JP2010083799A - Method for producing 1,2,4-oxadiazole derivative and method for producing (meth)acrylate 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 under mild conditions. <P>SOLUTION: The method for producing a 1,2,4-oxadiazole derivative represented by general formula (II) (wherein R<SP>1</SP>and R<SP>2</SP>are each an independently substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl or heterocyclic group) includes subjecting an O-acyl amidoxime compound represented by general formula (I) dissolved in an organic layer to a ring closure reaction in the presence of a water layer containing at least one inorganic basic compound. <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 the reaction to proceed at a high temperature of 80 ° C. or higher (preferably 100 ° C. or higher). When the reaction is performed at a low temperature of 80 ° C. or lower, the reaction is very slow, a long reaction time is required, and the reaction is not completed. There are few reports on a method in which the reaction is completed in a short time at a low temperature of 80 ° C. or lower. 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).
In addition, an example of producing a 1,2,4-oxadiazole derivative having a (meth) acrylate group from an O-acylamide oxime compound in one step has not been reported.
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 and an acrylate derivative under mild conditions.
Another object of the present invention is to provide a novel method for producing a 1,2,4-oxadiazole derivative having a (meth) acrylate group from an O-acylamide oxime compound in one step.

［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、又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を含む水層の存在下で閉環反応させることを含む、下記一般式（ＩＩ）

［式中、Ｒ¹及びＲ²は式（Ｉ）中のＲ¹及びＲ²と同義である］で表される１，２，４−オキサジアゾール誘導体の製造方法。 Means for solving the above problems are as follows.
[1] The following general formula (I) dissolved in the organic layer:

[Wherein, R ¹ and R ² each independently represents a substituted or unsubstituted alkyl group, alkenyl group, alkynyl group, aryl group, or heterocyclic group. ]
And a ring-closing reaction in the presence of an aqueous layer containing at least one inorganic basic compound, the following general formula (II):

[Wherein, R ¹ and R ² have the same meanings as R ¹ and R ² in formula (I)] method for producing a 1,2,4-oxadiazole derivative represented by.

［式中、Ｒ³は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、又はヘテロ環基を表し；Ｘはハロゲン原子を表し；Ｒ⁴は水素原子又はメチル基を表す。］で表される（メタ）アクリレート前駆体を、少なくとも１種の無機塩基性化合物を含む水層の存在下で、脱ハロゲン化反応させることを含む、下記一般式（AC）：

［式中、Ｒ³及びＲ⁴はそれぞれ、式（ACZ）中のＲ³及びＲ⁴と同義である。］で表される（メタ）アクリレート誘導体の製造方法。 [2] The following general formula (ACZ) dissolved in the organic layer:

[Wherein, R ³ represents a substituted or unsubstituted alkyl group, alkenyl group, alkynyl group, aryl group, or heterocyclic group; X represents a halogen atom; R ⁴ represents a hydrogen atom or a methyl group. The following general formula (AC), which comprises dehalogenating a (meth) acrylate precursor represented by the following formula in the presence of an aqueous layer containing at least one inorganic basic compound:

[Wherein, R ³ and R ⁴ have the same meanings as R ³ and R ^{4 in} formula (ACZ), respectively. ] The manufacturing method of the (meth) acrylate derivative represented by this.

［式中、Ｒ⁵及びＲ⁶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、又は下記一般式（Ａ）を表し、但し、Ｒ⁵及びＲ⁶の少なくとも１つは、下記一般式（Ａ）で表される基である。］

［式中、Ｌは、２価の連結基を表し、Ｘはハロゲン原子を表し、Ｒ⁴は水素原子又はメチル基を表し、＊は連結部位を示す。］で表される化合物を、少なくとも１種の無機塩基性化合物を含む水層の存在下で反応させて、下記一般式（IV）：

［式中、Ｒ⁵及びＲ⁶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、又は下記一般式（Ｂ）で表される基を表し、但し、Ｒ⁵及びＲ⁶の少なくとも１つは下記一般式（Ｂ）で表される基である。］

［式中、Ｌは、２価の連結基を表し、Ｒ⁴は水素原子又はメチル基を表し、＊は連結部位を示す。］で表される１，２，４−オキサジアゾール誘導体の製造方法。 [3] The following general formula (III) dissolved in the organic layer:

