WO2004087637A1

WO2004087637A1 - Production of n-alkylamide compounds

Info

Publication number: WO2004087637A1
Application number: PCT/JP2004/004561
Authority: WO
Inventors: Takaji Matsumoto; Tsukasa Sotoguchi
Original assignee: Takasago International Corporation
Priority date: 2003-03-31
Filing date: 2004-03-30
Publication date: 2004-10-14

Abstract

The present invention provides an efficient process for the production of N-acylaniline derivatives by selectively alkylating an amide group at the nitrogen atom. The process comprises reacting an amide compound of the formula (2): (wherein, R1 and R2 are each independently an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an aryl group or a substituted aryl group) with a sulfuric acid ester in the presence of a solid metal hydroxide to give an N-alkylamide compound of the formula (3): (wherein R3 is an alkyl group and R1 and R2 have each the same meaning as described above).

Description

DESCRIPTION

PRODUCTION OF N-ALKYLAMIDE COMPOUNDS

Technical Field

The present invention relates to a process for producing an N-alkylamide compound useful, for example, as intermediates for the synthesis of pharmaceuticals, agroσhemicals , etc.

Background Art

In recent years, N-acylaniline derivatives have been widely used as a therapeutic agent for insomnia, etc.

As such N-acylaniline derivatives, for example, N- acylaniline derivatives which are methylated on the amide nitrogen are described in Patent Reference 1. Concerning the method for N-methylation of an amide group. Patent Reference 1 discloses a method which comprises reacting m- acetamidoacetophenone compounds with either methyl iodide or dimethyl sulfate in the presence of phase transfer catalyst and sodium hydride or aqueous sodium hydroxide solution.

However, the method described in the Patent Reference 1 has a drawback of giving by-products which are formed by methylation on the acetyl groups of m-acetamidoacetophenone compounds and are isolated from the objective compound with difficulty, requiring an additional process for separating the desired m- (N-methylacetamido)acetophenone compounds and said by-products, which makes the operation rather complicated. Also, the method requires a phase transfer catalyst because of two phase reaction using dimethyl sulfate and aqueous sodium hydroxide solution. Thus, a process which makes it possible to selectively methylate the amide group on the nitrogen atom and gives the desired m- (N-methylaσetamido)acetophenone in a good yield, has been desired eagerly.

The Patent Reference 1: WO01/10868

Disclosure of the Invention

The present invention has been worked out in the light of the problem mentioned above and the aim of the present invention is to provide a process which makes it possible to selectively alkylate the amide groups on their nitrogen atom, giving the desired N-acylaniline derivatives in good yields .

For the purpose of solving the problems described above, intensive studies on various alkylating agents and alkylating conditions by the present inventors have resulted in finding that the desired N-alkylamide compounds can be obtained unexpectedly in good yields by using a sulfuric acid ester as an alkylating agent in the presence of a solid metal hydroxide without phase transfer catalyst . The present invention has been completed on the basis of this finding.

Namely, the present invention is as follows: 1) A process for producing an N-alkylamide compound of the formula ( 3 ) :

(wherein R¹ and R² are each independently an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an aryl group or a substituted aryl group and R³ is an alkyl group), which comprises reacting an amide compound of the formula ( 2 ) :

(wherein R¹ and R² have each the same meaning as described above) with a sulfuric acid ester in the presence of a solid metal hydroxide.

2) A process for producing an N-alkylamide compound of the formula ( 3) :

(wherein R¹ and R² are each independently an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an aryl group or a substituted aryl group, and R³ is an alkyl group), which comprises subjecting an acylaniline of the formula (1)

(wherein R¹ has the same meaning as described above) to N- acylation, and reacting the resulting amide compound of the formula ( 2 ) :

3) The process for producing an N-alkylamide compound as described above 1), wherein the compounds of the formula (2) are those of the formula (2a):

(wherein R¹ and R² are each independently an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an aryl group or a substituted aryl group), and the compounds of the formula (3) are those of the formula (3a) :

(wherein R³ is an alkyl group, and R¹ and R² have each the same meaning as described above) .

