JP2009298760A - Methods for manufacturing amides using organic carboxylic acid as n-acylating agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a manufacturing method comprising heating an organic carboxylic acid in the presence of an amine compound in a solvent-free state or in a proper aprotic solvent to perform an acylation reaction in one step reaction without requiring a specific device, without a special dehydrative condensation agent and without removing by-produced H<SB>2</SB>O from the system, by which the amide compound can simply be produced in a high yield without damaging environments. <P>SOLUTION: There is the manufacturing method comprising heating the organic carboxylic acid in the presence of the amine compound in a solvent-free state or in the proper aprotic solvent to perform the acylation reaction in one step reaction without requiring a specific device, without a special dehydrative condensation agent and without removing by-produced H<SB>2</SB>O from the system, by which the amide compound can be produced in a high yield. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a method for producing amides. More specifically, the present invention relates to a method for producing an amide by heating an organic carboxylic acid in the absence of a solvent or an aprotic solvent such as toluene or xylene in the presence of an amine.

  Amides are extremely useful compounds that have been extensively utilized as protection for amines and because of their usefulness. As methods for synthesizing these amides, various acylating agents and dehydrating condensing agents have been invented, and methods using them have been widely used (see Non-Patent Documents 1 and 2). However, these acylating agents are compounds derived from organic carboxylic acids, which are more expensive than the corresponding carboxylic acids, have limited availability, and may cause problems in handling and storage. Further, the method of obtaining an amide from an active intermediate obtained from an organic carboxylic acid and a dehydrating condensing agent and amines may cause problems such as disposal in mass production.

  So far, the following reports have been made as methods for obtaining amides from organic carboxylic acids and amines. That is, when an organic carboxylic acid and an amine are mixed, an amine salt of the carboxylic acid is formed, and in order to obtain an amide by heating, it is necessary to remove the water generated by using one of the excess from the system ( Non-Patent Document 3). Furthermore, there is an example in which acetanilide is produced while heating aniline in an acetic acid solvent and removing water generated in the middle of the reaction system (see Non-Patent Document 4). It is essential to remove them, and there are problems in terms of reaction operation and equipment.

Greene, T .; W. Wuts, P .; G. M.M. Protective Groups in Organic Synthesis, 4rd ed. Wiley-Interscience: New York, 2007, pp 773. Funasaka, S .; Kato, K .; Mukaiyama, T .; Chem. Lett. 2007, 36, 1456. Wagner, R.A. B. Zook, H .; D. Synthetic Organic Chemistry, John Wiley & Sons, Inc. : New York, 1961, p 567. M.u.ller, P.M. Chemiker-Zeitung 1912, 36, 1049.

The present invention has been made in view of these problems. That is, since it is usually difficult to acylate amines only with organic carboxylic acids, various reagents and dehydration condensation agents have been developed. As a result, they may be expensive, limited in availability, or problematic in handling, storage and disposal after reaction. Further, in the method of heating the amine salt of carboxylic acid, it is necessary to remove the generated water out of the system.
An object of the present invention is to provide a method for producing amides in a high yield without using a special operation such as using only an organic carboxylic acid as an acylating agent and removing generated water from the system.

As a result of intensive investigations in view of the above problems, the present inventors have made a one-step reaction without requiring a special apparatus, without using a special dehydrating condensing agent, and without removing by-product H ₂ O out of the system. The N-acylation reaction was carried out by heating the organic carboxylic acid in the absence of a solvent or in a suitable aprotic solvent in the presence of amines, and it was found that amides can be obtained in high yield. It came to complete. That is, the present invention relates to the following gist.

1 A method for producing an amide, which comprises reacting an amine with an organic carboxylic acid.

2 Amines are represented by the following general formula (1)
NHR ¹ R ² (1)
(In the formula, R ¹ and R ² are each independently a hydrogen atom or a linear or branched alkyl group having 1 to 30 carbon atoms which may have a substituent, or a carbon which may have a substituent. And R ¹ and R ² may be bonded to each other to form a cyclic structure with or without a heteroatom at the end, and may represent a cyclic structure. And the organic carboxylic acid represented by the following general formula (2)
R ³ COOH (2)
(In the formula, R ³ represents an alkyl group, an aryl group or an aralkyl group.) An acylation reaction is carried out by heating a compound represented by the following general formula (3 )
R ³ CONR ¹ R ² (3)
(Wherein R ¹ , R ² and R ³ are the same as described above).

