KR102559870B1 - Method for preparing carbamate compound - Google Patents

Abstract

The present invention relates to a carbamate derivative and a method for preparing the same, which includes (S100) reacting a compound represented by Chemical Formula 1 with a compound represented by Chemical Formula 2 in an organic solvent; and (S200) reacting the intermediate obtained in step (S100) with a compound represented by Formula 4; wherein, steps (S100) and (S200) are performed in one-pot.

Description

Method for preparing carbamate compounds {METHOD FOR PREPARING CARBAMATE COMPOUND}

The present invention relates to a method for preparing a carbamate derivative, and relates to a method for preparing a high-purity carbamate derivative in a one-pot process without purification.

A method for synthesizing a carbamate compound containing an imidazole group and a carbon-carbon triple bond using N,N-carbonyldiimidazole as an intermediate is known. At this time, in order to obtain a high-purity carbamate derivative, the intermediate was purified and dried before use.

However, the purification and drying process of the intermediate not only increased the production time of the carbamate derivative, but also increased the production cost. In addition, the intermediate has a characteristic of being decomposed upon contact with moisture in the air. Because of this, storage of the intermediate was very difficult, and storage costs were additionally incurred, further increasing production costs of carbamate derivatives. For example, when N,N-carbonyldiimidazole was left in the air for 24 hours, the GC analysis purity of the carbamate derivative decreased by about 10% or more. This phenomenon was more pronounced in summer when humidity was high. As such, if N,N-carbonyldiimidazole is stored incorrectly, it must be additionally purified, which further increases production cost.

International Patent Application International Publication No. WO 2015/006535 A2 (published on January 15, 2015)

The present invention is intended to provide a method for preparing a carbamate derivative in a one-pot process without intermediate purification.

In order to achieve the above object, the present invention (S100) reacting a compound represented by Formula 1 with a compound represented by Formula 2 in an organic solvent; and (S200) reacting the intermediate obtained in step (S100) with a compound represented by Formula 4 below, wherein steps (S100) and (S200) are performed in one-pot.

[Formula 1]

[Formula 2]

[Formula 4]

(In Formula 2 above,

이고, R ₁ and R ₂ are the same as or different from each other, and each independently halogen or

ego,

R ₂₁ is a C ₁ ~ C ₁₂ haloalkyl group).

In addition, in the present invention, an alkaline material may be additionally used in the step (S100).

Since the present invention produces a carbamate derivative in one-pot without purification of intermediates, the effect of reducing production time and production cost is exhibited, and the problem of storage of intermediates that change over time does not occur, thereby reducing storage costs.

1 is an NMR graph of the target compound synthesized in Example 1.

Hereinafter, the present invention will be described.

The present invention is a method for preparing a carbamate derivative containing an imidazole group and a carbon-carbon triple bond, comprising (S100) reacting the compound represented by Chemical Formula 1 with the compound represented by Chemical Formula 2 in an organic solvent; and (S200) reacting the intermediate obtained in step (S100) with the compound represented by Chemical Formula 4. Optionally, an alkaline material may be further used in step (S100).

However, in the present invention, the steps (S100) and (S200) are performed in one-pot. Accordingly, in the present invention, the intermediate represented by Chemical Formula 3 (eg, N,N-carbonyl diimidazole) can be continuously used in the reaction with the compound represented by Chemical Formula 4 without purification. As such, in the present invention, since there is no need to separately perform purification and drying processes of intermediates, production time can be shortened and production costs can be reduced. In addition, since the intermediate of the present invention does not come into contact with moisture in the air at all, a carbamate derivative having a purity of about 99% or more can be produced.

In addition, in the present invention, in the step (S100), the compound represented by Formula 1 may be used in a specific amount or more compared to the compound represented by Formula 2, or an alkaline material may be additionally used. Accordingly, since the present invention can capture acidic substances (eg, Cl atoms) generated as by-products during the synthesis reaction, carbamate derivatives with higher purity and yield can be prepared.

According to an example, (S100) reacting the compound represented by Formula 1 with the compound represented by Formula 2 in an organic solvent; and (S200) reacting the intermediate obtained in the step (S100) with the compound represented by Formula 4, wherein the (S100) and (S200) steps are performed in one-pot.

According to another example, (S100) reacting the compound represented by Formula 1 with the compound represented by Formula 2 under an organic solvent and an alkaline substance; and (S200) reacting the intermediate obtained in the step (S100) with the compound represented by Formula 4, wherein the (S100) and (S200) steps are performed in one-pot.

