JP2017171620A - Manufacturing method of acetamide derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a manufacturing method of an acetamide derivative capable of providing the acetamide derivative at high yield, easy to separate by-products, small in effect to environment and easily applicable to an industrial process.SOLUTION: There is provided a manufacturing method of an acetamide derivative represented by the following general formula (1), where X represents a halogen atom, Rand Rrepresent each independently an alkyl group having 1 to 4 carbon atoms. It has a reaction process for reacting a compound represented by the following general formula (A), dialkyl amine represented by the following general formula (B) in an aromatic organic solvent in presence of basic alkali metal inorganic salt.SELECTED DRAWING: None

Description

  The present invention relates to a method for producing an acetamide derivative useful as a synthetic raw material / synthetic intermediate for pharmaceuticals and agricultural chemicals.

  Acetamide derivatives such as 2-chloro-N, N-dimethylacetamide are useful compounds as raw materials and intermediates for producing pharmaceuticals and agricultural chemicals. As a method for producing such an acetamide derivative, for example, a method is known in which 2-chloro-N, N-dimethylacetamide is dropped into a dimethylamine aqueous solution to which sodium carbonate is added (Patent Document 1). Further, a method is known in which a dimethylamine aqueous solution and 2-chloro-N, N-dimethylacetamide are dropped and reacted in dichloromethane with sodium acetate added as a deoxidizer as required (Patent Document 2). ).

  Furthermore, a method of reacting dimethylamine and 2-chloro-N, N-dimethylacetamide in a two-phase mixture of a halogenated organic solvent and water in the presence of a phase transfer catalyst and sodium bicarbonate is known. (Patent Document 3). Further, a method is known in which 2-chloro-N, N-dimethylacetamide is added dropwise to a mixed solution of an alkali metal acetate aqueous solution and a chlorinated hydrocarbon solvent, and dimethylamine gas is introduced (patent). Reference 4).

JP 59-98075 A JP-A-3-223241 JP-A-6-247915 Chinese Patent Application No. 1721392

  However, as a result of studies by the present inventors, it has been found that the following problems exist in the method disclosed in the above-mentioned patent document. For example, in the case of the method disclosed in Patent Document 1, it was found that the yield of the desired 2-chloro-N, N-dimethylacetamide was low. Moreover, it is desired to suppress the use of halogen-based organic solvents such as dichloromethane used in the methods disclosed in Patent Documents 2 to 4 as much as possible due to the recent increase in environmental awareness. On the other hand, when an aromatic organic solvent such as toluene, which is frequently used industrially, is used as a reaction solvent in place of a halogen-based organic solvent such as dichloromethane, it has been found that the yield decreases.

  Furthermore, in the methods disclosed in Patent Documents 2 and 4, an alkali metal acetate such as sodium acetate is used as a deoxidizer. For this reason, acetic acid derived from the alkali metal acetate is generated as the reaction proceeds, so that it is necessary to remove the acetic acid generated in the reaction system. However, removal of acetic acid requires sophisticated equipment such as a rectification column, which complicates the purification process. Further, the method disclosed in Patent Document 3 is uneconomical because it requires the use of an expensive phase transfer catalyst.

  The present invention has been made in view of such problems of the prior art, and the problem is that an acetamide derivative can be obtained in a high yield and that a by-product can be easily separated. Another object of the present invention is to provide a method for producing an acetamide derivative that has little environmental impact and can be easily applied to an industrial process.

As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that the above-described problems can be solved by adopting the following configuration, and have completed the present invention. That is, according to this invention, the manufacturing method of the acetamide derivative shown below is provided.
[1] A method for producing an acetamide derivative represented by the following general formula (1), comprising a compound represented by the following general formula (A) and a dialkylamine represented by the following general formula (B): A method for producing an acetamide derivative comprising a reaction step of reacting in an aromatic organic solvent in the presence of a basic alkali metal inorganic salt.

（前記一般式（１）中、Ｘは、ハロゲン原子を示し、Ｒ₁及びＲ₂は、それぞれ独立に炭素数１〜４のアルキル基を示す）

(In the general formula (1), X represents a halogen atom, and R ₁ and R ₂ each independently represents an alkyl group having 1 to 4 carbon atoms)

（前記一般式（Ａ）中、Ｘは、それぞれ独立にハロゲン原子を示す。前記一般式（Ｂ）中、Ｒ₁及びＲ₂は、それぞれ独立に炭素数１〜４のアルキル基を示す）

(In the general formula (A), each X independently represents a halogen atom. In the general formula (B), R ₁ and R ₂ each independently represents an alkyl group having 1 to 4 carbon atoms).

