JP2002193886A - Method for producing 2-fluoro-3-oxoalkylcarboxylic ester - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for efficiently producing a high-purity 2-fluoro-3- oxoalkylcarboxylic ester useful as a raw material for an intermediate of medicines and agrochemicals by fluorinating a 3-oxoalkylcarboxylic ester while controlling formation of by-product. SOLUTION: In this method for producing the 2-fluoro-3-oxoalkylcarboxylic ester by fluorinating the 3-oxoalkylcarboxylic ester with a fluorine gas, the method for producing the 2-fluoro-3-oxoalkylcarboxylic ester is characterized in that the concentration of the 3-oxoalkylcarboxylic ester in the fluorination reaction solution is maintained at >=3 wt.%.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing 2-fluoro-3-oxoalkylcarboxylic acid esters useful as intermediates for pharmaceuticals and agricultural chemicals.

[0002]

2. Description of the Related Art Fluorine-containing dicarbonyl compounds such as 2-fluoro-3-oxoalkylcarboxylic acid esters are extremely useful as intermediates for pharmaceuticals, agricultural chemicals and the like.

As a method for producing these compounds, a method is known in which the corresponding dicarbonyl compound is directly fluorinated using fluorine gas. For example, J. Org. Chem., 57, 2
196 (1992), International Application Patent WO94 / 10120, International Application Patent WO95 / 14646, and JP-A-9-25
No. 5611 discloses that a corresponding dicarbonyl compound is directly fluorinated using fluorine gas to selectively obtain a desired fluorinated dicarbonyl compound such as a desired 2-fluoro-3-oxoalkylcarboxylic acid ester. The technology is disclosed.

However, the reaction of directly fluorinating a dicarbonyl compound using fluorine gas is a reaction which proceeds radically, and is a fluorinated dicarbonyl such as a desired 2-fluoro-3-oxoalkylcarboxylic acid ester. It is difficult to selectively obtain only the compound. For example, in the fluorination reaction of this reference, some monofluoro compounds, difluoro compounds, and further fluorinated compounds are produced.

[0005] However, in these references, water is added after the fluorination reaction, and extraction with dichloromethane or the like is only described. From this reaction product, some monofluoro compounds, difluoro compounds, and further fluorine compounds are extracted. Control of the formation of the compound
A technique for efficiently producing a fluorinated dicarbonyl compound such as an oxoalkylcarboxylic acid ester is not disclosed.

The present inventors have attempted to distill and separate the product from the reaction solution obtained by fluorinating 3-oxoalkyl carboxylic acid esters by a conventional method. However, 2,5-difluoro-3-oxoalkyl carboxylic acid Decomposition of perfluorinated 3-oxoalkylcarboxylic acid esters represented by esters generates hydrogen fluoride, which makes purification difficult. Therefore, the fluorinated 3-oxoalkylcarboxylic acid esters have been used as they are as the next reaction raw materials without being purified by distillation. For example, European Patent No. 0440372A1 discloses a technique for producing a triazole derivative which is an antifungal agent by reacting a 2-fluoro-3-oxoalkylcarboxylic acid ester with an amidine. However, as this raw material 2-
When a fluoro-3-oxoalkylcarboxylic acid ester is used, there are problems that the purity of the product is low, a compound having an unknown structure is easily generated, the reaction conditions are extremely narrow, and the production becomes difficult.

[0007]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to carry out the fluorination of a 3-oxoalkylcarboxylic acid ester by controlling the formation of by-products,
An object of the present invention is to provide a method for efficiently producing a 2-fluoro-3-oxoalkylcarboxylic acid ester useful as an intermediate material for medical and agricultural chemicals with high purity.

[0008]

Means for Solving the Problems The present inventors have conducted intensive studies in view of such a current situation. As a result, the fluorination of 3-oxoalkyl carboxylic acid ester (MOP) is a perfluorinated 3-oxoalkyl carboxylic acid typified by 2,5-difluoro-3-oxoalkyl carboxylic acid ester at the end of the reaction. It was found that the generation of the ester progressed rapidly, and as a result, the content of the 2-fluoro-3-oxoalkylcarboxylic acid ester was reduced.

