KR20210022320A - Method for purifying 1-(6-chlolopyridine-3-yl)-n-methylmethanamine - Google Patents

Abstract

The present application provides a method for purifying 1-(6-chloropyridin-3-yl)-N-methylmethanamine. It is possible to obtain 1-(6-chloropyridin-3-yl)-N-methylmethanamine with high purity.

Description

Purification method of 1-(6-chloropyridin-3-yl)-N-methylmethanamine {METHOD FOR PURIFYING 1-(6-CHLOLOPYRIDINE-3-YL)-N-METHYLMETHANAMINE}

The present invention relates to a method for purifying 1-(6-chloropyridin-3-yl)-N-methylmethanamine.

Acetamiprid is synthesized through 1-(6-chloropyridin-3-yl)-N-methylmethanamine (CPMMA) as a neonicotinoid-based raw material, and acetamiprid in high yield is obtained. Synthesis of high yield CPMMA is required for synthesis.

1-(6-chloropyridin-3-yl)-N-methylmethanamine (CPMMA) is synthesized through the reaction of 2-chloro-5-(chloromethyl)pyridine (CCMP) and methylamine as shown in I) below. I can. However, in this process, as shown in II) below, the product CPMMA and the reactant CCMP react to form 1-(6-chloropyridin-3-yl)-N-((6-chloropyridin-3-yl)methyl)-N -Impurities such as methylmethanamine (compound a) may be produced.

Therefore, an additional purification process is required to secure high-purity CPMMA. Previously, purification was performed using distillation, but it was difficult to purify to a high purity of 95% or more when using the distillation method. There is a need for a purification method to secure high purity CPMMA.

CN 106187868 A

The present invention is 1-(6-chloropyridin-3-yl)-N-methylmethanamine and 1-(6-chloropyridin-3-yl)-N-((6-chloropyridin-3-yl)methyl) -Difference in solubility of N-methylmethanamine in water; And 1-(6-chloropyridin-3-yl)-N-methylmethanamine in a mixed solution of an aqueous solution and an organic solution, using the fact that the solubility in the aqueous solution varies depending on the pH of the aqueous solution, high purity 1-(6) It is intended to provide a method of obtaining -chloropyridin-3-yl)-N-methylmethanamine.

An exemplary embodiment of the present specification is water, 1-(6-chloropyridin-3-yl)-N-methylmethanamine and 1-(6-chloropyridin-3-yl)-N-( Preparing a mixed solution (m1) containing (6-chloropyridin-3-yl)methyl)-N-methylmethanamine; Adjusting the pH of the water layer (w1) in the mixed solution (m1) to 5 to 7; Separating the water layer (w1) from the mixed solution (m1); And 1-(6-chloropyridin-3-yl)-N-methylmethanamine comprising the step of obtaining 1-(6-chloropyridin-3-yl)-N-methylmethanamine from the water layer (w1). Provides a method of purification of.

According to an exemplary embodiment of the present invention, 2 using a change in solubility in an aqueous solution of 1-(6-chloropyridin-3-yl)-N-methylmethanamine according to a change in pH of the aqueous solution without going through a separate distillation process. -A method for purifying chloro-5-(chloromethyl)pyridine is provided.

According to the purification method of 1-(6-chloropyridin-3-yl)-N-methylmethanamine according to an exemplary embodiment of the present invention, high purity 1-(6-chloropyridin-3-yl)-N-methyl It is possible to obtain methanamine, and the convenience of the purification process is improved.

In the present specification, the term'phase separation' refers to a phenomenon in which a material system forming one phase is split into two phases due to changes in variables such as temperature, pressure, and composition. In the present specification, the term'image' refers to a state in which certain substances are gathered in a space to create uniform physical properties from a macroscopic point of view.

In the present specification,'phase separation' may be used in the same sense as'layer separation', and may mean that a layer formed by one component is substantially positioned or arranged on a layer formed by another component. . In an exemplary embodiment, the'phase separation' may mean a solution-solution phase separation, and a solution and a solution may be divided into a boundary at an interface to form a two-phase.