[2] The reaction step is performed by adding the compound represented by the general formula (A) and the dialkylamine to a reaction system in which the alkali metal inorganic salt is dispersed in the aromatic organic solvent. The method for producing an acetamide derivative according to the above [1], which is a step of causing the reaction to occur.
[3] The above [1] or [2], wherein the alkali metal inorganic salt is at least one of sodium hydrogen carbonate and potassium hydrogen carbonate, and the aromatic organic solvent is at least one of toluene and xylene. A process for producing an acetamide derivative.
[4] X in the general formulas (1) and (A) is a chlorine atom, and R ₁ and R _{2 in the} general formulas (1) and (B) are a methyl group or an ethyl group. The method for producing an acetamide derivative according to any one of [1] to [3].

  According to the method for producing an acetamide derivative of the present invention, an acetamide derivative can be obtained with a high yield, the separation of by-products is easy, and the influence on the environment is small. For this reason, the manufacturing method of the acetamide derivative of this invention has few load etc. which are required for refinement | purification, and is easily applied to an industrial process.

  Embodiments of the present invention will be described below, but the present invention is not limited to the following embodiments. The method for producing an acetamide derivative of the present invention is a method for producing an acetamide derivative represented by the general formula (1). Then, as shown in the following reaction formula, the compound represented by the general formula (A) and the dialkylamine represented by the general formula (B) are non-halogenated in the presence of a basic alkali metal inorganic salt. A reaction step of reacting in an aromatic organic solvent of the system. Hereinafter, the method for producing an acetamide derivative of the present invention is also simply referred to as “the production method of the present invention”.

  The present inventors replaced the two-phase reaction solvent composed of water and a halogen-based organic solvent used in the conventional method in a two-phase reaction solvent of water and an aromatic organic solvent such as toluene. Thus, the reaction of the compound represented by the general formula (A) with the dialkylamine was studied. As a result, it was found that the yield was remarkably reduced when an aromatic organic solvent was used compared to when a halogen-based organic solvent was used for the organic phase of the reaction solvent. The reason for this is that a considerable amount of the acetamide derivative produced also migrated to the aqueous phase, and the amount migrated into the aromatic organic solvent, which is the organic phase, decreased and the recovery rate decreased. The result turned out.

  Therefore, the present inventors have made a reaction between the compound represented by the general formula (A) and the dialkylamine in an aromatic organic solvent substantially free of water, not in a two-phase reaction solvent. investigated. As a result, it was found that the target acetamide derivative can be obtained in high yield. In the present specification, “substantially no water” means that a trace amount of water generated by the progress of the reaction may be contained, but at least a solvent for dissolving the raw material compound and the target compound, It means that water as a reaction solvent is not contained. Furthermore, when the compound represented by the general formula (A) and the dialkylamine are reacted in the presence of a basic alkali metal inorganic salt, the alkali metal inorganic salt functions effectively as a deoxidizer and the reaction is smooth. It turns out to progress. When a basic alkali metal inorganic salt is used as a deoxidizing agent, the by-product generated by the progress of the reaction is an alkali metal halide such as sodium chloride (NaCl) that can be easily separated by a simple operation such as filtration. is there. For this reason, the production method of the present invention does not require sophisticated equipment such as a distillation column for removing by-products.

  As described above, according to the production method of the present invention, an acetamide derivative can be obtained with high yield, and it is not necessary to use a halogen-based organic solvent such as dichloromethane, and furthermore, by-products can be easily removed. Can do. In addition, since it is not necessary to use a relatively expensive phase transfer catalyst, according to the production method of the present invention, a high-purity acetamide derivative useful as a synthetic raw material / synthetic intermediate for pharmaceuticals and agricultural chemicals is produced by an industrial process. It can be manufactured in large quantities and at low cost.

  The production method of the present invention is a method for producing an acetamide derivative represented by the following general formula (1).

