WO2021215450A1

WO2021215450A1 - METHOD FOR PRODUCING α-FLUOROACRYLIC ACID ESTER

Info

Publication number: WO2021215450A1
Application number: PCT/JP2021/016085
Authority: WO
Inventors: 誠松浦; 寿美石原; 將神原; 麻衣日高; 真也高野; 洋介岸川
Original assignee: ダイキン工業株式会社
Priority date: 2020-04-20
Filing date: 2021-04-20
Publication date: 2021-10-28
Also published as: JP2021172661A; CN115443262A; JP6985636B2

Abstract

The present invention addresses the problem of providing a method for producing an α-fluoroacrylic acid ester at a high yield using a compound containing a specific halogen ion. This problem can be solved by a method comprising a step A for causing contact between a compound represented by formula (2) (where R1 and R2 are the same or different alkyl groups) and at least one species of halogen ion, among others, selected from the group consisting of a chlorine ion and a bromine ion.

Description

Method for producing α-fluoroacrylic acid ester

The present disclosure relates to a method for producing an α-fluoroacrylic acid ester.

α-Fluoroacrylic acid esters are synthetic intermediates for pharmaceuticals (eg, antibiotics), synthetic intermediates for optical fiber sheath materials, synthetic intermediates for paint materials, synthetic intermediates for semiconductor resist materials, and functionality. It is useful as a polymer monomer and the like.
As a method for producing an α-fluoroacrylic acid ester, for example, in Patent Document 1, 2.91 g (50 mmol) of potassium fluoride, 55.1 mg (0.250 mmol) of dibutylhydroxytoluene (BHT), and dimethyl are provided in a 100 mL eggplant flask. 45.0 g (250 mmol) of 2-fluoro-2-hydroxymethylmalonate and 11.5 mL (14.5 g) of sulfolane were added and mixed, and the mixture was added and mixed at 90 ° C. for 15 minutes under normal pressure, followed by 105 ° C. under reduced pressure. It is described that the methyl 2-fluoroacrylate was obtained as a mixture with methanol by heating at 1 hour and distilled at the same time as the reaction, and the yield was 70%.

Japanese Unexamined Patent Publication No. 2014-141477

In order to improve the productivity of α-fluoroacrylic acid ester, a method with high yield is required.

The main object of the present disclosure is to provide a method for producing a high-yield α-fluoroacrylic acid ester using a compound containing a specific halogen ion.

The present inventors have made intensive studies, as a result, 2-fluoro-2-hydroxymethyl-malonic acid esters, and at least one halogen ion selected from the group consisting of chlorine ion and bromine ion, or formula: M _m X _n (In the formula, M is a cation, X is a chloride ion or a bromine ion, m and n are positive integers, and when m is 2 or more, each M is the same as each other. When n is 2 or more, each X may be the same as or different from each other.) By reacting with the compound represented by (), the α-fluoroacrylic acid ester can be obtained. It has been found that it can be obtained in high yield.

The present disclosure includes the following aspects.
Item 1.
Equation (1):

(In the formula, R ¹ is an alkyl group.)
It is a method for producing a compound represented by
Equation (2):

(In the formula, R ² is an alkyl group and R ¹ has the same meaning as described above.)
A production method comprising a step A of contacting the compound represented by the above formula (1) with at least one halogen ion selected from the group consisting of chloride ions and bromine ions to obtain the compound represented by the formula (1).
Item 2.
Equation (1):

(In the formula, R ² is an alkyl group and R ¹ has the same meaning as described above.)
The compound represented by the formula (3):
M _m X _n (3)
(In the formula, M is a cation, X is a chloride ion or a bromine ion, m and n are positive integers, and when m is 2 or more, each M is the same as each other. May be different, and when n is 2 or more, each X may be the same as or different from each other.)
A production method comprising the step A of contacting with the compound represented by the above formula (1) to obtain the compound represented by the formula (1).
Item 3.
Item 2. The production method according to Item 2, wherein the amount of the compound represented by the formula (3) used is less than 0.2 mol with respect to 1 mol of the compound represented by the formula (2).
Item 4.
Item 2. The production method according to Item 2 or 3, wherein the amount of the compound represented by the formula (3) used is 0.1 mol or less with respect to 1 mol of the compound represented by the formula (2).
Item 5.
Nitrogen M is hydrogen ion, metal ion, or NR 4 ₊ ^(wherein each of R, same or different from each other, a hydrogen atom or an organic group, any two R are adjacent and bonded to each other Item 8. The production method according to any one of Items 2 to 4, wherein a ring may be formed together with an atom.
Item 6.
Item 6. The production method according to any one of Items 2 to 5, wherein M is a hydrogen ion, an alkali metal ion, an alkaline earth metal ion, or a quaternary ammonium.
Item 7.
Item 6. The production method according to any one of Items 2 to 6, wherein M is a hydrogen ion or an alkali metal ion.
Item 8.
Item 8. The production method according to any one of Items 2 to 7, wherein the step A is carried out in an organic solvent.
Item 9.
Item 8. The production method according to Item 8, wherein the water content of the organic solvent is 2000 ppm or less.
Item 10.
Item 8. The production method according to Item 8 or 9, wherein the organic solvent has a boiling point of 110 ° C. or higher.
Item 11.
Item 8. The production method according to any one of Items 8 to 10, wherein the organic solvent is at least one selected from the group consisting of a sulfur-containing solvent, a nitrogen-containing solvent, an ether solvent, and an ester solvent.
Item 12.
Item 8. The production method according to any one of Items 8 to 11, wherein the organic solvent is a sulfur-containing solvent.
Item 13.
Item 8. The production method according to any one of Items 8 to 10, wherein the organic solvent is at least one selected from the group consisting of sulfolane, dimethyl sulfoxide, dimethylformamide, diglyme, methylpyrrolidone, ethylene carbonate, and propylene carbonate. ..

