JPH11322728A - Production of heterocyclic compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a heterocyclic compound useful for physiologically active substances such as agrochemicals and drugs under mild conditions with ease in a high yield, by applying an amide compound as a starting substance. SOLUTION: An amide compound of formula I [wherein, R is O, S, a (substituted)heteroaryl or a (substituted)aryl; R<2> and R<3> are each H or an alkyl; (p) is 1-3; (q) is 0-2; (r) is 1-2; X is a halogen or an alkoxy], [e.g. 2-chloro-N- hydroxymethyl-N-(1-phenylethenyl)acetamide] is subjected to dehydrohalogenation or an alcohol-removing reaction to cause cyclization and to obtain a compound of formula II [e.g. 3-(1-phenylethenyl)-4-oxazolidone]. The above reaction is pref. conducted in such a solvent as methanol within the temp. range of -30 deg.C to 100 deg.C for about 0.1-30 h.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a method for producing a heterocyclic compound. More specifically, the present invention relates to a method for producing a heterocyclic compound in high yield by cyclizing an amide compound in the presence of a base.

[0002]

2. Description of the Related Art Conventionally, many compounds have been synthesized as heterocyclic compounds. Many of these heterocyclic compounds have been found to be useful as physiologically active substances such as agricultural chemicals and pharmaceuticals, and the heterocyclic compounds represented by the above general formula (2) are also used in such applications. it can.

In order to produce such a heterocyclic compound, a dialcoholamine is used as a starting material, and the desired product can be obtained by cyclizing it by a dehydration reaction.
Such methods include, for example, the Journal of Chemical Societ
y), p. 2338 (1936) discloses a method for obtaining morpholine by heating diethanolamine at 200 to 210 ° C. for 15 hours in the presence of concentrated hydrochloric acid.

However, in the above-mentioned method, the dehydration reaction must be carried out under the condition of heating at a high temperature for a long time in the presence of a strong acid. Is not applicable. Further, when trying to synthesize the compound represented by the above formula (2) by this method, there is a problem that it is difficult to obtain an amide compound as a starting material or to make the synthesis difficult.

[0005]

As described above, a method for efficiently producing a heterocyclic compound has not been known until now. An object of the present invention is to provide a method for producing a heterocyclic compound easily and in a high yield under mild conditions.

[0006]

Means for Solving the Problems The present inventors have intensively studied to solve the above problems. As a result, if the amide compound represented by the general formula (1) is used as a starting material and the compound is subjected to a dehydrohalogenation or dealcoholization reaction in the presence of a base to cyclize the compound, mild conditions near normal temperature can be obtained. It has been found that the desired heterocyclic compound can be produced under the conditions and quantitatively, and the present invention has been completed.

That is, the present invention provides the following general formula (1)

[0008]

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(Wherein R ¹ is an oxygen atom, a sulfur atom,
Or a substituted or unsubstituted heteroaryl group containing 1 to 2 nitrogen atoms, or a substituted or unsubstituted aryl group, R ² and R ³ are each independently a hydrogen atom or an alkyl group, R ² and R ³ may be linked to each other to form an alkylene group, p represents an integer of 1 to 3, q represents an integer of 0 to 2, r is an integer of 1 to 2, X is a halogen atom or an alkoxy group. ) Is cyclized by dehydrohalogenation or dealcoholation in the presence of a base to give a compound represented by the following general formula (2)

[0010]

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In the formula, R ¹ , R ² , R ³ , p, q and r are the same as those in the general formula (1). A method for producing a heterocyclic compound, characterized by obtaining a heterocyclic compound represented by｝.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION In the production method of the present invention, an amide compound represented by the above general formula (1) (hereinafter also referred to as a raw material amide compound) is used as a raw material.

As can be seen by comparing the general formulas (1) and (2), the structure of the target heterocyclic compound is basically determined by the structure of the starting amide compound. For this reason, R ¹ , R ² , R in the general formula (1)
³ , p, q and r are all appropriately selected according to the structure of the target heterocyclic compound.

