KR20230001684A - Method of manufactuing alkyl-D-alaninate, alkyl-D-alaninate, alkyl-D-alaninate derivative and medical or agriculture supplies comprising the same - Google Patents

Abstract

The present specification relates to a method for producing alkyl-D-alaninate, alkyl-D-alaninate, an alkyl-D-alaninate derivative, and pharmaceutical or agricultural products containing the same.

Description

Method of manufacturing alkyl-D-alaninate, alkyl-D-alaninate, alkyl-D-alaninate derivative, and medicine or agricultural product containing the same alaninate, alkyl-D-alaninate derivative and medical or agricultural supplies comprising the same}

The present specification relates to a method for producing alkyl-D-alaninate, alkyl-D-alaninate, an alkyl-D-alaninate derivative, and pharmaceuticals or agricultural products containing the same.

Methyl N- (2,6-dimethylphenyl) -D-alaninate (Methyl N- (2,6-dimethylphenyl) -D-alaninate) is metalaxyl-M, benalaxyl-M -M), is commercially important as a synthetic intermediate necessary for the manufacture of crop protection agents such as furalaxyl-M.

Common methods for synthesizing methyl N-(2,6-dimethylphenyl)-D-alaninate include Methyl (s)-2-(methanesulfonyloxy)propanoate or Methyl (s)-2-(p-toluenesulfonyloxy)propanoate and It is known to use an organic or inorganic base and 2,6-Dimethylamine. At this time, disubstituted impurity is generated due to overreaction, which reduces the commercial value of the product, which is difficult to remove by general purification methods such as crystallization or recrystallization.

Therefore, it is an important challenge to devise a specific method capable of reducing the content of disubstituted impurities produced by overreaction.

The present specification provides methods for producing alkyl-D-alaninate, alkyl-D-alaninate, alkyl-D-alaninate derivatives, and pharmaceuticals or agricultural products containing the same.

An exemplary embodiment of the present specification is to synthesize a compound of Formula 3 by reacting a compound of Formula 1 with a compound of Formula 2; and

Provided is a method for preparing an alkyl-D-alaninate comprising the step of distilling a composition containing the compound of Formula 3 at a pressure of 1 torr to 60 torr and a temperature of 60 ° C to 200 ° C.

[Formula 1]

[Formula 2]

[Formula 3]

In Formulas 1 to 3,

R1 is a methyl group or an aryl group substituted with a methyl group;

R2 and R3 are the same as or different from each other, and each independently hydrogen; heavy hydrogen; or a methyl group;

R4 is a methyl group.

In another exemplary embodiment of the present specification, synthesizing a compound of Formula 3 by reacting a compound of Formula 1 with a compound of Formula 2;

distilling the composition containing the compound of Chemical Formula 3 at a pressure of 1 torr to 60 torr and a temperature of 60 °C to 200 °C; and

A method for producing an alkyl-D-alaninate derivative comprising synthesizing a compound of Formula 6 below by adding a compound of Formula 5 to the distilled composition is provided.

[Formula 1]

[Formula 2]

[Formula 3]

[Formula 5]

[Formula 6]

In Formulas 1 to 3, 5 and 6,

R1 is a methyl group or an aryl group substituted with a methyl group;

R2 and R3 are the same as or different from each other, and each independently hydrogen; heavy hydrogen; or a methyl group;

R4 is a methyl group,

R5 is a methylene group substituted with a methoxy group; A methylene group substituted with a phenyl group; or a furanyl group.

Another embodiment of the present specification provides a composition comprising the compound of Formula 3 and the compound of Formula 4, wherein the content of the compound of Formula 4 is 0.1 area% or less based on the total GC area of the composition. .

[Formula 3]

[Formula 4]

In Formulas 3 and 4,

R2 and R3 are the same as or different from each other, and each independently hydrogen; heavy hydrogen; or a methyl group;

R4 is a methyl group.

Another embodiment of the present specification provides an alkyl-D-alaninate derivative prepared by reacting the compound of Formula 3 with the compound of Formula 5 in the above-described composition.

[Formula 5]

In Formula 5,

R5 is a methylene group substituted with a methoxy group; A methylene group substituted with a phenyl group; or a furanyl group.