According to the present disclosure, a method for producing a high-yield α-fluoroacrylic acid ester using a compound containing a specific halogen ion is provided.

The above summary of the present disclosure is not intended to describe each disclosed embodiment or all implementations of the present disclosure.
The subsequent description of the present disclosure will more specifically exemplify an embodiment of an example.
Guidance is provided through illustrations in some parts of the disclosure, and the examples can be used in various combinations.
In each case, the illustrated group can function as a non-exclusive and representative group.
All publications, patents and patent applications cited herein are incorporated herein by reference in their entirety.

<Terminology>
Unless otherwise specified, the symbols and abbreviations used herein can be understood in the context of the present specification in the meaning commonly used in the technical field to which the present disclosure belongs.
In the present specification, the phrase "contains" is used with the intention of including the phrase "consisting of" and the phrase "consisting of".
Unless otherwise specified, the steps, treatments, or operations described herein can be performed at room temperature.
In the present specification, room temperature can mean a temperature in the range of 10 to 40 ° C.
In the present specification, the notation "C _nm " (where n and m are numbers, respectively) has a carbon number of n or more and m or less, as is usually understood by those skilled in the art. Represents that.

As used herein, the term "organic group" means a group formed by removing one hydrogen atom from an organic compound.
The "organic group" includes, for example,
Hydrocarbon groups, which may have one or more substituents,
Non-aromatic heterocyclic group which may have one or more substituents Heteroaryl group which may have one or more substituents,
Cyano group,
Aldehyde group,
QO-,
QS-,
QCO-,
QSO _2- ,
QOCO- and QOSO _2-
(In these equations, Q is independent,
Hydrocarbon groups, which may have one or more substituents,
A non-aromatic heterocyclic group which may have one or more substituents, or a heteroaryl group which may have one or more substituents).
Can be mentioned.

Examples of the "substituent" include a halogen atom, a cyano group, an amino group, an alkoxy group, and an alkylthio group. The two or more substituents may be the same or different from each other.

In the present specification, examples of the "hydrocarbon group" include an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a cycloalkazienyl group, an aryl group, and an aralkyl group.

In the present specification, the "alkyl group" (including the "alkyl group" in the substituent such as "monoalkylamino group") includes, for example, a methyl group, an ethyl group, and a propyl group (n-propyl group, isopropyl). Groups), butyl groups (n-butyl group, isobutyl group, sec-butyl group, tert-butyl group), pentyl group, hexyl group and other linear or branched C _1-10 alkyl groups. ..

In the present specification _{, examples of the "C 1-3} alkyl group" include a methyl group, an ethyl group, an n-propyl group and an isopropyl group.

In the present specification, examples of the substituent of the alkyl group include halogen, alkoxy group, amino group, monoalkylamino group, dialkylamino group, aryl group, heteroaryl group and the like. The number of substituents can be selected from the range of 0 to the maximum number of substituents, and can be, for example, 0, 1, 2, or 3. When the number of substituents is 2 or more, each substituent may be the same as or different from each other.

In the present specification, examples of "halogen" include fluorine, chlorine, bromine, and iodine.

In the present specification, the "alkoxy group" includes, for example, a methoxy group, an ethoxy group, a propoxy group (n-propoxy group, isopropoxy group), a butoxy group (n-butoxy group, isobutoxy group, sec-butoxy group, tert). -Butoxy groups), pentyloxy groups, hexyloxy groups and the like, linear or branched C _1-6 alkoxy groups can be mentioned.

In the present specification, the "alkylthio group" includes, for example, methylthio group, ethylthio group, propylthio group (n-propylthio group, isopropylthio group), butylthio group (n-butylthio group, isobutylthio group, sec-butylthio group, sec-butylthio group, etc. _{Examples include linear or branched C 1-6} alkylthio groups such as tert-butylthio groups), pentylthio groups, and hexylthio groups.

In the present specification, the "monoalkylamino group" includes, for example, a linear or branched chain such as a methylamino group, an ethylamino group, a propylamino group, a butylamino group, a pentylamino group and a hexylamino group. Examples include mono-C _1-6 alkylamino groups.