Based on this finding, the inventors of the present invention have found that by fluorination, the concentration of 3-oxoalkylcarboxylic acid ester is controlled to suppress the by-product of 2,5-difluoro-3-oxoalkylcarboxylic acid ester. 2-fluoro-3-oxoalkylcarboxylic acid ester can be efficiently produced, and when the concentration of by-products is low, the 2-fluoro-3-oxoalkylcarboxylic acid ester can be purified by distillation. The inventors have found that the present invention has been completed.

That is, the present invention provides a compound represented by the general formula (1)

[0011]

Embedded image

(Wherein R ₁ is an alkyl group or an alkenyl group, and R ₂ represents a carboxylic acid-protecting group). A 3-oxoalkylcarboxylic acid ester represented by the general formula (2)

[0013]

Embedded image

(Wherein R ₁ and R ₂ are the same as defined above)
In the method for producing a 2-fluoro-3-oxoalkylcarboxylic acid ester represented by the formula, the concentration of the 3-oxoalkylcarboxylic acid ester in the fluorination reaction solution is 3 wt.
% Of 2-fluoro-3-characteristic
A method for producing an oxoalkyl carboxylic acid ester, and a method for producing a 2-fluoro-3-oxo-alkyl carboxylic acid ester by removing hydrogen fluoride from a reaction solution obtained by the above method, and then distilling off the 2-fluoro-3-oxoalkyl carboxylic acid ester. 3
-Oxoalkylcarboxylic acid esters.

[0015]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail.

In the present invention, 3-
The oxoalkyl carboxylic acid ester has the general formula (1)
Β containing an active methylene group represented by? It is a dicarbonyl compound.

In the general formula (1), R ₁ represents a substituent comprising a hydrocarbon having 1 to 10 carbon atoms, for example, an alkyl group and an alkenyl group. Examples of these substituents include, as an alkyl group, methyl, ethyl,
Examples include propyl, isopropyl, cyclopropyl, butyl, isobutyl, hexyl, cyclohexyl, and octyl groups. Examples of the alkenyl group include propenyl, butenyl, and hexenyl groups. These substituents R ₁
May be optionally substituted with a fluorine atom.

R ₂ may be any organic compound capable of forming an ordinary ester bond with a protecting group of a carboxylic acid, and is not limited.
Examples thereof include an alkenyl group and an aryl group.

Preferred examples of the 3-oxoalkylcarboxylic acid ester include 3-oxobutyric acid ester and 3-oxopentanoic acid ester.

Examples of the ester of the 3-oxoalkylcarboxylic acid ester represented by the general formula (1) include lower alkyl esters such as methyl ester and ethyl ester.

The first step of the present invention is a step of fluorinating a 3-oxoalkylcarboxylic acid ester with fluorine gas.

For example, International Patent Application WO 95/1464
No. 6 discloses a technique for directly fluorinating a 3-oxoalkylcarboxylic acid ester with a fluorine gas diluted with an inert gas such as nitrogen. According to this reference,
The reaction solution can be produced by fluorination as appropriate. For example, a 3-oxoalkylcarboxylic acid ester is charged into a reactor equipped with a stirrer and a thermometer, and the mixture is reacted while bubbling with stirring about 10% fluorine gas diluted with nitrogen. The reaction is completed, for example, at a temperature of 0 to 15 ° C. for 5 to 40 hours, depending on the amount of the raw materials and the blowing rate of the fluorine gas. In this reaction, the same amount of hydrogen fluoride as the reacted fluorine gas is generated, and usually, hydrogen fluoride is directly dissolved and contained in the reaction solution.

As a method of the fluorination reaction, a method of blowing a fluorine gas into a 3-oxoalkylcarboxylic acid ester, a method of adding a solution in which a fluorine gas is dissolved, a method of adding a solution of a fluorine gas, and a method of adding a solution of a fluorine gas to a 3-oxoalkylcarboxylic acid ester are used. Continuous methods such as a method of continuously blowing an -oxoalkylcarboxylic acid ester and a fluorine gas, and a method of continuously flowing a 3-oxoalkylcarboxylic acid ester and a fluorine gas in a reaction tube, and the like are particularly limited. Not something.

