JPH0333702B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing N-substituted alkoxycarboxylic acid amide compounds. More specifically, the present invention relates to a method for producing an N-substituted alkoxycarboxylic acid amide compound by reacting a hydroxyl-substituted amide compound with a halogen-substituted compound. N-substituted alkoxycarboxylic acid amide compounds are useful substances for applications such as raw materials for pharmaceuticals or agricultural chemicals such as anthelmintics, or various additives. Conventionally, methods for producing N-substituted alkoxycarboxylic acid amide compounds include a reaction between an alkoxy-substituted carboxylic acid chloride and an amine, and a reaction between an alkoxy-substituted carboxylic acid or an alkoxy-substituted carboxylic acid ester and an amine. ing. However, in the former method,
The raw material, alkoxy-substituted carboxylic acid chloride, is expensive and difficult to handle, and in the latter method, the reaction between carboxylic acid or carboxylic acid ester and amines does not necessarily proceed efficiently. The manufacturing method is not yet satisfactory. Also J.Pharm, and
Pharmacol., Vol. 9, pp. 855-863 (published in 1957), discloses a method for producing N-substituted alkoxycarboxylic acid amide compounds by reacting an alkoxy-substituted amide compound with a halogen-substituted compound. However, this method uses alcohol as a reaction solvent, an alkali metal alkoxide as a strong basic substance, and harsh reaction conditions such as 24 hours of reaction under boiling alcohol. However, as shown in Comparative Example 1, satisfactory results were not obtained. As a result of intensive studies by the present inventors to solve the above problems, we found that the general formula (1) HO-R ₁ -CONH ₂ ...(1) (wherein R ₁ is an alkyl group, an alkenylene group,
Indicates a phenylene group, a phenylenealkylene group, or an alicyclic group. ) and a halogen represented by the general formula (2) R ₂ -X...(2) (where R ₂ is an alkyl group or phenyl alkyl group, and X is a halogen atom). By reacting with a substituted compound in an aprotic polar solvent in the presence of a strong basic substance, the general formula (3) can be obtained. The inventors have discovered that an N-substituted alkoxycarboxylic acid amide compound represented by or R ₂ O-R ₁ -CONH-R ₂ (where R ₁ and R ₂ are the same as above) can be easily produced, and the present invention has been achieved. The hydroxyl-substituted amide compound applicable to the present invention is represented by the following general formula: HO-R ₁ -CONH ₂ (wherein R ₁ is an alkylene group, an alkenylene group,
Indicates a phenylene group, a phenylenealkylene group, and an alicyclic group. ) Hydroxyl group-substituted saturated fatty acid amides, hydroxyl group-substituted unsaturated fatty acid amides, hydroxyl group-substituted aromatic carboxylic acid amides, hydroxyl group-substituted alicyclic carboxylic acid amides, and these compounds have alkyl groups, aryl groups, nitro groups, Compounds into which halide groups, alkoxy groups, cyano groups, etc. have been introduced are also covered. Moreover, a hydroxyl group may be bonded to those substituents. To illustrate them,
For example, hydroxyacetamide, lactic acid amide, hydroxypropionamide, hydroxybutyramide, hydroxyvaleramide, chlorohydroxyheptanamide, hydroxyacrylamide, hydroxycrotonamide, hydroxycinnamide, salicylamide, hydroxybenzamide, hydroxytoluamide, hydroxymethyl benzamide,
Examples include hydroxynaphthamide, hydroxyanthraquinone carboxamide, methoxysalicylamide, hydroxynitrobenzamide, hydroxyphenylacetamide, hydroxyphenylpropionamide, and hydroxycyclohexane carboxamide. On the other hand, halogen-substituted compounds are represented by the following general formula: R ₂ -X (wherein, R ₂ represents an alkyl group or phenyl alkyl group, and X represents a halogen atom), halogenated alkanes, and halogenated alkyl Aryl can be given. Halogenated alkanes have the general formula
CnH ₂ n ₊₁ X (X is a halogen atom), n
is an integer between 1 and 20. Alkylaryl halide has the general formula ArCnH ₂ nX (where Ar represents an aromatic ring,
