JP2021095363A - Method of producing halogenated acrylic acid ester - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method capable of producing a halogenated acrylic acid ester by a safe and simple method and a method suitable for industrial production without using a highly toxic raw material. be. The present invention is represented by the formula (4), which comprises a step of reacting a compound represented by the formula (1) with a compound represented by the formula (2) in the presence of a base. The present invention relates to a method for producing a compound to be produced. [Each symbol in the formula is as described in the specification. ] [Selection diagram] None

Description

The present invention relates to a method for producing a halogenated acrylic acid ester and a synthetic intermediate thereof.

Halogenated acrylic acid esters, especially α-fluoroacrylic acid esters, are polymer monomers such as optical materials for optical fiber sheath materials, intermediates for paints, intermediates for semiconductor resist materials, and synthetic intermediates for pharmaceuticals. It is useful as such.

As a method for producing α-fluoroacrylic acid ester, α-fluoroacetate is reacted with oxalic acid in the presence of sodium methoxide, and the produced enol sodium salt intermediate is reacted with paraformaldehyde to form α-fluoroacrylic acid. Method for Producing Methyl Acid (Patent Document 1);
A method for producing methyl α-fluoroacrylate by reacting a 1-fluoroethane derivative with carbon monoxide and methanol in the presence of a transition metal catalyst and a base is known (Patent Document 2).

The method of Patent Document 1 is difficult to handle and cannot be safely performed because of the high toxicity of α-fluoroacetate. Moreover, since it is a reaction of two steps, it cannot be said that it is a simple method.
The method of Patent Document 2 is difficult to handle and cannot be safely performed because carbon monoxide is highly toxic. Moreover, since the reaction is carried out in an autoclave, it cannot be said that the method is suitable for industrial production.

CN 102211998 A WO 2014/034906 A1

An object of the present invention is to provide a method capable of producing a halogenated acrylic acid ester by a safe and convenient method and a method suitable for industrial production without using a highly toxic raw material.

As a result of diligent studies to solve the above problems, the present inventors have obtained a route using a compound represented by the following formula (1), which is easily available and has low toxicity, as a raw material in a safe and convenient method. , Have found that a halogenated acrylic acid ester can be produced by a method suitable for industrial production, and have completed the present invention.

That is, the present invention is as follows.
[1]
Including the step of reacting the compound represented by the formula (1) (hereinafter, also referred to as compound (1)) with the compound represented by the formula (2) (hereinafter, also referred to as compound (2)) in the presence of a base. A method for producing a compound represented by the formula (4) (hereinafter, also referred to as compound (4)).

[During the ceremony,
X ¹ , X ² and X ³ independently represent halogen atoms, respectively.
Y represents a halogen atom,
R represents a C _1-8 alkyl group, a C _3-8 cycloalkyl group, a C _7-14 aralkyl group or a C _6-10 aryl group.
Here, the C _1-8 alkyl group includes a halogen atom, a cyano group, a C _1-4 alkoxy group, a C _1-4 haloalkoxy group, an amino group which may be protected, and a carboxyl group which may be protected. , May be substituted with a group selected from a hydroxy group, which may be protected, a sulfanyl group, which may be protected, and a vinyl group.
The C _3-8 cycloalkyl group, C _7-14 aralkyl group and C _6-10 aryl group are a halogen atom, a cyano group, a C _1-4 alkyl group, a C _1-4 haloalkyl group and a C _1-4 alkoxy group. , C _1-4 haloalkoxy groups, optionally protected amino groups, optionally protected carboxyl groups, optionally protected hydroxy groups, optionally protected sulfanyl and vinyl groups Each group may be substituted. ]
[2]
The production method according to the above [1], wherein the reaction is carried out in a reaction system containing water.
[3]
The production method according to the above [1] or [2], wherein the reaction is carried out under a solvent containing water.
[4]
The production method according to the above [1] or [2], wherein water is added during the reaction.
[5]
The production method according to any one of the above [1] to [4], wherein the base is an alkali metal C _{1-4 alkoxide.}
[6]
The production method according to the above [5], wherein R in the formula (2) is a C _1-4 alkyl group and the base is RONa or ROK, which is used in the form of a solution of ROH.
[7]
The production method according to any one of the above [1] to [4], wherein the base is an alkali metal hydroxide and is used in the form of an aqueous solution.
[8]
The production method according to any one of the above [1] to [7], wherein the reaction is carried out in the range of 30 to 180 ° C.
[9]
The production method according to any one of the above [1] to [8], wherein Y is a fluorine atom.
[10]
The production method according to any one of the above [1] to [9], wherein R is a _{C1-2 alkyl group.}
[11]
The production method according to any one of the above [1] to [10], wherein both X ² and X ^{3 are fluorine atoms.}
[12]
The production method according to any one of the above [1] to [11], wherein X ^{1 is a fluorine atom.}

