JPH0784427B2 - Manufacturing method of intermediate raw materials for medical and agricultural chemicals - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for producing an intermediate raw material for medicines and agricultural chemicals by a novel method for producing oxyalkylamide. More specifically, the present invention provides a method for producing an intermediate raw material for medical and agricultural chemicals, which comprises obtaining an oxyalkylamide in a higher yield with acrylamide and a hydroxy compound.

<Problems to be Solved by the Prior Art and Invention> Conventionally, as a method for synthesizing an oxyalkylamide, for example, alkoxypropylamide, 1) a method for synthesizing an alkoxypropionitrile by oxidizing it with hydrogen peroxide solution [Zurnal Obsiche]・ Himmy (Zhur.Obschei Khim.) Vol. 26 71
9 (1956)], 2) Oxypropionitrile was added to Pb ₃ (PO
₄ ) ₃ , Cd (NO ₃ ) ₂ , Zn (NO ₃ ) ₂ , Pb (BO ₂ ) ₂ , ZnBr ₂ or Ti (SO ₄ ) ₂ oxidation method (JP-A-47-12338), 3)
A method for synthesizing 2 equivalents of sodium alkoxide and acrylamide by reacting them in a solvent such as methanol [Macromolecular chemistry (Makromol. Chem.) Volume 76]
82 (1964)] is known. In the methods 1) and 2), oxypropionitrile as a raw material is easily polymerized, and unstable acrylonitrile, which is explosive, is used as a raw material, so that it is difficult to handle. On the other hand, in the method 3),
It has been reported that it is necessary to use sodium methylate in an amount of twice the equivalent of acrylamide in order to prevent polymerization of acrylamide or oligomerization and obtain methoxypropylamide in good yield. However, even if such an amount of methoxypropyl methylate was used, the yield of the desired alkoxypropylamide was only 68%.

Therefore, it has been desired to develop a method for producing an oxyalkylamide such as an alkoxyalkylamide in a high yield using a raw material that is easy to handle.

<Means for Solving Problems> The inventors of the present invention have conducted extensive studies to achieve the above-mentioned object, and as a result, react a specific acrylamide and a hydroxy compound as raw materials in the presence of a specific amount of a base catalyst. As a result, they have found that an oxyalkylamide can be produced in an extremely high yield, and have completed the present invention.

That is, the present invention has the general formula [I] (However, R ¹ , R ² and R ³ are the same or different hydrogen atoms or a substituted or unsubstituted alkyl group.) And the general formula [II], R ⁴ OH ... [II] ( Wherein R ⁴ is a substituted or unsubstituted alkyl group or a substituted or unsubstituted aryl group), and 0.001 to 0.50 equivalents to 1 equivalent of the acrylamide represented by the general formula [I]. In the presence of a base catalyst of the general formula [III] (However, R ¹ , R ² , R ⁴ and R ⁴ are the same as the above.) A method for producing an intermediate raw material for medical and agricultural chemicals, which comprises obtaining an oxyalkylamide.

The most important feature of the present invention is that in the reaction of the acrylamide represented by the general formula [I] with the hydroxy compound represented by the general formula [II], a base catalyst is used with respect to 1 equivalent of the acrylamide represented by the general formula [I]. The reaction is carried out in the coexistence of 0.01 to 0.50 equivalent.

The base catalyst used in the present invention is not particularly limited, and known bases can be generally used. Specific examples of those suitably used as the base catalyst include sodium carbonate, potassium carbonate, potassium hydroxide, sodium hydroxide, anion exchange resin (OH type), sodium alcoholate, sodium hydride, potassium hydride and the like. Can be mentioned. Further, alkali metals such as sodium and potassium which react with a hydroxy compound existing in the reaction system to form a base can also be used according to the base. In particular, from an industrial point of view, sodium hydroxide, potassium hydroxide, lithium hydroxide and other alkali hydroxides and sodium carbonate, potassium carbonate and other alkali carbonates that are easy to handle and inexpensive can be reused repeatedly by recovery and regeneration. Anion exchange resin (OH type) is suitable.

