KR20110054670A - A process for preparing 2-cyano-3-hydroxy-n-[(4-trifluoromethyl)phenyl] but-2-enamide - Google Patents

Abstract

PURPOSE: A process for preparing 2-cyano-3-hydroxy-N-[(4-trifluoromethyl)phenyl]but-2-enamide is provided to easily remove by-products generated during the manufacturing process of final products. CONSTITUTION: A process for preparing 2-cyano-3-hydroxy-N-[(4-trifluoromethyl)phenyl]but-2-enamide of chemical formula 1 from a compound of chemical formula 5 comprises the steps of: activating a compound of chemical formula 2 to an esterified compound using a carbodiimide compound; and reacting the resultant with a compound of chemical formula 4 to prepare a compound of chemical formula 5. The carbodiimide compound is selected from 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide, 1,3-diisopropylcarbodiimide or 1,3-dicyclohexylcarbodiimide.

Description

A process for preparing 2-cyano-3-hydroxy-N-[(4,2-cyano-3-hydroxy-ene-[(4-trifluoromethyl) phenyl] but-2-eneamide -trifluoromethyl) phenyl] but-2-enamide}

The present invention relates to a 2-cyano-3-hydroxy-N-[(4-trifluoromethyl) phenyl] but-2-enamide compound represented by the following general formula (1) known from EP0527736. It relates to an improved process for the preparation of the compound of formula (5) which is an intermediate compound for preparation.

<Formula 1>

<Formula 5>

2-Cyano-3-hydroxy-N-[(4-trifluoromethyl) phenyl] but-2-enamide (2-Cyano-3-hydroxy-N-[(4-trifluoromethyl) ) phenyl] but-2-enamide) is a compound useful for the treatment of rheumatoid arthritis, which is known from EP0527736.

A brief summary of the process for preparing the compound of Formula 1 known in the literature can be represented by the following Scheme 1.

<Scheme 1>

According to Scheme 1, first, the compound of formula 3 and compound 4 are directly reacted to obtain a compound of formula 5, which is an intermediate compound, and hydrolyzed in an aqueous sodium hydroxide solution to finally prepare a compound of formula 1 as a target compound.

However, since the compound of Formula 3, which is a starting material used to prepare the compound of Formula 5, which is an intermediate compound in Scheme 1, is prepared by heating under an excess of thionyl chloride, SO ₂ gas, which is a toxic gas, is generated during the reaction. It is difficult to apply to, and has a big disadvantage of using an excess (2 equivalents) of the compound of formula 4 for use as an acid acceptor for hydrochloric acid generated during the reaction with the compound of formula (4).

In the preparation of the compound of formula (5), which is an intermediate, 4-trifluoromethylaniline hydrochloride is formed as an adduct. The above product is filtered off and the filtrate is distilled to obtain the compound of formula (5). During the filtration process, the 4-trifluoromethylaniline hydrochloride compound, which is an adduct, is partially dissolved into the filtrate and is present as an impurity in the intermediate compound of Formula 5, which makes it difficult to prepare the intermediate compound in high purity.

Therefore, the present invention was completed after studying to solve the problems occurring during the preparation of the compound of Formula 5, which is an intermediate compound for preparing the compound of Formula 1.

The present invention provides a method for preparing a compound of formula (5), which is an intermediate compound for preparing the compound of formula (1), which can be easily reacted with the compound of formula (4), which can easily remove by-products generated during the reaction process. Its purpose is to provide a method for producing a.

In order to achieve the above object, the present invention by using a carbodiimide compound to activate the compound of formula (2) as a starting material and then reacted with the compound of formula (4) to prepare a compound of formula (5) After hydrolysis, a method of preparing the compound of Formula 1 is provided.

<Formula 1>

<Formula 2>

<Formula 4>

<Formula 5>

The preparation method according to the present invention is shown in Scheme 2 below.

<Scheme 2>

First, the present invention is to prepare the following compound A which is an active ester compound by activating 5-methylisoazole-4-carboxylic acid, a compound of Formula 2, as a starting material under a nitrogen stream with a carbodiimide compound, and then A 5-methyl-N- [4- (trifluoromethyl) phenyl] -isosazole-4-carboxamide compound of the compound of formula 5, which is an intermediate compound, is reacted by reacting the compound, 4-trifluoromethylaniline compound. .

