JP2007001988A - Process for producing 2- (5-fluoro-2-nitrophenyl) -2-malonic acid diester derivative - Google Patents

Abstract

The present invention provides an industrially suitable method for producing a 2- (5-fluoro-2-nitrophenyl) -2-malonic acid diester derivative from a 2,4-difluoronitrobenzene derivative by a simple method. It is an object to provide a manufacturing method capable of achieving the above.
An object of the present invention is to react a 2,4-difluoronitrobenzene derivative with a malonic acid diester in an organic solvent in the presence of a metal alkoxide. It is solved by a process for producing a nitrophenyl) -2-malonic acid diester derivative.
[Selection figure] None

Description

  The present invention relates to a method for producing a 2- (5-fluoro-2-nitrophenyl) -2-malonic acid diester derivative from a 2,4-difluoronitrobenzene derivative by a simple method.

2- (5-Fluoro-2-nitrophenyl) -2-substituted acetic acid ester derivatives are useful compounds as synthetic intermediates for pharmaceuticals and agricultural chemicals, for example. Conventionally, as a method for producing a 2- (5-fluoro-2-nitrophenyl) -2-substituted acetate derivative from a 2,4-difluoronitrobenzene derivative, for example, in dimethyl sulfoxide in the presence of sodium hydride, A method of synthesizing dimethyl 2- (5-fluoro-2-nitrophenyl) malonate by reacting dimethyl malonate with a 2,4-difluoronitrobenzene derivative is disclosed (for example, see Non-Patent Document 1). However, in this method, sodium hydride having high ignitability is used, and hydrogen gas is generated due to the reaction, so that complicated operation is required, and there is a problem as an industrial production method.
Synthesis, 1993, 51

  An object of the present invention is to solve the above problems and to produce a 2- (5-fluoro-2-nitrophenyl) -2-malonic acid diester derivative from a 2,4-difluoronitrobenzene derivative by a simple method. An industrially suitable method for producing a 2- (5-fluoro-2-nitrophenyl) -2-malonic acid diester derivative is provided.

  The subject of this invention is general formula (1) in presence of a metal alkoxide.

(In the formula, R ¹ represents a hydrogen atom; an alkyl group, a cycloalkyl group, an aralkyl group, an aryl group, an alkoxy group, or an aryloxy group, which may have a substituent, and R ² and R ³ are: A hydrogen atom; a halogen atom; an alkyl group, a cycloalkyl group, an aralkyl group, an aryl group, an alkoxy group or an aryloxy group which may have a substituent;
A 2,4-difluoronitrobenzene derivative represented by the general formula (2)

（式中、Ｒ^４は、アルコキシカルボニル基、アラルキルオキシカルボニル基又はアリールオキシカルボニル基を示し、Ｒ^５は、アルキル基、アラルキル基又はアリール基を示す。）
で示されるマロン酸ジエステル誘導体を有機溶媒中で反応させることを特徴とする、一般式（３）

(In the formula, R ⁴ represents an alkoxycarbonyl group, an aralkyloxycarbonyl group or an aryloxycarbonyl group, and R ⁵ represents an alkyl group, an aralkyl group or an aryl group.)
Wherein the malonic acid diester derivative represented by the general formula (3) is reacted in an organic solvent.

(Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above.)
This is solved by a method for producing a 2- (5-fluoro-2-nitrophenyl) -2-malonic acid diester derivative represented by the following formula.

  According to the present invention, a 2- (5-fluoro-2-nitrophenyl) -2-malonic acid diester derivative can be produced from a 2,4-difluoronitrobenzene derivative by a simple method in an industrially suitable manner. I can do it.

The 2,4-difluoronitrobenzene derivative used in the reaction of the present invention is represented by the general formula (1). In the general formula (1), R ¹ represents a hydrogen atom; an alkyl group, a cycloalkyl group, an aralkyl group, an aryl group, an alkoxy group or an aryloxy group, which may have a substituent, and R ² and R ³ represents a hydrogen atom; a halogen atom; an alkyl group, a cycloalkyl group, an aralkyl group, an aryl group, an alkoxy group, or an aryloxy group, which may have a substituent.