The perfluorinated 3-oxoalkylcarboxylic acid ester represented by 2,5-difluoro-3-oxoalkylcarboxylic acid ester by-produced by excessive fluorination during this fluorination operation is obtained in the next step. In order to generate hydrogen fluoride by thermal decomposition in the distillation operation and decompose the 2-fluoro-3-oxoalkylcarboxylic acid ester, the content is preferably reduced as much as possible.

As the by-product perfluorinated 3-oxoalkylcarboxylic acid ester, 2,5-difluoro-3-
In addition to oxocarboxylic acid esters, 2,2,4-trifluoro-3-oxoalkylcarboxylic acid esters and 2,2,5-trifluoro-3-oxoalkylcarboxylic acid esters are exemplified.

The progress of the reaction can be confirmed by appropriately collecting the reaction solution and using gas chromatography. The concentration of the 3-oxoalkylcarboxylic acid ester as a raw material in the fluorination reaction solution is preferably 3% by weight or more. Is 10wt%
The above is maintained, and the molar ratio of the 2,5-difluoro-3-oxoalkylcarboxylic acid ester to the 2-fluoro-3-oxoalkylcarboxylic acid ester is 0.05 or less, preferably 0.01 or less.

By maintaining the concentration of the 3-oxoalkyl carboxylic acid ester in the fluorination reaction solution at 3 wt% or more, perfluorinated 3,3-difluoro-3-carboxylic acid ester or the like as a by-product is obtained. The formation of -oxoalkylcarboxylic acid esters can be suppressed, and as a result, the yield of 2-fluoro-3-oxoalkylcarboxylic acid esters can be increased.

When the concentration of the 3-oxoalkylcarboxylic acid ester in the fluorination reaction solution is less than 3 wt%, 2,5
By-production of -difluoro-3-oxoalkylcarboxylic acid ester proceeds. The molar ratio of 2,5-difluoro-3-oxoalkylcarboxylic acid ester to 2-fluoro-3-oxoalkylcarboxylic acid ester is 0.0
As the value exceeds 5, the produced 2-fluoro-3-oxoalkylcarboxylic acid ester is further fluorinated, and the generation of impurities proceeds rapidly, with the result that 2-fluoro-
A reduction in the content of 3-oxoalkylcarboxylic acid esters occurs.

The next step of the present invention is to remove by-product hydrogen fluoride from the reaction solution obtained by fluorinating the 3-oxoalkylcarboxylic acid ester.

Examples of the method for removing hydrogen fluoride from the reaction solution include a method of washing the reaction solution with water and a method of distilling the reaction solution under reduced pressure.

As for the method of washing with water, about 0.5 to 3 times the amount of water is used for the reaction solution, which is brought into good contact with the reaction solution, and hydrogen fluoride dissolved in the reaction solution is extracted with water and washed and removed. Hydrogen fluoride extracted into water exists as hydrofluoric acid. This extraction temperature is not particularly limited,
5 to 40 ° C is good. The extraction with water depends on the amount of water, but is preferably repeated 2 to 6 times, and usually 3 to 4 times is sufficient. In this water washing method, an organic solvent insoluble in water can be used in combination with water. As the organic solvent used in combination, for example, dichloromethane, chloroform,
One or two? Dichloroethane, toluene, xylene and the like can be used. When an organic solvent is used in combination, hydrogen fluoride in the reaction solution is efficiently extracted by water, and the reaction solution is extracted into an organic solvent layer. After removing the organic solvent from the organic solvent layer after water washing by distillation, the 2-fluoro-3-oxoalkylcarboxylic acid ester may be separated by distillation.

As a distillation treatment under reduced pressure, hydrogen fluoride can be removed by distillation under reduced pressure at a temperature of 50 ° C. or less, preferably 40 ° C. or less. Vacuum distillation, depending on the amount of hydrogen fluoride contained,
The pressure is gradually increased from normal pressure to about 4.00 KPa (30 Torr). The vacuum distillation time is not particularly limited, but is 3 to 15 hours.