In the general formula (1), R ¹ is a substituted or unsubstituted heteroaryl group containing one or two oxygen atoms, sulfur atoms, or nitrogen atoms, or a substituted or unsubstituted aryl group. . When the number of hetero atoms (ie, oxygen atom, sulfur atom, or nitrogen atom) contained in the above-mentioned substituted or unsubstituted heteroaryl group is 2, the same hetero atom is represented by two identical atoms. Also, different types of atoms may be provided one by one.

Among the above-mentioned R ¹ , preferred examples of the unsubstituted heteroaryl group include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrimidinyl, benzofuryl, benzothienyl, indolyl, Quinolyl group, thiazolyl group, pyrazolyl group, oxazolyl group,
A group having 3 to 8 carbon atoms such as a benzoxazolyl group is exemplified. Examples of a suitable group as the unsubstituted aryl group include groups having 6 to 14 carbon atoms such as a phenyl group, an anthranyl group, and a phenanthrenyl group.

In the above R ¹ , the substituted heteroaryl group and the substituted aryl group include, as the unsubstituted groups, an alkyl group such as a methyl group, an ethyl group and a propyl group;
Chlorine atom, bromine atom, iodine atom, halogen atom such as fluorine atom, alkoxy group such as methoxy group, ethoxy group, propoxy group, alkylthio group such as methylthio group, ethylthio group, propylthio group, cyano group, nitro group, and amino And a group substituted with a group. Among these substituents, an alkyl group having 1 to 3 carbon atoms, a halogen atom, an alkoxy group having 1 to 3 carbon atoms, a cyano group, and a nitro group are particularly preferable.

Specific examples of suitably used substituted aryl groups and substituted heteroaryls include methylphenyl, ethylphenyl, propylphenyl, butylphenyl, hexylphenyl, dimethylphenyl,
Methyl (ethyl) phenyl, ethyl (prolyl) phenyl, chlorophenyl, bromophenyl, fluorophenyl, dichlorophenyl, methoxyphenyl, ethoxyphenyl, propoxyphenyl, dimethoxyphenyl, cyanophenyl, nitrophenyl Group, chloro (methyl) phenyl group, methyl (methoxy)
Phenyl, methylthiophenyl, (trifluoromethyl) phenyl, (dimethyl) aminophenyl, chloro (nitro) phenyl, methylnaphthyl, chloronaphthyl, methoxynaphthyl, dimethylnaphthyl, methylfuryl, methoxy Thienyl, chlorothienyl, methylthienyl, methylpyrrolyl, chloropyrrolyl, methylpyridyl, chloropyridyl, dimethoxypyrimidinyl, methoxybenzofuryl, chlorobenzofuryl, methylbenzothienyl, methylindolyl, methylquinolyl Group, methylthiazolyl group, methylpyrazolyl group, methyloxazolyl group, methylbenzoxazolyl group and the like.

In the general formula (1), R ² and R ³ are each independently a hydrogen atom or an alkyl group. R ² and R ³ may be linked to each other to form an alkylene group.

Suitable alkyl groups include methyl, ethyl, propyl, i-propyl, butyl, i-butyl, s-butyl, t-butyl, pentyl, hexyl, and heptyl. Examples thereof include a linear or branched alkyl group having 1 to 12 carbon atoms such as a group, an octyl group, a nonyl group, and a decyl group.

Suitable alkylene groups formed when R ² and R ³ are linked to each other include a tetramethylene group and a pentamethylene group. These alkylene groups form a cycloalkane ring, specifically a cyclopentane ring, a cyclohexane ring and the like, together with the carbon atom to which R ² and R ³ are bonded.

In the general formula (1), X represents a halogen atom or an alkoxy group. Suitable halogen atoms include fluorine, chlorine, bromine, iodine and the like. Among them, chlorine atoms are particularly preferable because they are industrially easily available.