In the present specification, the "dialkylamino group" includes, for example, a dimethylamino group, a methylethylamino group, a diethylamino group, a dipropylamino group, a methylpropylamino group, an ethylpropylamino group, a dibutylamino group, a dipentylamino group, and the like. Examples thereof include linear or branched diC _1-6 alkylamino groups such as dihexylamino groups.

In the present specification, the "alkenyl group" includes, for example, a vinyl group, a 1-propene-1-yl group, a 2-propene-1-yl group, an isopropenyl group, a 2-butene-1-yl group, 4-. _{Examples thereof include a linear or branched C 2-10} alkenyl group such as a pentene-1-yl group and a 5-hexene-1-yl group.

In the present specification, the "alkynyl group" includes, for example, an ethynyl group, a 1-propyne-1-yl group, a 2-propyne-1-yl group, a 4-pentin-1-yl group, and a 5-hexyne-1. Examples thereof include a linear or branched C _2-10 alkynyl group such as an yl group.

_{In the present specification, examples of the "cycloalkyl group" include C 3-10} cycloalkyl groups such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group.

_{In the present specification, examples of the "cycloalkenyl group" include C 3-10} cycloalkenyl groups such as a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, and a cycloheptenyl group.

In the present specification, the "cycloalkazienyl group" includes, for example, a cyclobutadienyl group, a cyclopentadienyl group, a cyclohexadienyl group, a cycloheptadienyl group, a cyclooctadienyl group, and a cyclononazienyl group. _Examples include C 4-10 cycloalkadienyl groups such as groups and cyclodecadienyl groups.

As used herein, the "aryl group" can be, for example, monocyclic, bicyclic, tricyclic, or tetracyclic.
In the present specification, the "aryl group" can be, for example, a C _6-18 aryl group. In the present specification, examples of the "aryl group" include a phenyl group, a biphenylyl group, a naphthyl group, an anthryl group, a phenanthryl group, an acenaphtylenyl group and the like.

As used herein, the term "non-aromatic heterocyclic group" means a group formed by removing one hydrogen atom from a non-aromatic heterocycle.
Unless otherwise specified in the present specification, the "non-aromatic heterocyclic group" can be monocyclic, bicyclic, tricyclic, or tetracyclic.
Unless otherwise specified in the present specification, the "non-aromatic heterocyclic group" may be saturated or unsaturated.
Unless otherwise specified in the present specification, the "non-aromatic heterocyclic group" can be, for example, a 5- to 18-membered non-aromatic heterocyclic group.
In the present specification, unless otherwise specified, the "non-aromatic heterocyclic group" is, for example, 1 to 4 atoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom in addition to a carbon atom as ring-constituting atoms. It can be a non-aromatic heterocyclic group containing a hetero atom.
Unless otherwise specified, the "non-aromatic heterocyclic group" in the present specification includes, for example, tetrahydrofuryl, oxazolidinyl, imidazolinyl (eg, 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl), aziridinyl (eg, eg). 1-aziridinyl, 2-aziridinyl), pyrrolidinyl (eg 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl), piperidinyl (eg 1-piperidinyl, 2-piperidinyl, 3-piperidinyl), azepanyl (eg 1-azepanyl) , 2-azepanyl, 3-azepanyl, 4-azepanyl), azocanyl (eg 1-azocanyl, 2-azocanyl, 3-azocanyl, 4-azocanyl), piperazinyl (eg 1,4-piperazin-1-yl, 1) , 4-Piperazine-2-yl), diazepinyl (eg 1,4-diazepine-1-yl, 1,4-diazepine-2-yl, 1,4-diazepine-5-yl, 1,4-diazepine- 6-yl), diazocanyl (eg 1,4-diazocan-1-yl, 1,4-diazocan-2-yl, 1,4-diazocan-5-yl, 1,4-diazocan-6-yl, 1 , 5-Diazocan-1-yl, 1,5-diazocan-2-yl, 1,5-diazocan-3-yl), tetrahydropyranyl (eg tetrahydrofuran-4-yl), morpholinyl (eg 4-morpholinyl) ), Thiomorpholinyl (eg 4-thiomorpholinyl), 2-oxazolidinyl, dihydrofuryl, dihydropyranyl, dihydroquinolyl and the like.

As used herein, the "heteroaryl group" can be, for example, monocyclic or polycyclic (eg, bicyclic, tricyclic, tetracyclic).
In the present specification, the "heteroaryl group" can be, for example, a 5- to 18-membered heteroaryl group.
In the present specification, the "heteroaryl group" is, for example, a heteroaryl group containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom in addition to a carbon atom as a ring-constituting atom. There can be.
In the present specification, the "heteroaryl group" includes a "monocyclic heteroaryl group" and an "aromatic condensed heterocyclic group".

