KR20210030636A - Method for synthesizing compound - Google Patents

Abstract

The present invention relates to a method for preparing a compound of chemical formula 4, comprising the steps of: (a) preparing a compound of chemical formula 3 by using a compound of chemical formula 1 and a compound of chemical formula 2; and (b) preparing the compound of the chemical formula 4 by using the compound of the chemical formula 3 obtained in the step (a) and ROH. According to an embodiment of the present invention, a final product includes an environmentally friendly organic solvent having a high limiting concentration of residual solvents.

Description

Manufacturing method of compound {METHOD FOR SYNTHESIZING COMPOUND}

The present invention relates to a method for preparing a compound and a compound formed using the same. More specifically, the present invention relates to a method for preparing a compound containing an amide group.

The compound of Formula 4 is a substance used as a fungicide among crop protection agents, and the use of organic solvents at the end of the process is limited, and it is important to remove the organic solvents used in the drying process as much as possible.

Conventionally, in order to prepare the compound of Formula 4, toluene has been used in acylation, extraction and washing processes using alkoxyacetyl chloride as a reaction solvent. However, the compound of Formula 4 is a liquid having a viscous intrinsic property, and it is difficult to remove the toluene solvent from a solution containing the compound.

Toluene is a solvent with a particularly low limit of residual solvent (890ppm, PDE=8.9mg/day), and it is an important task to develop a process that excludes the use of toluene in the final step.

WO 00/76960 A1

The inventors of the present invention intend to provide a method for preparing a compound of Formula 4 using a solvent that is environmentally friendly and has a high reference value for the limiting concentration of the residual solvent.

The present invention is a step (a) of preparing a compound of formula 3 by using a compound of formula 1 and a compound of formula 2 below, and

It provides a method for preparing a compound of Formula 4 including the step (b) of preparing a compound of Formula 4 below using the compound of Formula 3 and ROH obtained in step (a).

In Formulas 2 to 4, X is a halogen group, X'is a halogen group, and R is an alkyl group.

The present invention provides a method for synthesizing the compound of Formula 4 through N-acylation and alkoxylation.

According to an exemplary embodiment of the present invention, by using a solvent having a high standard residual solvent concentration in the alkoxylation process, the final product is environmentally friendly and contains an organic solvent having a high limiting concentration of the residual solvent.

In particular, according to the method for preparing the compound of Formula 4 according to an exemplary embodiment of the present invention, the concentration of toluene in the final product may be 890 ppm or less.

In the present specification, the term "alkyl group" refers to an aliphatic hydrocarbon group unless otherwise defined, and may be a saturated aliphatic hydrocarbon group that does not contain a double bond or a triple bond.

In the present specification, the halogen group may be a fluoro group, a chloro group, a bromo group, or an iodo group.

In the present specification, the residual solvent limit value is based on the October 2016 revision of the ICH (International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use) guidelines for industrial Q3C impurities, unless otherwise defined.

Hereinafter, the manufacturing method according to the present invention will be described in detail.

In an exemplary embodiment, X is a chloro group.

In an exemplary embodiment, X'is a chloro group.

In one embodiment, R is a C _1-10 alkyl group.

In one embodiment, R is a C _1-6 alkyl group.

In one embodiment, R is a methyl group.

Step (a)

Step (a) is a step of preparing the compound of Formula 3 by using the N-acylation reaction of the compound of Formula 1 and the compound of Formula 2.

In an exemplary embodiment, the step (a) comprises reacting the compound of Formula 1 and the base with the compound of Formula 2 in a first solvent (a1); And extracting the compound of Formula 3 from the mixture obtained in step (a1) (a2).

The step (a1) is a step of forming a compound of Formula 3 or a salt thereof through an N-acylation reaction between the compound of Formula 1 and the compound of Formula 2.

In an exemplary embodiment, the step (a1) comprises: mixing the compound of Formula 1 and a base in a first solvent (a1-1); And mixing the compound of Formula 2 with the mixture obtained in step (a1-1) (a1-3).

As the base, a hydroxide, hydrate, hydride, alkoxide, or carbonate including an alkali metal or alkaline earth metal may be used. Specific examples include lithium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, potassium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium t-butoxide, sodium t-butoxide, sodium hydride, etc. May be used, but is not limited thereto. These bases may be used alone or in combination of two or more.