[13]
The compound represented by the formula (3), which comprises reacting the compound represented by the formula (1) with the compound represented by the formula (2) in the presence of a base (hereinafter, also referred to as the compound (3)). The manufacturing method of).

[During the ceremony,
X ¹ , X ² and X ³ independently represent halogen atoms, respectively.
Y represents a halogen atom,
R represents a C _1-8 alkyl group, a C _3-8 cycloalkyl group, a C _7-14 aralkyl group or a C _6-10 aryl group.
Here, the C _1-8 alkyl group includes a halogen atom, a cyano group, a C _1-4 alkoxy group, a C _1-4 haloalkoxy group, an amino group which may be protected, and a carboxyl group which may be protected. , May be substituted with a group selected from a hydroxy group, which may be protected, a sulfanyl group, which may be protected, and a vinyl group.
The C _3-8 cycloalkyl group, C _7-14 aralkyl group and C _6-10 aryl group are a halogen atom, a cyano group, a C _1-4 alkyl group, a C _1-4 haloalkyl group and a C _1-4 alkoxy group. , C _1-4 haloalkoxy groups, optionally protected amino groups, optionally protected carboxyl groups, optionally protected hydroxy groups, optionally protected sulfanyl and vinyl groups Each group may be substituted. ]

[14]
A method for producing a compound represented by the formula (4), which comprises reacting the compound represented by the formula (3) in the presence of water.

[During the ceremony,
X ² and X ³ independently represent halogen atoms, respectively.
Y represents a halogen atom,
R represents a C _1-8 alkyl group, a C _3-8 cycloalkyl group, a C _7-14 aralkyl group or a C _6-10 aryl group.
Here, the C _1-8 alkyl group includes a halogen atom, a cyano group, a C _1-4 alkoxy group, a C _1-4 haloalkoxy group, an amino group which may be protected, and a carboxyl group which may be protected. , May be substituted with a group selected from a hydroxy group, which may be protected, a sulfanyl group, which may be protected, and a vinyl group.
The C _3-8 cycloalkyl group, C _7-14 aralkyl group and C _6-10 aryl group are a halogen atom, a cyano group, a C _1-4 alkyl group, a C _1-4 haloalkyl group and a C _1-4 alkoxy group. , C _1-4 haloalkoxy groups, optionally protected amino groups, optionally protected carboxyl groups, optionally protected hydroxy groups, optionally protected sulfanyl and vinyl groups Each group may be substituted. ]

[15]
The formula (1) is characterized in that the compound represented by the formula (1) is reacted with the compound represented by the formula (2) in the presence of a base, and then the obtained reaction mixture is reacted in the presence of water. A method for producing a compound represented by 4).

[During the ceremony,
X ¹ , X ² and X ³ independently represent halogen atoms, respectively.
Y represents a halogen atom,
R represents a C _1-8 alkyl group, a C _3-8 cycloalkyl group, a C _7-14 aralkyl group or a C _6-10 aryl group.
Here, the C _1-8 alkyl group includes a halogen atom, a cyano group, a C _1-4 alkoxy group, a C _1-4 haloalkoxy group, an amino group which may be protected, and a carboxyl group which may be protected. , May be substituted with a group selected from a hydroxy group, which may be protected, a sulfanyl group, which may be protected, and a vinyl group.
The C _3-8 cycloalkyl group, C _7-14 aralkyl group and C _6-10 aryl group are a halogen atom, a cyano group, a C _1-4 alkyl group, a C _1-4 haloalkyl group and a C _1-4 alkoxy group. , C _1-4 haloalkoxy groups, optionally protected amino groups, optionally protected carboxyl groups, optionally protected hydroxy groups, optionally protected sulfanyl and vinyl groups Each group may be substituted. ]

[16]
A compound represented by the formula (3a).