In general formula (1), X represents a halogen atom. Examples of the halogen atom include a chlorine atom (Cl), a bromine atom (Br), and an iodine atom (I). Of these, a chlorine atom (Cl) is preferable. Further, in the general formula (1), R ₁ and R ₂ represents an alkyl group having 1 to 4 carbon atoms independently. The alkyl group may be linear or branched. The alkyl group preferably has 1 to 3 carbon atoms, more preferably 1 or 2. That is, examples of the alkyl group include a methyl group, an ethyl group, a propyl group, and a butyl group.

  In the production method of the present invention, a compound represented by the following general formula (A) and a dialkylamine represented by the following general formula (B) are mixed with an aromatic organic solvent in the presence of a basic alkali metal inorganic salt. Having a reaction step in which to react. By reacting the compound represented by the general formula (A) with a dialkylamine, the target acetamide derivative represented by the general formula (1) is formed.

  In general formula (A), X represents a halogen atom each independently. Specific examples of the halogen atom, including preferred ones, may be the same as those exemplified as X in the general formula (1).

In the general formula (B), R ₁ and R ₂ represents an alkyl group having 1 to 4 carbon atoms independently. Specific examples of the alkyl group, including preferred ones, may be the same as those exemplified as examples of R ₁ and R _{2 in} the general formula (1). That is, as the dialkylamine represented by the general formula (B), dimethylamine, diethylamine, dipropylamine, dibutylamine and the like can be used.

  Dimethylamine, which is a kind of dialkylamine represented by the general formula (B), is a gas under normal temperature and normal pressure conditions. For this reason, dimethylamine is used in the state of gas (dimethylamine gas) by blowing (bubbling) it into the reaction solvent. Although dimethylamine is available as an aqueous solution (40% or 50% aqueous dimethylamine solution, etc.), when a dimethylamine aqueous solution is used, the reaction solvent becomes a two-phase system of water and an aromatic organic solvent. For this reason, since the yield of the target acetamide derivative will fall, it is not preferable.

The basic alkali metal inorganic salt is a component that can function as a deoxidizing agent that reacts with an acid component (hydrogen halide) generated by the reaction. Examples of such alkali metal inorganic salts include sodium hydrogen carbonate (NaHCO ₃ ), potassium hydrogen carbonate (KHCO ₃ ), sodium carbonate (Na ₂ CO ₃ ), potassium carbonate (K ₂ CO ₃ ), and sodium monohydrogen phosphate. (Na ₂ HPO ₄ ), potassium monohydrogen phosphate (K ₂ HPO ₄ ), sodium dihydrogen phosphate (NaH ₂ PO ₄ ), potassium dihydrogen phosphate (KH ₂ PO ₄ ), sodium phosphate (Na ₃ PO ₄ ), and potassium phosphate (K ₃ PO ₄ ). Of these, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, and potassium carbonate are preferable, and sodium hydrogen carbonate and potassium hydrogen carbonate are more preferable because the target acetamide derivative can be obtained in a higher yield. These alkali metal inorganic salts can be used singly or in combination of two or more.

  Examples of the aromatic organic solvent include toluene, xylene, ethylbenzene, and chlorobenzene. Among these, non-halogen aromatic organic solvents are preferable in consideration of environmental influences. Furthermore, toluene and xylene are particularly preferable because the target acetamide derivative can be obtained in a higher yield. These aromatic organic solvents can be used singly or in combination of two or more.

  Basic alkali metal inorganic salts such as sodium hydrogen carbonate are usually hardly dissolved in aromatic organic solvents such as toluene. Therefore, the reaction system for reacting the compound represented by the general formula (A) with the dialkylamine is a dispersion in which a solid alkali metal inorganic salt is dispersed in an aromatic organic solvent. Therefore, in the reaction step, for example, the compound represented by the general formula (A) and the dialkylamine are respectively added to the reaction system in which the alkali metal inorganic salt is dispersed in the aromatic organic solvent. The method for adding the compound represented by the general formula (A) and the dialkylamine to the reaction system is not particularly limited. For example, these compounds can be added to the reaction system by a method such as bubbling if it is a gas, or by a method such as dropping if it is a liquid.

