KR100619436B1 - Amide Manufacturing Method Using Diphosgene - Google Patents

Abstract

The present invention is a novel process for the preparation of amide derivatives useful as intermediates in the synthesis of fine chemicals such as pharmaceuticals, pesticides, or natural substances, carboxylic acid derivatives diphosgene (diphosgene) It is a novel method for preparing amide derivatives directly from carboxylic acid derivatives by using a method of reacting with an amine derivative in the presence of triphenylphosphine.

Carboxylic acid, amide, diphosgene, triphenylphosphine

Description

Process for the preparation of amide derivatives by using diphosgene

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 medicinal and pesticides or in the total synthesis of natural substances. Amide derivatives are directly prepared from carboxylic acid derivatives by reacting carboxylic acid derivatives with primary or secondary amine derivatives in the presence of diphosgene and triphenylphosphine. It's a new way to do it.

Wherein R represents hydrogen, alkyl and substituted alkyl groups having 1 to 20 carbon atoms, or aryl and substituted aryl groups, and R ¹ and R ² each independently represent hydrogen, alkyl having 1 to 20 carbon atoms, substituted alkyl, aryl, substituted aryl groups Indicates.

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, and the overall synthesis process is simple, and the reaction is carried out at normal pressure and in mild conditions near room temperature. It is an object of the present invention to provide a new method for synthesizing an amide derivative having no synthesis of a new intermediate for activating the carboxyl group used in the present invention and hardly generating byproducts.

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 pages 1305, triphenylphosphine and carbon tetrabromide (CBr ₄ ) were reacted with reflux in THF solvent to form phosphonium salt, followed by carboxylic acid and amine derivatives. To obtain an 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 Vol. 20, 1990, which later added triphenylphosphine to produce phosphonium salts to react carboxylic acids with amine derivatives. Amide derivatives were obtained, but also by-products were produced and yields were low. Konrad Sandhoff et al., 1992, published in Tetrahedron 48, 28, 5855. During the synthesis of natural analogues, carboxylic acid derivatives were reacted with amine derivatives in the presence of hydroxybenzotrizole, dicyclohexylcarbodiimide (DCC) and ethyldiisopropylamine. An amide derivative was obtained. Sibi et al. Described the carboxylic acid derivatives in methylene chloride solvents using pyridinium salt (2-chloro-1-methylpyridinium iodide), which Mukayama et al. The amine derivative was refluxed for about 7 hours to obtain an amide derivative. In this case, pyridone (pyridone) is produced as an equivalent ratio as a 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 39, 253, 1998. Singh et al., 1999, in Synthetic Communications, Vol. 29, No. 8, page 3215, prepared anhydrides that react carboxylic acids with pivaloyl chloride to produce steric hindrance, followed by reaction with amine derivatives. Derivatives were synthesized. Georg et al. Converted organic acid fluorides to acid fluorides and then reacted with amine derivatives to obtain amide derivatives. Taddle et al., 2001, J. Org. Chem. On page 66, page 2534, triazine (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 form an amide derivative. The target compound was obtained by two-step reaction.

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 activated the carboxylic acid was synthesized, and then reacted with the amine derivative to synthesize an 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 production.

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. A new method for producing amide derivatives directly from carboxylic acid derivatives by reacting carboxylic acid derivatives with primary or secondary amine derivatives in the presence of diphosgene and triphenylphosphine. to be.

Wherein R represents hydrogen, an alkyl and substituted alkyl group having 1 to 20 carbon atoms, or an aryl and substituted aryl group, and R ¹ and R ² each independently represent hydrogen, an alkyl having 1 to 20 carbon atoms, substituted alkyl, aryl or a substituted aryl group; Indicates.

Diphosgene (triphosgene) and triphenylphosphine (triphenylphosphine) used in the present invention serves to activate a less reactive carboxyl group, diphosgene is 0.50 compared to the carboxylic acid derivative of the general formula (II) Mole times to 1.00 mole times are used, and triphenylphosphine (tripenylphosphine) uses 1.0 to 1.2 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 is as follows.