In the present specification, the "monocyclic heteroaryl group" includes, for example, a fryl group, a thienyl group, a pyridyl group, a pyrimidinyl group, a pyridadinyl group, a pyrazinyl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a thiazolyl group and an isothiazolyl group. , Oxazolyl group, isooxazolyl group, oxadiazolyl group, thiadiazolyl group, triazolyl group, tetrazolyl group, triazinyl group and the like.

In the present specification, the "polycyclic heteroaryl group" includes, for example, a quinolyl group, an isoquinolyl group, a quinazolyl group, a quinoxalyl group, a benzofuryl group, a benzothienyl group, a benzoxazolyl group, a benzoisooxazolyl group, and the like. Benthiazolyl group, benzoisothiazolyl group, benzoimidazolyl group, benzotriazolyl group, indolyl group, indazolyl group, pyrrolopyrazine group, imidazolidinyl group, imidazolipyrazinyl group, imidazolepyrazolopyridinyl group, Examples thereof include a pyrazorotienyl group and a pyrazorotriadinyl group.

In the present specification, examples of the substituent of the aryl group or the heteroaryl group include a halogen, an alkyl group, an alkoxy group, an amino group, a monoalkylamino group, a dialkylamino group and the like. The number of substituents can be selected from the range of 0 to the maximum number of substituents, and can be, for example, 0, 1, 2, 3, 4, 5, or 6. When the number of substituents is 2 or more, each substituent may be the same as or different from each other.

<Method for producing the compound represented by the formula (1)>
In one embodiment, equation (1):

(In the formula, R ¹ is an alkyl group.)
The method for producing the compound represented by is
Equation (2):

(In the formula, R ² is an alkyl group and R ¹ has the same meaning as described above.)
The compound represented by is at least one halogen ion selected from the group consisting of chloride ion and bromine ion, or formula (3) :.
M _m X _n (3)
(In the formula, M is a cation, X is a chloride ion or a bromine ion, m and n are positive integers, and when m is 2 or more, each M is the same as each other. May be different, and when n is 2 or more, each X may be the same as or different from each other.)
The step A is included in which the compound represented by the above formula (1) is obtained by contacting with the compound represented by the above formula (1).

The compound R ¹ represented by the formula (1) is preferably a C _1-3 alkyl group, more preferably a methyl group or an ethyl group, and particularly preferably a methyl group.

The compound represented by the formula (1) is preferably C _1-3 alkyl 2-fluoroacrylate, more preferably methyl 2-fluoroacrylate, or ethyl 2-fluoroacrylate, and particularly preferably methyl 2-fluoroacrylate. be.

The compound R ² represented by the formula (2) is preferably a C _1-3 alkyl group, more preferably a methyl group or an ethyl group, and particularly preferably a methyl group.

The compound represented by the formula (2) is particularly preferably a compound in which both ^{R 1} and R ^{2 are methyl groups.}

The compound represented by the formula (2) is a known compound, and a known method such as the method described in JP-A-6-184234, that is, specifically, α-fluoromalonate dimethyl ester is reacted with formaldehyde. It can be produced by a method of allowing it to be produced or a method similar thereto.

Examples of the cation represented by the compound M represented by the formula (3), for example, hydrogen ions, metal ions, in NR 4 ₊ ^(wherein each of R, same or different from one another, a hydrogen atom or an organic group Yes, any two Rs may be bonded to each other to form a ring with adjacent nitrogen atoms) and the like.

Specific examples of the metal can include alkali metals and alkaline earth metals.
Examples of the alkali metal include lithium, sodium, potassium, cesium and the like.
Examples of the alkaline earth metal include magnesium, calcium and the like.

The specific examples of _NR ^{4 +} is, _NH ^{4 +,} and primary to quaternary ammonium can be included.

Primary ammonium is given by the following formula (3A):

(In the formula, R ¹¹ is an organic group)
Can be represented by.
R ¹¹ can be preferably a hydrocarbon group, more preferably an alkyl group, a cycloalkyl group, or an aryl group, still more preferably an alkyl group, and particularly preferably a C _1-10 alkyl group.
_{Examples of the primary ammonium include protonated primary amines, and specifically, C 1-6} alkylamines such as methylamine, ethylamine, propylamine (n-propylamine, isopropylamine) and butylamine. , Propylamine such as aniline.

Secondary ammonium is given by the following formula (3B):

(In the formula, R ²¹ and R ²² are organic groups that are the same or different from each other, or are bonded to each other to form a ring with adjacent nitrogen atoms).
Can be represented by.
R ²¹ and R ²² can be preferably a hydrocarbon group, more preferably an alkyl group, a cycloalkyl group, or an aryl group, still more preferably an alkyl group, and particularly preferably a C _1-10 alkyl group.
Examples of the secondary ammonium include protonated secondary amines, and specifically, diC _1-6 alkylamines such as dimethylamine, diethylamine, ethylmethylamine and dipropylamine, pyrrolidine and imidazole. Examples thereof include protonated products such as piperidine and morpholine.

