CN103910628A - Production method of α-fluoroacrylate - Google Patents

Abstract

The present invention provides a method for producing an alpha-fluoroacrylate at a low production cost without using a highly toxic raw material compound. The method for producing a compound represented by the following formula (1) comprises a step A of bringing a compound represented by the following formula (2) into contact with an alkali metal halide to obtain a compound represented by the formula (1).[ in the formula, R¹Represents an alkyl group, R²Represents hydrogen, an alkyl group which may have a substituent, an aryl group which may have a substituent, or a heteroaryl group which may have a substituent.][ in the formula, R³Represents an alkyl group, and the other symbols have the same meanings as above.]

Description

Production method of α-fluoroacrylate

technical field

The present invention relates to a method for producing α-fluoroacrylate.

Background technique

α-Fluoroacrylate is used as a synthetic intermediate for pharmaceuticals (such as antibiotics), a synthetic intermediate for optical fiber sheath materials, a synthetic intermediate for coating materials, a synthetic intermediate for semiconductor resist materials, and functional polymers Monomers etc. are useful.

Conventionally, as a method for producing α-fluoroacrylate, for example, it is known to react fluoroacetate with formaldehyde in the presence of a strong base to obtain α-fluoroacrylate, that is, oxalic acid di(lower ) ester and fluoroacetate are mixed and the mixture is reacted with formaldehyde (Patent Document 1).

On the other hand, as a method for producing the α-fluoroacrylate substituted with β, it is known to produce β from chloromalonic acid and aldehydes other than formaldehyde in a one-pot method using spray-dried potassium fluoride. A method of substituted α-acrylate (Non-Patent Document 1).

patent documents

Patent Document 1: Specification of US Patent No. 3262968

non-patent literature

Non-Patent Document 1: Chemistry Letters, 1981, p.1259-1260

The method described in Patent Document 1 has problems such as high toxicity of raw material compounds.

On the other hand, according to the method described in Non-Patent Document 1, if formalin as an aqueous formaldehyde solution can be used instead of aldehydes other than formaldehyde, α- Fluoroacrylate. However, in reality, if water exists in this reaction, α-fluoroacrylate cannot be obtained basically, and therefore, according to the method described in Non-Patent Document 1, α-fluoroacrylate cannot be produced using formalin. Therefore, the inventors of the present invention attempted to produce α-fluoroacrylate according to the method described in Non-Patent Document 1 using formaldehyde gas and polyoxymethylene. However, α-fluoroacrylates were basically not obtained in any cases.

Contents of the invention

Therefore, an object of the present invention is to provide a method for producing α-fluoroacrylate at low production cost without using highly toxic raw material compounds.

The present invention includes the following aspects.

Item 1. A method for producing a compound represented by the following formula (1), comprising the step A of contacting the compound represented by the following formula (2) with an alkali metal halide to obtain the compound represented by the formula (1) .

[wherein, R ¹ represents an alkyl group, R ² represents hydrogen, an alkyl group that may have a substituent, an aryl group that may have a substituent, or a heteroaryl group that may have a substituent. ]

[In the formula, R ³ represents an alkyl group, and the meanings of other symbols are the same as above. ]

Item 2. The production method according to Item 1, wherein the alkali metal halide is potassium halide.

Item 3. The production method according to Item 1, wherein the alkali metal halide is potassium fluoride.

Item 4. The production method according to any one of Items 1 to 3, wherein step A is carried out in an organic solvent.

Item 5. The production method according to Item 4, wherein the organic solvent is a polar organic solvent.

Item 6. The production method according to Item 4, wherein the organic solvent is an organic solvent having a boiling point of 100° C. or higher.

Item 7. The production method according to any one of Items 4 to 6, wherein the organic solvent is sulfolane, dimethyl sulfoxide, glyme, diglyme, methylpyrrolidone, propylene carbonate ester or ethylene carbonate.

Item 8. The production method according to any one of Items 1 to 7, wherein step A is carried out under the condition that water is substantially absent.

Item 9. A composition comprising a compound represented by the following formula (1) and a compound represented by the following formula (3), the mass of the compound represented by the formula (3) being equal to that of the compound represented by the formula (1) The mass ratio is in the range of 0.01 to 10% (w/w).

[wherein, R ¹ represents an alkyl group, R ² represents hydrogen, an alkyl group that may have a substituent, an aryl group that may have a substituent, or a heteroaryl group that may have a substituent. ]

[wherein, R ⁴ and R ⁵ are the same or different, and represent hydrogen, an alkyl group that may have a substituent, an aryl group that may have a substituent, or a heteroaryl group that may have a substituent, and the meanings of other symbols are the same as above. ]

Invention effect

According to the present invention, α-fluoroacrylate can be produced at low production cost without using highly toxic raw material compounds.

