KR20210023487A - Method for continuous production of 1-(6-chloropyridin-3-yl)-n-methylmethanamine - Google Patents

Abstract

The present invention provides a method for continuous production of 1-(6-chloropyridin-3-yl)-N-methylmethanamine comprising a step of manufacturing a mixture by applying reactant A1 containing 2-chloro-5-(chloromethyl)pyridine, and reactant A2 containing methylamine to a microreactor. The present invention has an effect of economically shortening the manufacturing process time.

Description

1-(6-chloropyridin-3-yl)-N-methylmethanamine continuous production method {METHOD FOR CONTINUOUS PRODUCTION OF 1-(6-CHLOROPYRIDIN-3-YL)-N-METHYLMETHANAMINE}

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

Acetamiprid is a neonicotinoid-based insecticidal agent, and is a promising agent with high growth potential as a substitute for other neonicotinoid-based agents that are limited in use due to bee toxicity. Acetamiprid can be synthesized from 1-(6-chloropyridin-3-yl)-N-methylmethanamine (CPMMA), and in order to improve the synthesis process of acetamiprid, CPMMA can be synthesized in high yield. You need a process.

CPMMA is synthesized by the reaction of 2-chloro-5-(chloromethyl)pyridine (CCMP) and methylamine. However, when the product CPMMA and CCMP react in the synthesis process, a dimer is formed as a by-product. In order to increase the yield of CPMMA, such side reactions must be suppressed as much as possible. This side reaction can be suppressed by increasing the reaction rate between CCMP and methylamine or by increasing the number of equivalents of methylamine.

In general, the synthesis method of CPMMA is carried out in a semi-batch type reactor. In such a semi-batch type reactor, since the equivalent ratio between CCMP and methylamine is not kept constant, the yield of CPMMA decreases as the reaction proceeds. In addition, water, ethanol, chloroform, etc., which are used as solvents, do not have a high boiling point, so there is a limit to increasing the reaction rate by increasing the temperature.

In addition, the method of dropping raw materials in a semi-batch type reactor and introducing them has a high possibility of side reactions due to poor mixing efficiency. In addition, when the number of equivalents of methylamine is increased, there may be an economic disadvantage because a process for recovering methylamine is required after completion of the reaction.

CN 106699646 A

Conventionally, 1-(6-chloropyridin-3-yl)-N-methylmethanamine is reacted by dropping a 2-chloro-5-(chloromethyl)pyridine solution and a methylamine solution into a batch reactor. Was prepared. However, when a batch reactor is used for the production of 1-(6-chloropyridin-3-yl)-N-methylmethanamine, there is a problem in that the yield of the product is poor because side reactions are likely to occur.

In order to solve the above problem, the present invention prepares 1-(6-chloropyridin-3-yl)-N-methylmethanamine using a continuous reactor including a microreactor. In particular, by mixing the reactants through a microreactor in the process of introducing the reactants to increase the mixing rate and controlling the temperature and pressure of the continuous reactor, side reactions are suppressed, and 1-(6-chloropyridin-3-yl)-N-methylmethane It aims to increase the yield of amine.

Therefore, in the present invention, by improving the production method of 1-(6-chloropyridin-3-yl)-N-methylmethanamine using a conventional batch reactor through a continuous reaction, stable and high-yield 1-(6- Allows the continuous synthesis of chloropyridin-3-yl)-N-methylmethanamine.

In order to achieve the above object, the present invention comprises the step of preparing a mixture by supplying a reactant A1 containing 2-chloro-5-(chloromethyl)pyridine and a reactant A2 containing methylamine to a microreactor. (6-Chloropyridin-3-yl)-N-methylmethanamine is prepared in a continuous manner.

According to a preferred embodiment of the present invention, the continuous production method further comprises the step of reacting by supplying the mixture to a plug flow reactor P1 connected in series with the microreactor after the step of preparing the mixture. .

The present invention provides a method of preparing 1-(6-chloropyridin-3-yl)-N-methylmethanamine in a continuous reactor including a microreactor.