The tertiary ammonium is calculated by the following formula (3C):

(In the formula, R ³¹ to R ³³ are organic groups that are the same as or different from each other, and any two of them may be bonded to each other to form a ring with adjacent nitrogen atoms.)
Can be represented by.
R ³¹ to R ³³ can be preferably a hydrocarbon group, more preferably an alkyl group, a cycloalkyl group, or an aryl group, still more preferably an alkyl group, and particularly preferably a C _1-10 alkyl group.
Examples of the tertiary ammonium include protonated tertiary amines, and specific examples thereof include tri-C _1-6 alkylamines such as trimethylamine and triethylamine, and protonated products such as pyridine and quinoline.

The quaternary ammonium has the following formula (3D):

(In the formula, R ⁴¹ to R ⁴⁴ are organic groups that are the same or different from each other, and any two of them may be bonded to each other to form a ring with adjacent nitrogen atoms.)
Can be represented by.
R ⁴¹ to R ⁴⁴ can be preferably a hydrocarbon group, more preferably an alkyl group, a cycloalkyl group, or an aryl group, still more preferably an alkyl group, and particularly preferably a C _1-10 alkyl group.

Examples of the quaternary ammonium include tetra C _1-6 alkylammonium, and specifically, the following group:

(In the formula, Me is a methyl group, Et is an ethyl group, Pr is a propyl group, and Bu is a butyl group.)
The groups selected from are listed.

M is preferably a hydrogen ion, a metal ion, or NR 4 ₊ ^(wherein each of R, same or different from each other, a hydrogen atom or an organic group, any two R, adjacent bonded to each other A ring may be formed together with the nitrogen atom to form a ring), more preferably hydrogen ion, alkali metal ion, alkaline earth metal ion, or quaternary ammonium, and particularly preferably hydrogen ion or alkali metal ion. be.

M can be appropriately selected according to the valence of M and n, and is, for example, 1 or 2. When m is 2 or more, each M may be the same as or different from each other. For example, when m is 2, one M may be a hydrogen ion, the other M may be a metal ion, and the two Ms may be different types of metal ions.

N can be appropriately selected according to the valence of M and m, and is, for example, 1 or 2. When n is 2 or more, each X may be the same as or different from each other. For example, when n is 2, one X may be a chloride ion and the other X may be a bromine ion.

Examples of the compound represented by the formula (3) include HBr, LiBr, NaBr, KBr, CsBr, MgBr ₂ , CaBr ₂ , HCl, LiCl, NaCl, KCl, CsCl, MgCl ₂ , CaCl _{2 and the} like.

The compound represented by the formula (3) can be used alone or in combination of two or more.

The amount of at least one halogen ion selected from the group consisting of chlorine ions and bromine ions, or the amount of the compound represented by the formula (3) used (the chlorine ions contained in the compound represented by the formula (3) and The upper limit of the total molar amount of bromine ions) can be, for example, less than 0.2 mol, preferably 0.1 mol or less, relative to 1 mol of the compound represented by the formula (2).
The amount of at least one halogen ion selected from the group consisting of chlorine ions and bromine ions, or the amount of the compound represented by the formula (3) used (the chlorine ions contained in the compound represented by the formula (3) and The lower limit of the total molar amount of bromine ions) is, for example, 0.01 mol or more, preferably 0.02 mol or more, 0.03 mol or more, 0.04 with respect to 1 mol of the compound represented by the formula (2). It can be greater than or equal to the mole, or greater than or equal to 0.05 mol.
The amount of at least one halogen ion selected from the group consisting of chlorine ions and bromine ions, or the amount of the compound represented by the formula (3) used (the chlorine ions contained in the compound represented by the formula (3) and The total molar amount of bromine ions) is, for example, in the range of 0.01 mol or more and less than 0.2 mol, preferably 0.01 to 0.1 mol, with respect to 1 mol of the compound represented by the formula (2). Can be within range.

Step A is preferably carried out in an organic solvent. When the step A is carried out in an organic solvent, the contact of the compound represented by the formula (2) with the compound represented by the formula (3) is required by, for example, putting them into an organic solvent. It can be carried out by mixing according to the above.

The organic solvent can be a polar organic solvent or a non-polar organic solvent. The organic solvent is preferably a polar organic solvent.