The preferred alkoxy groups include:
Methoxy, ethoxy, propoxy, butoxy,
Examples thereof include groups having 1 to 4 carbon atoms such as a t-butoxy group.

In the general formula (1), p represents an integer of 1 to 3. Specific examples of the hydroxyalkyl group represented by (CH ₂ ) _p OH include a hydroxymethyl group, a hydroxyethyl group, and a hydroxypropyl group.

In the general formula (1), q represents an integer of 0 to 2. (CH ₂ ) _q X which is particularly preferable in combination with the above X
Specific examples of a halogenoalkyl group represented by and an alkoxyalkyl group include fluoromethyl group, fluoroethyl group, chloromethyl group, chloroethyl group, bromomethyl group, bromoethyl group, iodomethyl group, iodoethyl group, methoxymethyl group, Methoxyethyl group, ethoxymethyl group, ethoxyethyl group, propoxymethyl group,
Examples include a propoxyethyl group, a butoxymethyl group, a butoxyethyl group, and the like. In the general formula (1), r represents the number of carbonyl groups, and r is an integer of 1 or 2.

Among the raw material amide compounds, compounds that can be suitably used include those represented by the general formula (1):
R ¹ represents an oxygen atom, a sulfur atom, or a nitrogen atom
A substituted or unsubstituted heteroaryl group having 3 to 8 carbon atoms (however, not including the carbon number of the substituent) comprising 2;
Or a substituted or unsubstituted aryl group having 6 to 14 carbon atoms (however, the carbon number of the substituent is not included), and R ² and R ³ are each independently a hydrogen atom or an alkyl group having 1 to 12 carbon atoms. R ² and R ³ may be linked to each other to form an alkylene group, and X is a halogen atom or a group having 1 to 1 carbon atoms.
4 is an alkoxy group, p is an integer of 1 to 3,
Is an integer of 0 to 2, and r is an integer of 1 to 2, or (b) a compound in which X in the above (a) is a halogen atom, particularly a chlorine atom.

Specific examples of these preferred compounds include 2-chloro-N-hydroxymethyl-N- (1-phenylethenyl) acetamide (1) (a starting amide compound used in Example 1 described later). The numbers in parentheses represent the numbers of Examples in which the compound was used. The same applies hereinafter.), N-hydroxyethyl-N- (1-phenylethenyl) carbamoyl chloride (2), 2-chloro-
N-hydroxyethyl-N- (1-phenylethenyl)
Acetamide (3), N-hydroxyethyl-N- (1
-Phenylethenyl) oxamoylmethyl chloride (4), N-hydroxyethyl-N- (1-phenylethenyl) carbamoylmethyl chloride (5), N-hydroxypropyl-N- (1-phenylethenyl) oxamoyl Methyl chloride (6), 2-chloro-N-hydroxyethyl-N- (1-phenyl 1-propenyl)
Acetamide (7), N-hydroxyethyl-N- (1
-Phenyl 1-butenyl) oxamoylmethyl chloride (8), N-hydroxymethyl-N- (2-methyl-
1-phenyl-1-propenyl) oxamoyl chloride (9), N-hydroxyethyl-N- (2-methyl-
1-phenyl-1-propenyl) carbamoyl chloride (10), 2-chloro-N-hydroxyethyl-N-
(2-methyl-1-phenyl-1-propenyl) acetamide (11), N-hydroxyethyl-N- (2-methyl-1-phenyl-1-propenyl) oxamoylmethyl chloride (12), 2-fluoro- N-hydroxyethyl-N- (2-methyl-1-phenyl-1-propenyl) acetamide (13), 2-bromo-N-hydroxyethyl-N- (2-methyl-1-phenyl-1-)
Propenyl) acetamide (14), N-hydroxyethyl-N- (2-methyl-1-phenyl-1-propenyl) oxamoylmethyl bromide (15), 2-iodo-N-hydroxyethyl-N- (2-methyl -1-phenyl-1-propenyl) acetamide (16), N-
Hydroxyethyl-N- (2-methyl-1-phenyl-
1-propenyl) carbamoylmethyl chloride (1
7), 2-chloro-N-hydroxyethyl-N- (2-
Ethyl-1-phenyl-1-hexenyl) acetamide (18), N-hydroxyethyl-N- (cyclohexylphenyl) methenyl-oxamoylmethyl chloride (19), 2-chloro-N-hydroxyethyl-N-
[2-Methyl-1- (3-oxazolyl) -1-propenyl] acetamide (20), N-hydroxyethyl-
N- [2-methyl-1- (3-oxazolyl) -1-propenyl] -oxamoylmethyl chloride (21),
2-chloro-N-hydroxypropyl-N- [2-methyl-1- (p-cyanophenyl) -1-propenyl] acetamide (22), N-hydroxyethyl-N- [2
-Ethyl-1- (p-hydroxyphenyl) -1-hexenyl] -oxamoylmethyl chloride (23), 2
-Chloro-N-hydroxyethyl-N- (2-pyridylethenyl) acetamide (24), N-hydroxymethyl-N- [2-methyl-1- (2-pyridyl) -1-propenyl] -oxamoylmethyl chloride ( 25),
N-hydroxypropyl-N- [2-methyl-1- (2
-Methyl-4-thiazolyl)] oxamoylmethyl chloride (26), N-hydroxypropyl-N- [2-
Methyl-1- (2-methyl-4-thiazolyl)] oxamoylethyl chloride (27).