  The reaction temperature is not particularly limited, but it is preferable to carry out the reaction with moderate cooling from the viewpoint of suppressing the formation of by-products. Specifically, the reaction temperature is preferably -20 to 20 ° C. In addition, the time required for adding the compound represented by the general formula (A) and the dialkylamine to the reaction system by dropping or the like may be appropriately set so that the temperature of the reaction system does not increase too much. .5 to 10 hours, preferably about 1 to 6 hours. Furthermore, after adding the compound represented by the general formula (A) and the dialkylamine, it may be aged for about 15 minutes to 2 hours as necessary.

  After the reaction step, for example, (i) alkali metal halide such as sodium chloride (NaCl) as a by-product is removed by filtration, and (ii) the aqueous layer is separated from the filtrate as necessary. By removing and (iii) concentrating the obtained filtrate under reduced pressure, the target acetamide derivative represented by the general formula (1) can be obtained in high yield. The procedures (i) to (iii) may be performed in any order. For example, the reaction solution may be concentrated under reduced pressure, and then the alkali metal halide may be removed by filtration. In addition, an example of the reaction formula in the manufacturing method of this invention is shown below.

  EXAMPLES Hereinafter, although this invention is demonstrated concretely based on an Example, this invention is not limited to these Examples. In the examples and comparative examples, “parts” and “%” are based on mass unless otherwise specified.

Example 1
A 500 mL four-necked Kolben was charged with 126.0 g (1.50 mol) of sodium hydrogen carbonate and 146.8 g of toluene, and stirred while cooling. While maintaining the internal temperature at 5 ° C. or lower, 112.9 g (1.00 mol) of chloroacetyl chloride was added dropwise over 4 hours, and 49.6 g (1.10 mol) of dimethylamine gas was blown in over 4 hours. After stirring at −2 to 1 ° C. for 1 hour, the reaction solution was filtered under reduced pressure to separate inorganic salt crystals. The crystals were washed with 100 g of toluene and combined with the filtrate to obtain a filtrate washing solution. The aqueous layer in the filtrate was separated and removed, and then the toluene layer was concentrated under reduced pressure to obtain 113.2 g (0.93 mol) of oily 2-chloro-N, N-dimethylacetamide. The yield was 93.1%, the purity (GC area%) was 99.5%, and the content (GC internal standard method) was 99.9%. The results of NMR and IR are shown below.
¹ H-NMR (500 MHz, CDCl ₃ ): δ = 2.99 (s, 3H), 3.10 (s, 3H), 4.08 (s, 2H)
IR (cm < ^-1 >, neat): 2940 (C-H), 1654 (C = O)

(Example 2)
A 300 mL four-necked Kolben was charged with 75.1 g (0.75 mol) of potassium hydrogen carbonate and 71.7 g of toluene, and stirred while cooling. While maintaining the internal temperature at 0 to 3 ° C., 56.5 g (0.50 mol) of chloroacetyl chloride was added dropwise over 4 hours, and 24.8 g (0.55 mol) of dimethylamine gas was blown in over 4 hours. After stirring at 1 ° C. for 1 hour, the reaction solution was filtered under reduced pressure to separate inorganic salt crystals. The crystals were washed with 50 g of toluene and combined with the filtrate to obtain a filtrate. The filtrate was concentrated under reduced pressure to obtain 51.5 g (0.42 mol) of oily 2-chloro-N, N-dimethylacetamide. The yield was 84.8%.

(Example 3)
Sodium carbonate 53.0 g (0.50 mol) and toluene 71.7 g were placed in a 300 mL four-necked Kolben and stirred while cooling. While maintaining the internal temperature at 5 ° C. or less, 56.5 g (0.50 mol) of chloroacetyl chloride was added dropwise over 4 hours, and 24.8 g (0.55 mol) of dimethylamine gas was blown in over 4 hours. After stirring at 2 ° C. for 1 hour, the reaction solution was filtered under reduced pressure to separate inorganic salt crystals. The crystals were washed with 50 g of toluene and combined with the filtrate to obtain a filtrate. The filtrate was concentrated under reduced pressure to obtain 39.0 g (0.32 mol) of oily 2-chloro-N, N-dimethylacetamide. The yield was 64.0%.