[Wherein, R ⁵ and R ⁶ each independently represents a substituted or unsubstituted alkyl group, alkenyl group, alkynyl group, aryl group, or the following general formula (A), provided that R ⁵ and R ⁶ At least one is a group represented by the following general formula (A). ]

[Wherein, L represents a divalent linking group, X represents a halogen atom, R ⁴ represents a hydrogen atom or a methyl group, and * represents a linking site. In the presence of an aqueous layer containing at least one inorganic basic compound, the following general formula (IV):

[Wherein, R ⁵ and R ⁶ each independently represents a substituted or unsubstituted alkyl group, alkenyl group, alkynyl group, aryl group, or group represented by the following general formula (B), provided that R ^At least one of ⁵ and R ⁶ is a group represented by the following general formula (B). ]

[Wherein L represents a divalent linking group, R ⁴ represents a hydrogen atom or a methyl group, and * represents a linking site. ] The manufacturing method of the 1,2,4-oxadiazole derivative represented by this.

According to the method of the present invention, 1,2,4-oxadiazole derivatives and acrylate derivatives can be produced under mild conditions, for example, at a temperature of 80 ° C. or less and in a short time.
Moreover, according to the present invention, a 1,2,4-oxadiazole derivative having a (meth) acrylate group can be produced from an O-acylamide oxime compound in one step.

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 included as a lower limit value and an upper limit value.
Further, in this specification, the term “(meth) acrylate” is used as a term meaning both “acrylate” and “methacrylate”.
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 general formula (II), R ¹ and R ² are each independently a substituted or unsubstituted alkyl group (preferably a C ₁ -C ₁₂ alkyl group) or alkenyl group (preferably a C ₂ -C ₁₂ alkenyl group). group), an alkynyl group (preferably an alkynyl group of C ₂ -C _12), aryl group (preferably an aryl group having C ₆ -C _10), 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. Each of 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 limit. Examples of the substituent include a halogen atom, a hydroxy group, a C _{1 to} C ₁₂ carboxyl group, a cyano group, a nitro group, a substituted or unsubstituted C _{1 to} C ₁₂ alkyl group, and a C _{1 to} C ₁₂ alkenyl. group, an alkynyl group of C ₁ -C _12, aryl group of C ₆ -C _12, heterocyclic group, alkoxy group C ₁ -C _12, acyl group of _{C 1 ~C 12, C 1 ~C} 12 alkylthio group , an acyloxy group of _{C 1 ~C 12, C 1 ~C} 12 alkoxy group, C ₁ -C ₁₂ carbamoyl groups, C ₁ -C ₁₂ acylamino group, a sulfonyloxy group, alkoxy sulfonyl C ₁ -C ₁₂ Groups etc. are included.

  In addition, the production method of the present invention is a 1,2,4-oxadiazole having a (meth) acrylate group represented by the following general formula (IV) among the compounds represented by the general formula (II). This is particularly effective as a method for obtaining a derivative.

In the formula, R ⁵ and R ⁶ each independently represents a substituted or unsubstituted alkyl group, alkenyl group, alkynyl group, aryl group, or group represented by the following general formula (B).
Examples and preferred ranges of the substituted or unsubstituted alkyl group, alkenyl group, alkynyl group, or aryl group represented by R ⁵ and R ⁶ in the formula (IV), respectively, are represented by R in the formula (II). The examples and the preferred ranges represented by ¹ and R ² are the same.
However, in the formula (IV), at least one of R ⁵ and R ⁶ is a group represented by the following general formula (B).

In the formula, L represents a divalent linking group, and R ⁴ represents a hydrogen atom or a methyl group.
Since the chemical properties and structural characteristics of the divalent linking group hardly affect the progress of the reaction, the divalent linking group is not particularly limited. Examples of the divalent linking group include —CH ₂ —, —O—, —S—, —C (═O) —, —NR ⁷ —, —CH═CH—, —C≡C—, divalent. And a divalent linking group selected from the group consisting of combinations thereof. R ⁷ is an alkyl group having 1 to 7 carbon atoms or a hydrogen atom, preferably an alkyl group having 1 to 4 carbon atoms or a hydrogen atom, and is a methyl group, an ethyl group, or a hydrogen atom. More preferably, it is most preferably a hydrogen atom.