Another embodiment of the present specification provides a pharmaceutical or agricultural product containing the above-described alkyl-D-alaninate derivative.

The manufacturing method of one embodiment of the present specification can produce alkyl-D-alaninate having a low content of disubstituted impurities generated due to overreaction.

The manufacturing method of one embodiment of the present specification can produce high-purity alkyl-D-alaninate.

Hereinafter, this specification will be described in detail.

In this specification, when a part is said to "include" a certain component, it means that it may further include other components without excluding other components unless otherwise stated.

An exemplary embodiment of the present specification is to synthesize a compound of Formula 3 by reacting a compound of Formula 1 with a compound of Formula 2; and distilling a composition containing the compound of Chemical Formula 3.

[Formula 1]

[Formula 2]

[Formula 3]

In Formulas 1 to 3,

R1 is a methyl group or an aryl group substituted with a methyl group;

R2 and R3 are the same as or different from each other, and each independently hydrogen; heavy hydrogen; or a methyl group;

R4 is a methyl group.

In one embodiment of the present specification, the step of distilling the composition is a step of distilling the composition at a pressure of 1 torr to 60 torr and a temperature of 60°C to 200°C.

Both the compound of Formula 3 and the compound of Formula 4 are viscous liquids. This means that methods such as crystallization or recrystallization after dissolution cannot be used like materials with general solid properties, and even if washed with water while dissolved in an organic solvent, Chemical Formula 4 is hardly removed, and Chemical Formula 3 Losses reduce yield. Specifically, when the organic layer washing method in which the organic layer is separated by washing with water by phase separation without distillation is used, the content of Chemical Formula 4, which is an impurity generated in the reaction mixture, is hardly reduced. If this method of washing the organic layer with water is used, chemical formula 3 in the composition is rather lost by washing with water, resulting in a low yield.

The present applicant devised a method of distilling the compound of Formula 3 to remove Formula 4.

When distillation was performed outside the corresponding pressure and temperature ranges or without using a combination thereof, a composition containing Formula 3 could not be obtained by distillation from the reaction mixture.

On the other hand, when distillation is performed using the combination of the pressure and the temperature range in one embodiment of the present specification, the above disadvantages are secured, and the composition containing Formula 3 with a low content of Formula 4 is relatively high without loss of water washing. can be obtained in yield.

Since the combination of the pressure and the temperature range in one embodiment of the present specification is not a high temperature or vacuum pressure condition that is difficult to implement in a mass production process, there is an advantage in that the pressure and temperature are sufficiently applicable to mass production in a factory.

In one embodiment of the present specification, the step of distilling the composition is 1 torr to 50 torr, 1 torr to 40 torr, 1 torr to 30 torr, 1 torr to 20 torr, or 5 torr to 20 torr. It is a step of distillation at a pressure of

In one embodiment of the present specification, the step of distilling the composition is 70 ℃ to 200 ℃, 80 ℃ to 200 ℃, 90 ℃ to 200 ℃, 100 ℃ to 200 ℃, 110 ℃ to 200 ℃, It is a step of distilling at a temperature of 120 ° C to 200 ° C, or 130 ° C to 200 ° C.

In one embodiment of the present specification, the step of distilling the composition is a step of removing a disubstituted impurity generated due to an overreaction, and specifically, removing a disubstituted impurity, the compound represented by Formula 4 below. Through this, it is possible to prepare a compound of Formula 3 with high purity, that is, alkyl-D-alaninate, and use it as an intermediate to synthesize Metalaxyl-M and Benalaxyl-M ), the purity of final products such as furalaxyl-M may also be increased.

In one embodiment of the present specification, the step of distilling the composition is a step of preparing a composition in which the content of the compound represented by Formula 4 below is 0.1 area% or less based on the total GC area of the composition.

[Formula 4]

In Formula 4,

R2 and R3 are the same as or different from each other, and each independently hydrogen; heavy hydrogen; or a methyl group;

R4 is a methyl group.

In one embodiment of the present specification, in the step of distilling the composition, distillation may be performed one or more times, specifically, one or more times, two or more times, or three or more times.