In the steps (a1) and (a1-1), the equivalent ratio of the compound of Formula 1 and the base may be appropriately selected. In an exemplary embodiment, the equivalent ratio of the compound of Formula 1 and the base may be 1:1 to 1:2, but is not limited thereto.

In one embodiment, the first solvent may be an organic solvent capable of phase separation with water. In one embodiment, the first solvent may be at least one selected from the group consisting of toluene, xylene, acetonitrile, dioxane, tetrahydrofuran, 1,2-dichloroethane, dichloromethane, chloroform, and chlorobenzene. .

In one embodiment, the first solvent may be toluene. Toluene has an excellent solvent recovery rate, and thus has an advantage of improving economic efficiency in terms of solvent recycling.

The first solvent does not contain an ester solvent. Here, the ester solvent means a solvent containing an ester group. If the first solvent contains an ester solvent, an aqueous solvent such as alcohol is generated as the ester is decomposed by a base, and in step (a2), the alcohol is transferred to the aqueous layer, resulting in loss of the compound of Formula 3 and its salt to the aqueous layer. I can.

In an exemplary embodiment, in the step (a1), the temperature of the mixture obtained in step (a1-1) between the step (a1-1) and the step (a1-3) is set to -10°C to -5°C. It further includes the step of adjusting (a1-2). In this case, step (a1-3) may be a step of mixing the compound of Formula 2 with the mixture obtained in step (a1-2).

In the step (a1-2), if the internal temperature is not adjusted within the above range, subcomponents and impurities may increase.

In the step (a1-3), the amount of the compound of Formula 2 to be mixed may be appropriately selected. In the step (a1-3), the amount of the compound of Formula 2 to be mixed is 1 mol to 1.5 mol relative to 1 mol of the compound of formula 1 used in the step (a1-1); Alternatively, it may be 1 mol to 1.2 mol, but is not limited thereto.

In the step (a1-3), the method of mixing the compound of Formula 2 may be appropriately selected, but it is preferable to mix the compound by dropwise addition from the viewpoint of easy control of heat generation.

In the step (a1-3), the compound of Formula 2 may be mixed with stirring of the mixture.

In an exemplary embodiment, step (a1-3) is a step (a1-3) of mixing the compound of Formula 2 with the mixture obtained in step (a1-1) while maintaining the temperature of the mixture at 5°C or less. I can. In the process of mixing the compound of Formula 1 and the compound of Formula 2, if the temperature of the mixture exceeds 5°C, by-products may be formed, so it is preferable to mix while maintaining the temperature of the mixture at 5°C or less.

In an exemplary embodiment, the step (a1) further comprises a step (a1-4) of stirring the mixture obtained in step (a1-3) at a temperature of 5°C to 10°C after the step (a1-3). Includes. In the present invention, the temperature range at which the compound of Formula 1 and the compound of Formula 2 react is not clear. However, when the reaction is carried out at 5°C to 10°C, the effect of lowering the purity due to by-product generation is the least, so it is preferable to proceed with the reaction while maintaining the above range.

In the step (a1-4), the stirring time may be appropriately selected as long as it is an appropriate time enough to terminate the reaction in consideration of the amount of the reactant.

In an exemplary embodiment, the step (a2) includes mixing water or an aqueous solution with the mixture obtained in step (a1), and removing the water or aqueous solution from the mixture (a2-1); And removing the first solvent from the mixture obtained in step (a2-1) (a2-2).

In an exemplary embodiment, the (a2-1) step may be performed one or more times, and is preferably performed two or three times or more.

In an exemplary embodiment, the step (a2-1) is preferably performed at a temperature of 20° C. or less. If the step (a2-1) is performed at 20° C. or lower, it is possible to minimize the occurrence of subcomponents due to a change in pH or exothermic phenomenon in the work-up step after the compound of Formula 1 and the compound of Formula 2 terminate the reaction. .

In an exemplary embodiment, the step (a2-1) may be a step of mixing water or an aqueous solution with the mixture obtained in step (a1), and removing the water layer from the mixture layered into the water layer and the organic layer. Here, the organic layer contains the first solvent.

In one embodiment, the aqueous solution is a solution containing water and a solute (p). The solute (p) may be ammonium chloride, sodium hydrogen carbonate, or the like, but is not limited thereto.

In an exemplary embodiment, the (a2-1) step may be performed more than once, and the reaction in step (a1) is terminated by confirming that the pH of the aqueous layer is 3 to 4 in the first step (a2-1). It can be confirmed that it was done.

