JPH08157434A - Production of n-(2-hydroxyethyl)3-3-(4-nitrophenyl) propionamide - Google Patents

Abstract

PURPOSE: To obtain in high yield the subject compound useful as an intermediate for producing antiarrhythmic agents with the amounts of the halogenating agent etc., to be used limited, by reaction of 4-nitrophenylpropionic acid with a specified amount of a halogenating agent followed by condensation reaction of the reaction product with ethanolamine at specified temperatures. CONSTITUTION: (A) 4-Nitrophenylpropionic acid is reacted with (B) 1.0-1.2 molar times, based on the component A, of a halogenating agent (e.g. thionyl chloride, phosgene) to form (C) an acid halide derivative of the component A, which is, in turn, subjected to condensation reaction at 10-70 deg.C with (D) ethanolamine to obtain the objective compound. It is preferable that the condensation reaction be conducted in the presence of an inorganic base such as sodium hydroxide or sodium (bi)carbonate at 1 to 2 gram equivalent per mol of the component C.

Description

Detailed Description of the Invention

[0001]

The present invention relates to N- (2-hydroxyethyl) -3- (4-) which is useful as an intermediate for the production of pyrimidinedione derivatives which can be used as an active ingredient of antiarrhythmic agents.
It relates to a method for producing nitrophenyl) propionamide.

[0002]

2. Description of the Related Art N- (2-hydroxyethyl) -3-
(4-Nitrophenyl) propionamide and a method for producing it are already known as disclosed in JP-A-3-112948. In this publication, 4-nitrophenylpropionic acid was used as a starting material, and N-
Several methods have been described which can produce (2-hydroxyethyl) -3- (4-nitrophenyl) propionamide.

Among the methods described in the above publications, when the N- (2-hydroxyethyl) -3- (4-nitrophenyl) propionamide is produced industrially under more preferable conditions, 4 It is considered to be a method of converting -nitrophenylpropionic acid into an acid halogen compound and then condensing it with ethanolamine. However, when this method is adopted, according to the contents described in the above-mentioned publication, when 4-nitrophenylpropionic acid is converted into an acid halogen compound, the amount of the halogenating agent used therein is relatively large, and therefore the reaction After that, a problem remains in the post-treatment of the unreacted halogenating agent used in excess.

Further, the preferable temperature for condensing the acid halogen compound of 4-nitrophenylpropionic acid and ethanolamine is 0 to 10 ° C.
At the time of condensation, there is a problem that it is necessary to maintain the temperature at a relatively low temperature, and further, the amount of ethanolamine used is considerably larger than the stoichiometric amount.
When the industrial production method of (2-hydroxyethyl) -3- (4-nitrophenyl) propionamide is considered, the production is performed under more appropriate conditions than the conditions disclosed in the above publication. Is required.

[0005]

DISCLOSURE OF THE INVENTION In the present invention, 4-nitrophenylpropionic acid and ethanolamine are condensed to produce N- (2-hydroxyethyl) -3- (4-nitrophenyl) propionamide. In addition to solving the above-mentioned problems caused by the amount of halogenating agent used and the problem of the temperature range during condensation, the amount of ethanolamine used during condensation can be reduced, and the desired product can be obtained in high yield. It is an object of the present invention to provide a production method capable of performing, which is extremely superior to industrial production.

[0006]

Means for Solving the Problems As a result of intensive studies on various reaction conditions in order to achieve the above object, the present inventors have solved the above-mentioned problems by carrying out the reaction under the following conditions. Moreover, they have found that N- (2-hydroxyethyl) -3- (4-nitrophenyl) propionamide can be obtained in high yield, and have completed the present invention.

That is, the present invention condenses 4-nitrophenylpropionic acid with ethanolamine to produce N-
In producing (2-hydroxyethyl) -3- (4-nitrophenyl) propionamide, 4-nitrophenylpropionic acid is allowed to act on a halogenating agent in an amount of 1.0 to 1.2 times the molar amount of 4-nitrophenylpropionic acid. It is a method for producing N- (2-hydroxyethyl) -3- (4-nitrophenyl) propionamide, which comprises condensing it with an ethanolamine at a temperature of 10 to 70 ° C.

In the method of the present invention, first, 4-nitrophenylpropionic acid is converted into an acid halide derivative by using a halogenating agent, and as the halogenating agent which can be used in this reaction, thionyl chloride and ternary Examples include chlorides such as phosphorus chloride, phosphorus pentachloride, or phosgene.
Among these, it is more preferable to use thionyl chloride or phosgene. One kind of these is sufficient, but two or more kinds may be used.

The amount of halogenating agent used depends on the amount of 4-
1.0-1 per mole of nitrophenylpropionic acid.
It is preferably 2 mol. If this is less than 1.0 mol, the 4-nitrophenylpropionic acid used is
It is not preferable because the acid halide derivative is not sufficiently converted. Further, when it is used in an amount exceeding 1.2 mol, not only a further remarkable effect is not seen, but rather, problems such as treatment of the unreacted halogenating agent after the reaction occur. Not preferred because of

Any solvent or dispersant used in the above reaction may be used as long as it is inert to the halogenating agent. However, in this reaction, in particular,
It is more preferable to use toluene, xylene, benzene, chloroform, dichloromethane, ethylbenzene or the like used as a solvent or a dispersant in the condensation with ethanolamine in the next step.