Diphosgene and triphenylphosphine were added to dichloromethane at 0-5 ^° C. and stirred for about 5 minutes to form triphenylphosphinium dichloride salt (PPh ₃ Cl ₂ ). When the carboxylic acid derivative of (II) and triethylamine are added and stirred, an intermediate of the acid chloride form with increased reactivity of the carboxyl group is formed, and when the amine derivative is added and stirred while raising the temperature to room temperature, the binding electrons move and Through reconstitution, the desired amide derivative of general formula (I) can be obtained.

Diphosgene used as an activating reagent of carboxylic acid in the present invention is a hygroscopic agent capable of synthesizing nitrile derivatives from amide derivatives as Mai et al., Published on page 2203 of Tetrahedron Letters 27, 20, 1986. Seeger et al., 1996 J. Org. Chem. As published on 61,3883, the reagents used mainly for synthesizing 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.

In a 30 mL flask, add 15 mL of dichloromethane under nitrogen atmosphere, cool to 0-5 ^o C in an ice-bath, 524 mg (2.0 mmole) of triphenylphosphine, 198 mg of diphosgene. (1.0 mmole) was added and stirred for 5 minutes.

Add 272.3 mg (2.0 mmole) of p-toluic acid and 607 mg (6.0 mmole) of triethylamine and stir for 20 minutes, add 186.3 mg (2.0 mmole) of aniline, and then remove the ice bath When the mixture was naturally warmed to room temperature, stirred, and reacted, the acid was completely converted into an amide derivative by TLC after about 1 hour. Triethylamine hydrochloride produced as a solid was removed by filtration through a short tube silica gel filter, and the solvent of the filtrate was distilled off under reduced pressure to obtain 399 mg of an amide compound (yield 94.5%).

Example 2

In a 30 mL flask, add 15 mL of dichloromethane under nitrogen atmosphere, cool to 0-5 ^o C in an ice-bath, 524 mg (2.0 mmole) of triphenylphosphine, 198 mg of diphosgene. (1.0 mmole) was added and stirred for 5 minutes. Benzoic acid (244 mg (2.0 mmole) and triethylamine 607 mg (6.0 mmole) were added and stirred for 20 minutes. Methyl aniline (214 mg (2.0 mmole)) was added, followed by ice-water bath After removing the bath), the mixture was naturally warmed to room temperature, stirred, and reacted, and after about 1 hour, the benzoic acid was completely converted into an amide derivative by TLC. Triethylamine hydrochloride produced as a solid was removed by filtration through a short tube silica gel filter, and the solvent of the filtrate was distilled off under reduced pressure to obtain 460 mg of an amide compound (yield 93.6%).

Example 3

In a 30 mL flask, add 15 mL of dichloromethane under nitrogen atmosphere, cool to 0-5 ^o C in an ice-bath, 524 mg (2.0 mmole) of triphenylphosphine, 198 mg of diphosgene. (1.0 mmole) was added and stirred for 5 minutes. 512.5 mg (2.0 mmole) of 4-nitrobenzoic acid and 607 mg (6.0 mmole) of triethylamine were added thereto and stirred for 20 minutes. After adding 214 mg (2.0 mmole) of methylaniline (N-methylaniline), an ice-bath was added. ) And then naturally warmed to room temperature, stirred and reacted, and after about 1 hour, the acid was completely converted to amide derivative by TLC. Triethylamine hydrochloride produced as a solid was removed by filtration through a short tube silica gel filter, and the solvent of the filtrate was distilled off under reduced pressure to obtain 480 mg of an amide compound (yield 93.6%).