Detailed ways

In this specification, examples of "alkyl" (including "alkyl" in substituents such as "mono-alkylamino") include methyl, ethyl, propyl, isopropyl, butyl, C1-6 alkyl groups such as isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, and hexyl.

In this specification, as a "C1-3 alkyl group", a methyl group, an ethyl group, a propyl group, an isopropyl group etc. are mentioned, for example.

In this specification, examples of "alkoxy" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy C1-6 alkoxy groups such as pentyloxy, neopentyloxy, hexyloxy, etc.

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

In the present specification, examples of the "aryl group" include C6-18 aryl groups such as phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, and acenaphthylenyl.

In this specification, examples of "heteroaryl" include 5 to 14 heteroatoms containing 1 to 4 heteroatoms selected from nitrogen atoms, sulfur atoms, and oxygen atoms as atoms constituting the ring, in addition to carbon atoms. membered (monocyclic, bicyclic or tricyclic) heterocyclyl.

In this specification, specific examples of "heteroaryl" include:

(1) furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxazolyl Monocyclic aromatic heterocyclic groups such as diazolyl, thiadiazolyl, triazolyl, tetrazolyl, and triazinyl; and

(2) Quinolinyl, isoquinolyl, quinazolinyl, quinoxalinyl, benzofuryl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, Benzimidazolyl, benzotriazolyl, indolyl, indazolyl, pyrrolopyrazinyl, imidazopyridyl, imidazopyrazinyl, imidazothiazolyl, pyrazolopyridyl, pyrazolo Polycyclic (eg, bicyclic) aromatic heterocyclic groups such as thienyl and pyrazolotriazinyl.

The production method of the present invention is a production method of the compound represented by the following formula (1), which comprises contacting the compound represented by the following formula (2) with an alkali metal halide to obtain the compound represented by the above formula (1). Step A of the compound.

[wherein, R ¹ represents an alkyl group, R ² represents hydrogen, an alkyl group that may have a substituent, an aryl group that may have a substituent, or a heteroaryl group that may have a substituent. ]

[In the formula, R ³ represents an alkyl group, and the other meanings are the same as above. ]

R ¹ is preferably methyl or ethyl, more preferably methyl.

The "alkyl group that may have a substituent" represented by ^R2 is, for example, selected from halogen, alkyl (preferably C1-6 alkyl), alkoxy (preferably C1-6 alkoxy), amino, mono- An alkyl group substituted with one or more (for example, 1 to 3) substituents of alkylamino (preferably mono-C1-6 alkylamino) and di-alkylamino (preferably di-C1-6 alkylamino).

The "aryl group that may have substituents" represented by ^R2 is, for example, selected from halogen, alkyl (preferably C1-6 alkyl), alkoxy (preferably C1-6 alkoxy), amino, mono- An aryl group substituted with one or more (for example, 1 to 3) substituents of alkylamino (preferably mono-C1-6 alkylamino) and di-alkylamino (preferably di-C1-6 alkylamino).

The "heteroaryl group that may have substituents" represented by ^R2 is, for example, selected from halogen, alkyl (preferably C1-6 alkyl), alkoxy (preferably C1-6 alkoxy), amino, mono -Alkylamino (preferably mono-C1~6 alkylamino) and di-alkylamino (preferably di-C1~6 alkylamino) substituents substituted by one or more (for example 1~3) heteroaryl base.

^R2 is preferably hydrogen or alkyl, particularly preferably hydrogen.

The compound represented by the above formula (1) is preferably methyl-2-fluoroacrylate or ethyl-2-fluoroacrylate, particularly preferably methyl-2-fluoroacrylate.

R ³ is preferably a C1-3 alkyl group, more preferably a methyl group or an ethyl group, particularly preferably a methyl group.

The compound represented by the above formula (2) is particularly preferably a compound in which R ¹ and R ³ are both methyl groups and R ² is hydrogen.

The compound represented by the above formula (2) is a known compound, and can be obtained by a known method such as the method described in JP-A-6-184234, that is, by reacting dimethyl α-fluoromalonate with formaldehyde. by or in accordance with a method thereof.

As the alkali metal halide used in step A, for example, lithium halide (such as lithium fluoride, lithium chloride, lithium bromide, lithium iodide, etc.), sodium halide (such as sodium fluoride, sodium chloride, sodium bromide, etc.) , sodium iodide, etc.), potassium halides (such as potassium fluoride, potassium chloride, potassium bromide, potassium iodide, etc.), cesium halides (such as cesium fluoride, cesium chloride, cesium bromide, cesium iodide, etc.), etc.