According to the production method of the present invention, it is possible to increase the mixing ratio of the reactants, and to keep the temperature and pressure of the reactor higher, thereby minimizing side reactions that may occur in the batch reactor. Thus, a high yield of 1-(6-chloropyridin-3-yl)-N-methylmethanamine can be obtained.

In addition, it is possible to reduce the amount of methylamine compared to 2-chloro-5-(chloromethyl)pyridine due to the high mixing efficiency and reaction rate compared to the production method using the conventional batch reactor.

In addition, the continuous production method of 1-(6-chloropyridin-3-yl)-N-methylmethanamine of the present invention has a high yield of 1-(6-chloropyridin-3-yl) in a short time compared to a batch reactor. Since -N-methylmethanamine can be synthesized, it has the effect of economically shortening the manufacturing process time.

1 and 2 are process charts schematically showing a continuous method of preparing 1-(6-chloropyridin-3-yl)-N-methylmethanamine according to an exemplary embodiment of the present invention.

Hereinafter, the present invention will be described in detail. The following description is a description according to an exemplary embodiment of the present invention, and the following description does not limit the scope of the claims.

The inventors of the present invention have discovered that using a continuous reactor, it is possible to minimize side reactions that may occur when preparing 1-(6-chloropyridin-3-yl)-N-methylmethanamine in a batch reactor. The invention was completed.

As used herein, "continuous" or "continuous" should be understood to mean that the reactants can be continuously fed to the microreactor, as opposed to the batch method.

That is, the present invention provides 1-(6-chloropyridine comprising the step of preparing a mixture by supplying reactant A1 including 2-chloro-5-(chloromethyl)pyridine and reactant A2 including methylamine to a microreactor. It provides a continuous method for preparing -3-yl)-N-methylmethanamine.

More preferably, the continuous manufacturing method further includes the step of supplying the mixture to a plug flow reactor (P1) connected in series with the microreactor to react, and the step may be included after the step of preparing the mixture. have.

In the present specification, the continuous reactor refers to a reactor used to prepare 1-(6-chloropyridin-3-yl)-N-methylmethanamine, and in one embodiment, the continuous reactor is a microreactor ; And a plug flow reactor (P1) connected in series with the microreactor.

Referring to FIG. 1, the continuous reactor 100 for preparing 1-(6-chloropyridin-3-yl)-N-methylmethanamine is a type of reactor and includes a microreactor 103. . The reactant A1 is supplied to the first inlet 101 of the continuous reactor, and the reactant A2 is supplied to the second inlet 102. The reactants A1 and A2 are mixed in the microreactor 103 to form a mixture.

The mixture is supplied to a plug flow reactor (P1) 200 connected in series with the microreactor 103. The reaction of the reactants A1 and A2 proceeds from the moment when they are mixed, and the reaction may further proceed while flowing through the plug flow reactor. The mixture at the end of the plug flow reactor is discharged from the plug flow reactor P1 through the discharge unit 301, and the reaction may be terminated.

Hereinafter, more specifically, the continuous manufacturing method of the present invention will be described.

According to an exemplary embodiment of the present invention, the continuous production method includes (a) supplying a reactant A1 containing 2-chloro-5-(chloromethyl)pyridine and a reactant A2 containing methylamine to a microreactor to obtain a mixture. Manufacturing steps; And (b) supplying the mixture to a plug flow reactor (P1) connected in series with the microreactor to react.

First, step (a) will be described. Step (a) is a step in which reactant A1 and reactant A2 are mixed while passing through a microreactor to form a mixture. By rapidly mixing 2-chloro-5-(chloromethyl)pyridine and methylamine to uniformly distribute in the reactant through a microreactor, side reactions can be minimized. In addition, by using a microreactor, a continuous-type process rather than a batch-type process is possible, so when the method of the present invention is applied to mass production, a large improvement in productivity can be expected as well as an increase in reaction speed. have.