4) The process for producing an Kf-alkylamide compound as described above 2 ) , wherein the compounds of the formula (1) are those of the formula (la):

(wherein R¹ is an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an aryl group or a substituted aryl group) , and the compounds of the formula (2) are those of the formula (2a):

(wherein R³ is an alley1 group, and R¹ and R^a have each the same meaning as described above) .

5) The process for producing an M-alkylamide compound as described above 1), wherein the solid metal hydroxide is an alkali metal hydroxide or an alkaline earth metal hydroxide .

Best Mode for Carrying Out the Invention The following are the descriptions about the individual groups in the above formulae.

Alkyl groups represented by R¹ and R² include linear, branched, or cyclic alkyl groups of, for example, 1 to 6 carbon atoms. Specific examples of such alkyl groups include methyl, ethyl, n-propyl, 2-propyl, n-butyl, 2-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 2-methylbutyl, 3- methylbutyl, 2, 2-dimethylpropyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methylpent n-2-yl, 3-methylpentan-3-yl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylpentan-3-yl, cyclohexyl, etc. Among them, the alkyl groups of 1 to 3 carbon atoms are preferable.

Alkenyl groups include linear or branched alkenyl groups of, for example, 2 to 6 carbon atoms. Specific examples of such alkenyl groups include vinyl, propenyl, 1- butenyl, 2-butenyl, pentenyl, hexenyl, etc.

Aryl groups include aryl groups of, for example, 6 to 14 carbon atoms, and specific examples of the aryl groups include a phenyl group and a naphthyl group.

Substituted alkyl groups include those alkyl groups mentioned above, at least one hydrogen atom of which is substituted by a substituent such as alkoxy, halogen, cyano, acyl, substituted amino, etc.

Alkoxy groups include linear, branched or cyclic alkoxy groups of, for example 1 to 6 carbon atoms .

Specific examples of the alkoxy groups include methoxy, ethoxy, n-propoxy, 2-propoxy, n-butoxy, 2-butoxy, isobutoxy, tert-butoxy, n-pentyloxy, 2-methylbutoxy, 3- methylbutoxy, 2, 2-dimethylpropyloxy, n-hexyloxy, 2- methylpentyloxy, 3-methγlpentyloxy, 4-methylpentyloxy, 5- methylpentyloxy, cyclohexyloxy, etc. Halogen include fluorine, chlorine, bromine, iodine, etc.

Acyl groups include linear or branched acyl groups of, for example, 1 to 18 carbon atoms derived from carboxylic acids such as aliphatic carboxylic acids , aromatic carboxylic acids, etc. Specific examples of the acyl groups include formyl, acetyl, propionyl, butyryl, pivaloyl, pentanoyl, hexanoyl, lauroyl, stearoyl, benzoyl, etc.

Substituted amino groups include amino groups, two hydrogen atoms of which are replaced by two alkyl groups . Specific examples of such substituted amino groups include

N,N-dimethylamino, N,N-diethylamino, N,N-diisopropylamino,

ΘHC •

The substituents in the substituted alkenyl groups (e.g. the substituted vinyl group) include the same ones as described above

Substituted aryl groups include the same aryl groups as mentioned above, either, at least one hydrogen atom on which is replaced by substituent groups such as alkyl groups , halogenated alkyl groups , alkoxy groups , halogens , acyl groups, substituted amino groups, etc., or, two adjacent hydrogen atoms on which are replaced by an alkylenedioxy group (for example, alkylenedioxy ^'groups of 1 to 3 carbon atoms, including, more specifically, a methylenedioxy group, an ethylenedioxy group, a propylenedioxy group), wherein the alkyl groups, alkoxy groups, halogens, acyl groups and substituted amino groups are the same as described above.