As an organic solvent, for example
Non-aromatic hydrocarbon solvents (eg, alkanes such as pentane, hexane, heptane, octane, nonane, decane, dodecane, isododecane, tridecane, cyclohexane, methylcyclohexane, decahydronaphthalene);
Aromatic hydrocarbon solvents (eg benzene, toluene, xylene, diethylbenzene, mesitylene, tetralin, indene, naphthalene, methylnaphthalene);
Halogenated hydrocarbon solvents (eg dichloromethane, dichloroethane, chloroform, chlorobenzene);
Alcohol solvents (eg ethylene glycol, cellosolve, propylene glycol, carbitol, polyethylene glycol, polypropylene glycol);
Ether solvents (eg diethyl ether, diisopropyl ether, methyl t-butyl ether, diisoamyl ether, 1,2-dimethoxyethane, ethylene glycol derivatives (eg monogram, diethyl cellosolve, diglime, diethyl carbitol, triglime, tetraglyme), 1,1-dimethoxycyclohexane, phenetol, veratrol, dioxane, tetrahydrofuran);
Ester solvents (eg ethyl acetate, isopropyl acetate, 3-methoxy-3-methylbutyl acetate, dimethyl carbonate, diethyl malonate, ethylene carbonate, propylene carbonate, γ-butyrolactone, α-acetyl-γ-butyrolactone);
Ketone solvents (eg acetone, methyl ethyl ketone, methyl isobutyl ketone, diisobutyl ketone, acetophenone, propiophenone, isophorone);
Sulfur-containing solvents (eg, dimethylsulfoxide, sulfolane, diphenylsulfide); and nitrogen-containing solvents (eg, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazole). Amide solvents such as lydinone, N, N-dimethylacrylamide, N, N-dimethylacetoacetamide, N, N-diethylformamide, N, N-diethylacetamide, hexamethylphosphoramide, methylpyrrolidone, acetonitrile, benzonitrile, etc. Nitro solvent; nitro solvent such as nitrobenzene and o-nitrotoluene; quinoline, tetrahydroquinolin, dimethylimidazolidinone) and the like.

As the organic solvent, one type may be used alone, or two or more types may be used in combination.

The organic solvent is preferably at least one selected from the group consisting of a sulfur-containing solvent, a nitrogen-containing solvent, an ether solvent, an ester solvent, an aromatic hydrocarbon solvent, and a non-aromatic hydrocarbon solvent.

The organic solvent is more preferably
Sulfolane, dimethyl sulfoxide,
N, N-dimethylformamide, N, N-dimethylacetamide, quinoline, tetrahydroquinoline, methylpyrrolidone, dimethylimidazolidinone, hexamethylphosphoramide,
Ethylene glycol, polyethylene glycol, polypropylene glycol, monoglyme, diethyl cellosolve, diglyme, diethyl carbitol, triglyme, tetraglyme),
Ethylene carbonate, propylene carbonate,
Xylene, mesitylene, and alkanes (eg decane, dodecane)
It can be at least one selected from the group consisting of.

The organic solvent can be more preferably at least one selected from the group consisting of a sulfur-containing solvent, a nitrogen-containing solvent, an ether solvent, and an ester solvent.

The organic solvent is preferably at least one selected from the group consisting of, for example, sulfolane, dimethyl sulfoxide, dimethylformamide, diglyme, methylpyrrolidone, ethylene carbonate, and propylene carbonate.

The organic solvent is preferably an organic solvent having a boiling point of more than 105 ° C., more preferably 110 ° C. or higher, further preferably 120 ° C. or higher, and particularly preferably 150 ° C. or higher (boiling point under normal pressure). The upper limit of the boiling point is not particularly limited, but is usually 300 ° C. Since the organic solvent has such a high boiling point, the compound of the formula (1) having a relatively low boiling point can be distilled under reduced pressure to obtain a high yield.

The organic solvent preferably has a water content of 2000 ppm or less, more preferably 1000 ppm or less, still more preferably 500 ppm or less, and particularly preferably 100 ppm or less (for example, 90 ppm or less, 80 ppm or less, 70 ppm or less, 60 ppm or less, or 50 ppm or less). It is an organic solvent. The lower limit of the water content is not particularly limited, but is usually the detection limit or 10 ppm. Since the organic solvent has such a low water content, the compound of the formula (1) can be obtained in a high yield. The water content of the organic solvent can be measured by, for example, a Karl Fischer titer.

The amount of the organic solvent is usually 0 mL or more, preferably 0.01 mL or more, more preferably 0.05 mL or more, still more preferably 0.1 mL or more, relative to 1 g of the compound represented by the formula (2). Usually, it is 100 mL or less, preferably 10 mL or less, more preferably 5 mL or less, still more preferably 1 mL or less. The amount of the organic solvent is in the range of 0 to 100 mL, preferably in the range of 0.01 to 10 mL, and more preferably in the range of 0.1 to 1 mL with respect to 1 g of the compound represented by the above formula (2). Is.

Step A is preferably carried out in the absence of substantially water.
Here, "substantially absent of water" means that the water content of the reaction mixture in step A is 1.0% (w / w) or less at the start of the reaction.
The smaller the water content in the reaction system of step A, the higher the yield of the compound represented by the formula (1) can be obtained.

In the reaction of step A, a polymerization inhibitor may be used if desired. Examples of the polymerization inhibitor include dibutylhydroxytoluene (BHT), 4-methoxyphenol, hydroquinone, phenothiazine, benzoquinone, phenothiazine and the like. As the polymerization inhibitor, one type may be used alone, or two or more types may be used in combination.

The amount of the polymerization inhibitor is usually in the range of 0.0003 to 0.25 parts by weight, preferably 0.0005 to 0.05 parts by weight, based on 1 part by weight of the compound represented by the formula (2). It is within the range, more preferably within the range of 0.001 to 0.01 parts by weight.