In the step (a), the reactants A1 and A2 may be continuously supplied to the microreactor through the first inlet 101 and the second inlet 102 connected to the continuous reactor, respectively, as shown in FIG. have. In the manufacturing process as described above, since the concentration and flow rate of the reactants A1 and A2 can be easily controlled, as a result, it is easy to control the equivalent ratio of 2-chloro-5-(chloromethyl)pyridine and methylamine.

A pump may be used to supply the reactants A1 and A2, and a pump commonly used in the art may be used. In one embodiment, the reactants A1 and A2 may be supplied to the microreactor through a syringe pump, respectively.

In one embodiment, the connection position of the first inlet and the second inlet to the microreactor is not limited. Depending on the shape of the microreactor, the shape of the first inlet and the second inlet may be variously changed, such as vertical, horizontal, and Y-type. The reactants may be simultaneously injected into the first injection port and the second injection port, or the first reactant may be injected first through the first injection port, and then the second reactant may be injected into the second injection port in the middle of the flow. FIG. 1 shows only one embodiment of the positions of the first injection port and the second injection port, but is not limited thereto.

In one embodiment, reactant A1 may further contain a solvent, and if the solvent that may be included in reactant A1 is one capable of dissolving 2-chloro-5-(chloromethyl)pyridine, a conventional solvent in the art is appropriately used. Can be chosen.

In one embodiment, the reactant A2 may further include a solvent, and if it is capable of dissolving methylamine, a conventional solvent in the art may be appropriately selected.

The solvent that can be included in the reactants A1 and A2 is not limited, but a polar solvent is preferred, and for example, at least one solvent selected from the group consisting of water, alcohol, acetic acid, dimethylformamide and dimethyl sulfoxide may be used. I can.

The alcohol may be methanol, ethanol, propanol, butanol, normal-propanol, isopropanol, normal-butanol, 1-pentanol, 2-butoxyethanol, and ethylene glycol.

In the step of preparing the mixture, the supply equivalent ratio of the 2-chloro-5-(chloromethyl)pyridine and the methylamine is preferably 1:3 to 1:10. In one embodiment, the supply equivalent ratio of the 2-chloro-5-(chloromethyl)pyridine and the methylamine is 1:3 to 1:19. Here, the supply equivalent ratio of 2-chloro-5-(chloromethyl)pyridine and the methylamine is the 2-chloro-5-(chloromethyl)pyridine of the reactant A1 supplied to the microreactor for 1 second and supplied to the microreactor for 1 second. It may mean the equivalent ratio of methylamine in the reactant A2.

When the equivalent ratio of methylamine is less than the above equivalent ratio, a side reaction in which a dimer is formed occurs, and the synthesis yield of 1-(6-chloropyridin-3-yl)-N-methylamine decreases. On the other hand, if the equivalence ratio of methylamine is higher than the equivalence ratio, a large cost is consumed to finally recover the unreacted methylamine, and thus the economic efficiency of the synthesis process is lowered, so it is preferable to satisfy the equivalence ratio.

The 2-chloro-5-(chloromethyl)pyridine, methylamine, and solvent may be used as long as they are generally available, and the raw material itself or the solution itself may be purchased and used on the market.

The reactants A1 and A2 may further contain other additives within a limit that does not affect the reaction and yield.

Each concentration of the reactant A1 and the reactant A2, and the feed rate and feed amount to the microreactor may be appropriately adjusted within a range that satisfies the above equivalent ratio.

The total flow rate of the reactant A1 and the reactant A2 may vary depending on the shape or size of the microreactor, the size of the microchannel in the microreactor, and the like. In one embodiment, the total flow rate of the reactant A1 and the reactant A2 in the microreactor may be 3 mL/min or more, but is not limited thereto.

The microreactor is a mixer using continuous-type laminar flow diffusion rather than batch-type turbulence mixing. It is a type of reactor in which two or more solutions are mixed by mutual diffusion while passing through a channel.

The microreactor usable in the present invention includes, for example, a micromixing device, and may further include an inlet and an outlet connected to the outside of the microreactor. The micromixing device may have a plurality of microchannels having a width of each microchannel of 10 µm to 3000 µm, preferably 50 µm to 1600 µm. The microreactor may further include a heat exchanger for temperature control.