In an exemplary embodiment, the step (a2-1) is preferably performed repeatedly until the pH of the water becomes 7 to 8 after mixing water.

In an exemplary embodiment, in step (a2-2), as a method of removing the first solvent, a conventional method used to remove the solvent may be used without limitation, depending on the type of the first solvent. In an exemplary embodiment, a method of distilling under reduced pressure may be used as a method of removing the first solvent.

Step (b)

Step (b) is a step of preparing a compound of Formula 4 by using the alkoxylation of the compound of Formula 3 and the compound of Formula 4.

In an exemplary embodiment, the step (b) comprises the steps of reacting the compound of Formula 3 with ROH (b1); Removing ROH from the mixture obtained in step (b1) (b2); (B3) mixing a second solvent with the mixture obtained in step (b2); And extracting the compound of Formula 4 from the mixture obtained in step (b3) (b4).

The step (b1) is a step of forming a compound of Formula 4 or a salt thereof through alkoxylation of the compound of Formula 3 with ROH.

In an exemplary embodiment, the step (b1) includes mixing the compound of Formula 3 and ROH (b1-1); And mixing (b1-2) NaOR with the mixture obtained in step (b1-1).

In the steps (b1) and (b1-1), the content of ROH may be appropriately selected, but in an exemplary embodiment, the content of ROH may be 1 to 2 moles per 1 mole of the compound of Formula 3 have.

The step (b1-1) may be performed at room temperature and pressure.

In the steps (b1) and (b1-1), ROH is an alcohol-based solvent. In one embodiment, the ROH may be methanol, ethanol, propyl alcohol, isopropyl alcohol, etc., but is not limited thereto.

The limit value for the residual solvent of methanol is 3,000 ppm or less. Alcohol-based solvents are environmentally friendly solvents, and since the residual solvent tolerance is as high as methanol, using an alcohol-based solvent as a solvent in step (b1) can increase the allowable residual solvent value of the solvent in the final product.

In the steps (b1) and (b1-1), since only one type of ROH can be used to obtain the compound of Formula 4 as a single product, the number of ROH is preferably one.

In the step (b1-1), the mixing method of the compound of Formula 3 and ROH may be appropriately selected, and the mixing may involve stirring.

In an exemplary embodiment, the step (b1) further comprises a step (b1-3) of stirring the mixture obtained in the step (b1-2) at 20°C to 100°C after the step (b1-2). I can. If the reaction temperature exceeds the above range, by-products may be formed, so it is preferable to carry out within the reaction temperature.

In the step (b1-3), the stirring temperature may be 40°C to 80°C.

In the step (b1-3), the stirring time may be appropriately selected so that the reaction is completed in consideration of the amount of the reactant and the reaction rate.

In the step (b2), as a method of removing the ROH, a method commonly used to remove an alcohol-based solvent may be used, and in an exemplary embodiment, it may be a vacuum concentration method.

In the step (b3), the second solvent is an organic solvent capable of phase separation with water. In one embodiment, the second solvent may be one or more selected from the group consisting of ethyl acetate, isopropyl acetate, chloroform, dichloromethane, 1,2-dichloroethane, and methyl isobutyl ketone, but is not limited thereto.

In one embodiment, the second solvent may be ethyl acetate. The allowable standard value for the residual solvent of ethyl acetate is 5,000 ppm or less, and when ethyl acetate is used, the residual amount of toluene in the final product can be reduced.

In an exemplary embodiment, the step (b4) includes mixing water or an aqueous solution with the mixture obtained in step (b3), and removing the water or aqueous solution from the mixture (b4-1); And removing the second solvent from the mixture obtained in step (b4-1) (b4-2).

In an exemplary embodiment, the step (b4-1) may be performed one or more times, and it is preferable that the step (b4-1) is performed twice or three or more times.

In an exemplary embodiment, the step (b4-1) is preferably performed at a temperature of 20° C. or less.

In an exemplary embodiment, the step (b4-1) may be a step of mixing water or an aqueous solution with the mixture obtained in step (b3), and removing the water layer from the mixture layered into the water layer and the organic layer. Here, the organic layer includes a second solvent.

In one embodiment, the aqueous solution is a solution containing water and a solute (p). The solute (p) may be ammonium chloride, sodium hydrogen carbonate, or the like, but is not limited thereto.

In one embodiment, in step (b4-2), as a method of removing the second solvent, a conventional method used to remove the solvent may be used without limitation, depending on the type of the second solvent. In an exemplary embodiment, a method of distilling under reduced pressure may be used as a method of removing the second solvent.