[In the formula, X ² and X ³ independently represent a halogen atom, Y represents a halogen atom, and ^Ra represents a C _1-8 alkyl group. ]

According to the present invention, a halogenated acrylic acid ester can be produced by a safe and convenient method and a method suitable for industrial production without using a highly toxic raw material.

Hereinafter, the definition of the group used in the present specification will be described in detail. Unless otherwise stated, the group has the following definitions.

In the present specification, the compound represented by the formula is shown by assigning the number of the formula to "compound". For example, the compound represented by the formula (1) is represented as "compound (1)".
The numerical range represented by "-" or "-" in the present specification means a numerical range in which the numbers before and after "-" or "-" are the lower limit value or the upper limit value.
In the present specification, when the element symbol "C" with a numerical range of numbers before and after "-" is attached to the name of an arbitrary group, the numbers before and after "-" are the lower limit values. Alternatively, any group having an integer number of carbon atoms as the upper limit is shown. For example, an alkyl group having 1 to 3 carbon atoms may be referred to as "C _1-3 alkyl group", which is -CH ₃ , -C ₂ H ₅ , -C ₃ H _7, etc., respectively. Is shown. The same applies to other groups.

As used herein, the term "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

As used herein, the term "C _1-8 alkyl group" means a linear or branched saturated hydrocarbon group having 1 to 8 carbon atoms. _{Examples of the} "C 1-8 alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-. Examples thereof include dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl and the like, and C _1-4 alkyl groups are preferable.

In the present specification, the “C _1-4 alkyl group” means a linear or branched saturated hydrocarbon group having 1 to 4 carbon atoms. _{Examples of the} "C 1-4 alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, and a C _1-2 alkyl group is preferable.

In the present specification, the "C _1-2 alkyl group" means a linear or branched saturated hydrocarbon group having 1 to 2 carbon atoms. _{Examples of the} "C 1-2 alkyl group" include methyl and ethyl, with methyl being preferred.

As used herein, the term "C _1-4 alkoxy group" means a group represented by ^{the formula R 11} O- (where R ¹¹ represents a C _{1-4 alkyl group). Examples of the} "C 1-4 alkoxy group" include methoxy, ethoxy, propoxy, isopropoxy, butyloxy, isobutyloxy, sec-butyloxy and tert-butyloxy.

In the present specification, the "C _1-4 haloalkyl group" means a group in which one or more hydrogen atoms in the _{"C 1-4 alkyl group" are substituted with halogen atoms.} Examples of the "C _1-4 haloalkyl group" include fluoromethyl, 2-fluoroethyl, 3-fluoropropyl, 4-fluorobutyl, trifluoromethyl, difluoromethyl, perfluoroethyl, perfluoropropyl, chloromethyl and 2-chloroethyl. , Bromomethyl, 2-bromoethyl, iodomethyl, 2-iodoethyl and the like, with trifluoromethyl being preferred.

In the present specification, the “C _1-4 haloalkoxy group” means a group in which one or more hydrogen atoms in the _{“C 1-4 alkoxy group” are substituted with halogen atoms.} Examples of the "C _1-4 haloalkoxy group" include bromomethoxy, 2-bromoethoxy, 3-bromopropoxy, 4-bromobutoxy, iodomethoxy, 2-iodoethoxy, 3-iodopropoxy, 4-iodobutoxy, and the like. Fluoromethoxy, 2-fluoroethoxy, 3-fluoropropoxy, 4-fluorobutoxy, tribromomethoxy, trichloromethoxy, trifluoromethoxy, difluoromethoxy, perfluoroethoxy, perfluoropropoxy, perfluoroisopropoxy, 1,1,2,2- Examples thereof include tetrafluoroethoxy and 2-chloro-1,1,2-trifluoroethoxy.

In the present specification, the “C _3-8 cycloalkyl group” means a cyclic saturated hydrocarbon group having 3 to 8 carbon atoms. _{Examples of the} "C 3-8 cycloalkyl group" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

In the present specification, the "C _6-10 aryl group" means an aromatic hydrocarbon group having 6 to 10 carbon atoms. _{Examples of the} "C 6-10 aryl group" include phenyl, 1-naphthyl and 2-naphthyl, with phenyl being preferred.