Hereinafter, each process for producing the carbamate derivative according to the present invention will be described.

(a) (S100) step: synthesis of intermediates

First, the compound represented by Chemical Formula 1 is reacted with the compound represented by Chemical Formula 2 in an organic solvent to obtain an intermediate represented by Chemical Formula 3. Optionally, an alkaline material may be additionally used in step (S100).

The (S100) step may include (S110) adding an organic solvent to the compound represented by Formula 1 and stirring to form a first solution; (S120) dissolving the compound represented by Chemical Formula 2 in an organic solvent to form a second solution; and (S130) adding a second solution to the first solution. In this case, in the step (S110), an alkaline substance may be mixed with the compound represented by Formula 1 and used.

The compound represented by Chemical Formula 1 is a kind of reactant and may collect acidic substances (eg, Cl atoms) generated in the reaction.

The amount of the compound represented by Formula 1 may range from 1 to 20 equivalents based on 1 equivalent of the compound represented by Formula 2.

According to one example, the compound represented by Formula 1 may be used in the range of 7 to 20 equivalents, specifically 12 to 20 equivalents, based on 1 equivalent of the compound represented by Formula 2. In this case, since the excess compound of Formula 1 captures acidic substances (eg, Cl atoms) generated in the reaction, there is no need to additionally use an alkaline substance.

According to another example, the compound represented by Formula 1 may be used in an amount of 1 equivalent or more and less than 12 equivalents, specifically, 1 equivalent or more and less than 7 equivalents, based on 1 equivalent of the compound represented by Formula 2. In this case, the reaction may be accelerated while capturing Cl atoms generated during the reaction by additionally using an alkaline material.

이고, 구체적으로 F, Cl, Br, I 및

로 이루어진 군에서 선택될 수 있다. 이때, R₂₁은 C₁~C₁₂의 할로알킬기이고, 구체적으로 C₁~C₇의 할로알킬기일 수 있다. 여기서, 할로알킬기는 할로겐으로 치환된 알킬기로, 모노-뿐만 아니라 디-, 트리-할로알킬기를 포함한다.In the compound represented by Formula 2, R ₂ and R ₃ are the same as or different from each other, and each independently halogen or

And, specifically F, Cl, Br, I and

It can be selected from the group consisting of. In this case, R ₂₁ is a C ₁ ~ C ₁₂ haloalkyl group, and specifically may be a C ₁ ~ C ₇ haloalkyl group. Here, the haloalkyl group is an alkyl group substituted with halogen and includes mono- as well as di- and tri-haloalkyl groups.

The compound represented by Formula 2 may be embodied as a compound represented by any one of Formulas 2a to 2c, but is not limited thereto.

[Formula 2a]

[Formula 2b]

[Formula 2c]

In Formulas 2a to 2c,

X ₁ to X ₁₂ are halogen selected from the group consisting of F, Cl, Br, and I, and are the same as or different from each other.

According to one example, the compound represented by Formula 2 may be one or more selected from the group consisting of compounds B1 to B3 below.

The organic solvent usable in the present invention is not particularly limited, and according to an example, it may be at least one selected from the group consisting of a carbonate-based solvent, an alcohol-based solvent, a chloride-based solvent, a nitrile-based solvent, a heterocyclic solvent, an ether-based solvent, and an ester-based solvent. According to one example, the organic solvent may be methylene chloride.

The water content of this organic solvent is not particularly limited. However, when the content of water in the organic solvent is high, the reactant compound represented by Chemical Formula 2 (eg, triphosgene, etc.) may react with water to generate impurities. Therefore, it is desirable that the water content of the organic solvent is low. According to one example, it is preferable to remove moisture so that the water content of the organic solvent is about 10 to 1,000 ppm, specifically about 10 to 700 ppm, and more specifically about 10 to 300 ppm.

In the present invention, an alkaline substance may be additionally used during the reaction between the compound of Formula 1 and the compound of Formula 2 described above.

The alkaline material is a catalyst that promotes the reaction while neutralizing an acidic material (eg, Cl atom) generated as a by-product during synthesis, and may be, for example, amines.