In the present specification, the "water layer" means an aqueous solution mixed with pure water or other solutes. In one embodiment, the'water layer' is pure water, or the water is 1-(6-chloropyridin-3-yl)-N-methylmethanamine and/or 1-(6-chloropyridin-3-yl)- It may mean an aqueous solution mixed with N-((6-chloropyridin-3-yl)methyl)-N-methylmethanamine.

In the present specification, the term'mixture' is a type of mixture composed of two or more substances, and includes all states in which two or more substances are uniformly or unevenly mixed regardless of the state of the substance.

In the present specification, "concentration" means removing a solvent or the like from a solution, and may be performed, for example, by heating the solution using a heat source such as an electric heater or steam.

The present invention relates to a method for purifying 1-(6-chloropyridin-3-yl)-N-methylmethanamine. More specifically, the purification method is 1-(6-chloropyridin-3-yl)-N-methylmethanamine and 1-(6-chloropyridin-3-yl)-N-((6-chloropyridin-3- 1) It may be a method of separating 1-(6-chloropyridin-3-yl)-N-methylmethanamine from a mixture of methyl)-N-methylmethanamine.

An exemplary embodiment of the present invention is water, 1-(6-chloropyridin-3-yl)-N-methylmethanamine and 1-(6-chloropyridin-3-yl)-N-((6-chloropyridine- Preparing a mixed solution containing 3-yl)methyl)-N-methylmethanamine; Adjusting the pH of the water layer in the mixed solution (m1) to 5 to 7; Separating the water layer (w1) from the mixed solution (m1); And 1-(6-chloropyridin-3-yl)-N-methylmethanamine comprising the step of obtaining 1-(6-chloropyridin-3-yl)-N-methylmethanamine from the water layer (w1). Provides a method of purification of.

The inventors of the present invention confirmed that the solubility of 1-(6-chloropyridin-3-yl)-N-methylmethanamine (CPMMA) in water can be controlled by adjusting the pH of water. In particular, when the pH of water is adjusted to 5 to 7, 1-(6-chloropyridin-3-yl)-N-methylmethanamine (CPMMA) is maximized in water solubility, while 1-(6-chloropyridine-3 It was confirmed that the solubility of -yl)-N-((6-chloropyridin-3-yl)methyl)-N-methylmethanamine in water can be minimized, and the present invention was invented.

When the pH of the water layer is less than 5, 1-(6-chloropyridin-3-yl)-N-((6-chloropyridin-3-yl)methyl)-N-methylmethanamine (compound a) is also produced as a salt. Since salts of impurities are contained in the water layer, the purity of CPMMA decreases. In addition, when the pH of the water layer exceeds 7, the salt of 1-(6-chloropyridin-3-yl)-N-methylmethanamine (CPMMA) is not generated, so the amount of CPMMA transferred from the organic layer to the water layer is small, so that the water layer The yield of CPMMA that can be obtained from is reduced.

In an exemplary embodiment, the mixed solution (m1) is water, 1-(6-chloropyridin-3-yl)-N-methylmethanamine and 1-(6-chloropyridin-3-yl)-N-(( 6-chloropyridin-3-yl)methyl)-N-methylmethanamine, and the water exists as an aqueous layer (w1). That is, in the mixed solution m1, water may be included in the form of a layer.

In one embodiment, the step of preparing the mixed solution (m1) includes mixing an aqueous methylamine solution and 2-chloro-5-(chloromethyl)pyridine.

In an exemplary embodiment, the methylamine aqueous solution may be formed by dissolving methylamine gas in water, but the method of forming the methylamine solution is not limited.

In one embodiment, the mixture of the aqueous methylamine solution and 2-chloro-5- (chloromethyl) pyridine is to add 2-chloro-5- (chloromethyl) pyridine to the aqueous methylamine solution, or 2-chloro-5- ( It may be achieved by adding an aqueous methylamine solution to chloromethyl)pyridine. The addition method may be performed in a dropwise manner, for example, but is not limited thereto.

In an exemplary embodiment, the equivalent ratio of methylamine and 2-chloro-5-(chloromethyl)pyridine in the aqueous methylamine solution may be 3:1 to 10:1.