  The divalent cyclic group is a divalent linking group having at least one kind of cyclic structure. The divalent cyclic group is preferably a 5-membered ring, a 6-membered ring, or a 7-membered ring. The ring contained in the cyclic group may be a condensed ring. Further, the ring contained in the cyclic group may be any of an aromatic ring, an aliphatic ring, and a heterocyclic ring. Examples of the aromatic ring include a benzene ring and a naphthalene ring. Examples of the aliphatic ring include a cyclohexane ring. Examples of the heterocyclic ring include a pyridine ring and a pyrimidine ring.

The divalent linking group may further have a substituent. Examples of such a substituent include a halogen atom, a hydroxy group, a C _{1 to} C ₁₂ carboxyl group, a cyano group, a nitro group, and a substituent. or unsubstituted alkyl group of C ₁ -C _12, alkenyl group of _{C 1 ~C 12, C 1 ~C} 12 alkynyl group, an aryl group of C ₆ -C _12, heterocyclic group, a C ₁ -C ₁₂ alkoxy groups, C ₁ -C ₁₂ acyl group, C ₁ -C ₁₂ alkylthio group, C ₁ -C ₁₂ acyloxy group, an alkoxycarbonyl group having _{C 1 ~C 12, C 1 ~C} 12 carbamoyl groups, C ₁ -C ₁₂ acylamino group, a sulfonyloxy group, include alkoxy sulfonyl group such C ₁ -C _12.

  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.

  Examples of O-acylamide oxime compounds used as starting materials include compounds represented by the following general formula (III).

In the formula, R ⁵ and R ⁶ each independently represent a substituted or unsubstituted alkyl group, alkenyl group, alkynyl group, aryl group, or the following general formula (A), provided that at least R ⁵ and R ⁶ One is a group represented by the following general formula (A).

In the formula, L represents a divalent linking group, X represents a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a chlorine atom), and R ⁴ represents a hydrogen atom. Alternatively, it represents a methyl group, and * represents a linking site.
About R < ⁵ >, R < ⁶ > and L in the said formula (III), it is synonymous with each in the said formula (IV), and its preferable range is 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 addition, carboxylic acid analog compounds and nitrile compounds, which are raw materials for O-acylamide oxime compounds, are often readily available, but when they are difficult to obtain, they can be converted from precursors by general synthetic techniques. . For example, the following precursors can be converted.

Further, for example, the substituents R ¹ and R ² can be synthesized with reference to RODD'S CHEMIDTRY OF CARBON COMPOUNDS SECOND EDITION; ELSEVIER SCIENTIFIC PUBLISHING COMPANY.

Wherein, R ¹ and R ² each have the same meanings as R ¹ and R ² in the 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 dissolved in an organic layer, and ring closure is performed in the presence of an aqueous layer containing an inorganic basic compound. By reacting, a 1,2,4-oxadiazole derivative represented by the general formula (II) is produced.

  Examples of the solvent used in the organic layer include esters such as ethyl acetate, propyl acetate, and butyl acetate; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chlorobenzene, and o-dichlorobenzene; tetrahydrofuran, tetrahydro Ethers such as pyran, diethyl 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 -N, N-dialkylamides such as dimethylformamide, 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 that an O-acylamide oxime compound has been formed, it is desirable to carry out a ring-closing reaction in the presence of an aqueous layer containing an inorganic basic compound.

Examples of inorganic basic compounds used in the reaction include hydroxides such as sodium hydroxide, potassium hydroxide and calcium hydroxide; carbonates such as sodium carbonate and potassium carbonate; sodium bicarbonate and potassium bicarbonate. Bicarbonates; phosphates such as trisodium phosphate, tripotassium phosphate and potassium pyrophosphate; Preferred are carbonates such as sodium carbonate and potassium carbonate; and phosphates such as trisodium phosphate and tripotassium phosphate. More preferred are sodium carbonate and potassium carbonate.
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.

  The reaction is preferably allowed to proceed at a temperature of −10 ° C. to 120 ° C., more preferably 20 ° C. to 90 ° C., and even more preferably 40 to 70 ° 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 the present invention, a (meth) acrylate precursor represented by the following general formula (ACZ) is dissolved in an organic layer and dehalogenated in the presence of an aqueous layer containing an inorganic basic compound. And a method for producing a (meth) acrylate derivative represented by the following general formula (AC).