As used herein, the term "C _7-14 aralkyl group" means a "C _1-4 alkyl group" _{substituted with a "C 6-10 aryl group".} Examples of the "C _7-14 aralkyl group" include benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, (1-naphthyl) methyl, (2-naphthyl) methyl and the like. , Benzyl is preferred.

Examples of the protecting group of the "optionally protected amino group" include tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, acetyl, trifluoroacetyl and the like.

Examples of the protecting group of the "optionally protected carboxy group" include methyl, ethyl, tert-butyl, benzyl and the like.

Examples of the protecting group of the "hydroxy group which may be protected" include benzyl, trityl and the like.

Examples of the protecting group of the "sulfanil group which may be protected" include methyl, ethyl, benzyl, trityl and the like.

Hereinafter, the definition of each group in the formulas (1) to (4) will be described.
X ¹ represents a halogen atom.
X ¹ is preferably a fluorine atom, a chlorine atom or a bromine atom, more preferably a fluorine atom or a chlorine atom, and particularly preferably a fluorine atom.

X ² and X ³ independently represent halogen atoms, respectively.
X ² and X ³ are preferably independently fluorine atoms or chlorine atoms, respectively, and particularly preferably both fluorine atoms.

Y represents a halogen atom.
Y is preferably a fluorine atom.

R represents a C _1-8 alkyl group, a C _3-8 cycloalkyl group, a C _7-14 aralkyl group or a C _6-10 aryl group.
Here, the C _1-8 alkyl group includes a halogen atom, a cyano group, a C _1-4 alkoxy group, a C _1-4 haloalkoxy group, an amino group which may be protected, and a carboxyl group which may be protected. , May be substituted with a group selected from a hydroxy group, which may be protected, a sulfanyl group, which may be protected, and a vinyl group.
The C _3-8 cycloalkyl group, C _7-14 aralkyl group and C _6-10 aryl group are a halogen atom, a cyano group, a C _1-4 alkyl group, a C _1-4 haloalkyl group and a C _1-4 alkoxy group. , C _1-4 haloalkoxy groups, optionally protected amino groups, optionally protected carboxyl groups, optionally protected hydroxy groups, optionally protected sulfanyl and vinyl groups Each group may be substituted.
As a specific example of R,
Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2- Trifluoroethyl, 3,3,3-trifluoropropyl, 2,2,2-trifluoropropyl, 1H, 1H, 2H, 2H-nonafluorohexyl, 1H, 1H, 2H, 2H-tridecafluorooctyl, 1H , 1H, 6H-decafluorohexyl, 1H, 1H, 2H, 2H, 8H-dodecafluorooctyl, methoxymethyl, 2-trifluoromethoxyethyl, hydroxymethyl, 5-hydroxypentyl, 7-hydroxyheptyl, 3-aminopropyl , 4-carboxypentyl, 6-mercaptohexyl;
Cyclopentyl, cyclohexyl, 4-hydroxycyclohexyl;
Phenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl;
Benzyl, 4-fluorobenzyl, (4-trifluoromethylphenyl) methyl;
Undecay-10-en-1-yl;
And so on.

_{R is preferably a C 1-8} alkyl group that may be substituted with an amino group that may be protected, more preferably a C _1-8 alkyl group, and even more preferably a C _1-4 alkyl. It is a group, more preferably a C _1-2 alkyl group, and particularly preferably methyl.

Hereinafter, the production method of the present invention will be described.
In the present invention, compound (4) is produced by a method including a step of reacting compound (1) with compound (2) in the presence of a base.

[Each symbol in the formula has the same meaning as above. ]
As the compound (1), a commercially available product can be used, or the compound (1) can be produced by a method known per se.
As the compound (1), a compound represented by the following formula (1a) is preferable.

[Each symbol in the formula has the same meaning as above. ]
Among ^{them, compound (1a) in which X 1} is a fluorine atom, a chlorine atom or a bromine atom, and X ² and X ³ are independently fluorine atoms or chlorine atoms, respectively, is preferable, and X ¹ is fluorine. A compound (1a) which is an atom or a chlorine atom and in which ^{both X 2} and X ³ are fluorine atoms is more preferable.