Halogenated alkyl groups include the halogenated alkyl groups of 1 to 3 carbon atoms derived from the same alkyl group as mentioned above, at least one hydrogen atom of which is halogenated (e.g. fluorinated, chlorinated, brominated or iodinated) with halogen(s) (e.g., fluorine, chlorine, bromine or iodine). Specific examples of such halogenated alkyl groups include chloromethyl, bromomethyl, 2-chloroethyl, 3-bromopropyl, fluoromethyl, fluoroethyl, fluoropropyl, difluoromethyl, difluoroethyl, trichloromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 3, 3, 3-trifluoropropyl, pentafluoroethyl, perfluoro-n-propyl, perfluoroisopropyl, etc.

Specific examples of the aryl groups substituted by alkyl group(s) include tolyl, xylyl, etc.

The alkyl groups represented by R³ include linear or branched alkyl groups of 1 to 3 carbon atoms , and the specific examples of such alkyl groups include methyl, ethyl, n-propyl, 2-propyl, etc. Among them, methyl or ethyl is preferable.

Specific examples of the acylanilines represented by the formula (1) above and used in the present invention include 3 ' -aminoacetophenone, 3-propionylaniline, 3- butyrylaniline, 2 ' -aminoacetophenone, 2-propionylaniline, 2-butyrylaniline, 4 ' -aminoacetophenone, 4-propionylaniline, 4-butyrylaniline. Among them, the compounds of the formula (la):

(wherein R¹ has the same meaning as described above) are preferable .

Specific examples of the amide compounds represented by the formula (2) above include N-(3- acetylphenyl)acetamide, N- ( 3-propionylphenyl)acetamide, N- ( 3-butyrylphenyl)acetamide, N- (2-acetylphenyl)acetamide, N- ( 2-propionylphenyl)acetamide, N- ( 2-butyrylphenyl)acetamide, N- (4-acetylphenyl)acetamide, N- ( 4-propionylphenyl)acetamide, N- (4-butyrylphenyl)acetamide, 3- (3-ethoxy-l-oxo-2- propenyl) -N-acetanilide, 3-(3-(N' ,N' -dimethylamino) -1-oxo- 2-propenyl-N-acetanilide, etc. Among them, the compounds represented by the formula (2a):

(wherein R¹ and R² have each the same meaning as described above) are preferable.

Specific examples of the N-alkylamide compounds represented by the formula (3) above and obtainable by the process of the present invention include N-(3- acetylphenyl) -N-methylacetamide, N- (3-acetylphenyl) -N- ethylaσetamide, N- (2-acetylphenyl) -N-methylacetamide, N-(2- acetylphenyl) -N-ethylacetamide, N- ( 4-acetylphenyl) -N- methylacetamide, N-( 4-acetylphenyl) -N-ethylacetamide, 3-(3- ethoxy-l-oxo-2-propenyl) -N-methyl-N-acetanilide, 3- (3- (N' ,N' -dimethylamino) -l-oxo-2-propenyl-N-methyl-N- acetanilide, etc.

Among them, the compounds represented by the formula (3a):

(wherein R¹, R² and R³ have each the same meaning as described above) are preferable.

The following is the detailed description of the process of the present invention.

The amide compounds represented by the above formula (2) can be obtained by subjecting the acylanxlines represented by the above formula (1) to N-acylation. The N-acylation is carried out by reacting the acylaniline represented by the formula ( 1) with an acylating agent .

Examples of the acylating agents include acid chlorides such as acetyl chloride, propionyl chloride, butyryl chloride, benzoyl chloride, etc. and carboxylic acid anhydrides such as acetic anhydride, propionic anhydride, etc.

The amount used of the acylating agent is appropriately selected usually f om a range of about 1.0 to 2.0 equivalents, or preferably from a range of about 1.0 to 1.5 equivalents to the amount used of the acylaniline represented by the formula ( 1) .