Specifically, examples of amines include heterocyclic amine having 3 to 30 nuclear atoms, C ₁ ~ C ₁₂ alkylamine, C ₆ ~ C ₂₀ arylamine, C ₁ ~ C ₁₂ dialkylamine, C ₆ ~ C ₂₀ diarylamine, (C ₁ ~ C ₁₂ )alkyl (C ₆ ~ C ₂₀ ) arylamine, C 1 ~ C ₁₂ of trialkylamine, (C _{1 ~ C 12 ) dialkyl (C 6 ~ C 20 ) arylamine, (C 1 ~ C 12 )} alkyl (C ₆ ~ C ₂₀ ) diarylamine, and the like, and specifically pyridine, triethylamine, _diethylamine and the like, but is not _limited thereto.

According to one example, the alkaline substance may be at least one selected from the group consisting of pyridine, triethylamine, and diethylamine, and may specifically be triethylamine.

The content of the alkaline substance is preferably used in consideration of the content of the compound of Formula 1 and the type or content of the compound of Formula 2. According to one example, the total content of the compound of Formula 1 and the alkaline material may range from 1 to 20 equivalents based on 1 equivalent of the compound of Formula 2, and the mixing ratio between the compound of Formula 1 and the alkaline material may be 1: 1-2 equivalent ratio.

The reaction temperature of the step (S100) may be -5 to 100 °C, specifically about -5 to 80 °C, more specifically about -5 to 50 °C. In particular, step (S130) of step (S100) may be performed at a temperature of about -5 to 10 °C, specifically -5 to 5 °C.

(b) (S200) Step: Synthesis of Carbamate Derivatives

Then, the intermediate obtained in step (S100) is reacted with a compound represented by Formula 4 below.

Specifically, in step (S200), when the reaction in step (S100) is completed, the compound represented by Formula 4 is added dropwise to the intermediate and reacted. As described above, in step (S200), the reaction between the intermediate and the compound represented by Formula 4 is continuously performed in one-pot without purifying the intermediate produced in step (S100). Because of this, in the present invention, it is not necessary to carry out the purification and drying process of the intermediate. In addition, according to the present invention, a carbamate derivative having excellent yield and purity can be prepared without performing purification and drying processes of the intermediate.

The intermediate produced in the step (S100) is a compound represented by the following formula (3), which reacts directly with the compound of formula (4) without purification.

[Formula 3]

The use ratio (mixing ratio) between these intermediates and the compound represented by Formula 4 may be 1: 1 to 4 equivalence ratio, specifically 1: 1 to 3 equivalence ratio, and more specifically 1: 1 to 2 equivalence ratio.

The compound represented by Chemical Formula 4 can be used for both reagent and industrial purposes, and preferably has a low moisture content to minimize generation of impurities. Therefore, the water content of the compound represented by Formula 4 is preferably adjusted to about 100 to 2,000 ppm, specifically 100 to 1,000 ppm, and more specifically about 100 to 300 ppm.

The reaction temperature of the step (S200) is not particularly limited, and for example, the temperature may be -5 to 100 °C, specifically about -5 to 80 °C, more specifically about -5 to 50 °C. According to one example, step (S200) may be performed at about 25 to 40 °C.

(c) filtration and/or drying step

Then, optionally filtering and/or drying the product-containing mixture produced in step (S200) may be further performed.

In the filtration step, substances other than the target compound, the carbamate derivative, such as by-products (eg, hydrochloride salt, imidazole) or unreacted substances (eg, imidazole, intermediates, etc.) as residues are separated from the carbamate derivative and removed.

This filtration step may be performed by a method known in the art (eg, a filtering method, etc.). For example, a filter is used to remove by-products (eg hydrochloride salt, imidazole) or unreacted substances (eg imidazole) from the product-containing mixture.

After the filtration step, the filtrate (filtrate) may be washed with water several times to remove by-products (eg, hydrochloride salt, imidazole) or unreacted substances (eg, imidazole) remaining in the filtrate.

In the drying step, water is removed from the organic layer obtained in the filtration/washing step, concentrated in vacuo, and then recrystallized to obtain a carbamate derivative. This drying step can be performed by methods known in the art. For example, after removing moisture from the organic layer obtained in the filtration step using magnesium sulfate, it is filtered, and the filtrate is concentrated under vacuum, dissolved with isopropyl ether, and crystallized to obtain a carbamate derivative.

Through the above preparation method, the present invention can obtain a carbamate derivative having an imidazole group and a carbon-carbon triple bond in high purity and high yield. Specifically, the present invention can produce a carbamate derivative represented by the following Chemical Formula 5 with a purity of 99% or more and a yield of 60% or more through the above-described preparation method.