As another removing method, there is a method of forming an azeotropic composition by using an azeotropic agent and performing distillation. Compounds that form an azeotropic composition with hydrogen fluoride include, for example, dimethyl ether, diethyl ether, diisopropyl ether as ethers, trifluoroethyl chloride, chlorofluorocarbon 12, fluorocarbon 22, fluorocarbon as fluorinated hydrochlorocarbons Classes include butane, isobutane, and the like. These azeotropic agents may be added to the reaction solution or supplied while continuously bubbling.

In removing these hydrogen fluorides, a basic compound can be added as an additional method in addition to the above-described hydrogen fluoride removal. These basic substances include hydroxides of alkali metals and alkaline earth metals,
Carbonates, bicarbonates and the like can be used.

Although it is preferable to remove hydrogen fluoride as much as possible, it is removed to 2.0% by weight or less, preferably 1.0% by weight or less per reaction solution. If the reaction solution containing hydrogen fluoride in excess of 2.0% by weight is subjected to distillation separation in the next step, the purity and yield of the obtained 2-fluoro-3-oxoalkylcarboxylic acid ester are undesirably reduced.

The next step of the present invention is a step of distilling the reaction solution from which hydrogen fluoride has been removed to separate the desired 2-fluoro-3-oxoalkylcarboxylic acid ester.

The purification distillation of the 2-fluoro-3-oxoalkylcarboxylic acid ester is preferably carried out under reduced pressure, preferably 4.0.
At a pressure of 0 KPa (30 Torr) or less, the lower the operating temperature, the better, but preferably 125 ° C. or less. Above 125 ° C., 3-oxoalkyl carboxylic esters and their fluorinated derivatives are unstable and can thermally decompose.

By stopping the fluorination reaction early in the distillation purification step, it is possible to avoid the incorporation of unreacted raw material, 3-oxoalkylcarboxylic acid ester, into the product. -The oxoalkylcarboxylic acid ester can be returned to the fluorination step and reused as a raw material.

Thus, high-purity 2-fluoro-
A 3-oxoalkylcarboxylic acid ester can be efficiently produced.

[0040]

EXAMPLES The present invention will be described below in more detail with reference to examples, but the present invention is not limited to these examples. The names and abbreviations of the compounds used in Examples and Comparative Examples are shown below.

MOP: methyl 3-oxopentanoate MFOP: methyl 2-fluoro-3-oxopentanoate 2,5-DFOP: methyl 2,5-difluoro-3-oxopentanoate.

Example 1 A 10-liter stainless steel reaction vessel equipped with a thermometer and a stirrer was charged with 5000 g of MOP, and reacted while bubbling fluorine gas diluted to 10% with nitrogen. The reaction was stopped for 20 hours while maintaining the reaction temperature at 10 ° C. to obtain a reaction solution. When we took a part of it and analyzed it,
OP is 3.6 wt%, MFOP is 42.6 wt%, 2,
2.1 wt% of 5-DFOP was contained. 2,5-D
The molar ratio of FOP to MFOP was 0.04.

To 1 kg of the obtained fluorination reaction solution, 1 liter of water and 1 liter of chloroform were added, and the mixture was shaken at room temperature in a separating flask and allowed to stand. Take the chloroform layer, add new water and repeat the same operation.
Washing was performed twice.

The chloroform layer washed with water was heated to about 40 to 60 ° C. while bubbling a small amount of nitrogen.
The pressure was reduced to 26.7 KPa (200 Torr), and chloroform was distilled off.

Next, using this can solution, the degree of vacuum was reduced from normal pressure to 2.67 KPa (20 Torr), and the
After about 4 hours at 3 ° C., the pressure was reduced to 1.33K.
Batch distillation was performed at Pa (10 Torr) and a can temperature of 87 ° C., and the reaction was completed after about 15 hours. As a result, it was separated into four fractions: an initial fraction mainly composed of low-boiling substances, a fraction mainly composed of MOP, a main fraction mainly composed of MFOP, and a bottom mainly composed of high-boiling substances. Each fraction was analyzed by gas chromatography to determine the concentration of MFOP.