In the formula, R ³ is a substituted or unsubstituted alkyl group (preferably a C _{1 to} C ₁₂ alkyl group), an alkenyl group (preferably a C _{2 to} C ₁₂ alkenyl group), an alkynyl group (preferably a C ₂ to C ₁₂ group). A C ₁₂ alkynyl group), an aryl group (preferably a C _{6 to} C ₁₂ aryl group), or a heterocyclic group (preferably containing at least one hetero ring selected from N, O and S 5 X represents a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom or a bromine atom, preferably a chlorine atom); R ⁴ Represents a hydrogen atom or a methyl group. R ³ may further have a substituent, and since the chemical properties and structural characteristics of the substituent hardly affect the progress of the reaction, the type of the substituent is not particularly limited. Examples of the substituent include a halogen atom, a hydroxy group, a C _{1 to} C ₁₂ carboxyl group, a cyano group, a nitro group, a substituted or unsubstituted C _{1 to} C ₁₂ alkyl group, and a C _{1 to} C ₁₂ alkenyl. group, an alkynyl group of C ₁ -C _12, aryl group of C ₆ -C _12, heterocyclic group, alkoxy group C ₁ -C _12, acyl group of _{C 1 ~C 12, C 1 ~C} 12 alkylthio group , an acyloxy group having _{C 1 ~C 12, C 1 ~C} 12 alkoxy group, C ₁ -C ₁₂ carbamoyl groups, C ₁ -C ₁₂ acylamino group, a sulfonyloxy group, alkoxy sulfonyl C ₁ -C ₁₂ Groups etc. are included.

  The (meth) acrylate precursor represented by the general formula (ACZ) can be synthesized by a known method. As shown below, a method of producing by reacting a hydroxyl group with an acid halide, acid anhydride or carboxylic acid is simple.

Further, for example, the substituent R ³ can be synthesized with reference to RODD'S CHEMIDTRY OF CARBON COMPOUNDS SECOND EDITION; ELSEVIER SCIENTIFIC PUBLISHING COMPANY.

The preferred ranges of the organic layer solvent, inorganic basic compound, and reaction conditions such as reaction time and reaction temperature used for the above reaction are determined by the ring-closing reaction of the compound of the above formula (I). This is the same as the method for obtaining the compound. That is, the ring closure reaction of the compound of the formula (I) and the dehalogenation reaction of the compound of the formula (ACZ) by the method of the present invention proceed under similar reaction conditions. Of course, the method of allowing the two reactions to proceed simultaneously is an embodiment of the production method of the present invention. That is, in one embodiment of the production method of the present invention, an O-acylamide oxime compound represented by the following formula (IIIa) having a (meth) acrylate precursor group is converted to the following formula (IVa And a method for producing a 1,2,4-oxadiazole derivative represented by formula (III); and other embodiments, an O-acylamide oxime represented by the following formula (IIIb) having a (meth) acrylate precursor group A process for producing a 1,2,4-oxadiazole derivative represented by the following formula (IVb) having a (meth) acrylate group from a compound. Note that R ⁴ , R ⁵ , R ^6, and L in the following formulas have the same meanings as in the above formulas (IV) and (III).

  In the above example, the ring-closing reaction of the O-acylamide oxime compound proceeds, and the dehalogenation reaction also proceeds. From the O-acylamide oxime compound, 1, 2, 2, having a (meth) acrylate group in one step. 4-Oxadiazole derivatives can be produced.

  Examples of compounds that can be produced by the reaction include, for example, Exemplified Compounds D1 to D200 and D248 to D330 described in JP-A-2006-76992, Exemplified Compounds D1 to D166 and D179 described in JP-A-2007-2220. -D187, D221-D260, D281-D299, D307-D313, D318-D325 and D328-D331, Exemplified compounds D1-D166, D179-D184 and D218-D257 described in JP-A-2007-204705 it can. However, it is not limited to these.

  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]
[Synthesis of D-1]
D-1 was synthesized from ACZ-1 synthesized by a conventional method according to the following scheme.