[Formula 5]

Hereinafter, the present invention will be described in detail through examples. However, the following examples are only to illustrate the present invention, and the present invention is not limited by the following examples.

<Example 1> - Synthesis of 1H-Imidazole-1-carboxylic acid, 2-propyn-1-yl ester

A magnetic bar and a thermometer were installed in a 100 mL flask, and then 13.56 g of imidazole was added. Thereafter, 50.0 g of methylene chloride (moisture content: 100 ppm or less) was added to the flask, stirred, and then a solution obtained by dissolving 5.0 g of triphosgene in methylene chloride was slowly added dropwise at 5 ° C. or less, and the temperature was gradually raised and then refluxed. After the reaction was completed, it was gradually cooled to room temperature, and then 2.8 g of propargyl alcohol was slowly added dropwise to the flask and reacted. After the reaction was completed, the imidazole hydrochloride salt was removed by filtration, and water was added dropwise while stirring the filtrate, and then the imidazole hydrochloride salt and imidazole partially dissolved in the methylene chloride layer were removed by washing with water. The aqueous layer and the methylene chloride layer were separated, water was removed from the methylene chloride layer with magnesium sulfate, and the mixture was concentrated in vacuo. Thereafter, the crystals obtained by concentration were dissolved in isopropyl ether and recrystallized by cooling. Then, vacuum drying was performed to obtain 5.8 g of the target compound (yield: about 78%).

As a result of GC analysis, the purity of the target compound was 99.5% or more. In addition, NMR analysis of the target compound was as shown in FIG. 1 .

<Example 2> - Synthesis of 1H-Imidazole-1-carboxylic acid, 2-propyn-1-yl ester

5.0 g (yield: about 67%) of the target compound was obtained in the same manner as in Example 1, except that 6.78 g of imidazole and 10.1 g of triethylamine were used instead of 13.56 g of imidazole used in Example 1, and the triethylamine hydrochloride salt was removed by filtration instead of the imidazole hydrochloride salt.

As a result of GC analysis, the purity of the target compound was 99.5% or more.

<Example 3> - Synthesis of 1H-Imidazole-1-carboxylic acid, 2-propyn-1-yl ester

5.0 g (yield: about 67%) of the target compound was obtained in the same manner as in Example 1, except that 7.9 g of pyridine was used instead of 10.1 g of triethylamine used in Example 2, and pyridine hydrochloride was removed by filtration instead of the triethylamine hydrochloride salt.

As a result of GC analysis, the purity was more than 99.5%.

<Example 4> - Synthesis of 1H-Imidazole-1-carboxylic acid, 2-propyn-1-yl ester

5.2 g of the target compound (yield: about 70%) was obtained in the same manner as in Example 1, except that 7.3 g of diethylamine was used instead of 10.1 g of triethylamine used in Example 2, and the diethylamine hydrochloride salt was removed by filtration instead of the triethylamine hydrochloride salt.

As a result of GC analysis, the purity was more than 99.5%.

<Comparative Example 1> - Synthesis of 1H-Imidazole-1-carboxylic acid, 2-propyn-1-yl ester

As follows, the target compound was obtained in the same manner as in Example 2, except that triethylamine for capturing Cl atoms was not used. However, since the neutralization reaction was stronger than the main reaction, less than 5% of intermediates were produced, so the purity and yield of the target compound could not be measured.

A magnetic bar and a thermometer were installed in a 100 mL flask, and then 6.78 g of imidazole was added. Thereafter, 50.0 g of methylene chloride (moisture content: 100 ppm or less) was added to the flask, stirred, and then a solution obtained by dissolving 5.0 g of triphosgene in methylene chloride was slowly added dropwise at 5 ° C. or less, and the temperature was gradually raised and then refluxed. Thereafter, when the reaction was completed, it was gradually cooled and then 2.8 g of propargyl alcohol was slowly added dropwise to the flask to react. However, since the neutralization reaction was stronger than the main reaction and less than 5% of the intermediate was produced, it was difficult to synthesize the target compound.

<Comparative Example 2> - Synthesis of 1H-Imidazole-1-carboxylic acid, 2-propyn-1-yl ester

Instead of one-pot synthesis as in Example 1, it was carried out in two steps (synthesis after intermediate purification) as follows.