In the present invention, the carbodiimide compound used to activate the compound of formula (2) as the ester compound A is 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (EDC.HCl). 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide (EDC), 1,3-diisopropylcarbodiimide (DIC) or 1,3-dicyclohexylcarbodiimide Compounds (DCC) can be used to activate compounds of formula (2) as esterates, like compound A.

Reaction solvents include ethyl acetate, dichloromethane, acetonitrile, tetrahydrofuran (THF), 2-methyltetrahydrofuran, N, N-dimethylformamide (DMF), dimethylacetamide (DMA), dimethyl sulfoxide ( DMSO), N-methyl-2-pyrrolidine (NMP) or these mixed solvents can be used.

At this time, the reaction temperature for activating the compound of Formula 2 is preferably maintained in the range of -10 ℃ to 80 ℃, more preferably 0 ℃ to 40 ℃ range.

Carbonyl chloride compounds, such as the compound of formula (3) which is a starting material used in the preparation method of the compound of formula (I) known from the prior European Patent Publication No. 0527736, are more energy-efficient than carboxylic acid compounds such as the compound of formula (2) according to the present invention. As it is an unstable compound, it easily oxidizes when it comes into contact with moisture in some air. HCl gas is generated at this time, so handling is dangerous. In addition, SO ₂ gas, which is a toxic gas, is generated during the reaction with the compound of Formula 4, and thus it is difficult to apply to the mass production method.

On the other hand, the compound of formula (2) used as a starting material in the present invention is a stable compound, and does not easily react with moisture in the air, and is a solid material, which is easy to store and use, and can be easily purchased commercially, which is suitable for mass production.

In addition, when reacting with the compound of formula (3), which is a starting material known from the prior European Patent Publication No. 0527736, the compound of formula (4), which is a reactant, should be reacted with an excess, but using the compound of formula (2) according to the present invention as a starting material There is no need for an acid acceptor and can be reacted without the use of excess Formula 4 compounds.

In addition, when the compound of formula (3) known from EP0527736 is used as a starting material, it is difficult to remove 4-trifluoromethylaniline hydrochloride formed as an adduct when reacting with the compound of formula (4). In the compound 5, 4-trifluoromethylaniline hydrochloride is present as an impurity, but the present invention provides a compound B produced as a by-product after reaction with the compound of formula 4 by activating the compound of formula 2 as an esterified product (Urea of EDC.HCl). Compound) is easily dissolved in the water separation process because it is soluble in water to prepare a compound of formula 5 which is an intermediate compound of high purity.

In the present invention, after preparing an active esterified compound, a reaction mixture is added by adding 1 equivalent of 4-trifluoromethylaniline compound of Formula 4 to produce a compound of Formula 5, wherein 4-dimethylaminopyridine is used as a catalyst. The same catalyst can also be added for reaction.

In addition, the present invention does not first activate the compound of formula (2) as a starting material, the compound of formula (2), carbodiimide compound and formula (4) may be put together in the reaction solvent to proceed with the reaction to obtain a compound of formula (5).

After completion of the reaction of the compound of Formula 5, the by-product B compound (Urea compound of EDC.HCl) generated during the reaction was removed by washing under acidic or basic conditions, the organic layer was distilled, and then subjected to a hydrolysis reaction. Prepare the compound.

In the present invention, the hydrolysis reaction of the compound represented by Chemical Formula 5 to prepare the compound of Formula 1 may be a known method. After completion of the hydrolysis reaction, the precipitated solid is filtered by acidification to pH 4.5 or less using an acid. Compound 1 will be prepared.

The basic compound used in the hydrolysis reaction may be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonia, or a mixture thereof.

The present invention eliminates the need for the use of an excess of 4-trifluoromethylaniline, a compound of Formula 4, because an active ester compound is used in one reactor using a more stable Formula 2 compound instead of an unstable and highly active Formula 3 compound. This is particularly useful as a mass production method.

When the production method of the present invention described above is carried out, by-products generated during the reaction of the compound of Formula 2 and the compound of Formula 4 are easily removed and the intermediate compound, 5-methyl-N- [4- (trifluoromethyl) Phenyl] -isosazole-4-carboxamide compound can be prepared, and the intermediate compound is hydrolyzed to produce 2-cyano-3-hydroxy-N-[(4-trifluoro) as the compound of Formula 1 The overall reaction yield for synthesizing rhomethyl) phenyl] but-2-eneamide is about 98.6%, which shows a significantly higher yield and good quality (99.6% or more HPLC purity) compared to the prior art.