In an exemplary embodiment, the 2-chloro-5-(chloromethyl)pyridine may be mixed in the mixed solution while being contained in the organic solvent (b). Here, the organic solvent (b) containing 2-chloro-5- (chloromethyl) pyridine may be a solvent (b1) that can be mixed with water such as ethanol, or a solvent that is not mixed with water such as toluene, hexane, and ethyl acetate. It may be (b2).

In the present specification, a solvent that is mixed with water means a solvent that does not cause a phase separation phenomenon when mixed with water, and a solvent that does not mix with water means a solvent that causes a phase separation phenomenon when mixed with water.

In an exemplary embodiment, when the 2-chloro-5-(chloromethyl)pyridine is mixed with the mixed solution in a state in which it is contained in an organic solvent (b1) miscible with water, preparing a mixed solution and in the mixed solution It may further include removing the organic solvent (b1) between the steps of adjusting the pH of the water layer to 5 to 7.

In one embodiment, the mixture of the aqueous methylamine solution and 2-chloro-5- (chloromethyl) pyridine is 30 minutes to 2 hours; Alternatively, it may be made for 50 minutes to 1 hour 30 minutes.

In an exemplary embodiment, the step of preparing the mixed solution (m1) is adjusted to a temperature range of 60°C to 65°C after the step of mixing the aqueous methylamine solution and 2-chloro-5-(chloromethyl)pyridine. It includes the step of.

In an exemplary embodiment, the water, 1-(6-chloropyridin-3-yl)-N-methylmethanamine and 1-(6-chloropyridin-3-yl)-N-((6-chloropyridine- The pH of the mixed solution (m1) containing 3-yl)methyl)-N-methylmethanamine may be greater than 7, and in an exemplary embodiment, the pH is 11 to 11.5.

In an exemplary embodiment, in the step of preparing the mixed solution m1, the mixed solution m1 further includes water and an organic solvent capable of phase separation.

In one embodiment, after the step of adjusting the pH of the water layer (w1) in the mixed solution (m1) to 5 to 7, the step of adding an organic solvent capable of phase separation with water to the mixed solution (m1).

In the present specification, the organic solvent capable of being phase-separated from water may be used without limitation as long as it is a solvent capable of phase-separating from water as a liquid under temperature and pressure in the purification method of the present invention. In one embodiment, the organic solvent phase-separable from water is a temperature of 5 ℃ to 50 ℃; Preferably, it may mean an organic solvent phase-separated with water at a temperature of 10°C to 30°C. In an exemplary embodiment, the organic solvent capable of being phase-separated from water may mean an organic solvent that is phase-separated from water under a pressure of 800 hPa to 1200 hPa.

In the present specification, the organic solvent capable of being phase-separated from water may be diethyl ether, toluene, benzene, hexane, dichloromethane, ethyl acetate, or the like, but is not limited thereto.

A method of adjusting the pH of the water layer to 5 to 7 is not limited, and in an exemplary embodiment, an acid having a pH of less than 7 may be included in the water layer. In an exemplary embodiment, the acid having a pH of less than 7 may be included in the water layer in the form of an aqueous acid solution. In an exemplary embodiment, the acid less than pH 7 may be, for example, HCl, HI, HBr, H ₂ SO ₄ , HClO ₃ , HNO ₃ , H ₃ PO _4, etc., and adjust the pH of the water layer to 5 to 7 Any suitable amount required can be used.

In one embodiment, the step of adjusting the pH of the water layer (w1) to 5 to 7 increases the equivalent of 1-(6-chloropyridin-3-yl)-N-methylmethanamine or a salt thereof present in the water layer. It may be a step of letting go.

In one embodiment, the step of adjusting the pH of the water layer (w1) to 5 to 7 is 10 ℃ to 40 ℃; 20 ℃ to 40 ℃; Or it may be made at 20 ℃ to 30 ℃.

In one embodiment, the step of separating the water layer (w1) from the mixture (m1); And between the steps of obtaining 1-(6-chloropyridin-3-yl)-N-methylmethanamine from the aqueous layer (w1), the aqueous layer (w1) was separated from the mixed solution (m1), and 1-(6- It further comprises re-extracting chloropyridin-3-yl)-N-methylmethanamine.