The amount of the above-mentioned base catalyst used is 0.001 to 0.50, preferably 0.01 to 0.2, in terms of an equivalent amount to one equivalent amount of the acrylamide represented by the general formula [I] (hereinafter sometimes simply abbreviated as equivalent ratio).
It is in the range of 5. When the corresponding amount ratio is lower than 0.001, the reaction is difficult to occur, the yield of oxyalkylamide is low,
On the other hand, when the equivalent ratio exceeds 0.50, the amount of oligomers produced by the acrylamide polymerization reaction increases, and the yield of oxyalkylamide decreases sharply.

The raw material acrylamide used in the present invention is represented by the general formula [I], that is, (However, R ¹ , R ² and R ³ are the same or different hydrogen atoms or a substituted or unsubstituted alkyl group.). In the above general formula [I], R ¹ , R ² ,
The alkyl group represented by R ³ is not particularly limited, and a linear or branched group is used, but a lower alkyl group having 1 to 6 carbon atoms is particularly preferable. Typical examples are methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl group, iso-butyl group, cyclohexyl group and the like. Further, in the above general formula [I], the alkyl group represented by R ¹ , R ² and R ³ may be substituted with a substituent, and in this case, the kind of the substituent does not hinder the reaction. There is no limitation as long as it can be used according to the intended product.

Specific examples of the substituent include a substituted or unsubstituted alkenyl group having 2 to 6 carbon atoms; a substituted or unsubstituted alkynyl group having 2 to 6 carbon atoms; a substituted or unsubstituted alkoxy group having 1 to 6 carbon atoms; A substituted or unsubstituted alkoxyalkyl group having 1 to 6 carbon atoms; a substituted or unsubstituted alkylthio group having 1 to 6 carbon atoms; a substituted or unsubstituted haloalkyl group having 1 to 6 carbon atoms; a substituted or unsubstituted phenyl Group; a substituted or unsubstituted naphthyl group and the like can be mentioned. More specifically exemplifying representative substituents,
Allyl group, 2-methylallyl group, 1-methylallyl group,
2-propynyl group, 2-butynyl group, 1-butenyl group,
2-butenyl group, 2-methoxyethyl group, 2-ethoxyethyl group, methoxy group, ethoxy group, propoxy group, 2
-Methylthioethyl group, 2-ethylthioethyl group, 2-
Propylthioethyl group, 2-chloroethyl group, 2-promoethyl group, 2,2-dichloroethyl group, 2-chloroethyl group, phenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 3-methoxyphenyl group, 3-methyl Examples thereof include a phenyl group, a 4-acetylphenyl group, a 3,4-dimethoxyphenyl group, a 2-naphthyl group, a 2- (4-methylnaphthyl) group and a 1- (2-methylnaphthyl) group.

The hydroxy compound used in the present invention has the general formula [II], R ⁴
OH (provided that R ⁴ is a substituted or unsubstituted alkyl group or a substituted or unsubstituted aryl group). In the above general formula [II], the alkyl group represented by R ⁴ is not particularly limited, and a linear or branched group is used. Particularly, a lower alkyl group having 1 to 6 carbon atoms is preferable. Typical examples are methyl group, ethyl group, n-propyl group, n-butyl group, iso-butyl group, cyclohexyl group and the like. Further, in the general formula [II], the alkyl group represented by R ⁴ may be substituted with a substituent, and the kind of the substituent is not limited as long as it does not interfere with the reaction, The one according to can be used. For example, a substituted or unsubstituted alkenyl group having 2 to 6 carbon atoms; a substituted or unsubstituted alkynyl group having 2 to 6 carbon atoms; a substituted or unsubstituted alkoxy group having 1 to 6 carbon atoms; Examples thereof include a substituted or unsubstituted alkylthio group; a substituted or unsubstituted haloalkyl group having 1 to 6 carbon atoms; a substituted or unsubstituted phenyl group; and a substituted or unsubstituted naphthyl group. More specifically exemplifying representative substituents, allyl group, 2-methylallyl group, 2-methylallyl group, 1-methylallyl group,
2-propynyl group, 2-butynyl group, 1-butenyl group,
2-butenyl group, 2-methoxyethyl group, 2-ethoxyethyl group, 2-methylthioethyl group, 2-chloroethyl group, 2-bromoethyl group, 2,2-dichloroethyl group, 2
-Fluoroethyl group, phenyl group, 4-phenylsulfonylphenyl group, 2-hydroxyphenyl group, 4- (N,
N-dimethyl) aminophenyl group, 4-carbamoylphenyl group, 4-chlorophenyl group, 4-methylphenyl group, 3,4-dimethylphenyl group, 4-nitrophenyl group, 4-cyanophenyl group, 4-acetylphenyl group ,
4-methoxycarbonylphenyl group, 2-naphthyl group,
Examples thereof include a 2- (4-methylnaphthyl group and a 1- (2-methylnaphthyl group. Further, the aryl group represented by R ⁴ in the general formula [II] can be used without particular limitation. The group may be substituted with a substituent, and the kind of the substituent is not limited at all, and those which are necessary can be used.Specific examples include a phenyl group, a 4-chlorophenyl group, a 4-bromophenyl group, 4-fluorophenyl group, 3-fluorophenyl group, 4-nitrophenyl group,
4-methylsulfonylphenyl group, 2-hydroxyphenyl group, 4-ethylphenyl group, 4-methylphenyl group, 3,4-dimethylphenyl group, 4-ter-butylphenyl group, 4-trifluoromethylphenyl group, 4 -Carbamoylphenyl group, 4-methoxycarbonylphenyl group, 4-aminophenyl group, 4- (N, N-dimethyl) aminophenyl group, 4-cyanophenyl group, 4-methoxyphenyl group, 3,4-dimethoxyphenyl group , 3,4-diethoxyphenyl group, 4-acetylphenyl, 2,6-dimethylphenyl group, 2,6-dimethoxyphenyl group, 2,4-dichlorophenyl group, 2-methyl-4-chlorophenyl group and the like. .