In one embodiment of the present specification, through distillation of the composition, the content of the compound of Formula 4 based on the total GC area of the composition may be 0.1 area% or less, 0.09 area% or less, or 0.08 area% or less, , The lower the content of the compound of Formula 4, the better, so the lower limit is not particularly limited.

In one embodiment of the present specification, the content of the compound of Formula 2 is 2 to 10 equivalents based on the compound of Formula 1. In this case, there is an advantage in that side reactions can be controlled while the reaction rate is increased because the equivalent amount of Chemical Formula 2 is appropriate.

In another exemplary embodiment of the present specification, synthesizing a compound of Formula 3 by reacting a compound of Formula 1 with a compound of Formula 2; distilling the composition containing the compound of Chemical Formula 3 at a pressure of 1 torr to 60 torr and a temperature of 60 °C to 200 °C; and adding a compound of Formula 5 to the distilled composition to synthesize a compound of Formula 6 below.

[Formula 1]

[Formula 2]

[Formula 3]

[Formula 5]

[Formula 6]

In Formulas 1 to 3, 5 and 6,

R1 is a methyl group or an aryl group substituted with a methyl group;

R2 and R3 are the same as or different from each other, and each independently hydrogen; heavy hydrogen; or a methyl group;

R4 is a methyl group,

R5 is a methylene group substituted with a methoxy group; A methylene group substituted with a phenyl group; or a furanyl group.

In the present specification, when the aryl group is a monocyclic aryl group, the number of carbon atoms is not particularly limited, but preferably has 6 to 25 carbon atoms. Specifically, the monocyclic aryl group may be a phenyl group, a biphenyl group, a terphenyl group, and the like, but is not limited thereto.

When the aryl group is a polycyclic aryl group, the number of carbon atoms is not particularly limited. It is preferable that it is carbon number 10-24. Specifically, the polycyclic aryl group may be a naphthyl group, anthracenyl group, phenanthryl group, pyrenyl group, perylenyl group, chrysenyl group, fluorenyl group, and the like, but is not limited thereto.

In the present specification, the fluorenyl group may be substituted, and adjacent substituents may bond to each other to form a ring.

In one embodiment of the present specification, R1 is a methyl group; or a phenyl group substituted with a methyl group.

이며,

는 결합위치이다. In one embodiment of the present specification, R1 is a methyl group; or

is,

is the binding position.

In one embodiment of the present specification, R2 and R3 are the same as or different from each other, and each independently hydrogen; or a methyl group.

In one embodiment of the present specification, R2 and R3 are methyl groups.

In one embodiment of the present specification, R5 is a methylene group substituted with a methoxy group. In other words, R5 is a state in which any one of the methyl groups is substituted with a methoxy group. In this case, the compound of Formula 6 is Metalaxyl-M.

In one embodiment of the present specification, R5 is a methylene group substituted with a phenyl group. In other words, R5 is a state in which any one of the hydrogens in the methyl group is substituted with a phenyl group. In this case, the compound of Formula 6 is Benalaxyl-M.

In one embodiment of the present specification, R5 is a furanyl group. In this case, the compound of Formula 6 is Furalaxyl-M.

Another embodiment of the present specification provides a composition comprising the compound of Formula 3 and the compound of Formula 4, wherein the content of the compound of Formula 4 is 0.1 area% or less based on the total GC area of the composition.

[Formula 3]

[Formula 4]

In Formulas 3 and 4,

R2 and R3 are the same as or different from each other, and each independently hydrogen; heavy hydrogen; or a methyl group;

R4 is a methyl group.

In this specification, the description of the composition refers to the description of the method for preparing the alkyl-D-alaninate and its derivatives described above.

Another embodiment of the present specification provides an alkyl-D-alaninate derivative prepared by reacting the compound of Formula 3 with the compound of Formula 5 in the above-described composition.

[Formula 5]

In Formula 5,

R5 is a methylene group substituted with a methoxy group; A methylene group substituted with a phenyl group; or a furanyl group.

In this specification, the description of the alkyl-D-alaninate derivative refers to the description of the method for preparing the alkyl-D-alaninate and its derivative described above.