The initial fraction was 49 g and the MFOP was 0.6
wt%. The fraction mainly composed of MOP was 26 g, and contained 12.4 wt% of MFOP. MFO
The fraction mainly composed of P is 373 g, and the MFOP is 97.
7 wt% was contained. On the other hand, the can residue is 103 g,
MFOP was contained at 14.8 wt%. The material balance of MFOP was 98 wt%, and almost no decomposition was observed.

Example 2 In the same manner as in Example 1, 5000 g of MOP was charged and reacted while bubbling fluorine gas diluted to 10% with nitrogen. The reaction was stopped for 12 hours while maintaining the reaction temperature at 5 ° C. to obtain a reaction solution. When a part thereof was taken and analyzed, MOP was 14.6 wt% and MFOP was 43.1 w%.
t% and 2,5-DFOP were contained at 0.5 wt%.
The molar ratio of 2,5-DFOP to MFOP is 0.0
It was one.

1 liter of water and 1 liter of chloroform were added to 1 kg of the obtained fluorination reaction solution, and the mixture was shaken at room temperature in a separation flask and allowed to stand. Take the chloroform layer, add new water and repeat the same operation.
Washing was performed twice.

The chloroform layer washed with water was heated to about 40 to 60 ° C. while bubbling a small amount of nitrogen.
The pressure was reduced to 26.7 KPa (200 Torr), and chloroform was distilled off.

Next, using this can solution, the degree of vacuum was reduced from normal pressure to 2.67 KPa (20 Torr), and the
After about 4 hours at 3 ° C., the pressure was reduced to 1.33K.
Batch distillation was performed at Pa (10 Torr) and a can temperature of 87 ° C., and the reaction was completed after about 16 hours. As a result, it was separated into four fractions: an initial fraction mainly composed of low-boiling substances, a fraction mainly composed of MOP, a main fraction mainly composed of MFOP, and a bottom mainly composed of high-boiling substances. Each fraction was analyzed by gas chromatography to determine the concentration of MFOP.

The initial fraction was 50 g and the MFOP was 0.6
wt%. The fraction mainly composed of MOP was 92 g, and contained 3.5 wt% of MFOP. MFOP
Is 400 g and the MFOP is 93.1.
wt%. On the other hand, the can residue is 44 g, MF
OP was contained at 26.8 wt%. The material balance of MFOP was 99 wt%, and almost no decomposition was observed.

Comparative Example 1 As in Example 1, 5000 g of MOP was charged and reacted while bubbling a fluorine gas diluted to 10% with nitrogen. The reaction was stopped for 28 hours while maintaining the reaction temperature at 10 ° C. to obtain a reaction solution. When a part of the sample was taken and analyzed, MOP was 0.4 wt% and MFOP was 29.0 w.
t% and 10.1 wt% of 2,5-DFOP were contained. The molar ratio of 2,5-DFOP to MFOP was 0.31.

To 1 kg of the obtained fluorination reaction solution, 1 liter of water and 1 liter of chloroform were added, and the mixture was shaken at room temperature in a separation flask and allowed to stand. Take the chloroform layer, add new water and repeat the same operation.
Washing was performed twice.

The chloroform layer washed with water was heated to about 40 to 60 ° C. while bubbling a small amount of nitrogen.
The pressure was reduced to 26.7 KPa (200 Torr), and chloroform was distilled off.

Next, using this can solution, the degree of vacuum was reduced from normal pressure to 2.67 KPa (20 Torr), and the
After about 4 hours at 3 ° C., the pressure was reduced to 1.33K.
Batch distillation was performed at Pa (10 Torr) and a can temperature of 87 ° C., and the reaction was completed after about 13 hours. Thereby, it was separated into three fractions: an initial fraction mainly composed of low-boiling substances, a main fraction mainly composed of MFOP, and a bottom mainly composed of high-boiling substances. Each fraction was analyzed by gas chromatography to determine the concentration of MFOP.