Among them, sodium halide and potassium halide are preferable, and sodium chloride, sodium bromide, potassium fluoride, potassium chloride and potassium bromide are more preferable.

The amount of the alkali metal halide is usually within a range of 0.001 to 5 moles, preferably within a range of 0.01 to 1 mole, relative to 1 mole of the compound represented by the above formula (2).

Process A is preferably carried out in an organic solvent or without a solvent (neat).

When the step A is carried out in an organic solvent, the contact of the compound represented by the above formula (2) with the above-mentioned alkali metal halide can be carried out by, for example, putting them into the above-mentioned organic solvent and mixing them as necessary.

The organic solvent used in step A may be a polar organic solvent or a nonpolar organic solvent. The organic solvent used in step A is preferably a polar organic solvent.

As the organic solvent used in the step A, for example, dimethylsulfoxide, dimethylformamide, dimethylacetamide, ethylene glycol, polyethylene glycol, polypropylene glycol, ethylene glycol derivatives ( such as ethylene glycol dimethyl ether, diglyme, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether), quinoline, tetrahydroquinoline, methyl Pyrrolidone, dimethylimidazolinone, hexamethylphosphoramide, ethylene carbonate, propylene carbonate, xylene, mesitylene, alkanes (such as decane, dodecane), etc.

Among them, preferred are sulfolane, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, ethylene glycol dimethyl ether, diglyme, propylene carbonate, more preferably sulfolane, dimethyl sulfoxide, glyme, diglyme, methylpyrrolidone, propylene carbonate or ethylene carbonate.

These organic solvents may be used alone or in combination of two or more.

The organic solvent is an organic solvent preferably having a boiling point of 100°C or higher, more preferably 120°C or higher, still more preferably 150°C or higher. The upper limit of the boiling point is not limited, but is usually 300°C.

Since this organic solvent has such a high boiling point, the compound of the formula (1) having a relatively low boiling point can be obtained in high yield by distillation under reduced pressure.

As the organic solvent, for example, sulfolane is particularly preferable.

The amount of the organic solvent is usually in the range of 0 to 100 mL, preferably in the range of 0.01 to 10 mL, more preferably in the range of 0.1 to 1 mL, per 1 g of the compound represented by the above formula (2).

Step A is preferably implemented under the condition that water does not substantially exist.

Here, "water is not substantially present" means that the water content of the reaction mixture in the step A is 1.0% (w/w) or less at the start of the reaction.

When water exists in the reaction system of process A, the yield of the compound represented by formula (1) will fall.

In the reaction of the process A, a polymerization inhibitor can be used as desired. Examples of the polymerization inhibitor include dibutylhydroxytoluene (BHT), 4-methoxyphenol, hydroquinone, phenothiazine, benzoquinone, and phenothiazine.

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

The reaction temperature of the reaction of process A exists in the range of 60-160 degreeC normally, Preferably it exists in the range of 70-150 degreeC, More preferably, it exists in the range of 80-140 degreeC.

The reaction time can be further shortened by using a higher reaction temperature.

The reaction time of the reaction in Step A may be set to, for example, the time at which the yield reaches the maximum. Specifically, it is usually in the range of 1 to 24 hours, more preferably in the range of 1 to 12 hours, and even more preferably in the range of 2 to 24 hours. within 12 hours.

In the production method of the present invention, the produced compound represented by the formula (1) can be taken out from the reaction system by a method such as distillation under reduced pressure while reacting.

The yield of the raw material in the production method of the present invention is preferably 40% or more, more preferably 50% or more, and still more preferably 60% or more.

In the production method of the present invention, a compound represented by formula (3) is obtained together with a compound represented by formula (1).

[wherein, R ⁴ and R ⁵ are the same or different, and represent hydrogen, an alkyl group that may have a substituent, an aryl group that may have a substituent, or a heteroaryl group that may have a substituent, and the meanings of other symbols are the same as above. ]

Here, R ⁴ and R ⁵ are the same or different, are derived from the above-mentioned R ¹ , R ² or R ³ , and may be the same as any of them.

As this compound, dimethoxymethane is mentioned, for example.

The composition of the present invention contains the compound represented by the above formula (1) and the compound represented by the above formula (3), and the mass of the compound represented by the above formula (3) is equal to the mass of the compound represented by the above formula (1) The ratio is in the range of 0.01 to 10% (w/w).

This mass ratio can be determined by gas chromatography under the following conditions.