The N-acylation can be alternatively carried out, instead of using the acylating agent mentioned above, by allowing to react the carboxylic acid corresponding to the acylating agent in the presence of a dehydrating agent . Although there is no specific restriction as to the dehydrating agents so far as they are employable as dehydrocondensation agents , examples of such carboxylic acids include acetic acid, propionic acid, etc., and examples of the dehydrating agents include, inorganic dehydration agents such as concentrated sulfuric acid, diphosphorous pentoxide, anhydrous zinc chloride, etc., carbodiimides such as dicyclohexylcarbodixmide, diisopropylcarbodiimide, l-ethyl-3- (3- di ethylaminopropyl)carbodumide hydrochloride, etc., polyphosphoric acid, acetic anhydride, carbonyldiimxdazole and p-toluenesulfonyl chloride. The N-acylation can be carried out in the presence of a base, where necessary. Both inorganic and organic bases can be used as the base. Examples of the organic bases include triethylamine, diisopropylethylamine, N,N- dimethylaniline, piperidine, pyridine, 4- dimethylaminopyridine, 1, 5-diazabicyclo[4.3.0]non-5-ene, 1, 8-diazabicyclo[ 5. .0]undec-7-βne, tri-n-butylamine, N- methylmorpholine, etc., and examples of the inorganic bases include potassium carbonate, potassium hydroxide, lithium hydroxide, sodium bicarbonate, sodium carbonate, potassium bicarbonate, sodium hydroxide, etc.

The amount used of the base is appropriately selected usually from a range of about 0 to 3.0 equivalents, or preferably from a range of about 0 to 2.0 equivalents to the amount of acylaniline (1) used.

The N-acylation can be carried out, if necessary, in the presence of a solvent . Examples of the solvents used include aliphatic hydrocarbons such as pentane, hexane, heptane, octane, decane, cyclohexane, etc., aromatic hydrocarbons such as benzene, toluene, xylene, etc., halogenated hydrocarbons such as dichloromethane, 1,2- dichloroethane, chloroform, carbon tetrachloride, o- dichlorobenzene, etc., ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dimethoxyethane, ethylene glycol diethyl ether, tetrahydrofuran, 1,4-dioxane, 1, 3-dioxolane, etc., esters such as methyl acetate, ethyl acetate, n-butyl acetate, methyl propionate, etc., amides such as formamide, N,N-dimethylformamide, N,N- dimethylacetamide, etc. , sulfoxides such as dimethyl sulfoxide, etc. , cyano-containing compounds such as acetonitrile, etc. , N-methylpyrrolidone, etc. These solvents may be used solely or in appropriate combination with two or more solvents. The amount of the solvent used is appropriately selected usually from a range of about 2.0 to 10.0 times by volume of, or preferably from about 3.0 to 8.0 times by volume of the acylaniline (1) used.

The reaction temperature is appropriately selected usually from a range of about -10 to 100°C, or preferably from a range of about 0 to 80°C.

The reaction time is appropriately selected usually from about 30 minutes to 24 hours, or preferably from a range of about 1 hour to 8 hours . Acylanilines (1) of the formula (1), which are commercially available or appropriately in-house produced, are suitable for use.

The amide compounds of the formula ( 2 ) above thus obtained are then reacted with a sulfuric acid ester in the presence of a metal hydroxide to give the objective N- alkylamide compound of the formula (3) above.

Examples of the sulfuric acid esters include sulfates such as dimethyl sulfate, diethyl sulfate, diisopropyl sulfate, etc.; sulfonates such as methyl p-toluenesulfonate, ethyl p-toluenesulfonate, etc.,- etc.

The amount used of the sulfuric acid ester is appropriately selected usually from a range of about 1.0 to 3.0 equivalents , or preferably from a range of about 1.0 to 2.0 equivalents to the amide compound (2). There is no particular limitation to the solid metal hydroxide so long as it is in the form of a solid. Examples of such a solid form are granule, pellet, pearl, powder, flake, etc., preferably granule, pearl or powder. Examples of the solid metal hydroxide include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.; alkaline earth metal hydroxides such as magnesium hydroxide, calcium hydroxide, strontium hydroxide, barium hydroxide, etc.; etc. The amount used of the metal hydroxide is appropriately selected usually from a range of about 1.0 to 3.0 equivalents , or preferably from a range of about 1.0 to 2.0 equivalents to the amide compounds (2).