Specific examples of compound (1a) include 1-chloro-1,2,3-trifluoro-1-propene, 1,3-dichloro-1,2-difluoro-1-propene, 3-bromo-1,1. , 2-Trifluoro-1-propene, 3-chloro-1,1,2-trifluoro-1-propene, 1,1,2,3-tetrafluoro-1-propene are preferred, 3-chloro-1,3-chloro-1, 1,2-Trifluoro-1-propene and 1,1,2,3-tetrafluoro-1-propene are more preferable, and 1,1,2,3-tetrafluoro-1-propene is particularly preferable. Their structures are shown below.

The compound (1) may be either a cis form or a trans form, or a mixture thereof. In the case of a mixture, the mixing ratio is arbitrary.

As the compound (2), a commercially available product can be used.
_{As the compound (2), a C 1-8} alcohol which may be substituted with an amino group which may be protected is preferable, and methanol, ethanol, 1-propanol, 2-propanol, 3-aminopropanol and the like are preferable. Methanol and ethanol are more preferable, and methanol is particularly preferable.
The amount of compound (2) to be used is generally 0.001 to 10 mol, preferably 0.1 to 6.0 mol, per 1 mol of compound (1). Compound (2) may also serve as a reaction solvent, and the amount used in that case is the amount of solvent.

The base may be any base that can deprotonate the compound (2) and convert it into an anionic nucleophilic agent. For example, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide. _{Alkali metals C 1-4} alkoxides such as lithium methoxyd, sodium methoxyd, potassium methoxyd, lithium ethoxydo, sodium ethoxydo, potassium ethoxydo, potassium tert-butoxide; alkali metals such as lithium, sodium and potassium Alkali metal hydrides such as sodium hydroxide and lithium hydride; and phosphazene bases (iminophosphoran bases) having the following structures can be mentioned.

The base is preferably alkali metal hydroxides, alkali metal C _1-4 alkoxides or alkali metal hydrides, and more preferably alkali metal hydroxides or alkali metal C _1-4 alkoxides. is there. Suitable specific examples include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal C _1-4 alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide.
When the base is an alkali metal hydroxide, it is preferably used in the form of an aqueous solution.
When the base is an alkali metal C _1-4 alkoxide, it is preferably used in the form of an alcohol solution, and the alcohol is more preferably compound (2). That is, a preferred embodiment is an embodiment in which R in the formula (2) is a C _1-4 alkyl group and the base is RONa or ROK, and is used in the form of a ROH solution. Suitable specific examples are sodium methoxide / methanol solution (R = methyl), sodium ethoxide / ethanol solution (R = ethyl) and potassium tert-butoxide / tert-butanol solution (R = tert-butyl).
The amount of the base used is generally 0.001 to 10 equivalents, preferably 0.01 to 3.0 equivalents, relative to compound (1).

The reaction may be carried out in a solvent. Examples of the solvent include ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, methylcyclopentyl ether, tetrahydrofuran and 1,4-dioxane; N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone. , 1,3-Dimethyl-2-imidazolidinone and other amides; dimethyl sulfoxide and other sulfoxides; hexane, heptane, octane, cyclohexane and other saturated hydrocarbons; acetone, 2-butanone and other ketones; Examples include water, and these may be used as a mixture of two or more. A preferred solvent is N, N-dimethylformamide.
When the base is an alkali metal C _1-4 alkoxide and is used in the form of an alcohol solution, the reaction may be carried out without the above solvent.
The amount of the solvent used is usually 0.1 to 100 times the volume of compound (1).

The reaction is preferably carried out by adding (preferably dropping) a base to a mixture of compound (1) and compound (2) (including a solvent if necessary). Specifically, it is carried out by adding (preferably dropping) a base to a mixture obtained by adding compound (2) to a solution of compound (1) or a solvent of compound (1).
The reaction is usually carried out in the range of 30 to 180 ° C, preferably 60 to 130 ° C.
Completion of the reaction can be confirmed by thin layer chromatography or the like.

When water is present in the reaction system, the reaction between compound (1) and compound (2) proceeds to the formation of compound (4) via compound (3), but water is present in the reaction system. Otherwise, it will only produce compound (3).

[Each symbol in the formula has the same meaning as above. ]
Compound (3) reacts in the presence of water and is converted to compound (4).

[Each symbol in the formula has the same meaning as above. ]
Therefore, by carrying out the reaction between the compound (1) and the compound (2) in a reaction system containing water, the reaction can proceed to the production of the compound (4).

