JPH05186408A - Production of n-(hydroxyaryl)haloalkanoic acid amide - Google Patents

Abstract

PURPOSE:To efficiently obtain the subject high-purity N-(hydroxyaryl) haloalkanoic acid amide in high yield according to simple operation. CONSTITUTION:A hydroxyarylamine is made to react with a haloalkanoic acid halide in the presence of a base such as sodium hydrogencarbonate in an alcohol or an aqueous solution of the alcohol. The resultant reactional product is then subjected to a separating means, e.g. crystallization by addition of water to afford the objective N-(hydroxyaryl)haloalkanoic acid amide. This method is useful for reacting p-aminophenol with beta-chloropropionyl chloride and producing an N-(4-hydroxyphenyl)-beta-chloropropionic acid amide. Methanol, ethanol, isopropanol, etc., can be used as the alcohol and may be used as an aqueous solution. Since the alcohol is used as a solvent, the objective high-purity compound can be obtained in high yield even if a small amount of water is added in a crystallization step.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing an N- (hydroxyaryl) haloalkanoic acid amide from a hydroxyarylamine and a haloalkanoic acid halide.

[0002]

PRIOR ART AND PROBLEMS TO BE SOLVED BY THE INVENTION N-
(Hydroxyaryl) haloalkanoic acid amides such as N- (4-hydroxyphenyl) -β-chloropropionic acid amide are useful as intermediate raw materials for medicines and agricultural chemicals. As a method of producing this N- (hydroxyaryl) haloalkanoic acid amide, a method of reacting a hydroxyarylamine with a haloalkanoic acid halide in the presence of a base in an acetone solvent is known.

For example, N- (4-hydroxyphenyl)
-Β-Chloropropionic acid amide is obtained by reacting p-aminophenol and β-chloropropionic acid chloride in an acetone solvent in the presence of a carbonate, and then adding water or dilute hydrochloric acid to give an oily form. Obtained as a liquid or crystal (J. Prakt. 1962, 17, 4, p340-p345). However, in this method, as shown in FIG. 1, the solubility of the target compound, N- (4-hydroxyphenyl) -β-chloropropionic acid amide, in acetone is high.
Therefore, if the amount of water added is small, the yield of the target compound is extremely small. On the other hand, if a large excess of water or hydrochloric acid is added to increase the yield, not only a large volume reactor is required, but also the purity of the product is lowered. Therefore, it is difficult to obtain a high-purity target compound with a high yield using a small-volume reactor.

Further, since a reaction apparatus having a small volume is used, when the amount of acetone is halved, the liquid level rises due to the bubbling of carbon dioxide during the reaction, which not only makes the stirring operation difficult but also the yield. descend. Furthermore, when the amount of water added after the reaction is reduced and the amount of acetone is reduced by distillation, not only the crystals are scaled and the separation operation becomes complicated, but also the purity of the target compound decreases.

As described above, the conventional method cannot satisfy both the yield and the purity of the target compound.

Therefore, an object of the present invention is to obtain a high purity N-
It is an object of the present invention to provide an industrial production method by which a (hydroxyaryl) haloalkanoic acid amide can be efficiently obtained in a high yield and by a simple operation.

[0007]

The present inventors have conducted extensive studies in order to achieve the above object. As a result, when alcohol or an aqueous alcohol solution is used as a solvent, a highly pure target compound can be obtained efficiently and in a high yield. Then, the present invention was completed.

That is, the present invention provides a hydroxyarylamine represented by the general formula (I) H ₂ N-Ar-OH (I) (wherein Ar represents an arylene group) and the general formula (II). X-A-COY (II) (In the formula, A represents an alkylene group, X and Y are the same or different and each represent a halogen atom), and a haloalkanoic acid halide in the presence of a base. It is represented by the general formula (III) X-A-CONH-Ar-OH (III) (in the formula, Ar, A and X are the same as above) in which the reaction product is separated by reacting in alcohol or an aqueous alcohol solution. N-
Provided is a method for producing a (hydroxyaryl) haloalkanoic acid amide.

The arylene group of the substituent Ar in the general formula (I) includes a phenylene group and a naphthylene group. Preferred arylene groups include, for example, o-phenylene, m-phenylene, p-phenylene, 1,2-naphthylene, 1,4-naphthylene, 1,8-naphthylene,
2,6-naphthylene group and the like can be mentioned. Particularly preferred arylene groups include phenylene groups such as p-phenylene groups.

These arylene groups are various substituents which do not adversely influence the reaction, for example, halogen atom, lower alkyl group, lower alkoxy group, cycloalkyl group, aryl group, hydroxyl group, carboxyl group, lower alkoxycarbonyl group. And so on.