The temperature in the halogenation reaction of 4-nitrophenylpropionic acid is usually preferably 40 ° C. or higher and lower than the boiling point of the solvent or dispersant used. If this temperature is lower than 40 ° C, the reaction proceeds slowly and is not very practical. Further, even if the reaction is carried out under a pressure condition at a temperature exceeding the boiling point of the solvent or the dispersant, the reaction proceeds, but the effect is not so different.

In addition, in the halogenation reaction of 4-nitrophenylpropionic acid, the halogenating agent may be added all at once, but in this case, hydrogen chloride, sulfur dioxide and the like are added simultaneously with the addition. It is not so preferable because a large amount is generated in a short time. Therefore, it is more preferable to add the halogenating agent continuously or in a divided manner. Usually, it is added to 4-nitrophenylpropionic acid over about 10 minutes to 3 hours. However, this addition time depends on the amount of the raw material used, and is not limited to the above-mentioned time range.

Further, the present halogenation reaction can be carried out without a catalyst, but it is further carried out in the presence of N, N-dimethylformamide, pyridine, hexamethylphosphoric triamide or the like as a catalyst. This makes it possible to proceed the reaction more preferably. When these catalysts are used, the amount used is 0.01 to 20 mol%, more preferably 0.1 to 10 mol%, based on 4-nitrophenylpropionic acid. This amount is 0.01 mol%
If the amount is less than the above, the effect of using the catalyst is not seen, and even if the amount used exceeds 20 mol%, no further effect is seen.

The acid halogenated derivative of 4-nitrophenylpropionic acid obtained by the above operation is toluene,
Xylene, benzene, chloroform, dichloromethane,
Or in the state of being dissolved in a solvent such as ethylbenzene,
Used for condensation with ethanolamine in the next step. When the adjustment for obtaining the acid halogenated derivative is carried out in the above-mentioned solvent, it is possible to sufficiently use it for the following operations only by appropriately adjusting the concentration by concentrating the reaction solution or the like. .

The condensation in the method of the present invention is carried out by adding the acid halogenated derivative of 4-nitrophenylpropionic acid prepared above to an aqueous solution of ethanolamine. The amount of ethanolamine used is 4-
The amount is 1 to 2 mol, more preferably 1.0 to 1. per mol of the acid halogenated derivative of nitrophenylpropionic acid.
It is in the range of 5 moles. If this amount is less than 1 mol, the acid halogenated derivative of 4-nitrophenylpropionic acid will remain large, and if it is used in excess of 2 mol, there will be no further difference in effect, and conversely, 4-nitrophenylpropionic acid This is not preferable because decomposition of the acid halogenated derivative of on-acid will occur.

Further, the condensation of the acid halogenated derivative of 4-nitrophenylpropionic acid with ethanolamine is preferably carried out in the presence of an inorganic base, because hydrogen chloride is generated. Usually, this inorganic base is used by being added to an ethanolamine aqueous solution. The types of inorganic bases that can be used include sodium hydroxide,
Examples thereof include potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, and the like, but are not limited thereto. These may be used alone, or two or more kinds may be mixed and used.

The amount of the inorganic base used is 1 to 1 mol of the acid halogenated derivative of 4-nitrophenylpropionic acid.
It is advisable to use 2 gram equivalents. If this is less than 1 gram equivalent, ethanolamine is neutralized and consumed by hydrogen chloride generated during the condensation, thus increasing the required amount of ethanolamine. If it is used in excess of 2 gram equivalent, the decomposition of the acid-halogenated derivative of 4-nitrophenylpropionic acid will be large and the target N- (2-hydroxyethyl) -3- (4 It is not preferable because the yield of -nitrophenyl) propionamide decreases.

The reaction temperature for carrying out the condensation in the method of the present invention is preferably in the range of 10 to 70 ° C.
If the reaction temperature is less than 10 ° C, the reaction proceeds slowly and is not practical. If the temperature is higher than 70 ° C, 4-
Decomposition of the acid-halogenated derivative of nitrophenylpropionic acid becomes prominent, and the desired N- (2
It is not preferred because the yield of -hydroxyethyl) -3- (4-nitrophenyl) propionamide decreases.

The reaction time for carrying out the condensation is not constant depending on the reaction temperature, but it is usually in the range of 1 to 5 hours. The N- (2-hydroxyethyl) -3- (4-nitrophenyl) propionamide produced as above precipitates as crystals in the reaction solution, and is easily obtained as crystals by filtration. The obtained crystals can be directly used in the next step, or can be recrystallized using a solvent such as ethyl acetate.

[0020]

EXAMPLES The production method of the present invention will be described in more detail below with reference to examples.