All of the reactants used in the present invention are commercially available or can be easily synthesized by techniques well known in the art.

In addition, the method of controlling the temperature of the reactant in the present invention may be performed by an appropriate cooling means. The cooling means may include, but is not limited to, a jacket-type cooler surrounding the outside of the reactor, a cooler surrounding a part of the supply line of the reactant, and a double-tube cooler through which the refrigerant passes through the outer wall of the reactor.

When toluene is used as the first solvent, the content of toluene in the product obtained by using the method for preparing the compound of Formula 4 is 890 ppm or less.

When ethyl acetate is used as the second solvent, the content of ethyl acetate in the product obtained using the method for preparing the compound of Formula 4 is 5,000 ppm or less.

When methanol is used as the ROH, the content of methanol in the product obtained using the method for preparing the compound of Formula 4 is 3,000 ppm or less.

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>

_{Compound A (207.27 g, 1 mol) and NaHCO 3} (92.41 g, 1.1 mol) were added to a reactor containing toluene (600 mL) at room temperature, and the temperature inside the reactor was cooled to -10°C to -5°C. 2-chloroacetyl chloride (124,23g, 1.1 mol) was added dropwise while maintaining the temperature inside the reactor not to exceed 5°C, and stirred for 3 hours while maintaining the temperature inside the reactor at 5°C to 10°C.

_{When the reaction is complete, H 2} O (360 mL) is injected while maintaining the temperature inside the reactor not to exceed 20° C., stirred for 30 minutes while maintaining the temperature inside the reactor at 20° C., and allowed to stand to separate the aqueous layer. Discard after confirming that the pH is 3-4.

_{After adding H 2} O (360 mL) and NaHCO ₃ (8.3 g, 0.01 mol) to the separated organic layer, stirring for 30 minutes while maintaining the temperature inside the reactor at 20° C., and confirming that the pH of the aqueous layer is 7 to 8, The water layer is separated and discarded.

_{H 2} O (360 mL) was injected into the separated organic layer, stirred for 30 minutes while maintaining the temperature inside the reactor at 20° C., and after confirming that the pH of the aqueous layer was 7 to 8, the aqueous layer was separated and discarded.

The separated organic layer was concentrated under reduced pressure and distilled to remove toluene, and the compound B (278.08g, GC area% = 98.2%) was obtained.

Compound B (283.75 g, 1 mol) was added to a reactor containing MeOH (500 mL) at room temperature, and stirred at room temperature. NaOMe (59,42g, 1.1mol) was added, the temperature inside the reactor was raised to 50°C, and the mixture was stirred for 3 hours.

When the reactor was terminated, it was concentrated under reduced pressure to remove MeOH, and ethyl acetate (250 mL) was added and stirred.

_{H 2} O (100 mL) was injected while maintaining the temperature inside the reactor not to exceed 20° C., stirred for 30 minutes while maintaining the temperature inside the reactor at 20° C., and allowed to stand to separate and discard the aqueous layer.

The separated organic layer was concentrated under reduced pressure and distilled to remove ethyl acetate to obtain a final product.

The final product contained the above compound C (259.79 g, GC area% = 98.2 %).

In addition, when the method of the above example was carried out 3 times, it was confirmed that the content of MeOH in the final product was within the range of 1000 ppm to 2000 ppm, and the content of ethyl acetate was within the range of 500 ppm to 1500 ppm, and all 3 times toluene in the final product. Was not detected.

<Comparative Example>

_{Compound A1 (207.27 g, 1 mol) and NaHCO 3} (92.41 g, 1.1 mol) were added to a reactor containing toluene (600 mL) at room temperature, and the temperature inside the reactor was cooled to -10°C to -5°C.

While maintaining the temperature inside the reactor not to exceed 5° C., 2-methoxyacetyl chloride (119.38 g, 1.1 mol) was added dropwise, and stirred for 3 hours while maintaining the temperature inside the reactor at 5° C. to 10° C.

_{When the reaction is complete, H 2} O (360 mL) is injected so that the temperature inside the reactor does not exceed 20° C., stirred for 30 minutes while maintaining the temperature inside the reactor at 20° C., allowed to stand to separate layers, and the pH of the aqueous layer is 3 to Confirm that it is 4 and discard it.

_{H 2} O (360 mL) was added to the separated organic layer, stirred for 30 minutes while maintaining the temperature inside the reactor at 20° C., allowed to stand to separate the layers, and after confirming that the pH of the aqueous layer was 7 to 8, the aqueous layer was separated and Discard.