The microreactor is a mixer that mixes two or more types of fluids in a very small diameter channel, and has an advantage of inducing a uniform mixing reaction by excellent heat transfer and mass transfer efficiency because of a very large specific surface area value. have.

In one embodiment, the microreactor may be a T-mixer, a static mixer, a Slit-type-mixer, a coil-mixer, etc., but is not limited thereto.

The space time of the mixture in the microreactor can be appropriately selected.

Next, step (b) will be described. Step (b) is a step in which 2-chloro-5-(chloromethyl)pyridine and methylamine in the mixture passed through the microreactor flow through the plug flow reactor (P1) to further react.

In an exemplary embodiment, the space time in the plug flow reactor P1 of the mixture introduced from the microreactor to the plug flow reactor P1 may be 2 minutes to 10 minutes. In the present invention, the space time may be a value obtained by dividing the volume of the reaction solution by the volume flow rate of the reaction solution. In step (b), the volume of the plug flow reactor (P1) may be the same as the volume of the reaction solution.

The yield of 1-(6-chloropyridin-3-yl)-N-methylmethanamine using the continuous production method as described above is 95 mol% or more and 100 mol% or less. According to an exemplary embodiment of the present invention, 1-(6-chloropyridin-3-yl)-N-methylmethanamine can be obtained in a yield of 95 mol% or more within 2 to 10 minutes after the raw material passes through the microreactor. have. In the present invention, the yield of 1-(6-chloropyridin-3-yl)-N-methylmethanamine is 1- It may mean the content of (6-chloropyridin-3-yl)-N-methylmethanamine.

In one embodiment, since the residence time of the mixture in the reactor varies according to the length of the plug flow reactor (P1), the length of the plug flow reactor (P1) may be appropriately selected in consideration of the reaction rate and residence time of the mixture. I can. In one embodiment, the space time of the mixture in the plug flow reactor (P1) is 2 minutes to 10 minutes; Preferably 5 to 7 minutes; More preferably, it may be 5.5 minutes to 6.5 minutes.

The size, length, and shape of the microreactor and the plug flow reactor P1 are not limited and may be appropriately selected. However, when the diameter of the microreactor and the plug flow reactor (P1) is large, the temperature of the reactant may not reach the desired value due to insufficient heat transfer to the inside of the reactor, so that the reactor does not affect the reaction rate and yield. It is desirable to properly adjust the diameter. In the present specification, the diameter of the reactor may mean the maximum value of d when d is a point inside the reactor and the shortest distance from that point to the inner surface of the reactor.

In an exemplary embodiment, the pressure inside the microreactor is 2 bar to 20 bar. In one embodiment, the pressure inside the plug flow reactor (P1) is 2 bar to 20 bar. By setting the pressure inside the microreactor and the plug flow reactor P1 to 2 bar or more, evaporation of the solvent can be minimized to improve the reaction temperature and the reaction rate.

When the pressure inside the microreactor and plug flow reactor (P1) is less than 2 bar, the solution injected into the reactant vaporizes to form bubbles in the reactor, so that the reaction in the reactor may not be smooth, and the reaction in the reactor may not be more than 20 bar. In this case, since a pump operating at a high pressure and a pressure regulating device are required, the process control conditions may become difficult, so it is preferable to satisfy the above pressure range.

In an exemplary embodiment, the temperature inside the microreactor is 60°C to 150°C. In one embodiment, the temperature inside the plug flow reactor (P1) is 60 ℃ to 150 ℃.

If the internal temperature of the microreactor and plug flow reactor (P1) is less than 60°C, the reaction rate decreases to increase side reactions and reduce the yield of the product, and if it exceeds 150°C, the reactants and solvents vaporize and vaporize. Since additional pressure is applied to the inside of the reactor by gas, a problem may occur, so it is preferable to satisfy the above temperature range.