Example 1 19.52 g (0.1 mol) of 4-nitrophenylpropionic acid
And 0.37 g (0.005 mol) of N, N-dimethylformamide were suspended in 78 ml of toluene. The temperature of this suspension was raised to 60 ° C., 13.1 g (0.11 mol) of thionyl chloride was added thereto at the same temperature over 1 hour, and then the mixture was further reacted at the same temperature for 1 hour. Then, after toluene was distilled off from the reaction solution, 55 ml of toluene was further added to prepare an acid chloride solution of 4-nitrophenylpropionic acid. The solution obtained above was added to 170 g of an aqueous solution in which 9.16 g (0.15 mol) of monoethanolamine and 12.44 g (0.09 mol) of potassium carbonate were dissolved at 30 ° C. over 1 hour. After the addition was completed, the reaction solution was cooled to 0 ° C., the precipitated crystals were separated by filtration, and dried to obtain N- (2-hydroxyethyl)-
Crystal of 3- (4-nitrophenyl) propionamide 2
2.4 g was obtained. The yield was 94.0%.

Example 2 The procedure of Example 1 was repeated except that the condensation reaction between monoethanolamine and the acid chloride of 4-nitrophenylpropionic acid was carried out at a temperature of 20 ° C. Obtained N- (2-hydroxyethyl) -3- (4
The crystal of -nitrophenyl) propionamide was 22.4 g, and the yield was 94.0%.

Example 3 The procedure of Example 1 was repeated except that the condensation reaction of monoethanolamine and the acid chloride of 4-nitrophenylpropionic acid was carried out at a temperature of 40 ° C. Obtained N- (2-hydroxyethyl) -3- (4
The crystal of -nitrophenyl) propionamide was 22.5 g, and the yield was 94.4%.

Example 4 The procedure of Example 1 was repeated except that the condensation reaction of monoethanolamine with the acid chloride of 4-nitrophenylpropionic acid was carried out at a temperature of 50 ° C. Obtained N- (2-hydroxyethyl) -3- (4
The crystal of -nitrophenyl) propionamide was 22.2 g, and the yield was 93.2%.

Example 5 As in Example 1, except that the reaction of monoethanolamine with the acid chloride of 4-nitrophenylpropionic acid was carried out in an amount of 7.33 g (0.12 mol) of monoethanolamine. Operated. Obtained N-
The crystal of (2-hydroxyethyl) -3- (4-nitrophenyl) propionamide was 22.1 g, and the yield was 9
It was 2.8%.

Example 6 In Example 1, the kind of the inorganic base used in the reaction between monoethanolamine and the acid chloride of 4-nitrophenylpropionic acid was replaced with potassium carbonate, and 8.0 g (0.2 mol) of sodium hydroxide was used. Was performed in the same manner as in Example 1 except that the above was used. The obtained N- (2-hydroxyethyl) -3- (4-nitrophenyl) propionamide crystal was 22.1 g, and the yield was 92.8%.

Comparative Example 1 The procedure of Example 1 was repeated except that the condensation reaction of monoethanolamine with the acid chloride of 4-nitrophenylpropionic acid was carried out at a temperature of 80 ° C. Obtained N- (2-hydroxyethyl) -3- (4
The crystal of -nitrophenyl) propionamide was 17.9 g, and the yield was 75.1%.

Comparative Example 2 The procedure of Example 1 was repeated except that the condensation reaction between monoethanolamine and the acid chloride of 4-nitrophenylpropionic acid was carried out at a temperature of 0 ° C. Obtained N- (2-hydroxyethyl) -3- (4
The crystal of -nitrophenyl) propionamide was 20.2 g, and the yield was 84.8%.

[0029]

EFFECT OF THE INVENTION N- (2-hydroxyethyl) of the present invention
According to the method for producing -3- (4-nitrophenyl) propionamide, it is apparent that the amount of the halogenating agent used is small and the desired product can be obtained with a sufficient yield. Therefore, the treatment operation of the unreacted halogenating agent is unnecessary or very easy. Further, the temperature during the condensation reaction is also in a range that is very easy to operate, and further, the amount of ethanolamine used can be reduced, and from the viewpoint of an industrial production method,
This is a very useful method.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Yoshinori Tanaka 1900, Togo, Mobara-shi, Chiba Mitsui Toatsu Chemicals, Inc.

Claims (2)

[Claims] 1. When 4-nitrophenylpropionic acid is condensed with ethanolamine to produce N- (2-hydroxyethyl) -3- (4-nitrophenyl) propionamide, 4-nitrophenylpropionic acid is added. ,
N- (2-characterized in that it is condensed with ethanolamine at a temperature of 10 to 70 ° C after a halogenating agent of 1.0 to 1.2 times the amount of 4-nitrophenylpropionic acid is reacted to form an acid halogenated derivative. Hydroxyethyl) -3-
A method for producing (4-nitrophenyl) propionamide. 2. Condensation of an acid halogenated derivative of 4-nitrophenylpropionic acid with ethanolamine by coexisting with 1 to 2 gram equivalent of an inorganic base per mol of the acid halogenated derivative of 4-nitrophenylpropionic acid. The method according to claim 1, which is performed.