certain period of time to produce the corresponding alkenyl compound. When the above two electron-withdrawing groups are both carboxyl groups or ester groups, an α,β-unsaturated carboxylic acid or an α,β-unsaturated ester is produced. Details of each are provided in Examples 1-4 below.

[Example 1] Investigation of catalyst 400 mg of 4-hydroxybenzaldehyde and 511 mg of malonic acid were dissolved in 1.2 g of pyridine, and 0.1 equivalent (molar ratio) of catalyst was added to 4-hydroxybenzaldehyde. Stir for 120 minutes at 80° C. under sealed conditions. The yield of 4-hydroxycinnamic acid is calculated by analyzing the resulting solution by liquid chromatography.
The Hammett substituent constant σp of the substituent corresponding to R ² in Formula (1) used in Example 1 is greater than zero.

[Evaluation of coloring due to impurities]
Also, the coloration of the obtained solution due to impurities is evaluated by the APHA value based on the Hazen color number. Specifically, the obtained reaction solution is diluted with methanol to a solution weight of 8 g, and the hue of this solution is evaluated.

As can be seen from Table 1, for example, when glycine, DL-methionine, DL-α-alanine and DL-β-alanine were used as catalysts, the reaction yield was as high as almost 100%, and 4-hydroxycinnamon was obtained. Coloration is suppressed at the same time that acid is obtained.

[Example 2] Examination of solvents 400 mg of 4-hydroxybenzaldehyde and 511 mg of malonic acid were dissolved in 1.2 g of each solvent shown in Table 2 below, and 0.1 equivalent of glycine relative to 4-hydroxybenzaldehyde was added to this solution. Add and stir for 120 minutes at 80° C. under sealed conditions. The yield of 4-hydroxycinnamic acid is calculated by analyzing the resulting solution by liquid chromatography.

As can be seen from Table 2, for example, when pyridine and piperidine are used as solvents, 4-hydroxycinnamic acid can be obtained in a high reaction yield of almost 100%. This concludes that the use of an amine-based solvent improves the reaction efficiency in the reaction between the first compound and the second compound in the presence of an amine.

[Example 3] Synthesis of 4-hydroxycinnamic acid 20 g of 4-hydroxybenzaldehyde and 25.56 g of malonic acid are dissolved in 100 g of pyridine, and 1.23 g of glycine is added to this solution. The solution is stirred at 80° C. for 120 minutes under atmospheric pressure. After completion of the reaction, the solvent of the resulting solution was distilled off, 200 g of chloroform was added, and the mixture was stirred for several minutes to reprecipitate, followed by suction filtration and washing with chloroform to obtain 26.8 g of 4-hydroxycinnamic acid as powder. obtained (100% yield).

This reaction can also be used to synthesize aryl-substituted cinnamic acids with various substituents.

[Example 4] Examination of substrate (aryl-substituted aldehyde)
1.5 g of substituted benzaldehyde and 1.5 equivalents (molar ratio) of malonic acid relative to the substituted benzaldehyde are dissolved in 4.5 g of pyridine, 0.1 equivalent of glycine relative to the substituted benzaldehyde is added to the solution, and the mixture is sealed. Stir at 80° C. for 180 minutes. After completion of the reaction, the solvent of the resulting solution was distilled off, 10 times the weight of the substituted benzaldehyde was added to chloroform, and the mixture was stirred for several minutes to reprecipitate, followed by suction filtration and washing with chloroform to remove the substituted cinnamic acid. Obtained as a powder.
The Hammett substituent constant σp of the substituent corresponding to R ² in Formula (1) used in Example 4 is greater than zero.

[Example 5] Synthesis of 4-methyl-2-pentenoic acid The reaction according to the present invention can also be used to synthesize alkyl-substituted α,β-unsaturated carboxylic acids. Details are given below. 10 g of isobutyraldehyde and 21.6 g of malonic acid are dissolved in 30 g of pyridine and 1.04 g of glycine are added to this solution. The solution is stirred at 80° C. for 120 minutes under atmospheric pressure. After completion of the reaction, 20 g of methanol is added to the obtained solution and washed with 20 g of hexane. By evaporating the solvent from this solution, 15.6 of 4-methyl-2-pentenoic acid was obtained as a colorless oil (yield 99%).
The Hammett substituent constant σp of the substituent corresponding to R ² in Formula (1) used in Example 5 is greater than zero.