X represents a halogen atom), and n is an integer from 1 to 20. A benzene ring, a naphthalene ring, an anthracene ring, etc. can be used as the aromatic ring. Also applicable are those in which a substituent such as an alkyl group, alkenyl group, aryl group, nitro group, halide group, alkoxy group, or cyano group is introduced into the aromatic ring. On the other hand, any of chlorine, bromine, and iodine atoms can be used as the halogen atom. In the following examples of halogen-substituted compounds, chlorine-substituted compounds are shown as a representative. Examples of halogenated alkanes include chloromethane, chloroethane, chloropropane, chlorobutane, chloropentane, chlorohexane, chloroheptane, chlorodecane, chlorododecane, chlorotetradecane, and chlorooctadecane. On the other hand, for alkylaryl halides,
For example, benzyl chloride, phenethyl chloride, phenylpropyl chloride, chloromethylnaphthalene, chloromethylanthracene, chloromethyltoluene, chloromethylethylbenzene,
Chloromethylxylene, chloromethylstyrene,
Examples include nitrobenzyl chloride, chloromethylanisole, chloromethylbenzonitrile, and chlorobenzyl chloride. The reaction solvent used in the present invention is not particularly limited as long as it is an aprotic polar solvent, but suitable ones for carrying out the reaction include, for example, acetonitrile, dioxane, pyridine, dimethoxyethane,
Tetrahydrofuran, Tetrahydropyran,
Glymes such as benzonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, N-methylprolidone, hexamethylphosphoramide, sulfolane, oxepane, triglyme, tetraglyme,
Tetramethylurea, Tetraethylurea, 1,3-
Dimethyl-2-imidazolidinone, 1,3-dimethyl-3,4,5,6,-tetrahydro-2(H)
- Alkylureas such as pyrimidinone can also be mentioned. Among the above, more preferably used solvents include acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, sulfolane, tetraglyme, 1,3-dimethyl-2
- Examples include imidazolidinone. The amount of solvent used is not particularly limited, but it is 5 to 95% by weight, preferably 10 to 90% by weight based on the total amount of reactants including the solvent.
% by weight. On the other hand, the strong basic substance used in the present invention can be a solid substance, a solution prepared by dissolving it in a polar solvent such as water, or even a liquid substance, but it is possible to use a solid substance or a liquid substance. For this reason, it is preferable to start the reaction while at least a part of the strong basic substance is suspended, so it is preferable to use a solid strong basic substance. The strength of basicity is such that when dissolved or suspended in water, the pH of the aqueous solution is preferably 10 or more.
Anything above 11 can be used. However, ion exchange resins and other ion exchangers are not subject to this condition and will be exemplified later. There are many types of strong basic substances that meet such conditions, and any of them can be applied, but among them, those that are more suitable for carrying out the method of the present invention are, for example, alkali metal hydroxides and alkali metal hydroxides. metal oxides, alkaline earth metal hydroxides, and ion exchange resins. Examples of the above substances include sodium hydroxide, potassium hydroxide, lithium hydroxide, rubidium hydroxide, cesium hydroxide, lithium oxide, sodium oxide, potassium oxide, beryllium hydroxide, magnesium hydroxide, calcium hydroxide, water Strontium oxide, barium hydroxide,
These include OH type strongly basic ion exchange resins and free type weakly basic ion exchange resins. In addition, the relative amounts of the hydroxyl-substituted amide compound, halogen-substituted amide compound, and strong basic substance used as raw materials are determined by the reactivity between the halogen-substituted compound and the hydroxyl-substituted amide compound, or whether the desired product is mixed with the N-monosubstituted amide compound. It differs depending on whether the N,N-disubstituted amide compound is produced or not, and it is difficult to define it unambiguously, but in general, when producing an N-monosubstituted alkoxycarboxylic acid amide compound,
The amount of the halogen-substituted compound to be used is 0.2 to 15 times the mole of the amide compound, preferably 0.3 to 10 times the mole, and the amount of the strong basic substance to be used is 0.7 to 15 times the mole of the amide compound, preferably 1.0 to 15 times the mole. It is in the 10-fold molar range. When producing an N,N-disubstituted alkoxycarboxylic acid amide compound, the amount of halogen-substituted compound used is 1.0 to 30% based on the amide compound.