Specific examples of the hydroxyarylamine represented by the general formula (I) include p-aminophenol, m-aminophenol, o-aminophenol,
4-amino-3-methylphenol, 4-amino-3-
Methoxyphenol, 4-amino-3-fluorophenol, 4-amino-3-ethoxycarbonylphenol, 4-aminopyrocatechol, 4-amino-1-naphthol, 8-amino-1-naphthol, 6-amino-2
-Naphthol etc. are mentioned. Preferred hydroxyarylamines include aminophenols such as p-aminophenol and the like.

The amino group of the hydroxyarylamine may form a salt. Examples of the salt of hydroxyarylamine include mineral acid salts such as hydrochlorides and sulfates, organic acid salts such as acetates, and sulfonates such as p-toluenesulfonate.

The alkylene group A in the general formula (II) is an alkylene group having 1 to 4 carbon atoms, for example, a methylene group,
An ethylene group, a trimethylene group, a tetramethylene group and the like are included.

These alkylene groups may have a substituent such as a lower alkyl group or a halogen atom.

Preferred alkylene groups A include methylene group, --CH (CH ₃ )-, --CH (C ₂ H ₅ )-, --C.
(CH _{3) 2} -, ethylene group, -CH (CH ₃₎ CH _{2
-, - CH 2 CH (CH} 3) -, and the like trimethylene group. Particularly preferred alkylene group A includes ethylene group.

The halogen atoms of the substituents X and Y include fluorine, chlorine, bromine and iodine atoms. Of these, chlorine atom or bromine atom, particularly chlorine atom is preferable.

Specific examples of the haloalkanoic acid halide represented by the general formula (II) include, for example, α-chloroacetic acid chloride, α-chloroacetic acid bromide, α-bromoacetic acid bromide, α-chloropropionic acid chloride and α-
Chloropropionic acid bromide, α-bromopropionic acid bromide, α-chloroisobutyric acid chloride, α-bromoisobutyric acid bromide, α-chlorobutyric acid chloride,
β-chloropropionic acid chloride, β-chloropropionic acid bromide, β-chloropropionic acid iodide, β-bromopropionic acid bromide, β-fluoropropionic acid chloride, β-chlorobutyric acid chloride,
Examples include β-chloroisobutyric acid chloride and γ-chlorobutyric acid chloride.

The preferred haloalkanoic acid halide is α-
Examples thereof include chloropropionic acid chloride, α-chloropropionic acid bromide, α-bromopropionic acid bromide, and particularly α-chloropropionic acid chloride.

By reacting the hydroxyarylamine represented by the general formula (I) with the haloalkanoic acid halide represented by the general formula (II) in the presence of a base in an alcohol or an aqueous alcohol solution, An N- (hydroxyaryl) haloalkanoic acid amide represented by the general formula (III) is produced.

The amount of the haloalkanoic acid halide used is
Usually 0.7 per 1 mol of hydroxyarylamine
˜1.3 mol, preferably 0.9 to 1.1 mol, and more preferably 0.95 to 1.05 mol.

The base is not particularly limited as long as it captures hydrogen halide produced as a by-product, and includes an inorganic base and an organic base. Inorganic bases include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide; alkali earth metal hydroxides such as magnesium hydroxide, calcium hydroxide, strontium hydroxide and barium hydroxide. Alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; alkaline earth metal carbonates such as magnesium carbonate, calcium carbonate and barium carbonate; alkali metal carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and lithium hydrogen carbonate Hydrogencarbonate of the like. Examples of the organic base include triethylamine, tripropylamine, pyridine, N, N-dimethylaniline, 4-dimethylaminopyridine, N-methylmorpholine, N-methylpiperidine and the like.

Of these bases, alkali metal carbonates or alkaline earth metal carbonates; or alkali metal hydrogen carbonates are preferred. In particular, alkali metal carbonates such as sodium carbonate and potassium carbonate; and alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate are frequently used. It should be noted that when a carbonate or hydrogen carbonate is used, foaming may occur when the excess carbonate or the like is neutralized after the completion of the reaction.

The amount of the base used is usually 0.9 equivalent or more, preferably 1 to 2 with respect to the haloalkanoic acid halide.
The amount is equivalent, more preferably about 1 to 1.5 equivalent. When the hydroxyarylamine salt is used, the amount of the base used can be appropriately increased in order to free the amino group.