A magnetic bar and a thermometer were installed in a 100 mL flask, and then 13.56 g of imidazole was added. Thereafter, 50.0 g of methylene chloride (moisture content: 100 ppm or less) was added to the flask, stirred, and then a solution obtained by dissolving 5.0 g of triphosgene in methylene chloride was slowly added dropwise at 5 ° C. or less, and the temperature was gradually raised and then refluxed. After synthesizing the intermediate, the imidazole hydrochloride salt was removed by filtration, and water was added dropwise while stirring the filtrate, and then the imidazole hydrochloride salt and imidazole partially dissolved in the methylene chloride layer were removed by washing with water. The aqueous layer and the methylene chloride layer were separated, water was removed from the methylene chloride layer with magnesium sulfate, and the mixture was concentrated in vacuo. Thereafter, the crystals obtained by concentration were vacuum dried to obtain 4.82 g (yield: about 60%) of an intermediate (N,N-carbonyldiimidazole). As a result of GC analysis on the intermediate obtained at this time, the purity of the intermediate was 99.9%.

Thereafter, a magnetic bar and a thermometer were installed in a 100 mL flask, and then 4.82 g of N,N-carbonyl diimidazole was added. Thereafter, 50.0 g of methylene chloride (moisture content: 100 ppm or less) was added to the flask, stirred, and then 1.68 g of propargyl alcohol was slowly added dropwise thereto and reacted. After the reaction was completed, imidazole was removed by filtration, and water was added dropwise while stirring the filtrate, and then imidazole partially dissolved in the methylene chloride layer was removed by washing with water. The aqueous layer and the methylene chloride layer were separated, water was removed from the methylene chloride layer with magnesium sulfate, and the mixture was concentrated in vacuo. Thereafter, the crystals obtained by concentration were dissolved in isopropyl ether and recrystallized by cooling. Then, vacuum drying was performed to obtain 2.98 g of the target compound (yield: about 67%, yield: about 40% compared to starting material triphosgene).

As a result of GC analysis, the purity of the target compound was 99.5% or more.

Claims (11)

(S100) reacting the compound represented by Formula 1 with the compound represented by Formula 2 in an organic solvent; and
(S200) reacting the intermediate represented by Chemical Formula 3 obtained in step (S100) with a compound represented by Chemical Formula 4;
Including,
Steps (S100) and (S200) are performed in a one-pot method for producing a carbamate derivative represented by the following formula (5):
[Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

[Formula 5]

(In Formula 2 above,
R ₁ and R ₂ are the same as or different from each other, and each independently halogen or

ego,
R ₂₁ is a C ₁ ~ C ₁₂ haloalkyl group). According to claim 1,
A method for preparing a carbamate derivative, wherein the intermediate is continuously reacted with the compound represented by Chemical Formula 4 without purification. According to claim 1,
The method for preparing a carbamate derivative wherein the compound represented by Formula 1 is used in the range of 1 to 20 equivalents based on 1 equivalent of the compound represented by Formula 2. According to claim 1,
The method for preparing a carbamate derivative wherein the compound represented by Formula 1 is used in the range of 12 to 20 equivalents based on 1 equivalent of the compound represented by Formula 2. According to claim 1,
The method for preparing a carbamate derivative, wherein the compound represented by Formula 1 is used in an amount of 1 equivalent or more and less than 12 equivalents based on 1 equivalent of the compound represented by Formula 2. According to claim 1,
In the step (S100), an alkaline material is additionally used, a method for producing a carbamate derivative. According to claim 6,
The alkaline substance is an amine, a method for producing a carbamate derivative. According to claim 1,
A method for producing a carbamate derivative wherein the compound represented by Formula 2 is a compound represented by any one of Formulas 2a to 2c:
[Formula 2a]

[Formula 2b]

[Formula 2c]

(In Formulas 2a to 2c,
X ₁ to X ₁₂ are halogen selected from the group consisting of F, Cl, Br and I, which are the same as or different from each other). According to claim 1,
The organic solvent is at least one selected from the group consisting of carbonate solvents, alcohol solvents, chloride solvents, nitrile solvents, heterocyclic solvents, ether solvents and ester solvents. According to claim 1,
The step (S100) is performed at a temperature of -5 to 100 ° C., a method for preparing a carbamate derivative. According to claim 1,
The intermediate and the compound represented by Formula 4 are used in an equivalent ratio of 1: 1 to 4, a method for preparing a carbamate derivative.