In the present invention, it is particularly preferable to use a hydroxy compound in which R ⁴ is an unsubstituted alkyl group as a raw material because a high yield can be achieved.

The charged molar ratio of the compounds represented by the above general formulas [I] and [II] may be appropriately determined and used as necessary. Generally, for example, it is preferable to use the compound represented by the general formula [II] selected from the range of 1 to 10 mol per 1 mol of the compound represented by the general formula [I].

Moreover, it is preferable that the reaction is usually performed in an organic solvent. As the organic solvent, methanol, ethanol, iso
-Alcohols such as propanol and ter-butanol, hexane, cyclohexane, ether, tetrahydrofuran, dioxane, dimethoxyethane, N, N-dimethylformamide and dimethyl sulfoxide can be used.
In addition, one of the raw materials in the above reaction, the general formula [II]
It is particularly preferable to use the hydroxy compound represented by the formula (1) in an excess amount and also serve as a solvent in order to obtain the desired product in high yield.
For example, methanol is used for methoxylation, ethanol is used for ethoxylation, isopropanol is used for isopropoxylation, allyl alcohol is used for allyloxylation, and phenol is used for phenoxylation. Is preferred. Furthermore, the reaction temperature can be selected from a wide range. Generally, when an organic solvent is used, the temperature may be selected from 0 ° C to 110 ° C, preferably 20 ° C to 65 ° C. When no organic solvent is used, the temperature is from 0 ° C to the general formula [II] used in the above reaction. It may be selected from the boiling point range of the compound. The reaction time varies depending on the raw material, base catalyst, reaction temperature and type of organic solvent, but when an organic solvent is used, it is usually several tens of minutes to 72 hours, preferably 3 hours to 24 hours, and when no organic solvent is used. Usually, it may be selected from the range of several tens of minutes to 72 hours, preferably 3 hours to 15 hours. It is preferable to stir during the reaction. The method for isolating and producing the target product, that is, the oxyalkylamide compound represented by the general formula [II] is not particularly limited, and a known method can be employed. For example, the reaction solvent and excess hydroxy compound are distilled off from the reaction solution, and the residue is subjected to atmospheric distillation or vacuum distillation to obtain the desired product. Also,
In addition to purification by distillation, when the product is a solid, it can be purified by recrystallization.

<Effect> According to the method of the present invention, the reaction between the hydroxy compound and acrylamide proceeds extremely smoothly without the polymerization of acrylamide by using the specific raw material and the catalyst in a fixed ratio, and thus the yield is high. An oxyalkylamide can be obtained. Therefore, an industrially excellent method is provided in that an oxyalkylamide can be produced at low cost and the reaction operation is extremely easy.