[Example 6] Synthesis of 3-(4-hydroxyphenyl)propenenitrile This reaction can also be used to synthesize α,β-unsaturated nitrile compounds. Details are given below. 1.5 g of 4-hydroxybenzaldehyde and 1.57 g of cyanoacetic acid are dissolved in 4.5 g of pyridine, 0.092 g of glycine is added to this solution and stirred at 80° C. for 180 minutes under sealed conditions. After completion of the reaction, the solvent of the resulting solution is distilled off, 10 times the weight of the substituted benzaldehyde is added to chloroform, and the mixture is stirred for several minutes to reprecipitate, followed by suction filtration and washing with chloroform. -hydroxyphenyl)propenenitrile are obtained as a powder (89% yield).
The Hammett substituent constant σp of the substituent corresponding to R ² in Formula (1) used in Example 6 is greater than zero.

[Example 7] Synthesis of 4-acetoxystyrene This reaction can also be used to synthesize a hydroxystyrene protected body that is useful as a raw material for photosensitive materials, plastics, resins for solid-phase synthesis, etc., by appropriately conducting the reaction in the same vessel. can be used.
Details are given below. 80 g of 4-hydroxybenzaldehyde and 102.3 g of malonic acid are dissolved in 240 g of pyridine and 4.92 g of glycine are added to this solution. The solution is stirred at 80° C. for 120 minutes under atmospheric pressure and then heated to reflux at 140° C. for 8 hours. 100.3 g of acetic anhydride is added to the resulting solution and stirred at 80° C. for 2 hours under atmospheric pressure. Gas chromatography-mass spectrometry shows a conversion of 65% to 4-acetoxystyrene. After completion of the reaction, the solvent is distilled off from the resulting solution under reduced pressure, 240 g of hexane and 80 g of 1% hydrochloric acid are added, and the mixture is stirred for several minutes. Solids precipitated by these operations are separated by filtration, the resulting organic layer is washed with water, and the solvent is distilled off under reduced pressure to obtain 50.93 g of highly pure acetoxystyrene (yield: 48%).
The Hammett substituent constant σp of the substituent corresponding to R ² in Formula (1) used in Example 7 is greater than zero.

[Example 8] Synthesis of 4-acetoxystyrene 80 g of 4-hydroxybenzaldehyde and 102.3 g of malonic acid are dissolved in 240 g of pyridine, and 4.92 g of glycine is added to this solution. The solution is stirred at 80° C. for 120 minutes under atmospheric pressure. After that, 66.3 g of triethylamine is added to the resulting solution and heated to reflux at 140° C. for 8 hours. 100.3 g of acetic anhydride is added to the resulting solution and stirred at 80° C. for 2 hours under atmospheric pressure. Gas chromatography-mass spectrometry shows a conversion to 4-acetoxystyrene of 82%. After completion of the reaction, the solvent is distilled off from the obtained solution under reduced pressure, 240 g of hexane and 80 g of 2% by mass hydrochloric acid are added, and the mixture is stirred for several minutes. After washing the obtained organic layer with water, the solvent is distilled off under reduced pressure, and 80.20 g of high-purity acetoxystyrene is obtained by vacuum distillation (yield: 76%).

[Example 9] Synthesis of 3,4-diacetoxystyrene 80 g of 3,4-dihydroxybenzaldehyde and 120.5 g of malonic acid are dissolved in 320 g of pyridine, and 4.35 g of glycine is added to this solution. The solution is stirred at 80° C. for 120 minutes under atmospheric pressure. After that, 58.6 g of triethylamine is added to the resulting solution and heated to reflux at 140° C. for 8 hours. 177.4 g of acetic anhydride is added to the resulting solution and stirred at 80° C. for 2 hours under atmospheric pressure. After completion of the reaction, the solvent is distilled off from the resulting solution under reduced pressure, 240 g of toluene and 80 g of 2% by mass hydrochloric acid are added, and the mixture is stirred for several minutes. After washing the obtained organic layer with water, the solvent is distilled off under reduced pressure, and 73.02 g of 3,4-diacetoxystyrene is obtained (yield: 57%).