11.4 g of ACZ-1 was dissolved in a mixed solution of 40 mL of ethyl acetate and 20 mL of acetonitrile, and after adding 90 mL of 2.1 mL of triethylamine and 1 mol / L sodium carbonate aqueous solution, the mixture was stirred at 70 ° C. for 4 hours. After cooling, methanol was added to the organic layer, and the precipitated crystals were collected by filtration. Purification was performed by column chromatography to obtain 9.0 g (yield 92%) of D-1. The NMR spectrum of D-1 obtained was as follows.
¹ H-NMR (solvent: CDCl _3, standard: tetramethylsilane) [delta] (ppm):
1.60-1.70 (6H, m)
1.75-1.85 (6H, m)
1.85-1.95 (6H, m)
4.15 (6H, t)
4.25 (6H, t)
5.85 (3H, dd)
6.15 (3H, dd)
6.45 (3H, dd)
7.15 (3H, d)
7.45 (3H, dd)
7.75 (3H, s)
7.85 (3H, d)
9.30 (3H, s)

[Example 2]
[Synthesis of D-2]
D-2 was synthesized from ACZ-2 synthesized by a conventional method according to the following scheme.

13.0 g of ACZ-2 was dissolved in 60 mL of methyl ethyl ketone, and after adding 1.1 mL of triethylamine and 90 mL of 1 mol / L aqueous sodium carbonate solution, the mixture was stirred at 60 ° C. for 5 hours. After cooling, methanol was added to the organic layer, and the precipitated crystals were collected by filtration. Purification by column chromatography gave 9.7 g (yield 90%) of D-2. The NMR spectrum of D-2 obtained was as follows.
¹ H-NMR (solvent: CDCl ₃ , standard: tetramethylsilane) δ (ppm):
1.40-1.60 (12H, m)
1.65-1.75 (6H, m)
1.75-1.85 (6H, m)
4.15 (6H, t)
4.25 (6H, t)
5.80 (3H, dd)
6.15 (3H, dd)
6.45 (3H, dd)
7.10 (3H, dd)
7.90-8.00 (6H, m)
9.25 (3H, s)

[Comparative Example 1]
Reaction of ACZ-1 of Example 1 was carried out by the method described in the literature.
11.4 g of ACZ-1 was dissolved in 100 mL of tetrahydrofuran, and 2.0 g of tetra-n-butylammonium fluoride was added. Although it stirred at room temperature for 5 hours, the production | generation of D-1 was not able to be confirmed by HPLC.

Claims (3)

The following general formula (I) dissolved in the organic layer:

[Wherein, R ¹ and R ² each independently represents a substituted or unsubstituted alkyl group, alkenyl group, alkynyl group, aryl group, or heterocyclic group. ]
And a ring-closing reaction in the presence of an aqueous layer containing at least one inorganic basic compound, the following general formula (II):

[Wherein, R ¹ and R ² have the same meanings as R ¹ and R ² in formula (I)] method for producing a 1,2,4-oxadiazole derivative represented by. The following general formula (ACZ) dissolved in the organic layer:

[Wherein, R ³ represents a substituted or unsubstituted alkyl group, alkenyl group, alkynyl group, aryl group, or heterocyclic group; X represents a halogen atom; R ⁴ represents a hydrogen atom or a methyl group. The following general formula (AC), which comprises dehalogenating a (meth) acrylate precursor represented by the following formula in the presence of an aqueous layer containing at least one inorganic basic compound:

[Wherein, R ³ and R ⁴ have the same meanings as R ³ and R ^{4 in} formula (ACZ), respectively. ] The manufacturing method of the (meth) acrylate derivative represented by this. The following general formula (III) dissolved in the organic layer:

[Wherein, R ⁵ and R ⁶ each independently represents a substituted or unsubstituted alkyl group, alkenyl group, alkynyl group, aryl group, or the following general formula (A), provided that R ⁵ and R ⁶ At least one is a group represented by the following general formula (A). ]

[Wherein, L represents a divalent linking group, X represents a halogen atom, R ⁴ represents a hydrogen atom or a methyl group, and * represents a linking site. In the presence of an aqueous layer containing at least one inorganic basic compound, the following general formula (IV):

[Wherein, R ⁵ and R ⁶ each independently represents a substituted or unsubstituted alkyl group, alkenyl group, alkynyl group, aryl group, or group represented by the following general formula (B), provided that R ^At least one of ⁵ and R ⁶ is a group represented by the following general formula (B). ]

[Wherein L represents a divalent linking group, R ⁴ represents a hydrogen atom or a methyl group, and * represents a linking site. ] The 1,2,4-oxadiazole derivative represented by this is manufactured.