The target heterocyclic compound in the production method of the present invention is represented by the general formula (2). Specifically, it is a compound in which the raw material amide compound of the general formula (1) is cyclized by dehydrohalogenation or dealcoholation, and the structure of the compound is uniquely determined by the type of the raw material amide compound used. You. Therefore, R ¹ , R ² , R ³ , p, q and r in the general formula (2) are the same as those in the general formula (1).
Will be the same as

For example, when 2-chloro-N-hydroxymethyl-N- (1-phenylethenyl) acetamide (1) specifically exemplified as a raw material amide compound that can be suitably used, As a product, 3- (1-phenylethenyl) -4-oxazolidone in which R ¹ , R ² , R ³ , p, q and r in the general formula (2) are the same as the starting amide compound is obtained.

In the production method of the present invention, the starting amide compound is dehydrohalogenated in the presence of a base according to the type of X in the general formula (1) when X is a halogen atom, When X is an alkoxy group, it is cyclized by dealcoholation.

The base used at this time promotes the dehydrohalogenation / cyclization reaction or the dealcoholation / cyclization reaction and, in the case of the dehydrohalogenation reaction, captures the by-produced hydrogen halide. The base is not particularly limited as long as the base prevents decomposition of the raw material or the target substance or side reactions such as halogenation, and known bases can be used without any limitation. Specific examples of suitable bases include sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, metal alkoxides such as sodium phenoxide, lithium acetylide, acetylides such as sodium acetylide, Lithium diethylamide, lithium di-i
Metal amides such as -propylamide and sodium amide, amines such as trimethylamine, triethylamine, tripropylamine, tributylamine, di-i-propylethylamine, piperidine, pyrrolidine, pyridine, methyllithium, n-butyllithium, s- Butyllithium, t-butyllithium, organic lithiums such as phenyllithium, lithium hydride, sodium hydride,
Metal hydrides such as potassium hydride and calcium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and calcium hydroxide; alkali metals such as sodium carbonate, potassium carbonate and calcium carbonate Examples thereof include carbonates, alkali metal bicarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, alkali metal acetates such as sodium acetate, potassium acetate and calcium acetate, and calcium oxide and potassium formate.

Among the above bases, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide can be particularly preferably used because they give the desired heterocyclic compound in high yield.

