JP2010070528A - Method for producing 1,2,4-oxadiazole derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing a 1,2,4-oxadiazole derivative from an O-acyl amidoxime compound. <P>SOLUTION: The 1,2,4-oxadiazole derivative expressed by general formula (II) is produced by ring closure reaction of the O-acyl amidoxime compound expressed by general formula (I) (R<SP>1</SP>and R<SP>2</SP>are each alkyl, alkenyl, alkynyl, aryl or a heterocyclic group) in the presence of at least one kind of inorganic base compounds and at least one kind of phase transfer catalysts. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a method for producing a 1,2,4-oxadiazole derivative. 1,2,4-oxadiazole derivatives are useful as pharmaceuticals, agricultural chemicals, electron transport materials, liquid crystal materials, and the like.

As a method for producing 1,2,4-oxadiazole, ring closure of O-acylamide oxime is the most common method, and the O-acylamide oxime compound is heated at a high temperature or as a reaction aid. , Acetyl chloride, acetic anhydride, cyclic acid anhydride, a method using molecular sieve, and the like are known (Non-patent Document 1 and Patent Document 1). However, these methods generally require a reaction to proceed at a high temperature of 80 ° C. or higher, or a reaction for a long time, and a report on a method in which the reaction is completed in a short time near room temperature. There is almost no. In the case where tetrabutylammonium fluoride is used as a reaction aid, the reaction proceeds near room temperature, but there are almost no examples in which the substituent of O-acylamide oxime is an aryl group or a heterocyclic group (Non-Patent Document) 2) Or the yield is poor, and most is less than 50% (Non-patent Document 3).
Z. Chem., 1969, 9, pp. 58 Tetrahedron Lett., 2001, 42, 1441 Bioorg. Med. Chem. Lett., 2001, 11, 753 JP 2007-084449 A

  An object of the present invention is to provide a novel method capable of producing a 1,2,4-oxadiazole derivative under mild conditions.

［式中、Ｒ¹及びＲ²はそれぞれ独立に、置換もしくは無置換の、アルキル基、アルケニル基、アルキニル基、アリール基、またはヘテロ環基を表す。］で表されるＯ−アシルアミドオキシム化合物を、少なくとも１種の無機塩基性化合物及び少なくとも１種の相間移動触媒の存在下で閉環反応させることを特徴とする、下記一般式（ＩＩ）

［式中、Ｒ¹及びＲ²は前記と同じ］で表される１，２，４−オキサジアゾール誘導体の製造方法。
［２］ 一般式（Ｉ）及び一般式（ＩＩ）において、Ｒ¹及びＲ²がそれぞれ独立に、置換もしくは無置換の、アリール基又はヘテロ環基であることを特徴とする［１］の方法。
［３］ 下記一般式（ＩＩＩ）又は下記一般式（ＩＶ）

［式中、Ｒ³及びＲ⁴はそれぞれ独立に、置換もしくは無置換の、アリール基又はヘテロ環基を表し、ｍ及びｎはそれぞれ独立に１〜６の整数を表す。］で表されるＯ−アシルアミドオキシム化合物を、少なくとも１種の無機塩基性化合物及び少なくとも１種の相間移動触媒の存在下で閉環反応させることを特徴とする、下記一般式（Ｖ）又は下記一般式（ＶＩ）

［式中、Ｒ³、Ｒ⁴、ｍ及びｎは前記と同義］で表される１，２，４−オキサジアゾール誘導体の製造方法。
［４］ 前記少なくとも１種の無機塩基性化合物が、リン酸塩であることを特徴とする［１］〜［３］のいずれかの方法。
［５］ 前記少なくとも１種の相間移動触媒が、クラウンエーテル類であることを特徴とする［１］〜［４］のいずれかの方法。 Means for solving the above problems are as follows.
[1] The following general formula (I)

[Wherein, R ¹ and R ² each independently represents a substituted or unsubstituted alkyl group, alkenyl group, alkynyl group, aryl group, or heterocyclic group. The O-acylamide oxime compound represented by the general formula (II) is subjected to a ring-closing reaction in the presence of at least one inorganic basic compound and at least one phase transfer catalyst.