Specifically, the reaction is carried out in a reaction system containing water; the reaction is carried out in a solvent containing water; the reaction is carried out using an aqueous alkali metal hydroxide solution as a base; and the compound (2) containing water is used. The reaction is carried out; water is added during the reaction; and the like.
With respect to solvents containing water, N, N-dimethylformamide usually contains water in the range of 20 to 1300 ppm and tetrahydrofuran usually contains water in the range of 10 to 1800 ppm.
Regarding the water-containing compound (2), methanol usually contains water in the range of 100 to 5000 ppm, ethanol usually contains water in the range of 1 to 2000 ppm, and 2-propanol usually contains the range of 1 to 2000 ppm. Contains water.
In this specification, "ppm" is based on mass.
The amount of water in the reaction system is usually a catalytic amount with respect to 1 mol of compound (1).
It is considered that the catalytic amount of water exhibits a catalytic action on the compound (2), thereby promoting the reaction in which the compound (2) also reacts with the compound (3) to produce the compound (4). When water is present in a large amount instead of the catalytic amount, it is considered that it also acts as a raw material for reacting with the compound (3) to produce the compound (4).

The temperature of the reaction between compound (1) and compound (2) in a reaction system containing water is usually in the range of 30 to 180 ° C, preferably in the range of 60 to 130 ° C.
Completion of the reaction can be confirmed by thin layer chromatography or the like.

Alternatively, in a reaction system in the absence of water, compound (1) is reacted with compound (2) to give compound (3), which is then reacted in the presence of water to give compound (4). It may be manufactured.

In this case, as the solvent, a solvent containing no water is usually used, or a dehydrated solvent is used. Further, as the base, alkali metal C _1-4 alkoxides are preferably used. As the compound (2), a dehydrated compound (2) is used if necessary.

The temperature of the reaction between the compound (1) and the compound (2) in the reaction system in which water does not exist is usually in the range of 30 to 80 ° C., preferably in the range _{of, for example, when the base is an alkali metal C 1-4 alkoxide.} It is in the range of 50 to 80 ° C.

The reaction of compound (3) in the presence of water may be carried out after isolating compound (3) from the reaction mixture of compound (1) and compound (2), but since it can be easily carried out, compound It is preferable to carry out the reaction mixture of (1) and compound (2) as it is.
The temperature of the reaction of compound (3) in the presence of water is usually in the range of 80-180 ° C.
Completion of the reaction can be confirmed by thin layer chromatography or the like.

After completion of the reaction, the target compound (4) can be isolated and / or purified from the reaction mixture by a separation means such as concentration, crystallization, recrystallization, distillation, solvent extraction, distillation, chromatography and the like according to a conventional method. ..

Of the compound (3), the compound (3a) is a novel compound.

[In the formula, X ² and X ³ independently represent a halogen atom, Y represents a halogen atom, and ^Ra represents a C _1-8 alkyl group. ]
Among them, the compound (3a) in which ^{X 2} and X ³ are independently fluorine atoms or chlorine atoms, Y is a fluorine atom, and ^Ra is a C _{1-2 alkyl group is preferable.} A ^{compound (3a) in which both X 2} and X ³ are fluorine atoms, Y is a fluorine atom, and ^Ra is a C _1-2 alkyl group is more preferable.
Preferable specific examples of the compound (3a) include the following compounds.

Hereinafter, the present invention will be specifically described with reference to Examples, but the present invention is not limited to these examples.
[Analysis method]
The products obtained in Examples 1 to 3 were analyzed by GC and GC-MS. In each case, RTX-200 was used as the column, and the column was -20 ° C. for 5 min → 10 ° C./min → 250 ° C. for 20 min.
Moisture content was measured by the Karl Fischer titration method.