The reaction temperature of the reaction in step A is not particularly limited as long as the reaction proceeds.
The lower limit of the reaction temperature can be preferably 30 ° C., more preferably 50 ° C., and even more preferably 60 ° C.
The upper limit of the reaction temperature can be preferably 250 ° C., more preferably 200 ° C., and even more preferably 160 ° C.
The reaction temperature is, for example, in the range of 30 to 250 ° C., preferably in the range of 50 to 200 ° C., and more preferably in the range of 60 to 160 ° C.

The reaction of step A may include, for example, a step of reacting at a temperature T in the range of 100 to 120 ° C., preferably in the range of more than 105 ° C. and 120 ° C. or lower, more preferably in the range of 110 to 120 ° C. preferable. In the reaction of step A, it is also preferable to change the reaction temperature from a low temperature to a high temperature, and in addition to the step of reacting at temperature T, the step of reacting at a temperature lower than temperature T and / or a temperature higher than temperature T. It may include a step of reacting with.

The reaction in step A may be carried out under reduced pressure, normal pressure, or pressure, but is preferably under reduced pressure or normal pressure, for example, in the range of normal pressure to 5 kPa, preferably in the range of normal pressure to 10 kPa. Inside.

The reaction time of the reaction in step A may be set to, for example, the time at which the yield is maximized.

The generated compound represented by the formula (1) may be taken out from the reaction system by a method such as vacuum distillation while proceeding with the reaction.

The yield is preferably more than 70%, more preferably 75% or more, and particularly preferably 80% or more.

The produced compound represented by the formula (1) can be purified by a known purification method such as solvent extraction, drying, filtration, distillation, concentration, and a combination thereof, if desired.

Hereinafter, one embodiment of the present disclosure will be described in more detail by way of examples, but the present disclosure is not limited thereto.

[Example 1]
In a 100 mL eggplant flask, 1.66 g (13.9 mmol) of potassium bromide, 48 mg (0.22 mmol) of dibutylhydroxytoluene (BHT), 40.0 g (222 mmol) of dimethyl 2-fluoro-2-hydroxymethylmalonate, and sulfolane. 10.1 mL (12.7 g) (moisture content: 10 to 50 ppm) was added and mixed. It was heated at 100-120 ° C. under normal pressure for 175 minutes. Then, it was distilled under reduced pressure. At this time, 2.4 g of dimethyl 2-fluoro-2-hydroxymethylmalonate remained in the still, and methyl 2-fluoroacrylate was obtained in a yield of 18.9 g, and the yield was 87%.

[Example 2]
In a 25 mL eggplant flask, 0.66 g (5.55 mmol) of potassium bromide, 12 mg (0.055 mmol) of dibutylhydroxytoluene (BHT), 10.0 g (55.5 mmol) of dimethyl 2-fluoro-2-hydroxymethylmalonate, And sulfolane (moisture content: 10 to 50 ppm) 2.56 mL (3.2 g) was added and mixed. The mixture was heated at 100 to 120 ° C. under normal pressure for 15 minutes, and then distilled at the same time as the reaction under reduced pressure. At this time, the residual amount of dimethyl 2-fluoro-2-hydroxymethylmalonate in the still was 1% or less of the amount of dimethyl2-fluoro-2-hydroxymethylmalonate added during the reaction. The methyl 2-fluoroacrylate was obtained in a yield of 4.84 g, and the yield was 84%.

[Example 3]
In a 25 mL eggplant flask, 0.41 g (5.55 mmol) of potassium chloride, 12 mg (0.055 mmol) of dibutylhydroxytoluene (BHT), 10.0 g (55.5 mmol) of dimethyl 2-fluoro-2-hydroxymethylmalonate, and 2.56 mL (3.2 g) of sulfolane (moisture content: 10 to 50 ppm) was added and mixed. The mixture was heated under reduced pressure at 100 to 120 ° C. for 260 minutes and distilled off. At this time, 0.4 g of dimethyl 2-fluoro-2-hydroxymethylmalonate remained in the still, and methyl 2-fluoroacrylate was obtained in a yield of 4.27 g, and the yield was 77%.

[Example 4]
In a 25 mL eggplant flask, 0.66 g (5.55 mmol) of potassium bromide, 7.4 mg (0.06 mmol) of 4-methoxyphenol, 10.0 g (55.5 mmol) of dimethyl 2-fluoro-2-hydroxymethylmalonate, And sulfolane (moisture content: 10 to 50 ppm) 2.56 mL (3.2 g) was added and mixed. Distillation was carried out at the same time as the reaction for 745 minutes at 100 to 120 ° C. under reduced pressure. At this time, the residual amount of dimethyl 2-fluoro-2-hydroxymethylmalonate in the still was 1% or less of the amount of dimethyl2-fluoro-2-hydroxymethylmalonate added during the reaction. The methyl 2-fluoroacrylate was obtained in a yield of 4.5 g, and the yield was 78%.