The reaction conditions of the dehydrohalogenation / cyclization reaction or the dealcoholation / cyclization reaction in the production method of the present invention will be described below.

The above dehydrohalogenation / cyclization reaction or dealcoholation / cyclization reaction may be carried out without a solvent, but it is generally preferable to use a solvent. At this time, the solvent is not particularly limited, and a known solvent that does not react with the raw material and the product can be used. Specific examples of the solvent include aliphatic hydrocarbons such as pentane, hexane, heptane, and cyclohexane; aromatic hydrocarbons such as benzene, toluene, and xylene; 1,4-dioxane, diethyl ether, and di-i- Ethers such as propyl ether, 1,2-dimethoxyethane and tetrahydrofuran; halogenated hydrocarbons such as dichloromethane, carbon tetrachloride, chloroform and 1,2-dichloroethane; ketones such as acetone, methyl ethyl ketone and methyl-i-butyl ketone , Aromatic halogenated hydrocarbons such as chlorobenzene,
Esters such as methyl acetate, ethyl acetate, and butyl acetate;
Alcohols such as methanol, ethanol, 1-butanol and 2-butanol, amides such as N, N-dimethylformamide and N-methylpyrrolidone, nitriles such as acetonitrile, carbonates such as dimethyl carbonate, and sulfoxides such as dimethyl sulfoxide , Sulfur compounds such as carbon disulfide, and water. These solvents may be used alone or as a mixture of two or more.

When alcohols such as methanol and ethanol or a mixed solvent of alcohols and water are used among the above solvents, the reaction proceeds easily, and the desired heterocyclic compound is produced in high yield. Because you can get
Particularly preferred.

The amount of the solvent to be used at this time is not particularly limited, but the concentration of the amide compound represented by the above general formula (1) in the solvent is 0.1 to 50 from the viewpoint of economy and productivity.
It is preferred to use an amount which will range from 0.5% to 40% by weight, more preferably from 1% to 30% by weight.

The amount of the base used in the above reaction is not particularly limited.
In terms of equivalents to the raw material amide compound represented by the general formula (1), 0.9 equivalent to 20 equivalents, more preferably 0.1 equivalent.
It is preferably in the range of 9 to 10 equivalents.

The reaction may be carried out in a batch system or a flow system. The reaction is started when the starting amide compound comes into contact with the base. When the reaction is carried out batchwise, the reaction can be suitably carried out by appropriately charging predetermined amounts of the raw material amide compound, base and solvent in a reaction vessel and stirring the mixture under temperature control.

The reaction conditions may be appropriately set according to the types and amounts of the starting amide compound, base and solvent to be used so that the reaction is completed in about 0.1 to 30 hours in consideration of workability.

Generally, the reaction temperature is in the range of -30 to 100 ° C., preferably -20 to 100, for the purpose of preventing the formation of by-products and the coloring of the product and increasing the reaction efficiency.
It is good to carry out in the range of 80 ° C, more preferably in the range of -10 to 60 ° C. The reaction may be performed under normal pressure, under pressure, or under reduced pressure.

When the starting amide compound is brought into contact with the base under such conditions, hydrogen halide or alcohol is eliminated from the starting amide compound and cyclization occurs, whereby the target heterocyclic compound is formed. I do. The resulting heterocyclic compound can be isolated, for example, as follows. That is, first, an aqueous acid solution such as dilute hydrochloric acid is added to the reaction solution after the reaction to neutralize the base, and the residue is extracted with benzene, ether, chloroform, ethyl acetate or the like. Next, the extracted organic layer is washed with water or the like as necessary, and the organic layer is dried with a desiccant such as sodium sulfate, magnesium sulfate, or calcium chloride, and then isolated by distilling off the solvent. Can be done. The isolated heterocyclic compound can be purified by column chromatography, recrystallization, vacuum distillation, or the like, depending on the properties of the heterocyclic compound.

[0041]

The present invention will be described below with reference to examples and comparative examples, but the present invention is not limited to these examples.