3. The method for producing an amide according to 1 or 2 above, wherein the aprotic solvent is toluene or xylene.

[4] The method for producing an amide according to any one of [1] to [3], wherein the reaction is performed at 100 to 180 [deg.] C. without removing water generated during the reaction out of the system.

According to the present invention, an organic carboxylic acid is converted to an amine by a one-step reaction without using a special apparatus, without using a special dehydrating condensing agent, and without removing by-product H ₂ O out of the system. The present inventors have found that an amide compound can be produced in a high yield by heating in a solvent-free or suitable aprotic solvent in the presence of the above, thereby completing the present invention.

  In the present invention, the organic carboxylic acid described in 1 above is used as an acylating agent.

In the formula, R ¹ and R ² are the same or non-identical and have a hydrogen atom or a linear or branched alkyl group having 1 to 30 carbon atoms which may have a substituent, or a substituent. Represents an optionally substituted aryl group having 4 to 30 carbon atoms. Examples of the alkyl group include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, t-butyl group, n-hexyl group, cyclohexyl group, and n-octyl. Group, n-decyl group, eicosane group and the like. Examples of the substituent of the alkyl group include an aryl group, an alkoxy group, a hydroxy group, an ester group, an alkylthio group, a thiol group, a cyano group, a nitro group, and a halogen atom. Examples of the aryl group having 4 to 30 carbon atoms include a furan group, a pyrrole group, a phenyl group, a 1-naphthyl group, and a 2-naphthyl group. Examples of the substituent of the aryl group include an alkyl group, a halogenated alkyl group, an aryl group, an alkoxy group, a hydroxy group, a ketone group, an ester group, a carboxylic acid group, an alkylthio group, a thiol group, a cyano group, a nitro group, or a halogen atom. Can be mentioned. R ¹ and R ² may be bonded together to form a cyclic structure with or without a hetero atom.

  As shown in Scheme 1, the reaction relating to the present invention has two pathways: free organic carboxylic acid produced by equilibrium reacts with an amine again to form a salt or an amide. For example, acetylation of an aniline derivative is possible without removing water generated in an acetic acid solvent out of the system, but in the case of acetylation of a more basic aliphatic amine, more salt can be obtained by using acetic acid as a solvent. Since it is easy to form, it becomes difficult to produce free carboxylic acid at equilibrium. Accordingly, the formation of amide is disadvantageous and the yield decreases. In such a case, the amides can be obtained in good yields by reacting the amines in an aprotic solvent using 2 to 5 times the molar ratio of acetic acid. Even when an organic carboxylic acid other than acetic acid cannot be used as a solvent, the use of this method or the reaction without a solvent is advantageous. Although this reaction is considered to be an equilibrium reaction shown in Scheme 1, the presence of water produced in the reaction system does not interfere with this reaction, that is, the production of amides. For example, water is intentionally added to the reaction system before the reaction. It can also be understood from the fact that the reaction yield is hardly affected even if added to (see Example 8). In the present invention, the reaction can be performed without worrying about water and moisture, and therefore, the apparatus and the operation are easy to use.

  Moreover, when performing reaction, it is normally used by mixing with an aprotic solvent. The aprotic solvent is not particularly limited, and examples thereof include alkanes such as hexane, aromatic compounds such as toluene, and ethers such as dimethoxyethane. The amount of the carboxylic acid compound used for the amines is usually 0.5 to 4 times in molar ratio to the amines, although it depends on which one is expensive.

  Moreover, the reaction temperature (external temperature) at the time of performing the reaction is 100 ° C to 180 ° C, preferably 130 ° C to 150 ° C. The reaction time is usually 1 hour to 10 hours.

  After the reaction, the trifluoroacetamide compound can be isolated by a known extraction method, distillation method, crystallization method, chromatograph or the like.

  EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.