[Wherein, R ¹ and R ² are the same as described above] A method for producing a 1,2,4-oxadiazole derivative represented by the formula:
[2] The method according to [1], wherein in general formula (I) and general formula (II), R ¹ and R ² are each independently a substituted or unsubstituted aryl group or heterocyclic group .
[3] The following general formula (III) or the following general formula (IV)

[Wherein, R ³ and R ⁴ each independently represents a substituted or unsubstituted aryl group or heterocyclic group, and m and n each independently represents an integer of 1 to 6. A ring closure reaction in the presence of at least one inorganic basic compound and at least one phase transfer catalyst, the following general formula (V) or Formula (VI)

[Wherein R ³ , R ⁴ , m and n are as defined above], a method for producing a 1,2,4-oxadiazole derivative represented by:
[4] The method according to any one of [1] to [3], wherein the at least one inorganic basic compound is a phosphate.
[5] The method according to any one of [1] to [4], wherein the at least one phase transfer catalyst is a crown ether.

  According to the method of the present invention, a 1,2,4-oxadiazole derivative can be produced under mild conditions, for example, near room temperature and in a short time.

Hereinafter, the present invention will be described in detail. In the present specification, “to” is used to mean that the numerical values described before and after it are used as the lower limit and the upper limit. The present invention relates to a method for producing a 1,2,4-oxadiazole derivative. The 1,2,4-oxadiazole derivative obtained by the production method of the present invention is a compound represented by the following general formula (II).

In the general formula (II), R ¹ and R ² are each independently a substituted or unsubstituted alkyl group (preferably a C _{1 to} C ₂₀ alkyl group) or alkenyl group (preferably a C _{2 to} C ₂₀ alkenyl group). group), an alkynyl group (preferably an alkenyl group having C ₂ -C _20), aryl group (preferably an aryl group having C ₆ -C _18), or a Hajime Tamaki (preferably selected from N, O and S Represents a 5- to 7-membered monocyclic ring containing at least one hetero ring and a condensed ring with another ring). R ¹ and R ² are preferably a substituted or unsubstituted aryl group or heterocyclic group, and more preferably a substituted or unsubstituted benzene ring group (phenyl group) or naphthalene ring group (naphthyl group). is there. R ¹ and R ² may further have a substituent, and the chemical properties and structural characteristics of the substituent hardly affect the progress of the reaction. There is no. Examples of the substituent include a halogen atom, a hydroxy group, a carboxyl group, a cyano group, a nitro group, a substituted or unsubstituted C _{1 to} C ₂₀ alkyl group, a C _{2 to} C ₂₀ alkenyl group, and a C _{2 to} C ₂₀ alkynyl groups, C ₆ -C ₁₈ aryl groups, heterocyclic groups, C ₁ -C ₂₀ alkoxy groups, C ₂ -C ₂₀ acyl groups, C ₁ -C ₂₀ alkylthio groups, C ₂ -C ₂₀ an acyloxy group, an alkoxycarbonyl group having C ₁ -C _20, a carbamoyl group of C ₁ -C _20, an acylamino group of C ₂ -C _20, a sulfonyloxy group, include alkoxy sulfonyl group such C ₁ -C _20.

  The production method of the present invention is particularly effective as a method for obtaining a compound represented by the following general formula (V) or general formula (VI) among the compounds represented by the general formula (II).

In general formula (V) and general formula (VI), R ³ and R ⁴ are synonymous with R ¹ or R ² , and preferred ranges are also the same, and R ³ and R ⁴ are each substituted or unsubstituted. A benzene ring group (phenyl group) or a naphthalene ring group (naphthyl group) is particularly preferable. The benzene ring group (phenyl group) or naphthalene ring group (naphthyl group) may have a substituent, and examples of the substituent include examples of the substituent that R ¹ and R ² may have. It is the same. When R ³ and R ⁴ are each a phenyl group having a substituent at the p-position, the reaction proceeds more rapidly as the substituent is an electron-donating group, and conversely, it is an electron-withdrawing group. The reaction becomes slower. However, in spite of such a tendency, the reaction of the present invention can be completed within a realistic and economical time range according to the method of the present invention. Examples of applicable substituents in the present invention, halogen atom, hydroxy group, carboxyl group, a cyano group, a nitro group, a substituted or unsubstituted C ₁ -C ₂₀ alkyl group, alkenyl group C ₂ -C ₂₀ , an alkynyl group of C ₂ -C _20, aryl group of C ₆ -C _18, heterocyclic group, alkoxy group C ₁ -C _20, acyl group C ₂ -C _20, an alkylthio group of C ₁ -C _20, acyloxy group C ₂ -C _20, alkoxycarbonyl group of _{C 1 ~C 20, C 1 ~C} 20 carbamoyl group, an acylamino group of C ₂ -C _20, a sulfonyloxy group, alkoxy sulfonyl group C ₁ -C ₂₀ Etc. are included. In addition, even when a phenyl group having a substituent at the m-position or a phenyl group having a substituent at the o-position is used, there is a difference in reactivity due to electronic effects and steric effects due to the types of the respective substituents. In any case, it can be used in the same manner as a phenyl group having a substituent at the p-position.
m and n are each independently an integer of 1 to 6, preferably 2 (for example, 1- and 3-position substitution) or 3 (for example, 1, 3, and 5-position substitution), more preferably 3 is there.

