KR20050030753A - Novel process for the preparation of amide derivatives - Google Patents

Abstract

Provided is a novel method for preparing an amide derivative useful as an intermediate for the total synthesis of a natural material or a fine chemical material directly from a carboxylic acid derivative. The method comprises the steps of reacting a carboxylic acid represented by the formula II with an amine derivative in the presence of diphosgene to prepare an amide derivative represented by the formula I, wherein R is H, a substituted or unsubstituted C1-C20 alkyl group, or a substituted or unsubstituted aryl group; R1 and R2 are independently H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, or an alkoxy group. Preferably the amount of diphosgene is 0.33-1.00 times by mol to the amount of the carboxylic acid derivative. Preferably the reaction is carried out at a temperature of 0-45 deg.C.

Description

Novel process for the preparation of amide derivatives

The present invention is a novel method for preparing an amide derivative represented by the general formula (I) useful as an intermediate in the intermediate of fine chemicals such as s. The reaction of a carboxylic acid derivative with a primary amine or a secondary amine derivative in the presence of diphosgene is a new method for producing amide derivatives directly from carboxylic acid derivatives.

In the formula, R represents hydrogen, alkyl and substituted alkyl group having 1 to 20 carbon atoms, or aryl and substituted aryl group, and R ¹ and R ² each independently represent hydrogen, alkyl, substituted alkyl, aryl, substituted aryl group or alkoxy group.

The present invention is a method of obtaining an amide derivative directly from a carboxylic acid which is generally known to be remarkably inferior in reactivity. The purpose of the present invention is to provide a new method for synthesizing amide derivatives, which not only requires the synthesis of new intermediates for activating but also generates little by-products.

Several methods have been reported for the synthesis of amide derivatives as intermediates to synthesize useful compounds. Barstow et al. 1971 J. Org. Chem. In a paper published on 36, 1305 pages, triphenylphosphine and CBr ₄ were reflux reacted in THF solvent to form phosphonium salt, followed by reaction of carboxylic acid with amine derivative to obtain amide derivative. In this case, there is a problem that the first step is a relatively vigorous reaction condition in a two-step reaction, and haloform and triphenylphosphite are generated together as a by-product. Einhorn et al. Improved the previous method in a paper published on page 1105 of Synthetic Communications No. 20 of 1990. Later, triphenylphosphine was added to produce phosphonium salt to react carboxylic acid with amine derivative to obtain amide derivative. However, by-products were also produced and yields were low. Konrad Sandhoff et al., 1992, published in Tetrahedron 48, 28, 5855, obtained amide derivatives by reacting carboxylic acid derivatives with amine derivatives in the presence of hydroxybenzotrizole, dicyclohexylcarbodiimide and ethyldiisopropylamine during the synthesis of natural analogues. Sibi et al., Refluxed carboxylic acid derivatives and amine derivatives for 7 hours in methylene chloride solvent using 2-chloro-1-methylpyridinium iodide, which Mukayama et al. Used in the synthesis of beta-lactam in 1995, Synthetic Communications, Vol. 25, No. 8, 1255. An amide derivative was obtained, in which case pyridone is produced as an equivalent ratio by-product. Kessler et al. Synthesized amide derivatives by reacting carboxylic acid derivatives with amine derivatives in the presence of polyphosphoric acid anhydride and N-methylmorpholine in Tetrahedron Letters, vol. 39, 1998. Singh et al. Synthesized an amide derivative by reacting carboxylic acid with pivaloyl chloride to prepare an anhydride that can give steric hindrance in 1999, and then reacting with an amine derivative in a paper published in Synthetic Communications 29, 8, 3215. Georg et al. Converted organic acid fluoride to acid fluoride in 2000, Organic Letters, Vol. 25, No. 4091, and then reacted with amine derivatives to obtain amide derivatives. Taddle et al., 2001, J. Org. Chem. On page 66, page 2534, 2-chloro-4,6-dimethoxy- [1,3,5] triazine was used to obtain an intermediate that activated a carboxylic acid derivative, and then reacted with an amine derivative to obtain an amide derivative. The target compound was obtained.

As described above, a method of synthesizing an amide derivative directly from a known carboxylic acid derivative is used to synthesize another intermediate under violent conditions to react with an amine derivative or to increase the reactivity of the carboxyl group. First, the intermediate that synthesized the carboxylic acid was synthesized and then reacted with the amine derivative to synthesize the amide derivative. However, these conventional synthesis methods have a problem of separation from the by-products generated together with the desired product, and because of the multi-step reaction, there is a limit in industrial use such as a long manufacturing process and a low overall yield. That's how they didn't. The present inventors have made an effort to establish a preferable method while paying attention to the above problems, and as a result, the carboxylic acid derivative is directly reacted with the amine derivative in a short time under mild conditions near normal pressure and room temperature in a simple one-step reaction. The present invention was completed by developing a new method for synthesizing amide derivatives without formation.