[Example 1]
0.77 g (1.3 M, N, N-dimethylformamide) of 1,1,2,3-tetrafluoro-1-propene ( ^{compound (1) in which X 1} , X ² , X ^{3 and Y are all fluorine atoms)} 0.22 g of methanol (water content 400 ppm) was added to the solution (water content 300 ppm), 0.01 g of a 48% potassium hydroxide aqueous solution was added thereto, and the mixture was stirred at 120 ° C. for 2 hours. By GC analysis, a conversion of 35%, CH ₂ = CF-CF ₂ OCH ₃ in a yield of 5%, and CH ₂ = CF-COOCH ₃ in a yield of 30% were obtained. Moreover, when GC-MS analysis was carried out, two new peaks were confirmed. One was confirmed to match the peak and fragment with _{CH 2} = CF-COOCH ₃ of the pure product. In addition, the parent fragment 126 and other fragments 95, 81, 31 and the like were confirmed, and it was confirmed that the reaction was carried out via _{the intermediate CH 2} = CF-CF ₂ OCH _3. When this solution was further reacted for 12 hours, a conversion rate of 100%, CH ₂ = CF-CF ₂ OCH ₃ in a yield of 4%, and CH ₂ = CF-COOCH ₃ in a yield of 96% were obtained.

[Example 2]
0.77 g (1.3 M, N, N-dimethylformamide) of 1,1,2,3-tetrafluoro-1-propene ( ^{compound (1) in which X 1} , X ² , X ^{3 and Y are all fluorine atoms)} 0.22 g of methanol (water content 1200 ppm) was added to the solution (water content 800 ppm), 0.06 g of a 28% sodium methoxide methanol solution was added thereto, and the mixture was stirred at 120 ° C. for 8 hours. By GC analysis, conversion rate was 100%, CH ₂ = CF-CF ₂ OCH ₃ was 7%, and CH ₂ = CF-COOCH ₃ was 93%. Moreover, when GC-MS analysis was carried out, CH ₂ = CF-CF ₂ OCH ₃ and CH ₂ = CF-COOCH ₃ were confirmed as in Example 1.

[Example 3]
0.77 g (1.3 M, N, N-dimethylformamide) of 1,1,2,3-tetrafluoro-1-propene ( ^{compound (1) in which X 1} , X ² , X ^{3 and Y are all fluorine atoms)} To a solution (water content 100 ppm), 1.64 g of a 28% sodium methoxide methanol solution (water content 20 ppm) was added, and the mixture was stirred at 50 ° C. for 14 hours. By GC analysis, a conversion rate of 91%, CH ₂ = CF-CF ₂ OCH ₃ at 71%, and CH ₂ = CF-COOCH ₃ at 19% were obtained. Moreover, when GC-MS analysis was carried out, CH ₂ = CF-CF ₂ OCH ₃ and CH ₂ = CF-COOCH ₃ were confirmed as in Example 1.

According to the present invention, a halogenated acrylic acid ester can be produced by a safe and convenient method and a method suitable for industrial production without using a highly toxic raw material.

Claims (16)

A method for producing a compound represented by the formula (4), which comprises a step of reacting a compound represented by the formula (1) with a compound represented by the formula (2) in the presence of a base.

[During the ceremony,
X ¹ , X ² and X ³ independently represent halogen atoms, respectively.
Y represents a halogen atom,
R represents a C _1-8 alkyl group, a C _3-8 cycloalkyl group, a C _7-14 aralkyl group or a C _6-10 aryl group.
Here, the C _1-8 alkyl group includes a halogen atom, a cyano group, a C _1-4 alkoxy group, a C _1-4 haloalkoxy group, an amino group which may be protected, and a carboxyl group which may be protected. , May be substituted with a group selected from a hydroxy group, which may be protected, a sulfanyl group, which may be protected, and a vinyl group.
The C _3-8 cycloalkyl group, C _7-14 aralkyl group and C _6-10 aryl group are a halogen atom, a cyano group, a C _1-4 alkyl group, a C _1-4 haloalkyl group and a C _1-4 alkoxy group. , C _1-4 haloalkoxy groups, optionally protected amino groups, optionally protected carboxyl groups, optionally protected hydroxy groups, optionally protected sulfanyl and vinyl groups Each group may be substituted. ] The production method according to claim 1, wherein the reaction is carried out in a reaction system containing water. The production method according to claim 1 or 2, wherein the reaction is carried out in a solvent containing water. The production method according to claim 1 or 2, wherein water is added during the reaction. The production method according to any one of claims 1 to 4, wherein the base is an alkali metal C _{1-4 alkoxide.} The production method according to claim 5, wherein R in the formula (2) is a C _1-4 alkyl group and the base is RONa or ROK, which is used in the form of a solution of ROH. The production method according to any one of claims 1 to 4, wherein the base is an alkali metal hydroxide and is used in the form of an aqueous solution. The production method according to any one of claims 1 to 7, wherein the reaction is carried out in the range of 30 to 180 ° C. The production method according to any one of claims 1 to 8, wherein Y is a fluorine atom. The production method according to any one of claims 1 to 9, wherein R is a _{C1-2 alkyl group.} The production method according to any one of claims 1 to 10, wherein X ² and X ^{3 are both fluorine atoms.} The production method according to any one of claims 1 to 11, wherein X ^{1 is a fluorine atom.} A method for producing a compound represented by the formula (3), which comprises reacting a compound represented by the formula (1) with a compound represented by the formula (2) in the presence of a base.