Example 1 Synthesis of acetanilide (no solvent)
Acetic acid (368 mg, 10.62 mmol) was added to aniline (482 mg, 5.18 mmol) and heated at 160 ° C. for 4 hours. After the reaction, excess acetic acid was distilled off under reduced pressure, 10% Na ₂ CO ₃ (8 mL) was added to the residue, the aqueous layer was extracted with AcOEt (20 mL × 2), and the organic layers were combined and saturated brine (6 mL). And dried over Na ₂ SO ₄ . The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (AcOEt-hexane = 1: 2) to obtain the title compound (599 mg, 85.6%).
mp120 ° C

Example 2 Synthesis of N-acetylbenzylamine (no solvent)
Acetic acid (254 mg, 4.23 mmol) was added to benzylamine (215 mg, 2.01 mmol), and the temperature was increased to 110 ° C., 130 ° C., 150 ° C., 160 ° C. and heated for 10 hours. After the reaction, excess acetic acid was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (EtOAc) to obtain the title compound (289 mg, 96.5%).
mp61-63 ° C

Example 3 Synthesis of N-acetylphenethylamine (no solvent)
Acetic acid (380 mg, 6.33 mmol) was added to phenethylamine (372 mg, 3.07 mmol), and the mixture was heated at 160 ° C. for 2 hours. After the reaction, acetic acid was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (EtOAc) to obtain the title compound (474 mg, 94.6%).
mp53 ° C

Example 4 Synthesis of N-acetylphenethylamine (solvent free, xylene)
1) Acetic acid (445 mg, 7.41 mmol) was added to phenethylamine (438 mg, 3.61 mmol), and the mixture was heated at 130 ° C. for 6 hours. After the reaction, excess acetic acid was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (EtOAc) to obtain the title compound (548 mg, 93%).
mp53 ° C
2) Acetic acid (182 mg, 3.03 mmol) was added to a solution of phenethylamine (178 mg, 1.47 mmol) in xylene (1 mL) and heated at 160 ° C. for 2 hours. After the reaction, excess acetic acid and xylene were distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (EtOAc) to obtain the title compound (228 mg, 95.1%).

Example 5 Synthesis of N-acetyl-DL-1-phenylethylamine (no solvent, xylene)
1) Acetic acid (254 mg, 4.23 mmol) was added to DL-1-phenylethylamine (243 mg, 2.01 mmol), and the mixture was heated at 160 ° C. for 7 hours. After the reaction, excess acetic acid was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (EtOAc) to obtain the title compound (317 mg, 96.9%).
mp 77-78 ° C
2) Acetic acid (171 mg, 2.85 mmol) was added to a solution of DL-1-phenylethylamine (170 mg, 1.40 mmol) in xylene (1 mL), and the mixture was heated at 160 ° C. for 3 hours. After the reaction, excess acetic acid and xylene were distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (EtOAc) to obtain the title compound (217 mg, 95%).

Example 6 Synthesis of N-acetyl-DL-1-phenylethylamine (no solvent)
Acetic acid (394 mg, 6.56 mmol) was added to DL-1-phenylethylamine (395 mg, 3.26 mmol), and the mixture was heated at 160 ° C. for 3 hours. After the reaction, excess acetic acid was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (EtOAc) to obtain the title compound (510 mg, 95.9%).
mp 77-78 ° C

Example 7 N-phenethyl-3-phenylpropanamide (solvent free, xylene)
1) 3-Phenylpropionic acid (399 mg, 2.66 mmol) was added to phenethylamine (262 mg, 2.16 mmol) and heated at 160 ° C. for 3 hours. After the reaction, 10% Na ₂ CO ₃ (10 mL) was added, the aqueous layer was extracted with AcOEt (20 mL × 2), the organic layers were combined, washed with saturated brine (6 mL), and dried over Na ₂ SO ₄ . . The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (AcOEt-hexane = 1: 1) to obtain the title compound (448 mg, 81.9%).
mp 96.5-97.5 ° C
2) 3-Phenylpropionic acid (12.4 g, 82.6 mmol) was added to a xylene solution (50 mL) of phenethylamine (5.0 g, 41.3 mmol) and heated at 140 ° C. for 3.5 hours. After cooling the reaction solution, AcOEt (70 mL) was added, and the organic layer was washed with 10% Na ₂ CO ₃ (40 mL × 2), then with saturated brine (40 mL × 2), and dried over Na ₂ SO ₄ . The organic solvent was distilled off under reduced pressure, and the residue was recrystallized (AcOEt-hexane) to obtain the title compound (8.8 g, 84%). Further, the mother liquor was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (AcOEt-hexane = 1: 1) to obtain the title compound (0.4 g, 4%).