The present invention by using a stable compound of formula (2) to activate it to make an active ester compound and then reacted with the compound of formula (4) to prepare a compound of formula (5) and then hydrolyzed it, not only by-products can be easily removed, but also high purity and high A compound of formula 1 which is the target compound may be prepared in a yield.

The preparation method of the 2-cyano-3-hydroxy-N-[(4-trifluoromethyl) phenyl] but-2-enamide compound according to the present invention is described in more detail based on the following examples. As will be described, the present invention is not limited thereto.

< Example  1> Preparation of Compound of Formula 1 According to the Invention

13.6 g of 5-methylisoazole-4-carboxylic acid was added to 150 ml of ethyl acetate, and 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide / HCl 21.05 g was added at 20 to 30 ° C., followed by nitrogen. Stirred under air flow for 1 hour. 15.0 g of 4-trifluoromethylaniline was added to the reaction mixture, which was stirred for 24 hours at 20 to 30 ° C. 150 ml of purified water was added to the reaction mixture, and the organic layer was separated after stirring for 30 minutes. The separated organic layer was washed with 150 ml of purified water and then distilled. 150 ml of methanol, 150 ml of purified water, 105 ml of acetone, and 4.28 g of sodium hydroxide were added to an undried 5-methyl-N- [4- (trifluoromethyl) phenyl] -isosazole-4-carboxamide solid and stirred for 2 hours. It was. 20% hydrochloric acid was added to the reaction mixture, followed by acidification, followed by stirring at 3 to 8 ° C. for 2 hours, followed by filtration, washing, and vacuum drying to obtain 24.8 g of the compound of formula 1 as a target compound (yield 98.6%).

m / e 270.2 (parent ion);

¹ H NMR (DMSO-d ₆ ) δ 2.23 (s, 3H), 7.65 ~ 7.76 (dd, 4H), 10.85 (s, 1H)

< Example  2> Preparation of Compound of Formula 1 According to the Invention

4.34 g of 5-methylisoazole-4-carboxylic acid was added to 50 ml of dichloromethane, and 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide / HCl 6.6 g was added at 5-10 ° C., followed by nitrogen. Stirred under air flow for 1 hour. 5.0 g of 4-trifluoromethylaniline and 190 mg of 4-dimethylaminopyridine were added to the reaction mixture, and the mixture was stirred at 20 to 25 ° C. for 22 hours. 50 ml of purified water was added to the reaction mixture, and the organic layer was separated. 50 ml of purified water was added to the separated organic layer, 20% hydrochloric acid was added thereto, adjusted to pH 4, the organic layer was washed, and then distilled. 75 ml of methanol, 75 ml of purified water, 50 ml of acetone and 1.37 g of sodium hydroxide were added to 5-methyl-N- [4- (trifluoromethyl) phenyl] -isoazole-4-carboxamide, which was not dried, and stirred for 1 hour. . 20% hydrochloric acid was added to the reaction mixture, acidified, stirred for 1 hour at 5 to 10 ° C., filtered, washed and dried in vacuo to obtain 8.23 g of the compound of formula 1 as a target compound (yield 98.2%).

< Example  3> Preparation of Compound of Formula 1 According to the Invention

4.34 g of 5-methylisoazole-4-carboxylic acid was added to 50 ml of ethyl acetate, and 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide and HCl 6.6 g were added at 25 to 30 ° C. Stirred under air flow for 1 hour. 5.0 g of 4-trifluoromethylaniline and 190 mg of 4-dimethylaminopyridine were added to the reaction mixture, which was stirred at 25 to 30 ° C. for 24 hours. 50 ml of purified water was added to the reaction mixture, and the organic layer was separated. The separated organic layer was washed with 50 ml of purified water and then distilled. To an undried 5-methyl-N- [4- (trifluoromethyl) phenyl] -isosazole-4-carboxamide solid, 50 ml of methanol, 50 ml of purified water, 35 ml of acetone, and 1.91 g of potassium hydroxide were added and stirred for 2 hours. It was. 20% hydrochloric acid was added to the reaction mixture, followed by acidification, followed by stirring at 5 to 10 ° C. for 2 hours, followed by filtration, washing, and vacuum drying to obtain 8.13 g of the compound of the formula (1) as a target compound (yield 97.0%).