It is preferably in the range of 2.0 to 20 times the mole,
The amount of strong basic substances used is relative to the amide compound.
It is in the range of 1.5 to 20 times the mole, preferably 2.0 to 15 times the mole. The reaction temperature depends on the reactivity of the hydroxyl-substituted amide compound and halogen-substituted compound used, but is usually in the range of -20 to 100°C, preferably -10 to 90°C. As long as it is within this range, it is not necessarily necessary to keep the temperature constant during the reaction, but it is sufficient to keep track of the progress of the reaction and appropriately set the degree of reaction to carry out the reaction efficiently. Further, the reaction time also varies depending on the amide compound and halogen-substituted compound used as well as the reaction temperature, but it is 30 hours at the longest, and usually within 20 hours.
The progress of the reaction can be monitored by determining changes in the properties of the reaction system and the concentrations of raw materials and target products in the reaction solution using gas chromatography, high performance liquid chromatography, or the like. There are two types of N-substituted alkoxycarboxylic acid amide compounds produced by the method of the present invention: N,N-disubstituted alkoxycarboxylic acid amide compounds and N-monosubstituted alkoxycarboxylic acid amide compounds shown in general formula (3). , and their ease of preparation seems to depend mainly on the structure of the substituent R ₂ ,
When R ₂ is a methyl group or an ethyl group, the general formula (3)
N,N-disubstituted alkoxycarboxylic acid amide compounds are predominant, whereas when R ₂ is an alkyl group with a large number of carbon atoms or more than a propyl group or a phenylalkyl group, N-monosubstituted alkoxycarboxylic acid amide compounds are predominantly formed. be done. However, by appropriately selecting reaction conditions, it is possible to produce compounds with any structure. Next, embodiments of the method of the present invention will be described. First, the order and method of adding the hydroxyl-substituted amide compound, halogen-substituted compound, and strong basic substance may be any method. For example, the three raw materials may be added at the same time, or the third raw material may be added gradually. Usually, a method is adopted in which a hydroxyl-substituted amide compound and a halogen-substituted compound are added first, and then a strong basic substance is gradually added. However, when using a highly reactive halogen-substituted compound, it is preferable to add the halogen-substituted compound last. Further, the reaction temperature does not need to be kept constant during the reaction, and may be changed depending on the progress of the reaction. Usually, a method is adopted in which the reaction is started at a relatively low temperature and then the temperature is raised. Next, the desired product is separated, and by separating the metal halide produced as a by-product after the reaction for a predetermined period of time, and distilling off the solvent and raw materials from the liquid, the desired product can be obtained as a residue. However, in general, the residue is purified by operations such as vacuum distillation or recrystallization to separate the desired product. In addition, when by-product metal halides are dissolved in the reaction solution,
Alternatively, in the case of a non-volatile amide compound, after distilling off the solvent, the residue is washed with a solvent combination that forms two layers, such as benzene-water or chloroform-water, to remove metal halides and unreacted amide compounds. The target product may be dissolved in the organic layer and separated from the aqueous solution layer. Furthermore, if necessary, the target product separated from the organic layer is purified by operations such as distillation or recrystallization.