[Example 5]
In a 25 mL eggplant flask, 0.13 g (1.11 mmol) of potassium bromide, 12 mg (0.055 mmol) of dibutylhydroxytoluene (BHT), 10.0 g (55.5 mmol) of dimethyl 2-fluoro-2-hydroxymethylmalonate, And sulfolane (moisture content: 10 to 50 ppm) 2.56 mL (3.2 g) was added and mixed. The mixture was heated at 100 to 120 ° C. under normal pressure for 15 minutes, and then distilled at the same time as the reaction under reduced pressure. At this time, 1.1 g of dimethyl 2-fluoro-2-hydroxymethylmalonate remained in the still, and methyl 2-fluoroacrylate was obtained in a yield of 4.21 g, and the yield was 84%.

[Example 6]
In a 25 mL eggplant flask, 0.66 g (5.55 mmol) of potassium bromide, 12 mg (0.055 mmol) of dibutylhydroxytoluene (BHT), 10.0 g (55.5 mmol) of dimethyl 2-fluoro-2-hydroxymethylmalonate, And 2.56 mL (3.1 g) of propylene carbonate were added and mixed. The mixture was heated at 100 to 120 ° C. under normal pressure for 15 minutes, and then distilled at the same time as the reaction under reduced pressure. At this time, 1.40 g of dimethyl 2-fluoro-2-hydroxymethylmalonate remained in the still, and 3.64 g of methyl 2-fluoroacrylate was obtained as a yield, and the yield was 73%.

[Example 7]
In a 25 mL eggplant flask, 0.66 g (5.55 mmol) of potassium bromide, 12 mg (0.055 mmol) of dibutylhydroxytoluene (BHT), 10.0 g (55.5 mmol) of dimethyl 2-fluoro-2-hydroxymethylmalonate, And 2.56 mL (2.4 g) of jiglyme was added and mixed. The mixture was heated at 100 to 120 ° C. under normal pressure for 15 minutes, and then distilled at the same time as the reaction under reduced pressure. At this time, 1.70 g of dimethyl 2-fluoro-2-hydroxymethylmalonate remained in the still, and methyl 2-fluoroacrylate was obtained in a yield of 3.47 g, and the yield was 72%.

Claims

Equation (1):

(In the formula, R 1 is an alkyl group.)
It is a method for producing a compound represented by
Equation (2):

(In the formula, R 2 is an alkyl group and R 1 has the same meaning as described above.)
A production method comprising a step A of contacting the compound represented by the above formula (1) with at least one halogen ion selected from the group consisting of chloride ions and bromine ions to obtain the compound represented by the formula (1).
Equation (1):

(In the formula, R 1 is an alkyl group.)
It is a method for producing a compound represented by
Equation (2):

(In the formula, R 2 is an alkyl group and R 1 has the same meaning as described above.)
The compound represented by the formula (3):
M m X n (3)
(In the formula, M is a cation, X is a chloride ion or a bromine ion, m and n are positive integers, and when m is 2 or more, each M is the same as each other. May be different, and when n is 2 or more, each X may be the same as or different from each other.)
A production method comprising the step A of contacting with the compound represented by the above formula (1) to obtain the compound represented by the formula (1).
The production method according to claim 2, wherein the amount of the compound represented by the formula (3) used is less than 0.2 mol with respect to 1 mol of the compound represented by the formula (2).
The production method according to claim 2 or 3, wherein the amount of the compound represented by the formula (3) used is 0.1 mol or less with respect to 1 mol of the compound represented by the formula (2).
Nitrogen M is hydrogen ion, metal ion, or NR 4 + (wherein each of R, same or different from each other, a hydrogen atom or an organic group, any two R are adjacent and bonded to each other The production method according to any one of claims 2 to 4, wherein a ring may be formed together with an atom.
The production method according to any one of claims 2 to 5, wherein M is a hydrogen ion, an alkali metal ion, an alkaline earth metal ion, or a quaternary ammonium.
The production method according to any one of claims 2 to 6, wherein M is a hydrogen ion or an alkali metal ion.
The production method according to any one of claims 2 to 7, wherein the step A is carried out in an organic solvent.
The production method according to claim 8, wherein the water content of the organic solvent is 2000 ppm or less.
The production method according to claim 8 or 9, wherein the organic solvent has a boiling point of 110 ° C. or higher.
The production method according to any one of claims 8 to 10, wherein the organic solvent is at least one selected from the group consisting of a sulfur-containing solvent, a nitrogen-containing solvent, an ether solvent, and an ester solvent.
The production method according to any one of claims 8 to 11, wherein the organic solvent is a sulfur-containing solvent.
The production according to any one of claims 8 to 10, wherein the organic solvent is at least one selected from the group consisting of sulfolane, dimethyl sulfoxide, dimethylformamide, diglyme, methylpyrrolidone, ethylene carbonate, and propylene carbonate. Method.