The reaction of said amide compound with said sulfuric acid ester, namely the N-alkylation, is preferably carried out in the presence of a solvent. Examples of the solvents include, aliphatic hydrocarbons such as pentane, hexane, heptane, octane, decane, cyclohexane, etc., aromatic hydrocarbons such as benzene, toluene, xylene, etc., halogenated hydrocarbons such as dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride, o- dichlorobenzene , etc., ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dimethoxyethane, ethylene glycol diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,3-dioxolane, etc., alcohols such as methanol, ethanol, 2-propanol, n-butanol, 2- ethoxyethanol, benzyl alcohol, etc., polyvalent alcohols such as ethylene glycol, propylene glycol, 1, 2-propanediol, glycerol, etc., amides such as formamide, N,N- dimethylformamide, N,N-dimethylacetamide, etc., sulfoxides such as dimethyl sulfoxide, etc., cyano-containing organic compounds such as acetonitrile, etc., N-methylpyrrolidone and water. These solvents may be used solely or in appropriate combination with two or more solvents .

The amount of the solvent used is appropriately selected usually from a range of about 2.0 to 10.0 times by volume of, or preferably from a range of about 2.0 to 8.0 times by volume of the amide compound (2) used.

The reaction temperature is appropriately selected usually from a range of about 0 to 100°C, or preferably from a range of about 0 to 80°C.

The reaction time is appropriately selected usually from a range of about 30 minutes to 24 hours, or preferably from a range of about 1 hour to 8 hours .

The N-alkylamide compounds of the formula (3) above obtained by the process of the present invention may be appropriately subjected to treatment such as re-dissolution, concentration, chromatography, crystallization, etc.

The N-alkylamide compounds (3) thus obtained are useful as intermediates for the synthesis of, for example, pharmaceuticals, agrochemicals , etc.

Examples

The present invention will be described in more detail by referring to Examples and Comparison Examples given below, but those are not intended to limit the present invention in any way. Example 1

Preparation of N- (3-Acetylphenyl)acetamide

To a suspension of 3' -aminoacetophenone (50.9 g, 377 mmol) in toluene (250 ml) was added dropwise acetic anhydride (39.6 g, 388 mmol) at room temperature, and the mixture was kept at 55°C for one hour and then cooled to a temperature not more than 20°C. The crystals separated were filtered to give the objective compound (64.58 g; 96.8% yield) as a pale yellow powder.

Example 2

Preparation of N-( 3-Acetylphenyl)acetamide

To a mixture of 3 ' -aminoacetophenone (10.0 g, 74.0 mmol), triethylamine (8.98 g, 88.8 mmol) and toluene (50 ml) was added dropwise acetic anhydride (8.31 g, 81.4 mmol) at room temperature, and the mixture was kept at 30 to 40°C for 2 hours . The crystals separated were filtered at room temperature to give the objective compound (10.86 g; 82.8% yield) as a pale yellow powder.

Example 3

Preparation of N- (3-Acetylphenyl) -N-methylacetamide

To a solution of N-( 3-acetylphenyl)acetamide (10.0 g, 56.4 mmol) and sodium hydroxide (3.38 g, 84.6 mmol) in tetrahydrofuran (40 ml) was added dropwise a solution of dimethyl sulfate (10.67 g, 84.6 mmol) in tetrahydrofuran (10 ml) under cooling with ice, and the resultant solution was stirred at room temperature for 5 hours. To the reaction mixture were added toluene (50 ml) and IN hydrochloric acid (50 ml), and the organic layer was isolated and washed with saturated aqueous sodium bicarbonate (50 ml) and then concentrated. The residue was recrystallised from ethyl acetate-heptane to give the objective compound (7.66 g; 71.6% yield) as a white powder.

Example 4

Preparation of N-(3-Acetylphenyl) -N-methylacetamide To a solution of N- (3-acetylphenyl)acetamide (10.0 g, 56.4 mmol) and sodium hydroxide (3.38 g, 84.6 mmol) in toluene (50 ml) was added dropwise methyl p- toluenesulfonate (11.56 g, 62.1 mmol) at 12°C, and the resultant mixture was stirred at 50°C for 5 hours. The reaction mixture was then washed with water (50 ml), and the organic layer was washed with saturated aqueous sodium chloride (50 ml), and concentrated. The residue was recrystallized from toluene-heptane to give the objective compound (6.46 g; 59.9% yield) as a white powder.