_{H 2} O (360 mL) was added to the separated organic layer, stirred for 30 minutes while maintaining the temperature inside the reactor at 20° C., allowed to stand to separate the layers, and after confirming that the pH of the aqueous layer was 7 to 8, the aqueous layer was separated and Discard.

The separated organic layer was concentrated under reduced pressure for 2 hours at a pressure of 1 bar or less in a water bath at 60° C. and distilled to remove toluene, thereby obtaining a final product.

The final product contained the compound C1 (271.94g, GC area% = 95.2%).

In addition, when the method of the above example was carried out three times, the contents of toluene in the final product were all in the range of 1000 ppm to 2000 ppm.

The GC area% in Examples and Comparative Examples refers to the ratio of the peak area of the compound C or C1 to the area of the entire peak when measuring the GC of the final product.

In the above Examples and Comparative Examples, the residual solvent was measured by a gas chromatography method, and a high purity (99.5% or more) solvent standard sample and an analysis sample were each analyzed by GC to determine the GC area% of the solvent, and each sample was The weight or concentration at the time of sampling was quantitatively analyzed and measured.

In the comparative example, the content of toluene is the content after toluene is removed to the maximum in the vacuum concentration condition.

As described in the above Examples and Comparative Examples, when the manufacturing method according to an exemplary embodiment of the present invention is used, the residual amount of toluene in the final product is small, so that a more environmentally friendly and highly usable compound can be prepared.

Claims (12)

Step (a) of preparing a compound of Formula 3 using a compound of Formula 1 and a compound of Formula 2 below, and

A method for preparing a compound of Formula 4 including the step (b) of preparing a compound of Formula 4 using the compound of Formula 3 and ROH obtained in step (a):

In Formulas 2 to 4, X is a halogen group, X'is a halogen group, and R is an alkyl group. The method according to claim 1, wherein the step (a) comprises the step (a1) of reacting the compound of Formula 1 and the base with the compound of Formula 2 in a first solvent; And extracting the compound of Formula 3 from the mixture obtained in step (a1) (a2). The method of claim 2, wherein the first solvent is toluene. The method according to claim 2, wherein the step (a1) comprises: mixing the compound of Formula 1 and a base in a first solvent (a1-1); And mixing the compound of Formula 2 with the mixture obtained in step (a1-1) (a1-3). The method according to claim 4, wherein the step (a1) adjusts the temperature of the mixture obtained in the step (a1-1) between the step (a1-1) and the step (a1-3) to -10°C to -5°C. Further comprising the step (a1-2),
The step (a1-3) is a step of mixing the compound of Formula 2 with the mixture obtained in step (a1-2). The method of claim 4, wherein the step (a1) further comprises a step (a1-4) of stirring the mixture obtained in the step (a1-3) at a temperature of 5°C to 10°C after the step (a1-3). The method of preparing a compound of Formula 4 to. The method according to claim 2, wherein the step (a2) comprises: mixing water or an aqueous solution with the mixture obtained in step (a1), and removing the water or aqueous solution from the mixture (a2-1); And removing the first solvent from the mixture obtained in step (a2-1) (a2-2). The method according to claim 1, wherein the step (b) comprises the steps of reacting the compound of Formula 3 with ROH (b1); Removing ROH from the mixture obtained in step (b1) (b2); (B3) mixing a second solvent with the mixture obtained in step (b2); And (b4) extracting the compound of Formula 4 from the mixture obtained in step (b3). The method of claim 8, wherein the step (b1) comprises: mixing the compound of Formula 3 and ROH (b1-1); And mixing (b1-2) NaOR with the mixture obtained in step (b1-1). The method of claim 9, wherein the step (b1) further comprises a step (b1-3) of stirring the mixture obtained in the step (b1-2) at 20°C to 100°C after the step (b1-2). Phosphorus A method for preparing a compound of Formula 4. The method of claim 8, wherein the second solvent is at least one selected from the group consisting of ethyl acetate, isopropyl acetate, chloroform, dichloromethane, 1,2-dichloroethane, and methyl isobutyl ketone. . The method of claim 8, wherein the step (b4) comprises: mixing water or an aqueous solution with the mixture obtained in step (b3), and removing the water or aqueous solution from the mixture (b4-1); And removing the second solvent from the mixture obtained in step (b4-1) (b4-2).