  Examples of the halogen atom include a fluorine atom, a bromine atom, and an iodine atom.

  As the alkyl group, an alkyl group having 1 to 10 carbon atoms is particularly preferable, for example, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, etc. Is available. These alkyl groups include various isomers.

  The cycloalkyl group is particularly preferably a cycloalkyl group having 3 to 7 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group. These cycloalkyl groups include various isomers.

  As the aralkyl group, an aralkyl group having 7 to 10 carbon atoms is particularly preferable, and examples thereof include a benzyl group, a phenethyl group, a phenylpropyl group, and a phenylbutyl group. These aralkyl groups include various isomers.

  As the aryl group, an aryl group having 6 to 14 carbon atoms is particularly preferable, and examples thereof include a phenyl group, a tolyl group, a naphthyl group, and an anthranyl group. These aryl groups include various isomers.

  As said alkoxy group, a C1-C12 alkoxy group is especially preferable, for example, a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a benzyloxy group etc. are mentioned. These alkoxy groups include various isomers.

  As the aryloxy group, an aryloxy group having 6 to 14 carbon atoms is particularly preferable, and examples thereof include a phenoxy group and a tolyloxy group. These aryloxy groups include various isomers.

  The alkyl group, cycloalkyl group, aralkyl group, aryl group, alkoxy group or aryloxy group may have a substituent. Examples of the substituent include at least one selected from a substituent formed through a carbon atom, a substituent formed through an oxygen atom, and a substituent formed through a nitrogen atom.

  Examples of the substituent formed through the carbon atom include an alkyl group such as a methyl group, an ethyl group, and a propyl group; an aralkyl group such as a benzyl group; an aryl group such as a phenyl group; and a cyano group.

  Examples of the substituent formed through the oxygen atom include an alkoxy group such as a methoxy group, an ethoxy group, a propoxy group, a butoxy group, and a benzyloxy group; and an aryloxy group such as a phenoxy group.

  Examples of the substituent formed through the nitrogen atom include a nitro group and an amino group.

The malonic acid diester used in the reaction of the present invention is represented by the general formula (2). In the general formula (2), R ⁴ represents an alkoxycarbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group or a butoxycarbonyl group; an aralkyloxycarbonyl group such as a benzyloxycarbonyl group; an aryl such as a phenoxycarbonyl group An oxycarbonyl group is mentioned. These groups include various isomers. Examples of R ⁵ include an alkyl group such as a methyl group, an ethyl group, and a propyl group; an aralkyl group such as a benzyl group; and an aryl group such as a phenyl group. These groups include various isomers.

  The use amount of the malonic acid diester is preferably 1.0 to 5.0 times mol, more preferably 1.2 to 3.0 times mol based on the 2,4-difluoronitrobenzene derivative.

  Examples of the metal atom of the metal alkoxide used in the reaction of the present invention include, for example, a group 1A atom such as lithium atom, sodium atom, potassium atom, etc. described in Physics and Chemistry Dictionary 4th edition (Iwanami Shoten); magnesium atom, 2A group atoms such as calcium atoms; 3B group atoms such as aluminum can be mentioned.

  Examples of the metal alkoxide include group 1A metal alkoxides such as lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, and potassium t-butoxide; group 2A such as magnesium methoxide and calcium methoxide. Metal alkoxides: Group 3B metal alkoxides such as aluminum isopropoxide are used.

  The amount of the metal alkoxide to be used is preferably 1.0 to 5.0 times mol, more preferably 1.2 to 3.0 times mol for the 2,4-difluoronitrobenzene derivative. These metal alkoxides may be used alone or in combination of two or more.