The present invention is a novel method for preparing an amide derivative represented by the general formula (I) useful as an intermediate in the intermediate of fine chemicals such as s. The reaction of a carboxylic acid derivative with a primary amine or a secondary amine derivative in the presence of diphosgene is a new method for producing amide derivatives directly from carboxylic acid derivatives.

Wherein R represents hydrogen, an alkyl and substituted alkyl group having 1 to 20 carbon atoms, or an aryl and a substituted aryl group, and R ¹ and R ² each independently represent a hydrogen, alkyl, substituted alkyl, aryl, substituted aryl or alkoxy group. The estimated reaction mechanism of the present invention is as follows.

The diphosgene used in the present invention serves to activate a less reactive carboxyl group, and uses 0.33 mole times to 1.00 mole times, preferably 0.50 mole times to 1.00 mole times, compared to the carboxylic acid derivative of the general formula (II). As the amine derivative, both primary and secondary aliphatic amines and primary and secondary aromatic amines can be used, and 1.0 to 2.0 mole times, preferably 1.0 to 1.2 mole times, compared to the carboxylic acid derivative of the general formula (II). . Tertiary amines such as triethylamine are used to neutralize HCl generated on the presumed mechanism, and the reaction temperature is reacted at 0 to 45 ^° C., preferably 0 to 25 ^° C. As the reaction solvent, all common organic solvents such as chloroform, dichloromethane and toluene can be used. Referring to the reaction sequence constituting the present invention based on the reaction mechanism presented above as follows.

Addition and stirring of the carboxylic acid derivative of formula (II) and triethylamine in dichloromethane at 0-5 ^° C. form an intermediate in the form of a mixed anhydride with increased reactivity of the carboxyl group, as shown in the mechanism. When the amine derivative is introduced, the amide derivative of the general formula (I) can be obtained through the transfer and reconstitution of the binding electrons, as shown in the above mechanism.

In the present invention, diphosgene used as an activator of carboxylic acid is used as an absorbent for synthesizing nitrile derivatives from amide derivatives, as Mai et al., Published on page 2203 of Tetrahedron Letters 27, 20, 1986, or Seeger et al. In 1996. J. Org. Chem. As published on 61,3883, the reagents used mainly for the synthesis of isocyanate derivatives from amines were first identified and developed by the present inventors as reagents for activating carboxylic acids to synthesize amide derivatives. Hereinafter, the present invention will be described in more detail with reference to Examples. However, the present invention is not limited to the methods presented in the Examples.

Example 1.

30 to mL flask under a nitrogen atmosphere Benzoic acid 244 mg (2.0 mmole) and dichloromethane, 15mL, diphosgene 396 mg (2.0 mmloe ) and triethylamine 607 mg (6.0 mmole) an input to at ice-bath 0 to 5 with stirring ^o Cool to C. 195 mg (2.0 mmole) of N, O-dimethylhydroxylamine hydrochloride was added, the ice-bath was removed, and the temperature was naturally raised to room temperature. After stirring and reacting, the benzoic acid was completely converted into amide derivative by TLC after about 1 hour. . Triethylamine hydrochloride produced as a solid was removed by filtration through a short path silica gel filter, and the solvent of the filtrate was distilled off under reduced pressure to obtain 320 mg of amide as a target compound (yield 97%).

Example 2

Into a 30 mL flask, 272 mg (2.0 mmole) of p-toluic acid, 15 mL of dichloromethane, 396 mg (2.0 mmloe) of diphosgene and 607 mg (6.0 mmole) of triethylamine were added to the 30 mL flask under nitrogen atmosphere. Cool to 5 ^o C. 195 mg (2.0 mmole) of N, O-dimethylhydroxylamine hydrochloride was added and the ice-bath was removed to naturally warm to room temperature, and stirred and reacted. After about 1 hour, p-toluic acid was completely converted into amide derivative by TLC. Can be. Triethylamine hydrochloride produced as a solid was removed by filtration using a short path silica gel filter, and the solvent of the filtrate was distilled off under reduced pressure to obtain 333 mg of amide as a target compound (yield 93%).