In the production method of the present invention, the reaction is carried out in alcohol or an aqueous alcohol solution. When the reaction is carried out in alcohol or an aqueous alcohol solution, a high-purity target compound can be obtained in a high yield even if the amount of water added is small in the crystallization step after completion of the reaction. This is
This is probably due to the following reasons. That is, as shown in FIGS. 1 to 3, in a single solvent system, an alcohol of N- (hydroxyaryl) haloalkanoic acid amide produced, for example, N- (4-hydroxyphenyl) -β-chloropropionic acid amide. There is no big difference in the solubility in acetone and acetone. However, when water coexists, the solubility of the compound in an alcohol-water mixed solvent is acetone-, even if the water content is small.
It becomes significantly smaller than that in the case of a water mixed solvent. Therefore, it is considered that the target product is crystallized in good yield when a small amount of water is added in the separation operation of the target compound. 1 is a graph showing the solubility of N- (4-hydroxyphenyl) -β-chloropropionic acid amide in a water-acetone mixed solvent at 25 ° C., and FIG. 2 is 25 ° C.
FIG. 3 is a graph showing the solubility of N- (4-hydroxyphenyl) -β-chloropropionic acid amide in a water-methanol mixed solvent in FIG.
2 is a graph showing the solubility of -hydroxyphenyl) -β-chloropropionic acid amide in a water-isopropanol mixed solvent. Moreover, since the amount of water added can be reduced, the volume of the reactor can be reduced. Furthermore, when alcohol or an aqueous alcohol solution is used as the solvent, the stirring operation and the separation operation can be smoothly performed, and thus a high-purity N- (hydroxyaryl) haloalkanoic acid amide can be obtained easily and efficiently.
Furthermore, alcohols and water are generally considered to be unsuitable as reaction solvents for alkanoic acid halides because they readily react with alkanoic acid halides, especially in the presence of a base. However, in the production method of the present invention, even if an alcohol or an aqueous alcohol solution is used as a reaction solvent, the side reaction can be significantly suppressed by selecting the reaction conditions, and a high-purity target compound can be obtained in a high yield. ..

The alcohol includes, for example, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol, pentanol, hexanol, octanol, methyl cellosolve, ethyl cellosolve and the like. These alcohols can be used alone or in combination of two or more. In order to improve the purity and yield of the target compound, an alcohol having usually 1 to 8 carbon atoms, preferably an alcohol having 1 to 6 carbon atoms, more preferably an alcohol having 1 to 4 carbon atoms, particularly an alcohol having 1 to 3 carbon atoms is used. Used.

When alcohol is used alone,
The solubility of hydroxyarylamine is low, and the reaction rate and yield may be reduced. In such cases,
By using an aqueous alcohol solution as the reaction solvent, the target compound can be obtained in high yield. When the hydroxyarylamine is dissolved in the alcohol alone to some extent, the target compound can be obtained in good yield even in the alcohol alone solvent.

The preferred solvent is an aqueous alcohol solution. The content of water in the solvent can be appropriately determined in consideration of the solubility of the reaction components and the target compound, etc., but is usually 0 to 2 times by weight, preferably 0 to 1 times by weight, and further the amount of alcohol. It is preferably 0 to 0.5 times by weight.

The amount of the solvent can be appropriately selected in consideration of the operability of stirring and separation, the solubility of the reaction components and the target compound, etc., but at the end of the reaction, the N- (hydroxyaryl) haloalkanoic acid amide formed is dissolved. It is preferable that the amount is necessary to achieve this. For example, in the case of producing N- (4-hydroxyphenyl) -β-chloropropionic acid amide, it varies depending on the content ratio of alcohol and water, but with respect to 100 parts by weight of p-aminophenol used as a raw material, Usually 100 to 600 parts by weight, preferably 2
It is from 00 to 500 parts by weight.

The reaction between the hydroxyarylamine and the haloalkanoic acid halide can be carried out, for example, as follows.

Hydroxyarylamine is dissolved or dispersed in the alcohol or aqueous alcohol solution, and a base such as sodium hydrogen carbonate is added with stirring. Then, under cooling, a haloalkanoic acid halide is dropped to react.
The reaction may be carried out in suspension.

The reaction is preferably carried out in a homogeneous system, but as described above, the solubility of hydroxyarylamine may be small in some cases. In such a case, in order to make the reaction system homogeneous, it is effective to increase the amount of solvent or the proportion of water in the solvent, but if the proportion of water is increased, the product may precipitate during the reaction. The liquid level may rise. Therefore, the reaction is often carried out in suspension.