In an exemplary embodiment, the re-extraction of 1-(6-chloropyridin-3-yl)-N-methylmethanamine is performed by separating the aqueous layer (w1) from the mixed solution (m1), and the remaining organic layer and pH 5 to 7 Preparing a mixed solution (m2) containing the water layer (w2) of; Separating the water layer (w2) from the mixed solution (m2); And mixing the water layer (w2) with the water layer (w1), and obtaining 1-(6-chloropyridin-3-yl)-N-methylmethanamine from the water layer (w1) This is a step of obtaining 1-(6-chloropyridin-3-yl)-N-methylmethanamine from the mixture of (w1) and the water layer (w2).

In one embodiment, the step of preparing the mixed solution (m2) comprises the steps of separating the water layer (w1) from the mixed solution (m1) and mixing water with the remaining organic layer to prepare a mixed solution including the organic layer and the water layer; And forming a mixed solution (m2) including an organic layer and an aqueous layer (w2) having a pH of 5 to 7 by adjusting the pH of the water layer to 5 to 7.

In one embodiment, the step of preparing the mixed solution (m2) is to separate the water layer (w1) from the mixed solution (m1) and mix an aqueous solution having a pH of 5 to 7 in the remaining organic layer, and a mixed solution comprising an organic layer and an aqueous layer (w2) (m2) is formed.

In an exemplary embodiment, the step of re-extracting 1-(6-chloropyridin-3-yl)-N-methylmethanamine may be performed at least once; Alternatively, it may be performed two or more times. In one embodiment, as the number of re-extraction steps increases, the amount of 1-(6-chloropyridin-3-yl)-N-methylmethanamine in the final product increases.

In an exemplary embodiment, the step of obtaining 1-(6-chloropyridin-3-yl)-N-methylmethanamine from the water layer (w1) includes concentrating the water layer (w1). In one embodiment, as a method for concentrating the water layer w1, any conventional method capable of removing water from the water layer w1 may be used without limitation.

Hereinafter, the present application will be described in more detail through examples according to the present application and comparative examples not according to the present application, but the scope of the present application is not limited by the examples presented below.

<Example 1>

A solution obtained by dissolving 2 g of 1-(6-chloropyridin-3-yl)-N-methylmethanamine in 5 ml of dichloromethane was added to the flask, and 4.5 ml of 40 wt% of an aqueous methylamine solution was added thereto. Heat over time. After cooling, it is allowed to stand until phase separation between the water layer and the organic layer occurs. After recovering the organic layer and adding 10 mL of water to the reaction mixture, Conc. HCl is added to adjust the pH to 6.5. Then, it is allowed to stand until phase separation between the water layer and the organic layer occurs. The aqueous layer was separated and concentrated to obtain 1.35 g of product. In the above product, the GC peak area ratio of CPMMA and compound a(1-(6-chloropyridin-3-yl)-N-((6-chloropyridin-3-yl)methyl)-N-methylmethanamine) is 99: It was 1.

<Example 2>

Conc. 1.32g of the product was obtained in the same manner as in Example 1, except that HCl was added to adjust the pH to 5.8 instead of 6.5. In the above product, the GC peak area ratio of CPMMA and compound a was 98:2.

<Comparative Example 1>

Conc. 1.62 g of the product was obtained in the same manner as in Example 1, except that HCl was added to adjust the pH to 3 instead of 6.5. In the above product, the GC peak area ratio of CPMMA and compound a was 94:6.

<Comparative Example 2>

Conc. 0.15 g of the product was obtained in the same manner as in Example 1, except that HCl was added to adjust the pH to 10 instead of 6.5. In the above product, the GC peak area ratio of CPMMA and compound a was 99:1.

<Amount of synthesized CPMMA and compound a before purification>

A solution obtained by dissolving 2 g of 1-(6-chloropyridin-3-yl)-N-methylmethanamine in 5 mL of dichloromethane was added to the flask, and 4.5 mL of 40 wt% of an aqueous methylamine solution was added thereto. Heat over time. After cooling, it is allowed to stand until phase separation between the water layer and the organic layer occurs.