  In the method of the present invention, an O-acylamide oxime compound represented by the following general formula (I) is used as a starting material.

In the formula, R ¹ and R ² each independently represents a substituted or unsubstituted alkyl group, alkenyl group, alkynyl group, aryl group, or heterocyclic group. R ¹ and R ² in the formula have the same meanings as those in the general formula (II), and preferred ranges are also the same.

  The O-acylamide oxime compound represented by the general formula (I) can be synthesized by a known method. A method of producing by reacting an amide oxime with an acylating agent such as an acid halide or an acid anhydride is simple.

In formula, R < ¹ > and R < ² > is synonymous with each in the said general formula (I) and (II).

  The O-acylamide oxime compound produced by the above method may be isolated, or may be used as a starting material for the ring-closure reaction step according to the production method of the present invention as it is without isolation. The above reaction is usually performed in a solvent. Examples of solvents that can be used include esters such as ethyl acetate, propyl acetate and butyl acetate; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chlorobenzene and o-dichlorobenzene; tetrahydrofuran, tetrahydropyran, diethyl Ethers such as ether, 1,4-dioxane, ethylene glycol dimethyl ether and cyclopentyl methyl ether; Aliphatic hydrocarbons such as hexane and heptane; Aromatic hydrocarbons such as benzene, toluene and xylene; N, N-dimethylformamide N, N-dialkylamides such as N, N-dimethylacetamide; and N-alkyllactams such as N-methyl-2-pyrrolidone; These solvents can be used alone or in admixture of two or more. The reaction proceeds at a temperature of about -20 ° C to 60 ° C, preferably at a temperature of about -10 ° C to 20 ° C. The reaction time is usually 0.5 to 96 hours, preferably 0.5 to 8 hours. The amount of the amide oxime used is 1 to 20 molar equivalents, preferably 1 to 6 molar equivalents (respectively) per 1 mol of the acylating agent. The progress of the reaction may be promoted in the presence of a base, and the amount of the base used is 1 to 10 molar equivalents, preferably 1 to 2 molar equivalents relative to 1 mol of the amide oxime.

  In the production method of the present invention, as shown below, the O-acylamide oxime compound represented by the general formula (I) is reacted in the presence of at least one inorganic basic compound and at least one phase transfer catalyst. A 1,2,4-oxadiazole derivative represented by the general formula (II) is produced by ring-closing reaction. The phase transfer catalyst used in the method of the present invention may be a cation having phase transfer activity, and does not need to act as a catalyst that moves between two phases in the reaction shown below. .

  This reaction is usually performed in the presence of a solvent. Examples of solvents that can be used include esters such as ethyl acetate, propyl acetate and butyl acetate; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chlorobenzene and o-dichlorobenzene; tetrahydrofuran, tetrahydropyran, diethyl Ethers such as ether, 1,4-dioxane, ethylene glycol dimethyl ether and cyclopentyl methyl ether; Aliphatic hydrocarbons such as hexane and heptane; Aromatic hydrocarbons such as benzene, toluene and xylene; N, N-dimethylformamide N, N-dialkylamides such as N, N-dimethylacetamide; N-alkyllactams such as N-methyl-2-pyrrolidone; and mixtures thereof. Preferred are methyl ethyl ketone, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone and mixtures thereof. As described above, an O-acylamide oxime compound may be produced from an amide oxime and an acylating agent, and the ring closure reaction may be subsequently performed from the mixture. Even if the above-mentioned base is mixed in the mixture, the reaction progress may be hindered. Don't be. In this case, after confirming the formation of the O-acylamide oxime compound, it is desirable to add an inorganic basic compound and a phase transfer catalyst to carry out a ring-closing reaction.