Another embodiment of the present specification provides a pharmaceutical or agricultural product containing the above-described alkyl-D-alaninate derivative.

At this time, not only the state containing the alkyl-D-alaninate derivative as it is, but also pharmaceuticals or agricultural products including a state modified for each use, that is, changed through an essential chemical reaction.

In the present specification, the agricultural products may be various agricultural chemicals such as herbicides, crop protection agents, and fungicides.

Hereinafter, the present specification will be described in more detail through examples. However, the following examples are only for exemplifying the present specification, and are not intended to limit the present specification.

[Example]

[Example 1]

Methyl (s)-2-(methanesulfonyloxy)propanoate (20.00 g, 109.78 mmol), triethylamine (12.22 g, 120.75 mmol) and 2,6 -Dimethylaniline (106.43 g, 274.45 mmol) was added, and the internal temperature was raised to 120 to 130°C, followed by stirring.

After confirming that the amount of unreacted methyl (s)-2-(methanesulfonyloxy)propanoate remaining in the reaction mixture was 1.0 area% or less (GC analysis result), the reaction mixture was cooled to room temperature. Thereafter, the internal pressure is lowered to 60 torr at room temperature. Crude methyl N- (2,6-dimethylphenyl) -D-alaninate obtained by distillation was gradually heated from 60 ° C to 200 ° C while the internal pressure was in the range of 60 ~ 1 torr, and the internal temperature was gradually increased to toluene (100 mL). ) After diluting with 1N HCl aqueous solution (20 mL), the obtained organic layer was washed once with distilled water (30 mL) and then concentrated under reduced pressure to obtain methyl N-(2,6-dimethylphenyl with a purity of 98.52 GC area%) )-D-alaninate was obtained in 80% yield.

[Comparative Example 1]

In a reactor containing toluene (20 mL) at room temperature, methyl (s)-2-(methanesulfonyloxy)propanoate (20.00 g, 109.78 mmol), triethylamine (12.22 g, 120.75 mmol), 2,6 -Dimethylaniline (106.43 g, 274.45 mmol) was added, and the internal temperature was raised to 120 to 130°C, followed by stirring.

After confirming that the amount of unreacted methyl (s)-2-(methanesulfonyloxy)propanoate remaining in the reaction mixture was 1.0 area% or less (GC analysis result), the reaction mixture was cooled to room temperature, and then H ₂ O ( 40 mL) was added to dissolve the produced solids, diluted in toluene (100 mL), washed three times with 1N HCl aqueous solution (40 mL), and the obtained organic layer was washed twice with 1N NaOH solution (40 mL) and then washed with water. The organic layer was washed once with distilled water (30 mL) and then concentrated under reduced pressure to obtain methyl N-(2,6-dimethylphenyl)-D-alaninate having a purity of 97.24 GC area% in 68% yield.

[Comparative Example 2]

In a reactor containing toluene (20 mL) at room temperature, methyl (s)-2-(methanesulfonyloxy)propanoate (20.00 g, 109.78 mmol), triethylamine (12.22 g, 120.75 mmol), 2,6 -Dimethylaniline (106.43 g, 274.45 mmol) was added, and the internal temperature was raised to 120 to 130°C, followed by stirring.

After confirming that the amount of unreacted methyl (s)-2-(methanesulfonyloxy)propanoate remaining in the reaction mixture was 1.0 area% or less (GC analysis result), the reaction mixture was cooled to room temperature. Thereafter, the internal pressure was lowered to 100 torr at room temperature, and the internal temperature was gradually raised from 60 ° C to 200 ° C while the internal pressure was in the range of 100 to 61 torr. -D-alaninate could not be obtained.

[Experimental Example 1]

Samples were taken from the synthesis of Example 1 and Comparative Examples 1 and 2, and GC / FID (Gas Chromatography with Flame Ionization Detector) analysis was measured using Shimadzu, GC-2030 under the following conditions. The results are summarized in Table 1 below. At this time, each purity and content means GC area% based on the total GC area measured by GC / FID.

At this time, GC / FID analysis of the reaction mixture was measured by Shimadzu, GC-2030 under the following conditions.