Example 4

In a 30 mL flask, add 15 mL of dichloromethane under nitrogen atmosphere, cool to 0-5 ^o C in an ice-bath, 524 mg (2.0 mmole) of triphenylphosphine, 198 mg of diphosgene. (1.0 mmole) was added and stirred for 5 minutes. 491.4 mg (2.0 mmole) of 4-chlorobenzoic acid and 607 mg (6.0 mmole) of triethylamine were added thereto and stirred for 20 minutes. After adding 214 mg (2.0 mmole) of methylaniline (N-methylaniline), an ice-bath was added. ) And then naturally warmed to room temperature, stirred and reacted, and after about 1 hour, the acid was completely converted to amide derivative by TLC. Triethylamine hydrochloride produced as a solid was removed by filtration through a short tube silica gel filter, and the solvent of the filtrate was distilled off under reduced pressure to obtain 462 mg of an amide compound (yield 94.0%).

Example 5

In a 30 mL flask, add 15 mL of dichloromethane under nitrogen atmosphere, cool to 0-5 ^o C in an ice-bath, 524 mg (2.0 mmole) of triphenylphosphine, 198 mg of diphosgene. (1.0 mmole) was added and stirred for 5 minutes. 272.3 mg (2.0 mmole) of p-toluic acid and 607 mg (6.0 mmole) of triethylamine were added thereto, stirred for 20 minutes, 146.3 mg (2.0 mmole) of butylamine was added thereto, and then the ice bath was removed. When the temperature was raised to naturally stirred and reacted, it was confirmed that the acid was completely converted to an amide derivative by TLC after about 1 hour. Triethylamine hydrochloride produced as a solid was removed by filtration through a short tube silica gel filter, and the solvent of the filtrate was distilled off under reduced pressure to obtain 358 mg of an amide compound (yield 93.6%).

 Example 6

In a 30 mL flask, add 15 mL of dichloromethane under nitrogen atmosphere, cool to 0-5 ^o C in an ice-bath, 524 mg (2.0 mmole) of triphenylphosphine, 198 mg of diphosgene. (1.0 mmole) was added and stirred for 5 minutes. 244 mg (2.0 mmole) of benzoic acid and 607 mg (6.0 mmole) of triethylamine were added thereto, stirred for 20 minutes, 146.3 mg (2.0 mmole) of butylamine was added thereto, and then the ice bath was removed to naturally raise the temperature to room temperature. After stirring and reacting for about 1 hour, TLC showed that the benzoic acid was completely converted into an amide derivative. Triethylamine hydrochloride produced as a solid was removed by filtration through a short tube silica gel filter, and the solvent of the filtrate was distilled off under reduced pressure to obtain 335 mg of an amide compound (yield 95.0%).

Conventional known methods of synthesizing amide derivatives directly from carboxylic acid derivatives may be carried out by first synthesizing another intermediate under violent conditions to activate an inactive carboxyl group to react with an amine derivative or to increase the reactivity of the carboxyl group. After synthesizing the intermediate combined with an acid, the intermediate was reacted with an amine derivative to synthesize an 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. It was a way they did not. In contrast, the present invention can react like a simple one-step reaction and can react carboxylic acid derivatives directly with amine derivatives in a short time under mild conditions near normal pressure and room temperature to synthesize amide derivatives without generating byproducts. By the method, the whole synthesis process is simple and can be completed in a short time, and the synthesis method of the new amide derivative having little by-product is generated. Compared to the previous methods, the process of isolating and purifying the target compound is also easy, without causing any environmental problems, which will greatly contribute to economic efficiency.

Claims (3)

Amide of formula (I), characterized in that the carboxylic acid derivative of formula (II) amide) derivative manufacturing method.

Wherein R represents hydrogen, an alkyl and substituted alkyl group having 1 to 20 carbon atoms, or an aryl and substituted aryl group, and R ¹ and R ² each independently represent hydrogen, an alkyl having 1 to 20 carbon atoms, substituted alkyl, aryl or a substituted aryl group; Indicates. The general formula (I), wherein the diphosgene is reacted in the presence of triphenylphosphine using 0.50 to 1.00 mole times compared to the carboxylic acid derivative of general formula (II). Amide (amide) derivative of the manufacturing method. Amide (amide) derivative manufacturing method of formula (I), characterized in that the reaction temperature is 0 to 45 ^o C in claim 1.