Example 1 In a 200 ml four-necked corbene equipped with a thermometer, 4.51 g of 2-chloro-N-hydroxymethyl-N- (1-phenylethenyl) acetamide, 80 ml of ethanol and 1N sodium hydroxide were added. Add 22 ml of aqueous solution and add
Stirred at C for 12 hours. Thereafter, the reaction solution was ice-cooled, and 1N hydrochloric acid was added to make the reaction solution acidic. Under reduced pressure, the solvent was distilled off using a rotary evaporator, and the mixture was extracted with ethyl acetate. After the organic layer was washed with water, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography. As a result, 3.57 g of the desired product, 3- (1-phenylethenyl) -4-oxazolidone, was added to a viscous liquid. As obtained. The yield is 94.4%.
Met. High performance liquid chromatography (hereinafter HPLC)
As a result, the purity was 99.0%.

Examples 2 to 27 The same procedures and operations as in Example 1 were carried out except that the amide compounds and bases shown in Tables 1 to 5 were used.
Tables 1 to 5 show the results obtained when the analysis was performed using C.

[0044]

[Table 1]

[0045]

[Table 2]

[0046]

[Table 3]

[0047]

[Table 4]

[0048]

[Table 5]

COMPARATIVE EXAMPLE 1 In a 200 ml four-necked colben equipped with a thermometer, 2-hydroxy-N-hydroxyethyl-N- (2-methyl-
1-phenyl-1-propenyl) acetamide 4.99
g and concentrated hydrochloric acid (3 ml) were added, and the mixture was heated at 200 ° C. for 15 hours. Thereafter, the reaction solution was ice-cooled, and calcium oxide was added to neutralize the reaction solution. Then, the mixture was extracted with chloroform, the organic layer was washed with water, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography.
(2-methyl-1-phenyl-1-propenyl) -5
0.21 g of morpholinone was obtained as a viscous liquid. The yield was 4.5%. When analyzed by HPLC, the purity was 74.8%.

Comparative Example 2 In a 200 ml four-necked colben equipped with a thermometer, 4.14 g of 2-hydroxy-N-hydroxymethyl-N- (1-phenylethenyl) acetamide, p-toluenesulfonic acid monohydrate 0.04 g of the product and 100 ml of toluene were added, and the mixture was refluxed for 30 hours while removing generated water.
Thereafter, the reaction solution was washed with water, and the solvent was distilled off under reduced pressure. When the residue was purified by column chromatography, 0.30 g of 3- (1-phenylethenyl) -4-oxazolidone, which was the target substance, was obtained as a viscous liquid. The yield was 7.9%. When analyzed by HPLC, the purity was 87.3%.
Met.

Comparative Examples 1 and 2 are examples in which dialcoholamine is dehydrated using a strong acid, but the yield and purity of the target product are lower than those of the method of the present invention.

[0052]

According to the production method of the present invention, a heterocyclic compound expected to be used as a physiologically active substance such as an agricultural chemical or a medicine can be produced under mild conditions and with a high yield. Further, its purity is sufficiently high, and the production method of the present invention can be said to be extremely useful industrially.

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Claims (1)

[Claims] [Claim 1] The following general formula (1) (In the formula, R ¹ is an oxygen atom, a sulfur atom, or nitrogen atom comprising one or two substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted aryl group, R ² and R ³ is each independently a hydrogen atom or an alkyl group; R ² and R ³ may be mutually connected to form an alkylene group; p represents an integer of 1 to 3;
And r is an integer of 1 to 2, and X is a halogen atom or an alkoxy group. ) Is cyclized by dehydrohalogenation or dealcoholation in the presence of a base to give a compound represented by the following general formula (2): 中 In the formula, R ¹ , R ² , R ³ , p, q, and r are the same as those in the general formula (1). A method for producing a heterocyclic compound, characterized by obtaining the heterocyclic compound represented by｝.