Furthermore, when using a solvent with high affinity for water such as dimethyl sulfoxide as a reaction solvent, there is a method of adding water to the reaction solution and separating the target product as an oil layer, or a method of adding water to the reaction solution and separating the target product as an oil layer, or using water such as benzene, toluene, or chloroform. A method of extracting and separating the target substance using a solvent that forms two layers can also be applied. In the method of the present invention, highly versatile and inexpensive hydroxyl-substituted amide compounds such as lactic acid amide and salicylamide can be used as raw materials for producing N-substituted alkoxycarboxylic acid amide compounds, and N- Since the substituted alkoxycarboxylic acid amide compound can be manufactured, it becomes possible to manufacture the N-substituted alkoxycarboxylic acid amide compound industrially and at low cost. Next, the present invention will be further explained by examples. Example 1 Preparation of O-butoxy-N-butyl salicylamide: Add 44 g of salicylamide and 96 g of 1-bromobutane to 200 ml of N,N-dimethylformamide, and slowly add 59 g of potassium hydroxide while stirring in an ice bath. and started the reaction. Thereafter, the reaction was carried out for 5 hours while gradually increasing the temperature, and the reaction temperature finally reached 20°C. After the reaction, the insoluble part was separated, the solvent and raw materials were distilled off from the liquid, and the residue was recrystallized with benzene to obtain 61 g of O-butoxy-N-butyl salicylamide with a melting point of 40-41°C (yield 77%). ) was obtained. Comparative Example 1 Production of O-butoxy-N-butylsalicylamide: 62 g of O-butoxybenzamide, 48 g of 1-bromobutane, and 24 g of sodium ethoxide were added to 200 ml of ethyl alcohol, and the reaction was carried out for 24 hours while the ethyl alcohol was boiling. Ivy. The treatment after the reaction was carried out in the same manner as in Example 1, and 25 g (yield: 31%) of O-butoxy-N-butylsalicylamide was obtained. Example 2 Preparation of β-benzyloxy-N-benzylpropionamide: 29 g of β-hydroxypropionamide and 120 g of benzyl bromide in 200 ml of dimethyl sulfoxide.
Then, while stirring in an ice bath, 42 g of sodium hydroxide was gradually added. Then at 20℃ 4
A time reaction was performed. The post-reaction treatment was carried out in the same manner as in Example 1, and recrystallized from benzene to a melting point of 59-60°C.
65 g (yield 76%) of β-benzyloxy-N-benzylpropionamide was obtained. Example 3 Preparation of O-ethoxy-N,N-diethyl benzamide: 1,3-dimethyl-2-imidazolidinone 200
44g salicylamide and 115g bromoethane in ml
88 g of potassium hydroxide were gradually added while stirring in an ice bath. Thereafter, the reaction was carried out at 20°C for 4 hours. After the reaction, the insoluble portion was separated and the liquid was distilled to collect a fraction at 113-115°C/0.1 mmHg to obtain 59 g (yield: 83%) of O-ethoxy-N,N-diethylbenzamide. Examples 4 to 7 Reactions were carried out in the same manner as in Example 3 using the combinations of raw materials, strong basic substances, and solvents listed in Table 1 under the conditions listed in Table 1. After the reaction, treatment was carried out in exactly the same manner as in Example 3, and the results shown in Table 2 were obtained.

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Claims (1)

[Claims] 1 General formula (1) HO−R ₁ −CONH ₂ …(1) (However, R ₁ is an alkyl group, an alkenylene group,
Indicates a phenylene group, a phenylenealkylene group, or an alicyclic group. ) and a halogen represented by the general formula (2) R ₂ -X...(2) (where R ₂ is an alkyl group or phenyl alkyl group, and X is a halogen atom). General formula (3) characterized by reacting with a substituted compound in an aprotic polar solvent in the presence of a strong basic substance. or _R2O - _R1 -CONH- _R2 (However, _R1 and _R2 are the same as above) A method for producing an N-substituted alkoxycarboxylic acid amide compound.