Example 4
In a 300 mL four-necked Kolben, 69.1 g (0.50 mol) of potassium carbonate and 71.7 g of toluene were added and stirred while cooling. While maintaining the internal temperature at −1 to 4 ° C., 56.5 g (0.50 mol) of chloroacetyl chloride was added dropwise over 4 hours, and 24.8 g (0.55 mol) of dimethylamine gas was blown in over 4 hours. . After stirring at 0 ° C. for 1 hour, the reaction solution was filtered under reduced pressure to separate inorganic salt crystals. The crystals were washed with 100 g of toluene and combined with the filtrate to obtain a filtrate washing solution. The filtrate was concentrated under reduced pressure to obtain 32.5 g (0.27 mol) of oily 2-chloro-N, N-dimethylacetamide. The yield was 53.4%.

(Example 5)
Sodium hydrogen carbonate 63.0 g (0.75 mol) and xylene 84.5 g were placed in a 300 mL four-necked Kolben and stirred while cooling. While maintaining the internal temperature at 0 to 3 ° C., 56.5 g (0.50 mol) of chloroacetyl chloride was added dropwise over 4 hours, and 24.8 g (0.55 mol) of dimethylamine gas was blown in over 4 hours. After stirring at −2 to 1 ° C. for 1 hour, the reaction solution was filtered under reduced pressure to separate inorganic salt crystals. The crystals were washed with 50 g of xylene and combined with the filtrate to obtain a filtrate. The filtrate was concentrated under reduced pressure to obtain 50.7 g (0.42 mol) of oily 2-chloro-N, N-dimethylacetamide. The yield was 83.3%.

(Example 6)
Sodium hydrogen carbonate 63.0 g (0.75 mol) and toluene 84.5 g were placed in a 300 mL four-necked Kolben, and stirred while cooling. While maintaining the internal temperature at 0 to 11 ° C., 56.5 g (0.50 mol) of chloroacetyl chloride and 40.2 g (0.55 mol) of diethylamine were simultaneously added dropwise over 4 hours. After stirring at −1 to 1 ° C. for 1 hour, the reaction solution was filtered under reduced pressure to separate inorganic salt crystals. The crystals were washed with 50 g of toluene and combined with the filtrate to obtain a filtrate. The filtrate was concentrated under reduced pressure to obtain 66.3 g (0.44 mol) of oily 2-chloro-N, N-diethylacetamide. The yield was 88.6%.

(Example 7)
A 300 mL four-necked Kolben was charged with 71.0 g (0.50 mol) of sodium monohydrogen phosphate and 84.5 g of toluene, and stirred while cooling. While maintaining the internal temperature at 0 to 3 ° C., 56.5 g (0.50 mol) of chloroacetyl chloride was added dropwise over 4 hours, and 24.8 g (0.55 mol) of dimethylamine gas was blown in over 4 hours. After stirring at 2 ° C. for 1 hour, the reaction solution was filtered under reduced pressure to separate inorganic salt crystals. The crystals were washed with 50 g of toluene and combined with the filtrate to obtain a filtrate. The filtrate was concentrated under reduced pressure to obtain 35.0 g (0.27 mol) of oily 2-chloro-N, N-dimethylacetamide. The yield was 57.6%.

(Comparative Example 1)
Sodium acetate 135.4g (1.65mol) and methylene chloride 330.0g were put into 1000mL four neck Kolben, and it stirred, cooling. While maintaining the internal temperature at 3 to 4 ° C., 169.4 g (1.5 mol) of chloroacetyl chloride and 186.9 g (1.65 mol) of 40% dimethylamine aqueous solution were simultaneously added dropwise over 2 hours. After stirring at 2 to 3 ° C. for 1 hour, 411.9 g of water was added to dissolve inorganic salt crystals precipitated in the reaction solution. After the methylene chloride layer was separated, 165 g of methylene chloride was added to the aqueous layer for secondary extraction. The methylene chloride layers were combined and concentrated under reduced pressure to obtain 226.8 g of a mixed solution of methylene chloride, acetic acid, and 2-chloro-N, N-dimethylacetamide. The obtained mixed solution was distilled under reduced pressure to obtain 91.2 g (0.75 mol) of a fraction having a GC purity (area%) of 99.3% of 2-chloro-N, N-dimethylacetamide. The yield of 2-chloro-N, N-dimethylacetamide was 50.0%.