< Example  4> Preparation of Compound of Formula 1 According to the Invention

4.34 g of 5-methylisoazole-4-carboxylic acid was added to 50 ml of ethyl acetate, and 5.73 ml of 1,3-diisopropylcarbodiimide (DIC) was added at 0-5 ° C. and stirred for 1 hour under a nitrogen stream. It was. 5.0 g of 4-trifluoromethylaniline and 190 mg of 4-dimethylaminopyridine were added to the reaction mixture, which was then stirred at 20 to 25 ° C. for 24 hours. 50 ml of purified water was added to the reaction mixture, and the organic layer was washed and then distilled. To an undried 5-methyl-N- [4- (trifluoromethyl) phenyl] -isosazole-4-carboxamide solid, 50 ml of methanol, 50 ml of purified water, 35 ml of acetone, and 1.43 g of sodium hydroxide were added and stirred for 1 hour. It was. 20% hydrochloric acid was added to the reaction mixture, acidified, stirred for 1 hour at 5 to 10 ° C., filtered, washed and dried in vacuo to obtain 7.99 g of the compound of formula 1 as a target compound (yield 95.3%).

< Example  5> Preparation of Compound of Formula 1 According to the Invention

4.34 g of 5-methylisoazole-4-carboxylic acid was added to 50 ml of acetonitrile and 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide and HCl 6.6 g at 5 to 10 ° C. under nitrogen stream. Was added and stirred for 45 minutes. 5.0 g of 4-trifluoromethylaniline was added to the reaction mixture, which was stirred for 1 hour at 5 to 10 ° C and for 22 hours at 20 to 25 ° C. 50 ml of ethyl acetate and 50 ml of purified water were added to the reaction mixture, and the organic layer was separated. 50 ml of purified water was added to the separated organic layer, adjusted to pH 9 with 5% aqueous sodium hydroxide solution, and the organic layer was washed and distilled. To an undried 5-methyl-N- [4- (trifluoromethyl) phenyl] -isosazole-4-carboxamide solid, 50 ml of methanol, 50 ml of purified water, 35 ml of acetone, and 1.37 g of sodium hydroxide were added. Stirred for 1 h. 20% hydrochloric acid was added to the reaction mixture, followed by acidification, followed by stirring at 5˜10 ° C. for 2 hours, followed by filtration, washing, and vacuum drying to obtain 8.09 g of the compound of formula 1 as a target compound (yield 96.5%).

< Example  6> Preparation of Compound of Formula 1 According to the Invention

To 50 ml of ethyl acetate, 4.34 g of 5-methylisoazole-4-carboxylic acid and 6.6 g of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide / HCl were added, followed by nitrogen flow at 25 to 30. Stir at 1 ° C. for 1 h. 5.0 g of 4-trifluoromethylaniline was added to the reaction mixture, which was stirred at 35 to 40 ° C for 4 hours. 50 ml of purified water was added to the reaction mixture, and the organic layer was separated. 75 ml of purified water was added to the organic layer, 20% hydrochloric acid was added thereto, adjusted to pH 4, and the organic layer was washed and then distilled. To an undried 5-methyl-N- [4- (trifluoromethyl) phenyl] -isosazole-4-carboxamide solid, 25 ml of methanol, 25 ml of purified water, 50 ml of acetone, and 1.37 g of sodium hydroxide were added. Stirred for 1 h. 20% hydrochloric acid was added to the reaction mixture, acidified, stirred for 2 hours at 5 to 10 ° C., filtered, washed, and dried in vacuo to obtain 8.14 g of the compound of formula 1 as a target compound (yield 97.1%).