[During the ceremony,
X ¹ , X ² and X ³ independently represent halogen atoms, respectively.
Y represents a halogen atom,
R represents a C _1-8 alkyl group, a C _3-8 cycloalkyl group, a C _7-14 aralkyl group or a C _6-10 aryl group.
Here, the C _1-8 alkyl group includes a halogen atom, a cyano group, a C _1-4 alkoxy group, a C _1-4 haloalkoxy group, an amino group which may be protected, and a carboxyl group which may be protected. , May be substituted with a group selected from a hydroxy group, which may be protected, a sulfanyl group, which may be protected, and a vinyl group.
The C _3-8 cycloalkyl group, C _7-14 aralkyl group and C _6-10 aryl group are a halogen atom, a cyano group, a C _1-4 alkyl group, a C _1-4 haloalkyl group and a C _1-4 alkoxy group. , C _1-4 haloalkoxy groups, optionally protected amino groups, optionally protected carboxyl groups, optionally protected hydroxy groups, optionally protected sulfanyl and vinyl groups Each group may be substituted. ] A method for producing a compound represented by the formula (4), which comprises reacting the compound represented by the formula (3) in the presence of water.

[During the ceremony,
X ² and X ³ independently represent halogen atoms, respectively.
Y represents a halogen atom,
R represents a C _1-8 alkyl group, a C _3-8 cycloalkyl group, a C _7-14 aralkyl group or a C _6-10 aryl group.
Here, the C _1-8 alkyl group includes a halogen atom, a cyano group, a C _1-4 alkoxy group, a C _1-4 haloalkoxy group, an amino group which may be protected, and a carboxyl group which may be protected. , May be substituted with a group selected from a hydroxy group, which may be protected, a sulfanyl group, which may be protected, and a vinyl group.
The C _3-8 cycloalkyl group, C _7-14 aralkyl group and C _6-10 aryl group are a halogen atom, a cyano group, a C _1-4 alkyl group, a C _1-4 haloalkyl group and a C _1-4 alkoxy group. , C _1-4 haloalkoxy groups, optionally protected amino groups, optionally protected carboxyl groups, optionally protected hydroxy groups, optionally protected sulfanyl and vinyl groups Each group may be substituted. ] The formula (1) is characterized in that the compound represented by the formula (1) is reacted with the compound represented by the formula (2) in the presence of a base, and then the obtained reaction mixture is reacted in the presence of water. A method for producing a compound represented by 4).

[During the ceremony,
X ¹ , X ² and X ³ independently represent halogen atoms, respectively.
Y represents a halogen atom,
R represents a C _1-8 alkyl group, a C _3-8 cycloalkyl group, a C _7-14 aralkyl group or a C _6-10 aryl group.
Here, the C _1-8 alkyl group includes a halogen atom, a cyano group, a C _1-4 alkoxy group, a C _1-4 haloalkoxy group, an amino group which may be protected, and a carboxyl group which may be protected. , May be substituted with a group selected from a hydroxy group, which may be protected, a sulfanyl group, which may be protected, and a vinyl group.
The C _3-8 cycloalkyl group, C _7-14 aralkyl group and C _6-10 aryl group are a halogen atom, a cyano group, a C _1-4 alkyl group, a C _1-4 haloalkyl group and a C _1-4 alkoxy group. , C _1-4 haloalkoxy groups, optionally protected amino groups, optionally protected carboxyl groups, optionally protected hydroxy groups, optionally protected sulfanyl and vinyl groups Each group may be substituted. ] A compound represented by the formula (3a).

[In the formula, X ² and X ³ independently represent a halogen atom, Y represents a halogen atom, and ^Ra represents a C _1-8 alkyl group. ]