Column: [HP-5 ] (0.25 mm ID × 30 m L, 0.25 μm d.f. capillary)

Oven temperature

Initial Value & Hold Time: 50℃, 5min

Program Rate: 10℃/min

Final Value & Hold Time: 320℃, 18min

Injector temperature: 340℃

Detector temperature: 340℃

Gas Flow rate: Column (N ₂ ): 1 mL/min

Split ratio: 1/20

Injection volume: 1.0 uL

distillation Purity (GC area%) chemical formula 4
Impurity transference number Comparative Example 1
(Distillation X) Distillation X 97.24 1.40 area % 68% Comparative Example 2
(Distilled O) Distillation O
Pressure: 100 to 61 torr
Temperature: 60 ~ 200℃ In the distillation process, the product
not obtained 0% Example 1
(Distilled O) Distillation O
Pressure: 60 to 1 torr
Temperature: 60 ~ 200℃ 98.52 0.03 area % 80%

Through Table 1, it can be seen that, when distillation is not performed, impurities of Formula 4 are not well removed, and the yield is remarkably lowered due to washing with water. The final product could not be obtained because the target compound was not trapped. In contrast, when distillation is performed under the conditions of the present specification, it can be confirmed that the yield is high while significantly removing impurities of Formula 4.

Claims (8)

synthesizing a compound of Formula 3 by reacting a compound of Formula 1 with a compound of Formula 2; and
Method for producing alkyl-D-alaninate comprising the step of distilling a composition containing the compound of Formula 3 at a pressure of 1 torr to 60 torr and a temperature of 60 ° C to 200 ° C:
[Formula 1]

[Formula 2]

[Formula 3]

In Formulas 1 to 3,
R1 is a methyl group or an aryl group substituted with a methyl group;
R2 and R3 are the same as or different from each other, and each independently hydrogen; heavy hydrogen; or a methyl group;
R4 is a methyl group. The method according to claim 1, wherein the step of distilling the composition is a step of preparing a composition in which the content of the compound of Formula 4 is 0.1 area% or less based on the total GC area of the composition. Alkyl-D-alaninate Manufacturing method:
[Formula 4]

In Formula 4,
R2 and R3 are the same as or different from each other, and each independently hydrogen; heavy hydrogen; or a methyl group;
R4 is a methyl group. The method according to claim 1, wherein the content of the compound of Formula 2 is 2 to 10 equivalents based on the compound of Formula 1. synthesizing a compound of Formula 3 by reacting a compound of Formula 1 with a compound of Formula 2;
distilling the composition containing the compound of Chemical Formula 3 at a pressure of 1 torr to 60 torr and a temperature of 60 °C to 200 °C; and
A method for producing an alkyl-D-alaninate derivative comprising synthesizing a compound of Formula 6 below by adding a compound of Formula 5 to the distilled composition:
[Formula 1]

[Formula 2]

[Formula 3]

[Formula 5]

[Formula 6]

In Formulas 1 to 3, 5 and 6,
R1 is a methyl group or an aryl group substituted with a methyl group;
R2 and R3 are the same as or different from each other, and each independently hydrogen; heavy hydrogen; or a methyl group;
R4 is a methyl group,
R5 is a methylene group substituted with a methoxy group; A methylene group substituted with a phenyl group; or a furanyl group. In a composition comprising a compound of Formula 3 and a compound of Formula 4 below,
A composition in which the content of the compound of Formula 4 is 0.1 area% or less based on the total GC area of the composition:
[Formula 3]

[Formula 4]

In Formulas 3 and 4,
R2 and R3 are the same as or different from each other, and each independently hydrogen; heavy hydrogen; or a methyl group;
R4 is a methyl group. An alkyl-D-alaninate derivative prepared by reacting the compound of Formula 3 with the compound of Formula 5 in the composition of claim 5:
[Formula 5]

In Formula 5,
R5 is a methylene group substituted with a methoxy group; A methylene group substituted with a phenyl group; or a furanyl group. A pharmaceutical product containing the alkyl-D-alaninate derivative of claim 6. An agricultural product comprising the alkyl-D-alaninate derivative of claim 6.