By maintaining the internal pressure of the microreactor and the plug flow reactor (P1) at 2 bar to 20 bar, and maintaining the internal temperature at 60°C to 150°C, 2-chloro-5-(chloromethyl)pyridine and methyl The reaction rate of the amine can be increased, and side reactions can be minimized due to the rapid reaction rate, thereby obtaining a high yield of 1-(6-chloropyridin-3-yl)-N-methylmethanamine.

The pressure inside the microreactor and the plug flow reactor P1 can be adjusted through a conventional pressure regulator used in the art. In one embodiment, a back pressure regulator may be used, and the back pressure regulator may be provided at the end of the plug flow reactor P1. The end of the plug flow reactor P1 may mean a downstream direction of the flow, that is, a portion at which the flow ends.

The internal temperature of the microreactor and the plug flow reactor (P1) can be controlled through a conventional heating bath used in the art. In an exemplary embodiment, the temperature inside the reactor may be maintained at 60° C. or higher by using a constant temperature system such as a constant temperature water bath or an oven.

In an exemplary embodiment, the continuous method for producing 1-(6-chloropyridin-3-yl)-N-methylmethanamine comprises (c) a mixture from the plug flow reactor (P1) after step (b). It further comprises the step of injecting into the reactor (P2).

In an exemplary embodiment, the reactor P2 may be a batch reactor 300 as shown in FIG. 2.

In an exemplary embodiment, as shown in FIG. 2, a discharge part 301 from which the mixture is discharged may be connected to an end of the plug flow reactor P1, and the mixture flows through the discharge part 301. It can be injected into the reactor P2 from the reactor P1.

In an exemplary embodiment, the reactor P2 may contain a basic solution for the purpose of terminating the reaction of the mixture. As long as the basic solution satisfies a pH of 7 or higher, a conventional basic solution may be used. In one embodiment, the basic solution may contain sodium hydroxide. The basic solution may be injected into the reactor P2, for example, through the third inlet 302 as shown in FIG. 2.

Hereinafter, the present invention will be described in more detail through the following examples, but the scope of the present invention is not limited to the following examples.

<Example 1>

A micro reactor (Supelco, T-mixer, 381 μm in diameter) and a 1/16 inch diameter tubular flow reactor connected in series to the micro reactor were prepared.

A solution in which 20% by weight of 2-chloro-5-(chloromethyl)pyridine is dissolved in ethanol and a solution in which 40% by weight of methylamine is dissolved in water are injected into the microreactor, respectively. At this time, the equivalent ratio of 2-chloro-5-(chloromethyl)pyridine and methylamine is 1:9, the total flow rate of the solution is 3 mL/min, and the temperature inside the reactor is maintained at 70°C through a constant temperature water bath. The pressure was maintained above 6 bar via a preset back pressure regulator.

After passing through the microreactor, the reaction time of the reactants in the tubular flow reactor was 5 minutes and 30 seconds, and the reaction was terminated by introducing the solution discharged from the end of the reactor into an ethyl acetate solution in which sodium hydroxide was dissolved.

As a result of GC measurement, the content of 1-(6-chloropyridin-3-yl)-N-methylmethanamine in the product was 97.7 mol%.

<Example 2>

1-(6-chloropyridin-3-yl)-N-methylmethanamine was prepared in the same manner as in Example 1, except that the temperature inside the reactor was maintained at 90°C.

As a result of GC measurement, the content of 1-(6-chloropyridin-3-yl)-N-methylmethanamine in the product was 98.2 mol%.

<Example 3>

A micro reactor (Supelco, T-mixer, 381 μm in diameter) and a 1/16 inch diameter tubular flow reactor connected in series to the micro reactor were prepared.

A solution in which 40% by weight of 2-chloro-5-(chloromethyl)pyridine is dissolved in ethanol and a solution in which 40% by weight of methylamine is dissolved in water are injected into the microreactor, respectively. At this time, the equivalent ratio of 2-chloro-5-(chloromethyl)pyridine and methylamine is 1:7, the total flow rate of the solution is 3mL/min, and the temperature inside the reactor is maintained at 90°C through a constant temperature water bath. The pressure was maintained above 6 bar via a preset back pressure regulator.