(Comparative Example 2)
Sodium acetate 135.4g (1.65mol) and toluene 216.3g were put into 1000mL four neck Kolben, and it stirred, cooling. While maintaining the internal temperature at 0 to 5 ° C., 169.4 g (1.5 mol) of chloroacetyl chloride and 147.3 g (1.65 mol) of 50% dimethylamine aqueous solution were simultaneously added dropwise over 2 hours. After stirring at 1 to 3 ° C. for 1 hour, 450.0 g of water was added to dissolve the inorganic salt crystals precipitated in the reaction solution. After separating the toluene layer, 108.2 g of toluene was added to the aqueous layer for secondary extraction. The toluene layers were combined and concentrated under reduced pressure to obtain 221.0 g of a mixed solution of toluene, acetic acid, and 2-chloro-N, N-dimethylacetamide. The obtained mixed solution was distilled under reduced pressure to obtain 66.0 g (0.54 mol) of a fraction having a GC purity (area%) of 99.3% of 2-chloro-N, N-dimethylacetamide. The yield of 2-chloro-N, N-dimethylacetamide was 36.2%.

(Comparative Example 3)
99.2 g of toluene was placed in a 200 mL four-necked Kolben and stirred while cooling. The internal temperature was kept at 2 to 3 ° C., and 47.3 g (1.05 mol) of dimethylamine gas was blown in over 6 hours. Subsequently, 56.5 g (0.5 mol) of chloroacetyl chloride was dropped over 3 hours while maintaining the internal temperature at 2 to 5 ° C. The crystals of dimethylamine hydrochloride precipitated in the reaction solution were filtered under reduced pressure, and the crystals were washed with 180.7 g of toluene. The filtrate and the washing solution were combined and concentrated under reduced pressure to obtain 19.8 g (0.16 mol) of oily 2-chloro-N, N-diethylacetamide. The yield was 32.6%.

  Table 1 shows a summary of the above examples and comparative examples.

  The production method of the present invention is suitable as a method for industrially producing an acetamide derivative such as 2-chloro-N, N-dimethylacetamide useful as a raw material or intermediate for producing a pharmaceutical or the like.

As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that the above-described problems can be solved by adopting the following configuration, and have completed the present invention. That is, according to this invention, the manufacturing method of the acetamide derivative shown below is provided.
[1] A method for producing an acetamide derivative represented by the following general formula (1), comprising a compound represented by the following general formula (A) and a dialkylamine represented by the following general formula (B): A method for producing an acetamide derivative comprising a reaction step in which a basic alkali metal inorganic salt is dispersed in an aromatic organic solvent and reacted in a reaction system substantially free of water .

As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that the above-described problems can be solved by adopting the following configuration, and have completed the present invention. That is, according to this invention, the manufacturing method of the acetamide derivative shown below is provided.
[1] A method for producing an acetamide derivative represented by the following general formula (1), comprising a compound represented by the following general formula (A) and a dialkylamine represented by the following general formula (B): the basic alkali metal inorganic salt is dispersed in an aromatic organic solvent, have a reaction step of reacting in a substantially reaction system water is not present, the alkali metal inorganic salts, sodium hydrogen carbonate and potassium hydrogen carbonate At least method of any der Ru acetamide derivative.

（前記一般式（１）中、Ｘは塩素原子を示し、Ｒ₁及びＲ₂はメチル基を示す）

(In the general formula (1), X represents a chlorine atom, and R ₁ and R ₂ represent a methyl group)

（前記一般式（Ａ）中、Ｘは塩素原子を示す。前記一般式（Ｂ）中、Ｒ₁及びＲ₂はメチル基を示す）

(In the general formula (A), X represents a chlorine atom. In the general formula (B), R ₁ and R ₂ represent a methyl group)

[2] The reaction step is performed by adding the compound represented by the general formula (A) and the dialkylamine to a reaction system in which the alkali metal inorganic salt is dispersed in the aromatic organic solvent. The method for producing an acetamide derivative according to the above [1], which is a step of causing the reaction to occur.
[3] before Symbol aromatic organic solvent, the production method of the acetamide derivative according to the at least one of toluene and xylene [1] or [2].