Example 8 N-phenethyl-3-phenylpropanamide (xylene + water solvent)
To a xylene solution (1.5 mL) of phenethylamine (150 mg, 1.24 mmol) was added 3-phenylpropionic acid (372 mg, 2.48 mmol) and water (0.45 mL, 27.7 mmol), and the mixture was heated at 140 ° C. for 3 hours. . After cooling the reaction solution, AcOEt (50 mL) was added, and the organic layer was washed with 5% NaHCO ₃ (20 mL × 2), then saturated brine (20 mL × 2), and dried over Na ₂ SO ₄ . The organic solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (AcOEt-hexane = 1: 1) to obtain the title compound (280 mg, 89%).
mp92-94 ° C

Example 9 N-phenethylcinnamic amide (no solution)
Cinnamic acid (367 mg, 2.48 mmol) was added to phenethylamine (150 mg, 1.24 mmol), and the mixture was heated at 150 ° C. for 8.5 hours. After cooling the reaction solution, AcOEt (50 mL) was added, and the organic layer was washed with 10% HCl (10 mL × 2), 5% NaHCO ₃ (10 mL × 2), then saturated brine (20 mL × 2), and Na ₂ and dried over SO _4. The organic solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (AcOEt-hexane = 1: 1) to obtain the title compound (215 mg, 69%).
mp126-127 ° C

Example 10 Synthesis of Paranitroacetanilide (Acetic Acid)
A solution of para nitroaniline (138 mg, 1.007 mmol) in acetic acid (6 mL) was heated to reflux at 140 ° C. for 8 hours. After the reaction, acetic acid was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (EtOAc-hexane = 1: 1) to obtain the title compound (154 mg, 85%).
mp218 ° C

Example 11 Synthesis of N-acetylindoline (acetic acid)
A solution of indoline (158 mg, 1.33 mmol) in acetic acid (1 mL) was heated to reflux at 140 ° C. for 5 hours. After the reaction, acetic acid was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (EtOAc-hexane = 1: 1) to obtain the title compound (207 mg, 96.8%).
mp106-108 ° C

According to the present invention, no special equipment is required, no special dehydration condensing agent is used, and by-product H ₂ O is not removed from the system, and the organic carboxylic acid coexists with amines in a one-step reaction. The amides can be produced in a high yield by performing an N-acylation reaction by heating in a solvent-free or suitable aprotic solvent. Therefore, amides can be provided at a lower cost and with a simpler operation.

Claims (4)

  A method for producing an amide, comprising reacting an amine with an organic carboxylic acid. Amines are represented by the general formula (1)
NHR ¹ R ² (1)
(In the formula, R ¹ and R ² are each independently a hydrogen atom or a linear or branched alkyl group having 1 to 30 carbon atoms which may have a substituent, or an optionally substituted carbon. And an aryl group having a number of 4 to 30. In addition, R ¹ and R ² may be bonded to each other to form a cyclic structure with or without a heteroatom at the terminal. The organic carboxylic acid is represented by the following general formula (2)
R ³ COOH (2)
(In the formula, R ³ represents an alkyl group, an aryl group or an aralkyl group.) An acylation reaction is carried out by heating the compound represented by the following formula (3).
R ³ CONR ¹ R ² (3)
The method for producing an amide according to claim 1, wherein an amide compound represented by the formula (wherein R ¹ , R ² and R ³ are the same as above) is produced.   The method for producing an amide according to claim 1 or 2, wherein the aprotic solvent is toluene or xylene.   The method for producing an amide according to any one of claims 1 to 3, wherein the reaction is carried out at 100 to 180 ° C without removing water produced during the reaction out of the system.