By using the production method according to one aspect of the present invention as described above, it is possible to produce alkenyl compounds such as α,β-unsaturated carboxylic acids useful as various starting materials in high yields. Furthermore, by utilizing the following reaction, it is highly advantageous because it can be efficiently converted into an industrially important styrene derivative.

Claims (5)

A hydrogen atom of at least one hydroxy group of a hydroxy group-containing alkenyl compound having at least one hydroxy group obtained by a method for producing an alkenyl compound represented by the following formula (A) including the following first step and second step: A production method for obtaining an alkenyl derivative, comprising a third step of converting to a protecting group by substitution to obtain an alkenyl derivative, wherein the first step, the second step and the third step are continuously performed. A method for producing an alkenyl derivative, wherein the reaction is performed in the same reaction vessel as
(First step) a first compound which is malonic acid or a malonic acid ester having an optionally substituted linear, branched or cyclic alkyl group having 1 to 30 carbon atoms; , and a second compound represented by the following formula (3) are reacted in a solvent containing an amine in the presence of an amino acid at a first temperature set in the range of 50 to 200 ° C., and represented by the following formula (B). obtaining an alkenyl compound comprising
The above amino acids are glycine, alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, β-alanine, sarcosine and proline. At least one selected from the group consisting of;

(In the above formula (3), R ³ is a hydrogen atom, and R ⁴ is a linear, branched or cyclic alkyl group having 1 to 30 carbon atoms which may have a substituent; Linear, branched or cyclic alkenyl group optionally having 1 to 30 carbon atoms; Linear, branched or cyclic alkynyl group optionally having 1 to 30 carbon atoms and an aryl group having 6 to 30 carbon atoms which may have a substituent; R ⁴ has at least one hydroxy group as a substituent,
The alkyl group, the alkenyl group and the alkynyl group may contain a heteroatom-containing group in place of at least one methylene group contained in the alkyl group, the alkenyl group and the alkynyl group, and the aryl group is A heteroatom may be included in place of at least one carbon atom in the ring structure. )

(In the formula (B), R ² is a carboxyl group derived from the malonic acid or an alkyloxycarbonyl group derived from the malonic acid ester, and each of R ³ and R ⁴ is R ³ of the formula (3). and from the same options as ^R4 .)
(Second step) After the first step, a step of heating the second compound at a second temperature higher than the first temperature to obtain an alkenyl compound represented by the following formula (A).

(In Formula (A) above, each of R ³ and R ⁴ is selected from the same options as R ³ and R ⁴ in Formula (3) above.) The method for producing an alkenyl derivative according to claim 1, wherein the first temperature is set in the range of 50 to 100°C, and the second temperature is set in the range of 100 to 200°C. The second compound is a compound represented by the following formula (4),
3. The method for producing an alkenyl derivative according to claim 1 or 2, wherein the alkenyl compound A is a hydroxystyrene derivative.

(In the above formula (4), R ⁶ to R ⁹ each independently represent a hydrogen atom; a hydroxy group; a linear, branched or cyclic chain having 1 to 30 carbon atoms which may be substituted; and a linear, branched or cyclic alkoxy group having 1 to 30 carbon atoms which may have a substituent;
The alkyl group and the alkoxy group may contain a heteroatom-containing group instead of at least one methylene group contained in the alkyl group and the alkoxy group. ) 2. The method for producing an alkenyl derivative according to claim 1 , wherein said protecting group is an acetyl group. The production method according to any one of claims 1 to 4 , wherein the amine is at least one selected from the group consisting of alkylamines having up to 20 carbon atoms, cyclic amines and aromatic amines.