[Conditions of Gas Chromatography]

Column: DB-5MS60m, 0.25mm, 0.25μm

Carrier gas: He

Gasification chamber temperature: 300°C

Column oven: 40°C (10 minutes) heating up 8°C/min 200°C

Detector temperature: 320°C

Detector FID

For the composition of the present invention, the ratio of the mass of the compound represented by the above formula (3) to the mass of the compound represented by the above formula (1) is in the range of 0.01 to 10% (w/w), preferably 0.01 In the range of ~5% (w/w), more preferably in the range of 0.01-3% (w/w), still more preferably in the range of 0.01-1% (w/w), still more preferably in the range of 0.01- In the range of 0.5% (w/w), it can be suitably used, for example, as a synthetic intermediate for pharmaceuticals (such as antibiotics), a synthetic intermediate for optical fiber sheath materials, a synthetic intermediate for coating materials, and a semiconductor resist. Synthesis intermediates of pharmaceutical materials and synthesis intermediate compositions of monomers of functional polymers, etc., are advantageous in terms of production costs of the compositions, and thus are also advantageous in terms of production costs of final products.

The compound represented by the formula (1) obtained by the production method of the present invention can be purified as desired by known purification methods such as solvent extraction, drying, filtration, distillation, concentration, and combinations thereof.

Example

Example 1

Put 2.91g (50mmol) of potassium fluoride, 55.1mg (0.250mmol) of dibutylhydroxytoluene (BHT), and 45.0g of dimethyl-2-fluoro-2-hydroxymethylmalonate into a 100mL eggplant-shaped flask (250mmol) and sulfolane 11.5mL (14.5g) and mix. It heated at 90 degreeC for 15 minutes under normal pressure, then heated at 105 degreeC under reduced pressure for 1 hour, and distilled while reacting, and methyl-2-fluoroacrylate was obtained in the form of the mixture with methanol.

Yield 18.2 g (26.8 g as mixture with methanol), 70% yield.

This mixture contains dimethoxymethane. The ratio of the mass of dimethoxymethane to the mass of methyl-2-fluoroacrylate calculated by gas chromatography under the following conditions was 0.16% (w/w).

[Conditions of Gas Chromatography]

Column: DB-5MS60m, 0.25mm, 0.25μm

Carrier gas: He

Gasification chamber temperature: 300°C

Column oven: 40°C (10 minutes) heating up 8°C/min 200°C

Detector temperature 320°C

Detector FID

According to the present invention, α-fluoroacrylate can be produced at low production cost and in high yield without passing through an intermediate that is difficult to isolate.

Claims (9)

1. a manufacture method for the compound shown in following formula (1), is characterized in that:

Comprise the operation A that the compound shown in following formula (2) is contacted and obtain the compound shown in described formula (1) with alkali metal halide,

In formula, R ¹represent alkyl, R ²represent hydrogen, can there is substituent alkyl, can there is substituent aryl and maybe can there is substituent heteroaryl,

In formula, R ³represent alkyl, the implication of other symbol is the same.

2. manufacture method as claimed in claim 1, is characterized in that:

Described alkali metal halide is potassium halide.

3. manufacture method as claimed in claim 1, is characterized in that:

Described alkali metal halide is Potassium monofluoride.

4. the manufacture method as described in any one in claim 1～3, is characterized in that:

Operation A implements in organic solvent.

5. manufacture method as claimed in claim 4, is characterized in that:

Described organic solvent is polar organic solvent.

6. manufacture method as claimed in claim 4, is characterized in that:

Described organic solvent is the organic solvent with 100 DEG C of above boiling points.

7. the manufacture method as described in any one in claim 4～6, is characterized in that:

Described organic solvent is tetramethylene sulfone, dimethyl sulfoxide (DMSO), glyme, diglyme, methyl-2-pyrrolidone, propylene carbonate or NSC 11801.

8. the manufacture method as described in any one in claim 1～7, is characterized in that:

Operation A does not substantially exist under the condition of water and implements.

9. a composition that contains the compound shown in the compound shown in following formula (1) and following formula (3), is characterized in that:

In formula, R ¹represent alkyl, R ²represent hydrogen, can there is substituent alkyl, can there is substituent aryl and maybe can there is substituent heteroaryl,

In formula, R ⁴and R ⁵identical or different, represent hydrogen, can there is substituent alkyl, can there is substituent aryl and maybe can there is substituent heteroaryl, the implication of other symbol is the same,

The mass ratio of the compound shown in the quality of the compound shown in described formula (3) and described formula (1) is at 0.01～10%(w/w) scope in.