After passing through the microreactor, the reaction time of the reactants in the tubular flow reactor was 6 minutes and 30 seconds, and the reaction was terminated by introducing the solution discharged from the end of the reactor into an ethyl acetate solution in which sodium hydroxide was dissolved.

As a result of GC measurement, the content of 1-(6-chloropyridin-3-yl)-N-methylmethanamine in the product was 95.5 mol%.

<Comparative Example 1>

10 equivalents of methylamine are dissolved in water, added to a reactor in the form of a fed batch (semi-batch), and heated and stirred at 60°C.

A solution obtained by dissolving 2 g of 2-chloro-5-(chloromethyl)pyridine in 10 ml of ethanol is added dropwise to the aqueous methylamine solution for 1 hour. At this time, the equivalent ratio of 2-chloro-5-(chloromethyl)pyridine and methylamine is 1:10. Then, the mixture was heated and stirred at 60° C. for 2 hours.

Thereafter, an aqueous sodium hydroxide solution is added to the solution to neutralize hydrochloric acid generated during the reaction. Thereafter, ethyl acetate was added to terminate the reaction.

As a result of GC measurement, the content of 1-(6-chloropyridin-3-yl)-N-methylmethanamine in the product was 96.5 mol%.

Comparing the above Examples and Comparative Examples, when the continuous manufacturing method according to the present invention is used, the reaction time is significantly shorter from several hours to several minutes compared to the case of using a batch type reactor, but the synthesis yield is similar or higher. Can be confirmed.

100: continuous reactor
101: first inlet
102: second inlet
103: micro reactor
200: plug flow reactor
300: batch reactor
301: discharge unit
302: third inlet

Claims (11)

1-(6-chloropyridin-3-yl) comprising the step of preparing a mixture by supplying reactant A1 including 2-chloro-5-(chloromethyl)pyridine and reactant A2 including methylamine to a microreactor -N-methylmethanamine continuous production method. The method according to claim 1, further comprising the step of supplying the mixture to a plug flow reactor (P1) connected in series with the microreactor to react 1-(6-chloropyridin-3-yl)-N-methylmethane. A method for the continuous production of amines. The method of claim 1, wherein the pressure inside the microreactor is 2 bar to 20 bar. 1-(6-chloropyridin-3-yl)-N-methylmethanamine. The method of claim 1, wherein the temperature inside the microreactor is 60°C to 150°C. 1-(6-chloropyridin-3-yl)-N-methylmethanamine. The method of claim 2, wherein the pressure inside the plug flow reactor (P1) is 2 bar to 20 bar. 1-(6-chloropyridin-3-yl)-N-methylmethanamine. The method for producing 1-(6-chloropyridin-3-yl)-N-methylmethanamine according to claim 2, wherein the temperature inside the plug flow reactor (P1) is 60°C to 150°C. The method according to claim 1, wherein the first inlet through which the reactant A1 is supplied to the microreactor; And a second injection port through which the reactant A2 is supplied. 1-(6-chloropyridin-3-yl)-N-methylmethanamine. The method according to claim 1, wherein the microreactor is 1- (6-chloropyridine-3- 1) -N-methylmethanamine continuous production method. The method according to claim 1, wherein the supply equivalent ratio of the 2-chloro-5-(chloromethyl)pyridine and the methylamine is 1:3 to 1:10 1-(6-chloropyridin-3-yl)-N- A continuous method for producing methylmethanamine. The method for producing 1-(6-chloropyridin-3-yl)-N-methylmethanamine according to claim 2, wherein the space time in the plug flow reactor (P1) of the mixture is 2 to 10 minutes. . The method according to claim 1, wherein the yield of the 1-(6-chloropyridin-3-yl)-N-methylmethanamine is 95 mol% or more 1-(6-chloropyridin-3-yl)-N-methylmethane A method for the continuous production of amines.

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