The ring closure reaction of O-acylamide oxime compounds is presumed to proceed by addition reaction of amino group to carbonyl group, followed by dehydration reaction. From the conventional knowledge, it is considered that the basic compound increases the reaction rate of either or both of them, but in the present invention, an inexpensive and safe inorganic basic compound is used in combination with the phase transfer catalyst. It becomes possible. Examples of inorganic basic compounds applicable to this reaction include hydroxides such as sodium hydroxide, potassium hydroxide and calcium hydroxide; carbonates such as sodium carbonate and potassium carbonate; carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate. Hydrogen salts; phosphates such as trisodium phosphate, tripotassium phosphate, potassium pyrophosphate, and the like. Preferred are carbonates such as sodium carbonate and potassium carbonate; and phosphates such as trisodium phosphate and tripotassium phosphate. More preferred are phosphates, among which trisodium phosphate and tripotassium phosphate are preferred.
The usage-amount of the said inorganic basic compound is 0.1-20 molar equivalent with respect to O-acylamide oxime compound, Preferably it is 0.1-6 molar equivalent.

Examples of the phase transfer catalyst used in the reaction include tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, tetra-n-butylammonium iodide, tetra-n-butylammonium sulfate, tetrahydrogensulfate. Quaternary ammonium salts such as n-butylammonium chloride, triethylbenzylammonium chloride, trioctylmethylammonium chloride; quaternary phosphonium salts such as trimethylphenylphosphonium bromide; pyridinium salts such as n-dodecylpyridinium chloride; 18-crown-6 , 15-crown-5 and the like crown ethers. Preferably, tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, tetra-n-butylammonium iodide, tetra-n-butylammonium sulfate, tetra-n-butylammonium hydrogensulfate, and triethylbenzyl chloride Quaternary ammonium salts such as ammonium; and crown ethers such as 18-crown-6 and dibenzo-18-crown-6.
The amount of the phase transfer catalyst used is 0.0001 to 2 molar equivalents, preferably 0.001 to 1 molar equivalents, relative to the O-acylamide oxime compound.

  The reaction is preferably allowed to proceed at a temperature of −10 ° C. to 120 ° C., more preferably 0 ° C. to 80 ° C., and even more preferably 0 to 60 ° C. Although there is no restriction | limiting in particular about reaction time, About 30 minutes-8 hours are economically preferable.

  If necessary, the target compound represented by the above formula (II) obtained by the above method is usually used in a conventional manner, for example, recrystallization, reprecipitation, distillation, etc. Can be separated and purified. More specifically, adsorption column chromatography using a carrier such as silica gel, alumina, magnesium-silica gel type florisil; Sephadex LH-20 (Pharmacia), Amberlite XAD-11 (Rohm and A method using a synthetic adsorbent such as partition column chromatography using a carrier such as Diaion HP-20 (manufactured by Mitsubishi Kasei); a method using ion exchange chromatography; or a silica gel or an alkyl Can be separated and purified by eluting with an appropriate eluent by a suitable combination of normal phase / reverse phase column chromatography (preferably high performance liquid chromatography) using activated silica gel. .

  In addition, although the aspect which manufactures the compound represented by general formula (II) from the compound represented by the said general formula (I) was demonstrated in detail above, from the compound represented by general formula (III) In the embodiment for producing the compound represented by the general formula (V), and the embodiment for producing the compound represented by the general formula (VI) from the compound represented by the general formula (IV), the target production is performed according to the above conditions. You can get things.

  The features of the present invention will be described more specifically with reference to examples and comparative examples. The materials, amounts used, ratios, processing details, processing procedures, and the like shown in the following examples can be changed as appropriate without departing from the spirit of the present invention. Therefore, the scope of the present invention should not be construed as being limited by the specific examples shown below.