The reaction temperature is usually 50 ° C or lower, preferably -10 ° C to 40 ° C, more preferably 0 ° C to 30 ° C. When the reaction temperature exceeds 50 ° C, side reactions are likely to occur. For example, N- (4-hydroxyphenyl)
When -β-chloropropionic acid amide is produced,
When the reaction is carried out at a temperature above 50 ° C, the produced target compound decomposes with time and N- (4-hydroxyphenyl)
Acrylamide is easily produced as a by-product.

After the reaction is completed, the reaction product is separated to obtain the desired compound. Separation of the reaction products
For example, it can be carried out by subjecting it to conventional separation means such as filtration, concentration, crystallization, recrystallization, solvent extraction, column chromatography and the like.

Upon separation, excess base present in the reaction mixture may be neutralized with acid, if desired. The type of the acid is not particularly limited and may be an organic acid such as acetic acid or formic acid, but usually a mineral acid such as hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid is preferably used. These acids are, for example, concentrated hydrochloric acid,
It is preferable to charge the solution in the form of a commercially available high-concentration solution such as concentrated sulfuric acid or a gas such as hydrogen chloride gas, or to dilute it with a solvent capable of dissolving the target compound such as alcohol, and to charge it. When these acids are charged as a dilute aqueous solution, the product N- (hydroxyaryl) haloalkanoic acid amide, for example, N- (4-hydroxyphenyl) -β-chloropropionic acid amide, precipitates and is therefore neutralized. Processing may not be performed smoothly. Further, in this case, particularly when the base is a carbonate or a hydrogen carbonate, the precipitated crystallized substance floats on the liquid surface due to the attachment of bubbles of carbon dioxide gas generated by the neutralization reaction, and a uniform stirring operation is performed. Not only it tends to be difficult, but the liquid level rises, which is not preferable in terms of reaction operation and safety. The neutralization reaction is usually
The reaction is completed when the pH of the reaction mixture becomes 5 or less.

As the separating means, crystallization by adding water is preferable. When crystallizing by adding water,
The target compound with high purity can be obtained in high yield by a simple operation.

The amount of water added is usually 0.5 to 10 times, preferably 1 to 5 times, and more preferably 1 to 2 times the amount of alcohol in the solvent. When acetone is used as a solvent, it is necessary to add water in an amount of 10 times or more the amount of acetone in order to obtain the target compound with a high yield. In this case, the purity of the target compound decreases as described above.

The crystallized crystals are subjected to a conventional separation means such as centrifugation and filtration, and then subjected to a conventional drying method such as reduced pressure or blast drying to obtain highly pure N-.
A (hydroxyaryl) haloalkanoic acid amide is obtained. The drying temperature can be appropriately selected, but 100 ° C. or lower is preferable. If it exceeds 100 ° C, the target compound may decompose. For example, in the case of N- (4-hydroxyphenyl) -β-chloropropionic acid amide, 1
If it is dried at a temperature over 00 ° C, it decomposes over time and N
-(4-hydroxyphenyl) acrylamide,
Purity decreases.

[0038]

According to the method of the present invention, since the reaction is carried out in an alcohol or an aqueous alcohol solution, a high purity N-
The (hydroxyaryl) haloalkanoic acid amide can be efficiently obtained in a high yield and by a simple operation.

[0039]

The present invention will be described in more detail based on the following examples, but the invention is not intended to be limited by these examples.

Example 1 A 500 ml flask was charged with 120 g of methanol and 29 parts of water.
g and p-aminophenol 37.5 g (0.35 mol) were charged, and with stirring, 37.5 g of sodium hydrogen carbonate.
(0.45 mol) was added. Then, while maintaining the internal temperature at 30 ° C or lower, β-chloropropionyl chloride 4
8 g (purity 95%, 0.35 mol) was added dropwise over 3 hours. After further stirring at room temperature for 1 hour, 9 g of concentrated hydrochloric acid was added dropwise to neutralize excess sodium hydrogen carbonate. The pH of the reaction mixture at this time was 2.8. Only the salt produced as a by-product was precipitated in the reaction mixture. Next, pure water 21
When 0 g was added dropwise, the sodium chloride was dissolved and new scaly crystals were deposited. The crystals were separated by filtration and then dried under reduced pressure at 60 ° C. to obtain white scale-like N- (4-hydroxyphenyl) -β-chloropropionic acid amide.