< Example  7> Preparation of Compound of Formula 1 According to the Invention

50 ml of ethyl acetate, 4.34 g of 5-methylisoazole-4-carboxylic acid, 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide, 6.6 g of HCl, 4-trifluoromethylaniline 5.0 g was added thereto and stirred for 24 hours at 25 ° C to 30 ° C under a nitrogen stream. 50 ml of purified water was added to the reaction mixture, and the organic layer was separated. The separated organic layer was washed with 50 ml of purified water and then distilled. To an undried 5-methyl-N- [4- (trifluoromethyl) phenyl] -isosazole-4-carboxamide solid, 50 ml of methanol, 50 ml of purified water, 35 ml of acetone, and 1.37 g of sodium hydroxide were added and stirred for 1 hour. It was. 20% hydrochloric acid was added to the reaction mixture, followed by acidification, followed by stirring at 0˜10 ° C. for 2 hours, followed by filtration, washing, and vacuum drying to obtain 8.08 g of the compound of formula 1 as a target compound (yield 96.4%).

The reaction solvent, the presence or absence of the catalyst, the type of the active compound and the difference in the washing process between the embodiments of the present invention are shown in Table 1 below.

As can be seen in Examples 1 to 7, the present invention is a significant difference depending on the reaction solvent (dichloromethane, acetonitrile, ethyl acetate) according to the present invention in the step of synthesizing intermediate 5 compound by activating the compound of formula (2) There was no significant difference in yield of the final target compound according to the use of 4-dimethylaminopyridine (DMAP) as a catalyst.

In addition, it was confirmed that the intermediate 5 compound prepared by the preparation method according to the present invention can easily remove the by-products by the difference in work-up process (washing only with water, washing after adjusting pH 4, washing after adjusting pH 9). Can be.

In particular, the present invention, as can be seen in Example 7, the compound of formula (2), carbodiimide compound and formula (4) can be easily prepared even by reacting the mixture of the compound of formula (2), compound of formula (4), easy removal of by-products It was.

Therefore, the present invention can easily remove the by-products generated during the manufacturing process of the compound of Formula 1, which is the target compound, and can be usefully used as a method for preparing the compound of Formula 1 prepared in high purity and high yield.

Claims (6)

In the process for producing 2-cyano-3-hydroxy-N-[(4-trifluoromethyl) phenyl] but-2-enamide, which is a compound represented by the following formula (1): 2-Cyano-3-hydroxy, which is a compound represented by the following Chemical Formula 1, characterized in that the following Chemical Formula 2 is prepared by activating a compound represented by Chemical Formula 2 as an esterified product using a carbodiimide compound Process for the preparation of -N-[(4-trifluoromethyl) phenyl] but-2-enamide. <Formula 1>

<Formula 2>

<Formula 4>

<Formula 5>

The carbodiimide compound of claim 1, wherein the carbodiimide compound is 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (EDC.HCl), 1- [3- (dimethylamino) propyl] -3 -Ethylcarbodiimide (EDC), 1,3-diisopropylcarbodiimide (DIC) or 1,3-dicyclohexylcarbodiimide (DCC) method for producing a compound of formula (I). A compound according to claim 1, wherein the compound of formula 2 is ethyl acetate, dichloromethane, acetonitrile, tetrahydrofuran (THF), 2-methyltetrahydrofuran, N, N-dimethylformamide (DMF), dimethylacetamide (DMA) , Dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidine (NMP) or a method for producing a compound of formula 1 characterized in that the activation in a mixed solvent thereof. In the process for producing 2-cyano-3-hydroxy-N-[(4-trifluoromethyl) phenyl] but-2-enamide, which is a compound represented by the following formula (1): 2-Cyano-3-hydroxy-N-[(4- is a compound represented by the following Chemical Formula 1, wherein the compound of Chemical Formula 2 is reacted together to form a carbodiimide compound. Method for producing trifluoromethyl) phenyl] but-2-enamide. <Formula 1>

<Formula 2>

<Formula 4>

<Formula 5>

The carbodiimide compound according to claim 4, wherein the carbodiimide compound is 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (EDCHCl), 1- [3- (dimethylamino) propyl]-. A process for preparing a compound of formula 1 characterized in that it is selected from 3-ethylcarbodiimide (EDC), 1,3-diisopropylcarbodiimide (DIC) or 1,3-dicyclohexylcarbodiimide (DCC). A compound according to claim 4, wherein the compound of formula (2), the carbodiimide compound and the compound of formula (4) are selected from ethyl acetate, dichloromethane, acetonitrile, tetrahydrofuran (THF), 2-methyltetrahydrofuran, N, N-dimethylformamide ( DMF), dimethylacetamide (DMA), dimethylsulfoxide (DMSO), N-methyl-2-pyrrolidine (NMP) or a mixed solvent thereof.