[Example 1]
The following compound D-3B was synthesized according to Example 1 described in JP-A-2006-076992.
Next, compound D-3 was synthesized according to the following scheme using synthesized compound D-3B as a starting material.

D-3B (29.0 g) and N, N-dimethylaniline (18.6 g) were dissolved in 300 mL of ethyl acetate, cooled in an ice bath, and trimesic acid trichloride (10.2 g) was dissolved in 30 mL of ethyl acetate. And dropped. After stirring at room temperature for 1 hour, the organic layer was washed with 200 mL of 2% hydrochloric acid, and then washed twice with 200 mL of water. The organic layer was concentrated under reduced pressure to obtain 33 g of a solid. This solid was confirmed by HPLC to be D-3C and several impurities.
This solid was dissolved in 150 mL of tetrahydrofuran, tripotassium phosphate (24.5 g) as an inorganic basic compound, and 18-crown-6 (company name: Aldrich product number: 186651) (3.0 g) as a phase transfer catalyst. ) Was added. The mixture was stirred at room temperature for 2 hours, and disappearance of D-3C and formation of D-3 were confirmed by HPLC. 200 mL of methylene chloride was added and washed 3 times with 200 mL of water. Crystals were precipitated by adding 800 mL of methanol to the organic layer, filtered, washed with methanol, and dried. The crystals were dissolved in ethyl acetate, adsorbed with alumina and silica gel, recrystallized with methanol, and 28.8 g of 1,2,4-oxadiazole compound (D-3) (white crystals, yield). 92.5%, HPLC purity 96%). The NMR spectrum of D-3 obtained was as follows.
1H-NMR (solvent: CDCl ₃ , standard: tetramethylsilane) δ (ppm): 0.85 (9H, t), 1.25-1.35 (12H, m), 1.35-1.45 ( 6H, m), 1.70-1.80 (6H, m), 3.95 (6H, t), 6.95 (6H, d), 8.05 (6H, d), 9.10 (3H) , S).

[Example 2]
In Example 1, acetonitrile was used instead of tetrahydrofuran, potassium carbonate (16.0 g) as an inorganic salt compound was used instead of tripotassium phosphate, and another phase transfer catalyst was used instead of 18-crown-6. The reaction was allowed to proceed in the same manner as in Example 1 except that some tetra-n-butylammonium hydrogen sulfate (3.5 g) was used. After stirring at room temperature for 6 hours, disappearance of D-3C and formation of D-3 were confirmed by HPLC. Thereafter, by the same isolation procedure as in Example 1, the 1,2,4-oxadiazole compound (D-3) was obtained in a yield of 91.2% and HPLC purity of 95%.

[Comparative Example 1]
In Example 1, the reaction was carried out in the same manner as in Example 1, except that tripotassium phosphate and 18-crown-6 were not added, but tetra-n-butylammonium fluoride (3.0 g) was added instead. However, even after stirring for 8 hours, disappearance of D-3C could not be confirmed by HPLC, and formation of D-3 could not be confirmed.

Claims (5)

The following general formula (I)

[Wherein, R ¹ and R ² each independently represents a substituted or unsubstituted alkyl group, alkenyl group, alkynyl group, aryl group, or heterocyclic group. The O-acylamide oxime compound represented by the general formula (II) is subjected to a ring-closing reaction in the presence of at least one inorganic basic compound and at least one phase transfer catalyst.

[Wherein, R ¹ and R ² are the same as described above] A method for producing a 1,2,4-oxadiazole derivative represented by the formula: ^2. The method according to claim 1, wherein in the general formula (I) and the general formula (II), R ¹ and R ² are each independently a substituted or unsubstituted aryl group or heterocyclic group. The following general formula (III) or the following general formula (IV)

[Wherein, R ³ and R ⁴ each independently represents a substituted or unsubstituted aryl group or heterocyclic group, and m and n each independently represents an integer of 1 to 6. A ring closure reaction in the presence of at least one inorganic basic compound and at least one phase transfer catalyst, the following general formula (V) or Formula (VI)

[Wherein R ³ , R ⁴ , m and n are as defined above], a method for producing a 1,2,4-oxadiazole derivative represented by: The method according to claim 1, wherein the at least one inorganic basic compound is a phosphate. The method according to claim 1, wherein the at least one phase transfer catalyst is a crown ether.