The organic layer was recovered and concentrated to obtain 1.79 g of product, and the aqueous layer was recovered and concentrated to obtain 0.05 g of product. In the organic layer product, the GC peak area ratio of CPMMA and compound a was 91:9.

GC measurement conditions in the above Examples and Comparative Examples are as follows.

1) GC unit: Nexis GC-2030 / SHIMADZU

2) Column: DB-5 MS (30m × 0.25mm ID, 0.25㎛ capillary)

From Examples 1 and 2, it was confirmed that when the pH of the water layer was adjusted within the range of the present invention, CPMMA moved from the organic layer to the water layer, and the amount of CPMMA obtained from the water layer increased.

Comparing Examples 1 and 2 with Comparative Example 1, it can be seen that when the pH of the water layer is less than 5, the impurity a in the organic layer moves to the water layer, and the purity of CPMMA obtained from the water layer is lowered.

Comparing Examples 1 and 2 with Comparative Example 2, when the pH of the water layer is more than 7, it is difficult to move CPMMA from the organic layer to the water layer, and it can be seen that the amount of CPMMA that can be obtained from the water layer is reduced.

Claims (8)

Water, 1-(6-chloropyridin-3-yl)-N-methylmethanamine and 1-(6-chloropyridin-3-yl)-N-((6-chloropyridin-3-yl)methyl)- Preparing a mixed solution (m1) containing N-methylmethanamine;
Adjusting the pH of the water layer (w1) in the mixed solution (m1) to 5 to 7;
Separating the water layer (w1) from the mixed solution (m1); And
1-(6-chloropyridin-3-yl)-N-methylmethanamine comprising the step of obtaining 1-(6-chloropyridin-3-yl)-N-methylmethanamine from the water layer (w1) Purification method. The method according to claim 1, wherein in the step of preparing the mixed solution (m1), the mixed solution (m1) further comprises an organic solvent capable of phase separation with water 1-(6-chloropyridin-3-yl)-N-methylmethane Method for purifying amines. The method of claim 1, further comprising the step of adding an organic solvent capable of phase separation with water to the mixed solution (m1) after the step of adjusting the pH of the water layer (w1) to 5 to 7 Method for purifying pyridin-3-yl)-N-methylmethanamine. The method of claim 1, wherein the preparing of the mixed solution (m1) comprises mixing an aqueous methylamine solution and 2-chloro-5-(chloromethyl)pyridine. ) -N-methylmethanamine purification method. The method according to claim 4, wherein the preparing of the mixed solution (m1) comprises adjusting the mixed solution to a temperature range of 60°C to 65°C after the step of mixing the aqueous methylamine solution and 2-chloro-5-(chloromethyl)pyridine. A method for purifying 1-(6-chloropyridin-3-yl)-N-methylmethanamine comprising the step. The method according to claim 2 or 3, further comprising: separating the water layer (w1) from the mixed solution (m1); And between the step of obtaining 1-(6-chloropyridin-3-yl)-N-methylmethanamine from the aqueous layer (w1), the aqueous layer (w1) was separated from the mixed solution (m1), and 1-(6) from the remaining organic layer. 1-(6-chloropyridin-3-yl)-N-methylmethanamine purification method further comprising the step of re-extracting -chloropyridin-3-yl)-N-methylmethanamine. The method according to claim 6, wherein the re-extraction of 1-(6-chloropyridin-3-yl)-N-methylmethanamine comprises separating the water layer (w1) from the mixed solution (m1), and the remaining organic layer and pH 5 to 7 Preparing a mixed solution (m2) including a water layer (w2); Separating the water layer (w2) from the mixed solution (m2); And mixing the water layer (w2) with the water layer (w1),
The step of obtaining 1-(6-chloropyridin-3-yl)-N-methylmethanamine from the water layer (w1) includes 1-(6-chloropyridine- A method for purifying 1-(6-chloropyridin-3-yl)-N-methylmethanamine, which is a step of obtaining 3-yl)-N-methylmethanamine. The method according to claim 6, wherein the step of re-extracting 1-(6-chloropyridin-3-yl)-N-methylmethanamine is performed one or more times. 1-(6-chloropyridin-3-yl)- Method for purifying N-methylmethanamine.