Example 5

Preparation of N- ( 3-Acetylphenyl) -N-methylacetamide

Pearl-like sodium hydroxide (18.1 g) and N-(3- acetylphenyl)acetamide (50.1 g) were added to toluene (180 ml) while stirring at room temperature, and N,N- dimethylformamide (DMF) (20 ml) was added thereto at 17°C in a water bath. To the solution was added dropwise dimethyl sulfate (42.7 g) at 10°C, and the mixture was allowed to react at the same temperature for 3 hours, poured into water (100 ml) and concentrated to give the objective compound (53.2 g; 98.7% yield).

Comparison Example 1 Preparation of N- (3-Acetylphenyl) -N-methylacetamide

In a stream of nitrogen, 60% sodium hydride (4.51 g, 112.9 mmol) was suspended in tetrahydrofuran (40 ml), and the suspension was cooled to 0°C. To the suspension was added dropwise a solution of 3' -aminoacetophenone (20.0 g, 112.9 mmol) and dimethyl sulfate (14.2 g, 112.9 mmol) in tetrahydrofuran (160 ml) at the temperature not higher than 10°C. The resultant mixture was allowed to react at 5°C for further 1 hour. A high performance liquid chromatography (HPLC) analysis of the reaction mixture revealed that 9.2% of the starting material, 3' -aminoacetophenone, still remained.

Comparison Example 2

Preparation of N- (3-Acetylphenyl) -N-methylacetamide In a stream of nitrogen, 60% sodium hydride (5.42 g, 135.4 mmol) was suspended in tetrahydrofuran (40 ml) and the suspension was cooled to 0°C. To this suspension was added dropwise a solution of 3 ' -aminoacetophenone (20.0 g, 112.9 mmol) and dimethyl sulfate (17.08 g, 135.4 mmol) in tetrahydrofuran (160 ml) at the temperature not higher than 10°C, and the resultant mixture was allowed to react at 5°C for further 1 hour. A high performance liquid chromatography (HPLC) analysis of the reaction mixture revealed that, although no starting material, i.e. 3'- aminoacetophenone, was detected, N-( 3-propionylphenyl) -N- methylacetamide formed by methylation of the acetyl group was by-produced to the extent of . % .

Industrial Applicability

The process of the present invention is characterized in that an amide compound of the formula ( 2 ) is reacted with a sulfuric acid ester in the presence of a solid metal hydroxide without phase transfer catalyst. This makes it possible to selective alkylation of the amide group on the nitrogen atom, whereby the by-produced compounds alkylated at the alkyl moiety of the acyl group substituting the phenyl group or of the N-acyl group are substantially eliminated and thus the objective N-alkylamide compounds (3) are produced efficiently in good yields, which are the effect of the present invention. The process of the present invention is an industrially excellent one, giving the objective N-alkylamide compounds (3) efficiently and in good yields without substantial productxon of any by- products even when the size of the production is scaled up.

Claims

1. A process for producing an N-alkylamide compound of the formula ( 3 ) :

2. A process for producing an N-alkylamide compound of the formula ( 3 ) :

(wherein R¹ and R² are each independently an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an aryl group or a substituted aryl group, and R³ is an alkyl group) , which comprises subjecting an acylaniline of the formula ( 1) :

(wherein R¹ has the same meaning as described above) to N- acylation, and reacting the resulting amide compound of the formula (2):

3. The process for producing an N-alkylamide compound as claimed in claim 1 , wherein the compounds of the formula (2) are those of the formula (2a)

(wherein R³ is an alkyl group, and R¹ and R² have each the same meaning as described above).

4. The process for producing an N-alkylamide compound as claimed in claim 2 , wherein the compounds of the formula (1) are those of the formula (la):

5. The process for producing an N-alkylamide compound as claimed in claim 1 , wherein the solid metal hydroxide is an alkali metal hydroxide or an alkaline earth metal hydroxide.