( Reference Example 3)
Sodium carbonate 53.0 g (0.50 mol) and toluene 71.7 g were placed in a 300 mL four-necked Kolben and stirred while cooling. While maintaining the internal temperature at 5 ° C. or less, 56.5 g (0.50 mol) of chloroacetyl chloride was added dropwise over 4 hours, and 24.8 g (0.55 mol) of dimethylamine gas was blown in over 4 hours. After stirring at 2 ° C. for 1 hour, the reaction solution was filtered under reduced pressure to separate inorganic salt crystals. The crystals were washed with 50 g of toluene and combined with the filtrate to obtain a filtrate. The filtrate was concentrated under reduced pressure to obtain 39.0 g (0.32 mol) of oily 2-chloro-N, N-dimethylacetamide. The yield was 64.0%.

( Reference Example 4)
In a 300 mL four-necked Kolben, 69.1 g (0.50 mol) of potassium carbonate and 71.7 g of toluene were added and stirred while cooling. While maintaining the internal temperature at −1 to 4 ° C., 56.5 g (0.50 mol) of chloroacetyl chloride was added dropwise over 4 hours, and 24.8 g (0.55 mol) of dimethylamine gas was blown in over 4 hours. . After stirring at 0 ° C. for 1 hour, the reaction solution was filtered under reduced pressure to separate inorganic salt crystals. The crystals were washed with 100 g of toluene and combined with the filtrate to obtain a filtrate washing solution. The filtrate was concentrated under reduced pressure to obtain 32.5 g (0.27 mol) of oily 2-chloro-N, N-dimethylacetamide. The yield was 53.4%.

( Reference Example 6)
Sodium hydrogen carbonate 63.0 g (0.75 mol) and toluene 84.5 g were placed in a 300 mL four-necked Kolben, and stirred while cooling. While maintaining the internal temperature at 0 to 11 ° C., 56.5 g (0.50 mol) of chloroacetyl chloride and 40.2 g (0.55 mol) of diethylamine were simultaneously added dropwise over 4 hours. After stirring at −1 to 1 ° C. for 1 hour, the reaction solution was filtered under reduced pressure to separate inorganic salt crystals. The crystals were washed with 50 g of toluene and combined with the filtrate to obtain a filtrate. The filtrate was concentrated under reduced pressure to obtain 66.3 g (0.44 mol) of oily 2-chloro-N, N-diethylacetamide. The yield was 88.6%.

( Reference Example 7)
A 300 mL four-necked Kolben was charged with 71.0 g (0.50 mol) of sodium monohydrogen phosphate and 84.5 g of toluene, and stirred while cooling. While maintaining the internal temperature at 0 to 3 ° C., 56.5 g (0.50 mol) of chloroacetyl chloride was added dropwise over 4 hours, and 24.8 g (0.55 mol) of dimethylamine gas was blown in over 4 hours. After stirring at 2 ° C. for 1 hour, the reaction solution was filtered under reduced pressure to separate inorganic salt crystals. The crystals were washed with 50 g of toluene and combined with the filtrate to obtain a filtrate. The filtrate was concentrated under reduced pressure to obtain 35.0 g (0.27 mol) of oily 2-chloro-N, N-dimethylacetamide. The yield was 57.6%.

Table 1 shows a summary of the above examples , reference examples, and comparative examples.

Claims (4)

A method for producing an acetamide derivative represented by the following general formula (1),
A reaction step in which a compound represented by the following general formula (A) and a dialkylamine represented by the following general formula (B) are reacted in an aromatic organic solvent in the presence of a basic alkali metal inorganic salt. A process for producing an acetamide derivative.

(In the general formula (1), X represents a halogen atom, and R ₁ and R ₂ each independently represents an alkyl group having 1 to 4 carbon atoms)

(In the general formula (A), each X independently represents a halogen atom. In the general formula (B), R ₁ and R ₂ each independently represents an alkyl group having 1 to 4 carbon atoms).   The reaction step is a step of reacting the compound represented by the general formula (A) and the dialkylamine by adding them to a reaction system in which the alkali metal inorganic salt is dispersed in the aromatic organic solvent. A method for producing an acetamide derivative according to claim 1. The alkali metal inorganic salt is at least one of sodium bicarbonate and potassium bicarbonate;
The method for producing an acetamide derivative according to claim 1, wherein the aromatic organic solvent is at least one of toluene and xylene. X in the general formulas (1) and (A) is a chlorine atom,
The method for producing an acetamide derivative according to any one of claims 1 to 3, wherein R ₁ and R _{2 in the} general formulas (1) and (B) are a methyl group or an ethyl group.