<Examples> In order to describe the present invention more specifically, examples will be given below, but the present invention is not limited to these examples.

Example 1 35.5 g of acrylamide and sodium hydroxide were placed in a 500 ml three-necked flask equipped with a stirrer, a thermometer and a reflux condenser.
0.20 g and 300 ml of methanol were added, and the mixture was heated under reflux with stirring for 10 hours, and then methanol was distilled off. The residue was recrystallized from ether to give 3-methoxypropionamide (bp 89-90 ° C / 0.9mmHg; mp45.5-46.0 ° C) as white crystals.
0.24 g (yield 97.6%) was obtained.

Example 2 For the reaction of producing 3-methoxypropylamide from methanol and acrylamide, the reaction conditions were as follows: 1 equivalent of acrylamide and 10 equivalents of methanol, and the reaction temperature.
The reaction was carried out by setting the temperature to 60 ° C. and changing the amount of sodium methylate in the range of 0.0005 equivalent to 1.0 equivalent to 1 equivalent of acrylamide as shown in Table 1. The yield is
After the reaction was carried out by gas chromatography until the acrylamide disappeared, the desired product, 3-methoxypropylamide, was isolated and determined from the yield.

After the reaction, isolation of 3-methoxypropylamide was performed by adding ammonium chloride to neutralize, filtering, and distilling the filtrate.

The results are also shown in Table 1.

Example 3 In the same manner as in Example 1, methanol was allowed to react with acrylamide in the presence of various base catalysts shown in Table 2, and 3
-Methoxypropionamide was synthesized. The respective reaction conditions and yields are shown in Table 2 together.

Example 4 In the same manner as in Example 1, the acrylamide derivative shown in Table 3 was reacted with various hydroxy compounds in the presence of various base catalysts adjusted to an equivalent ratio of 0.01 to synthesize an oxyalkylamide. . The respective reaction conditions and yields are shown in Table 3 together. It was confirmed that the yield of the method of the present invention was improved by 20% or more compared to the yield of the conventional method of reacting a large amount of sodium alkoxide with acrylamide.

Example 5 In a 300 ml three-necked flask equipped with a stirrer, a thermometer and a reflux condenser, 12.06 g of acrylamide, 23.0 g of 4-chlorobenzyl alcohol, 0.11 g of sodium hydroxide and 150 ml of ter-butanol were charged, and the mixture was allowed to stand at room temperature for 24 hours. After stirring for an hour, tert-
Butanol was distilled off. The residue was recrystallized from ether to obtain 31.06 g (yield 90.3%) of 3- (4-chlorobenzyl) propionamide (mp92.5-93.5 ° C) as white crystals.
The infrared absorption spectrum of this product was measured to be 1660 cm.
^-1 shows absorption based on the carbon-oxygen double bond of the amide group. The elemental analysis values were C66.85%, H7.42% and N8.00%, which were in good agreement with the theoretical values of C67.02%, H7.31% and N7.82%.

Furthermore, ¹ H-NMR (δ; ppm: tetramethylsilane standard, deuterated chloroform solvent) was measured. The analysis results are as follows.

A triple line for two protons is shown at 2.45 ppm, and
Corresponds to the ethylene proton. Two protons at 3.69 ppm
Corresponding to the methylene proton of (b).
It was A singlet for two protons is shown at 4.41 ppm, (c)
Corresponding to the methylene proton of. 5.70 to 6.45 ppm
A broad single line for two rotons is shown,
Corresponding to the proton of De. Proton 4 at 7.15 ppm
Showing a single line for each of the benzene ring protons in (e)
Corresponding. Also, when the mass spectrum was measured, m /
e214 to M Peak corresponding to +1 at m / e125To the peak corresponding to m / e73Each peak corresponding to

Claims (1)

[Claims] 1. A general formula [I] (However, R ¹ , R ² and R ³ are the same or different hydrogen atoms or a substituted or unsubstituted alkyl group.) And (b) the general formula [II], R ⁴ OH [II] (Provided that R ⁴ is a substituted or unsubstituted alkyl group or a substituted or unsubstituted aryl group), and 0.001 to 0.50 relative to 1 equivalent of the acrylamide represented by the general formula [I]. By reacting in the presence of an equivalent amount of a base catalyst, the general formula [III], To obtain an oxyalkylamide represented by