  The organic solvent used in the reaction of the present invention is not particularly limited as long as it does not inhibit the reaction. For example, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aliphatic hydrocarbons such as hexane and cyclohexane Aromatic hydrocarbons such as benzene, toluene and xylene; amides such as N, N-dimethylformamide and N, N′-dimethylimidazolidinone; nitriles such as acetonitrile and propionitrile; dimethyl sulfoxide and the like Preferably, aliphatic hydrocarbons, aromatic hydrocarbons, amides, dimethyl sulfoxide, more preferably cyclohexane, toluene, N, N-dimethylformamide, dimethyl sulfoxide are used.

  The amount of the organic solvent used is appropriately adjusted depending on the homogeneity and stirring properties of the reaction solution, but is preferably 1 to 50 times by weight, more preferably 1.5 to 20 weights with respect to the 2,4-difluoronitrobenzene derivative. Is double. These organic solvents may be used alone or in combination of two or more.

  In the reaction of the present invention, for example, a 2,4-difluoronitrobenzene derivative, a malonic acid diester, a metal alkoxide, and an organic solvent are mixed and reacted. As a preferred embodiment of the present invention, a malonic acid diester, a metal alkoxide, and an organic solvent And preferably at 20 to 140 ° C., more preferably at 30 to 120 ° C. (If necessary, the alcohol formed under a pressure of 0.001 to 0.1 MPa was removed by simple distillation or azeotropic distillation. After or while removing), a 2,4-difluoronitrobenzene derivative is added and reacted.

  The target 2- (5-fluoro-2-nitrophenyl) -2-malonic acid diester derivative obtained by the reaction of the present invention is, for example, generally used for column chromatography, distillation, recrystallization and the like after completion of the reaction. Separated and purified by various methods.

  Next, the present invention will be specifically described with reference to examples, but the scope of the present invention is not limited thereto.

Example 1
Under a argon atmosphere, 3.40 g (62.9 mmol) of sodium methoxide and 30 ml of dimethyl sulfoxide were added to a glass flask having an internal volume of 200 ml equipped with a stirrer, a thermometer, a distillation device and a dropping funnel, and then stirred at room temperature Then, 8.48 g (62.9 mmol) of dimethyl malonate having a purity of 98% was slowly added dropwise over 5 minutes. Furthermore, 10 ml of cyclohexane was added, and after raising the temperature to 100 to 105 ° C., the produced methanol was azeotropically distilled (distilled) together with cyclohexane. After repeating this operation (distilling off methanol) twice, the mixture was cooled to 70 ° C., and 5.10 g (31.4 mmol) of 2,4-difluoronitrobenzene having a purity of 98% was gently added dropwise over 10 minutes. It was made to react at -80 degreeC for 1 hour. After completion of the reaction, the reaction mixture was cooled to room temperature, 100 ml of toluene was added, and 5.25 ml (31.4 mmol) of 6 mol / l hydrochloric acid was gently added dropwise with stirring. Then, the organic layer was separated, washed with 50 ml of water and 50 ml of saturated saline in this order, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting concentrate was purified by silica gel column chromatography (filler: Daisogel 1002W, developing solvent: hexane: ethyl acetate = 9: 1 (volume ratio)) to give white crystals, 5.60 g of dimethyl 2- (5-fluoro-2-nitrophenyl) malonate having a purity of 98% (area percentage of high performance liquid chromatography) was obtained (isolation yield 64%).
The physical properties of dimethyl 2- (5-fluoro-2-nitrophenyl) malonate were as follows.