Example 3

In a 30 mL flask, add 304 mg (2.0 mmole) of 4-methyoxybenzoic acid, 15 mL of dichloromethane, 396 mg of diphosgene (2.0 mmloe), and 425 mg (4.2 mmole) of triethylamine under a nitrogen atmosphere, and stir at 0 to 0 in an ice-bath. Cool to 5 ^o C. 214mg (2.0 mmole) of N-methylaniline was added and the ice-bath was removed to naturally warm to room temperature, and stirred and reacted. After about 1 hour, 4-methyoxybenzoic acid was completely converted into amide derivative by TLC. Triethylamine hydrochloride produced as a solid was removed by filtration using a short path silica gel filter, and the solvent of the filtrate was distilled off under reduced pressure to obtain 454 mg of the target compound amide (yield 94%).

Example 4

In a 30 mL flask, under nitrogen atmosphere, 313 mg (2.0 mmole) of 4-chlorobenzoic acid, 15 mL of dichloromethane, 396 mg (2.0 mmloe) of diphosgene, and 425 mg (4.2 mmole) of triethylamine were added and stirred in an ice-bath. Cool to 5 ^o C. 214mg (2.0 mmole) of N-methylaniline was added and the ice-bath was removed to naturally warm to room temperature, and stirred and reacted. After about 1 hour, 4-chlorobenzoic acid was completely converted into amide derivative by TLC. Triethylamine hydrochloride produced as a solid was removed by filtration using a short path silica gel filter, and the solvent of the filtrate was distilled off under reduced pressure to obtain 462 mg of amide as a target compound (yield 94%).

Example 5

In a 30 mL flask, add 256 mg (2.0 mmole) of cyclohexane carboxylic acid, 15 mL of dichloromethane, 396 mg (2.0 mmloe) of diphosgene, and 425 mg (4.2 mmole) of triethylamine under nitrogen atmosphere. ^o Cool to C. 106 mg (2.0 mmole) of aniline was added, the ice-bath was removed, the temperature was raised naturally to room temperature, stirring, and reaction. After about 1 hour, TLC showed that the cyclohexane carboxylic acid was completely converted into an amide derivative. Triethylamine hydrochloride produced as a solid was removed by filtration using a short path silica gel filter, and the solvent of the filtrate was distilled off under reduced pressure to obtain 400 mg of amide as a target compound (yield 92%).

 Example 6

Into a 30 mL flask under nitrogen atmosphere, 334 mg (2.0 mmole) of 4-nitrobenzoic acid, 20 mL of dichloromethane, 396 mg (2.0 mmloe) of diphosgene and 607 mg (6.0 mmole) of triethylamine were added and stirred in an ice-bath. To 5 ^o C. 195 mg (2.0 mmole) of N, O-dimethylhydroxylamine hydrochloride was added and the ice-bath was removed to naturally warm to room temperature, and stirred and reacted. After about 1 hour, 4-nitrobenzoic acid was completely converted into amide derivative by TLC. Can be. Triethylamine hydrochloride produced as a solid was removed by filtration using a short path silica gel filter, and the solvent of the filtrate was distilled off under reduced pressure to obtain 408 mg of the target compound amide (yield 97%).

Conventionally known methods of synthesizing amide derivatives directly from carboxylic acid derivatives synthesize another intermediate under vigorous conditions to activate a less reactive carboxyl group to react with an amine derivative or combine with a carboxylic acid first to increase the reactivity of the carboxyl group. Synthesized intermediates were reacted with amine derivatives to synthesize amide derivatives. However, these conventional synthesis methods have a problem of separation from the by-products generated together with the desired product, and because of the multi-step reaction, there is a limit in industrial use such as a long manufacturing process and a low overall yield. It was a way they did not. In contrast, the present invention is a simple one-step reaction, a new method that can synthesize the amide derivative without generating by-products by directly reacting the carboxylic acid derivative with the amine derivative in a short time under mild conditions near normal pressure and room temperature. It is a new synthetic process that can not only complete the reaction in a short and short time but also produces little by-products.It is a new synthetic process with excellent reaction reliability and reproducibility. The separation and purification of the target compound can be facilitated without causing any damage, which will greatly contribute to economic efficiency.

Claims (3)

A method for preparing an amide derivative of the general formula (I) below, wherein the carboxylic acid derivative of the general formula (II) is reacted with an amine derivative in the presence of diphosgene. Wherein R represents hydrogen, an alkyl and substituted alkyl group having 1 to 20 carbon atoms, or an aryl and a substituted aryl group, and R ¹ and R ² each independently represent a hydrogen, alkyl, substituted alkyl, aryl, substituted aryl or alkoxy group. The method for preparing an amide derivative of Formula (I) according to claim 1, wherein diphosgene is used in an amount of 0.33 to 1.00 mole times compared to the carboxylic acid derivative of Formula (II). The method of claim 1, wherein the reaction temperature is 0 to 45 ^° C.