The initial fraction was 71 g and MFOP was 2.9.
wt%. 218 mainly for MFOP
g, and MFOP contained 98.8 wt%.
On the other hand, the can residue is 248 g and MFOP is 15.1 wt.
% Was included. During the distillation operation up to this point, coloring of the kettle liquid, decomposition of the composition, and formation of heavy components were observed.
The material balance of OP decreased to 85 wt%.

Comparative Example 2 In the same manner as in Example 1, 5000 g of MOP was charged and reacted while bubbling fluorine gas diluted to 10% with nitrogen. The reaction was stopped for 32 hours while maintaining the reaction temperature at 0 ° C. to obtain a reaction solution. When a part thereof was taken and analyzed, MOP was 1.3 wt% and MFOP was 39.2 wt%.
%, 2,5-DFOP was contained at 6.0 wt%.
The molar ratio of 2,5-DFOP to MFOP is 0.1
It was 4.

1 liter of water and 1 liter of chloroform were added to 1 kg of the obtained fluorination reaction solution, and the mixture was shaken at room temperature in a separation flask and allowed to stand. Take the chloroform layer, add new water and repeat the same operation.
Washing was performed twice.

The chloroform layer washed with water was heated to about 40 to 60 ° C. while bubbling a small amount of nitrogen.
The pressure was reduced to 26.7 KPa (200 Torr), and chloroform was distilled off.

Next, using this can solution, the degree of vacuum was reduced from normal pressure to 2.67 KPa (20 Torr), and the
After about 4 hours at 3 ° C., the pressure was reduced to 1.33K.
Batch distillation was performed at Pa (10 Torr) and a can temperature of 87 ° C., and the reaction was completed after about 15 hours. Thereby, it was separated into three fractions: an initial fraction mainly composed of low-boiling substances, a main fraction mainly composed of MFOP, and a bottom mainly composed of high-boiling substances. Each fraction was analyzed by gas chromatography to determine the concentration of MFOP.

The initial fraction was 69 g, and the MFOP was 0.3
wt%. MFOP-based fractions are 319
g, and MFOP was contained at 98.5% by weight. On the other hand, the can residue is 140 g, and MFOP is 23.1 wt%.
Was included. During the distillation operation so far, coloring of the kettle liquid,
Decomposition of the composition and formation of heavy components were observed, and MFOP
Was reduced to 92 wt%.

[0062]

The fluorinated 3-oxoalkyl carboxylic acid ester has been used without purification because it contains many fluorinated compounds as impurities and is difficult to produce selectively. However, according to the present invention, generation of impurities can be controlled, and 2-fluoro-3-oxoalkylcarboxylic acid esters can be produced with high selectivity and high purity. For this reason, the quality of useful pharmaceuticals derived from 2-fluoro-3-oxoalkylcarboxylic acid esters as starting materials can be improved, the production cost can be reduced, and the economic effect is large.

 ──────────────────────────────────────────────────続 き The continuation of the front page F term (reference) 4H006 AA02 AC30 AD11 AD16 BE53 BM10 BM71 BR10

Claims (3)

[Claims] 1. A compound of the general formula (1) (Wherein R ₁ is an alkyl or alkenyl group, R ₂
Represents a protecting group for carboxylic acid), and fluorinates a 3-oxoalkylcarboxylic acid ester represented by the general formula (2). (Wherein R ₁ and R ₂ are the same as defined above)
A method for producing a -fluoro-3-oxoalkylcarboxylic acid ester, wherein the concentration of a 3-oxoalkylcarboxylic acid ester in a fluorination reaction solution is maintained at 3 wt% or more. A method for producing a carboxylic acid ester. 2. The 2-fluoro-3-oxoalkylcarboxylic acid ester is separated by distillation after removing hydrogen fluoride from the reaction solution obtained by the method according to claim 1. A method for producing a 3-oxoalkylcarboxylic acid ester. 3. The method according to claim 1, wherein the 3-oxoalkyl carboxylic acid ester is a lower alkyl ester of 3-oxobutyric acid or 3-oxopentanoic acid.