EI-MS (m / e); 225 (M-N0 ₂ ), CI-MS (m / e); 272 (M + 1)
¹ H-NMR (CDCl ₃ , δ (ppm)); 3.82 (6H, s), 5.40 (1H, s), 7.20 to 7.35 (2H, m), 8.1 to 8.2 (lH, m)

Example 2
Sodium methoxide (11.0 g, 0.2 mol) and dimethyl sulfoxide (30 ml) are added to a glass flask having an internal volume of 500 ml equipped with a stirrer, a thermometer, a distillation apparatus, and a dropping funnel under an argon atmosphere. The temperature was raised to 120 ° C., and then 27.0 g (0.2 mol) of dimethyl malonate having a purity of 98% was slowly dropped over 30 minutes while removing methanol under a reduced pressure of 0.010 to 0.013 MPa. Stir for 2 hours. Subsequently, the mixture was cooled to 100 ° C. under the same pressure, and 16.2 g (0.1 mol) of 2,4-difluoronitrobenzene having a purity of 98% was slowly dropped over 30 minutes, and further, 1 at the same pressure and the same temperature. Reacted for hours. After completion of the reaction, the reaction mixture was cooled to room temperature, 100 ml of toluene was added, and 40 ml (0.2 mol) of 5 mol / l hydrochloric acid was slowly added dropwise with stirring. Subsequently, the organic layer was separated, washed with 50 ml of water and 50 ml of saturated saline in this order, and dried over anhydrous magnesium sulfate. When this organic layer was analyzed by high performance liquid chromatography (absolute quantitative method), 20.6 g (yield 76%) of dimethyl 2- (5-fluoro-2-nitrophenyl) malonate was produced.

Example 3
Under a argon atmosphere, 3.40 g (62.9 mmol) of sodium methoxide and 20 ml of dimethyl sulfoxide were added to a 100 ml glass flask equipped with a stirrer, thermometer, reflux condenser and dropping funnel, and then at room temperature. While stirring, 8.31 g (62.3 mmol) of dimethyl malonate having a purity of 99% was slowly added dropwise over 5 minutes. After cooling to 20 ° C., 5.10 g (31.4 mmol) of 2,4-difluoronitrobenzene was slowly added dropwise over 5 minutes, and the temperature was raised to 80 ° C. and reacted for 1 hour. After completion of the reaction, the reaction mixture was cooled to room temperature, 100 ml of ethyl acetate was added, and 5.25 ml (31.4 mmol) of 6 mmol / l hydrochloric acid was slowly added dropwise with stirring. Next, the organic layer was separated, washed with 30 ml of water and 30 ml of saturated saline in this order, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting concentrate was purified by silica gel column chromatography (filler: Daisogel 1002W, developing solvent: hexane: ethyl acetate: 9: 1 (volume ratio)) to give white crystals, 6.55 g of dimethyl 2- (5-fluoro-2-nitrophenyl) malonate having a purity of 97.2% (area percentage of high performance liquid chromatography) was obtained (isolation yield 75%).

Claims (3)

In the presence of a metal alkoxide, general formula (1)

(In the formula, R ¹ represents a hydrogen atom; an alkyl group, a cycloalkyl group, an aralkyl group, an aryl group, an alkoxy group, or an aryloxy group, which may have a substituent, and R ² and R ³ are: A hydrogen atom; a halogen atom; an alkyl group, a cycloalkyl group, an aralkyl group, an aryl group, an alkoxy group or an aryloxy group which may have a substituent;
A 2,4-difluoronitrobenzene derivative represented by the general formula (2)

(In the formula, R ⁴ represents an alkoxycarbonyl group, an aralkyloxycarbonyl group or an aryloxycarbonyl group, and R ⁵ represents an alkyl group, an aralkyl group or an aryl group.)
Wherein the malonic acid diester represented by the general formula (3) is reacted in an organic solvent.

(Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above.)
A method for producing a 2- (5-fluoro-2-nitrophenyl) -2-malonic acid diester derivative represented by the formula: The process for producing a 2- (5-fluoro-2-nitrophenyl) -2-malonic acid diester derivative according to claim 1, wherein R ¹ , R ² and R ³ are hydrogen atoms.   The method for producing a 2- (5-fluoro-2-nitrophenyl) -2-malonic acid diester derivative according to claim 1 or 2, wherein the metal atom of the metal alkoxide is a group 1A atom, a group 2A atom or a group 3B atom.