Yield: 62.6 g Yield: 91% Purity: 99.8% Example 2 In a 1 L flask, 240 g of isopropanol and 40 water.
g and 75 g (0.69 mol) of p-aminophenol were charged, and 42 g (0.39 mol) of sodium carbonate was added with stirring. Subsequently, while keeping the internal temperature at 30 ° C. or lower, 91 g of β-chloropropionic acid chloride (purity 9
9%, 0.70 mol) was added dropwise over 3 hours. After further stirring at room temperature for 1 hour, 9.6 g of concentrated hydrochloric acid was added dropwise to neutralize excess sodium carbonate. Next, when 430 g of pure water was dropped, scale-like crystals were deposited. The crystals are filtered off,
After rinsing with 120 g of pure water, drying under reduced pressure at 60 ° C., N
-(4-Hydroxyphenyl) -β-chloropropionic acid amide was obtained.

Amount: 124 g Yield: 89% Purity: 98.3% Example 3 80 g methanol and 19 g water in a 500 ml flask.
And p-aminophenol 25.6 g (0.23 mol)
Was charged and, with stirring, 21.8 g of sodium hydrogen carbonate
(0.26 mol) was added. Then, while keeping the internal temperature at 10 ° C or lower, β-chloropropionyl chloride 3
1 g (purity 98%, 0.24 mol) was added dropwise over 2 hours. After further stirring at room temperature for 1 hour, 3.7 g of concentrated sulfuric acid
Was added dropwise to neutralize excess sodium hydrogen carbonate. The pH of the reaction mixture at this time was 2.3. Next, pure water 1
40 g was added dropwise to precipitate crystals. The crystals were separated by filtration and then dried under reduced pressure at 60 ° C. to obtain N- (4-hydroxyphenyl) -β-chloropropionic acid amide.

Amount: 37 g Yield: 81% Purity: 99.9% Comparative Example 1 A 500 ml flask was charged with 80 g of acetone and 25.6 g (0.23 mol) of p-aminophenol, and the mixture was stirred and hydrogencarbonate. 21.8 g (0.26 mol) of sodium
Was added. Then, while keeping the internal temperature below 10 ° C,
31 g of β-chloropropionyl chloride (purity 98
%, 0.24 mol) was added dropwise over 2 hours. After further stirring at room temperature for 1 hour, 140 g of a 2% hydrochloric acid aqueous solution was added dropwise to precipitate crystals. The crystals were separated by filtration and then dried under reduced pressure at 60 ° C. to obtain N- (4-hydroxyphenyl) -β-chloropropionic acid amide.

Amount: 13 g Yield: 29% Purity: 99.8% Comparative Example 2 A 2-L flask was charged with 80 g of acetone and 25.6 g (0.23 mol) of p-aminophenol, and the mixture was stirred with stirring.
21.8 g (0.26 mol) of sodium hydrogen carbonate were added. Subsequently, while keeping the internal temperature at 10 ° C. or lower, 31 g of β-chloropropionyl chloride (purity 99%,
24 mol) was added dropwise over 2 hours. After further stirring at room temperature for 1 hour, 1120 g of a 2% hydrochloric acid aqueous solution was added dropwise.
The reaction mixture was once separated, but crystals were precipitated by further stirring. The crystals were separated by filtration and then dried under reduced pressure at 60 ° C. to obtain N- (4-hydroxyphenyl) -β-chloropropionic acid amide.

Amount: 47 g Yield: 86% Purity: 82.6%

[Brief description of drawings]

FIG. 1 is a graph showing the solubility of N- (4-hydroxyphenyl) -β-chloropropionic acid amide in a water-acetone mixed solvent.

FIG. 2 is a graph showing the solubility of N- (4-hydroxyphenyl) -β-chloropropionic acid amide in a water-methanol mixed solvent.

FIG. 3 is a graph showing the solubility of N- (4-hydroxyphenyl) -β-chloropropionic acid amide in a water-isopropanol mixed solvent.

Claims (3)

[Claims] 1. A hydroxyarylamine represented by the general formula (I) H ₂ N—Ar—OH (I) (wherein Ar represents an arylene group), and a general formula (II) X—A—. COY (II) (wherein A represents an alkylene group, X and Y are the same or different and each represents a halogen atom), and a haloalkanoic acid halide in the presence of a base, an alcohol or an aqueous alcohol solution. N- represented by the general formula (III) XA-CONH-Ar-OH (III) (wherein Ar, A and X are the same as described above)
Process for producing (hydroxyaryl) haloalkanoic acid amide. 2. The method for producing an N- (hydroxyaryl) haloalkanoic acid amide according to claim 1, wherein the hydroxyarylamine and the haloalkanoic acid halide are reacted in an aqueous alcohol solution. 3. The N- (hydroxyaryl) according to claim 1, wherein the reaction product is crystallized by adding water and separated.
Process for producing haloalkanoic acid amide.