KR101344765B1 - Process for preparing 4,5-dihydrooxazol-2-ylbenzene derivatives - Google Patents

Abstract

The present invention relates to a method for preparing a 4,5-dihydrooxazol-2-ylbenzene compound or a salt thereof by cyclizing a hydroxyalkyl benzamide compound.

Description

Process for preparing 4,5-dihydrooxazol-2-ylbenzene derivatives

The present invention relates to a process for the preparation of 4,5-dihydrooxazol-2-ylbenzene derivatives.

4,5-dihydrooxazol-2-ylbenzene derivatives are known to have pesticidal effects. [International Patent Publication WO 2003/016304, Chinese Patent Publication CN 101863884]

 International Publication No. WO 2003/016304 does not disclose a specific method for the preparation of 4,5-dihydrooxazolylaniline derivatives. In Chinese Patent Application No. CN 101863884, a method for preparing a compound represented by the following Chemical Formula I-a is shown by the preparation method shown in Scheme 1 below.

[Reaction Scheme 1]

According to the preparation method according to Scheme 1, the amide represented by the formula (III-2) by reacting the acyl chloride compound represented by the formula (III-3) with the bromoethylamine represented by the formula (V) Prepare the compound. Then, the amide compound represented by the formula (III-2) is cyclized to prepare a 4,5-dihydrooxazolyl compound represented by the formula (III-1). Then, the nitro group of the compound represented by the formula (III-1) is reduced to prepare an amine compound represented by the formula (III). Then, the 4,5-dihydrooxazol-2-ylbenzene derivative represented by the general formula (Ia) is reacted by reacting the amine compound represented by the general formula (III) with the carboxylic acid compound represented by the general formula (IV). Prepared.

However, the conventional production method according to Scheme 1 has a limitation in that it is commercially available because the production process is composed of multiple steps and the yield of the final desired compound is very low.

Therefore, there is an urgent need for development of an improved manufacturing method capable of more efficiently synthesizing 4,5-dihydrooxazol-2-ylbenzene derivatives useful as agricultural agents such as insecticides.

It is an object of the present invention to provide a method for commercially preparing 4,5-dihydrooxazol-2-ylbenzene derivatives or salts thereof.

In order to solve the above problems, the present invention

Preparing a 4,5-dihydrooxazol-2-ylbenzene derivative represented by the following Chemical Formula 1 by cyclizing the hydroxyalkyl benzamide compound represented by the following Chemical Formula 2; It is characterized by a method for producing a 4,5-dihydrooxazol-2-ylbenzene derivative or a salt thereof.

[Reaction Scheme 2]

(In Reaction Scheme 2, R ₁ is a halogen atom or a C ₁ -C ₄ haloalkyl group substituted with 1 to 8 halogen atoms; R ₂ represents a halogen atom or a cyano group; R ₃ , R ₄ , R ₅ , And R ₆ are the same as or different from each other and are a hydrogen atom or a C ₁ -C ₄ alkyl group.)

The cyclization reaction of the present invention is relatively mild in the reaction conditions, it is easy to handle the reaction reagent used.

The cyclization reaction of the present invention makes it possible to synthesize the desired 4,5-dihydrooxazol-2-ylbenzene derivative in a high yield of at least 75%.

The cyclization reaction of the present invention is capable of synthesizing the desired 4,5-dihydrooxazol-2-ylbenzene derivative in excellent production yield regardless of the kind of the parent nucleus or peripheral substituents to which the hydroxyalkylamide group is bound. .

Therefore, the present invention is useful as a method for commercially mass-producing 4,5-dihydrooxazol-2-ylbenzene derivatives represented by Formula 1 or salts thereof.

Hereinafter, a method for preparing 4,5-dihydrooxazol-2-ylbenzene derivative represented by Chemical Formula 1 or a salt thereof according to the present invention will be described in detail.

For a method of cyclizing a hydroxyalkylamide group to convert it into a 4,5-dihydrooxazole group, see Chem. Eur. J., 1998, 4, p. 819. In the cyclization reaction of hydroxyalkylamides, hydroxyalkylamide groups are generally activated to chloroamide groups using thionyl chloride (SO ₂ Cl), and then cyclized under appropriate basic conditions to give 4,5-dihydro. The process proceeds in two steps to conversion to oxazole groups. However, the above-mentioned general manufacturing method has a large difference in the production yield depending on the parent nucleus or peripheral substituents to which the hydroxyalkylamide group is bound. In addition, since many side reactions occur in the process of activating with chloroamide group, it acts as a factor to lower the production yield.

Furthermore, the hydroxyalkyl benzamide compound represented by Formula 2, which is used as a raw material of the present invention, has a selective ring for the hydroxyalkylamide group due to the structural characteristic of having two amide groups in one molecular structure. It is not easy to induce the reaction. That is, due to the chemical structural characteristics of the hydroxyalkyl benzamide compound represented by Formula 2, the production yield is very low by general cyclization reaction.

However, in the present invention, by performing a selective cyclization reaction for the hydroxyalkyl amide group in the compound represented by the formula (2), 4,5-dihydrooxazole represented by the formula (1) in a high production yield It was possible to synthesize 2-ylbenzene derivatives. In particular, the production method of the present invention can obtain the desired cyclized compound in excellent production yield regardless of the kind of the parent nucleus or peripheral substituents to which the hydroxyalkylamide group is bound.

In the cyclization reaction of the compound represented by Formula 2 according to the present invention, (diethylamino) sulfur trifluoride (DAST) or para-toluenesulfonate (TsOH) is selected as a reaction reagent.

In addition, the cyclization reaction of the present invention can be carried out in the presence of a conventional organic or inorganic base. Tri (C ₁ -C ₆ ) alkylamine may be used as the organic base, and specifically trimethylamine, triethylamine, diethylisopropylamine, or the like may be used. As the inorganic base, hydroxides, hydrides and C ₁ -C ₆ alkoxides of alkali metals or alkaline earth metals can be used. Specifically, lithium hydroxide, sodium hydroxide, calcium hydroxide, sodium hydride, potassium hydride, sodium methoxide, potassium methoxide And the like can be used. The base may be used in the range of 1 to 3 molar ratios, preferably 1 to 1.5 molar ratios, relative to the compound represented by Formula 2.

The solvent used in the cyclization reaction of the present invention can be used as long as it is a solvent which does not participate in the reaction as a general organic solvent. Such solvents include, for example, ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane; Halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and chlorobenzene; Aromatic hydrocarbons such as benzene, toluene and xylene; Aliphatic hydrocarbons such as normal hexane, cyclohexane and heptane; Nitriles such as acetonitrile and propionitrile; One or two isomers selected from the group consisting of can be appropriately selected and used.

Cyclization reaction temperature of this invention is -70 degreeC-150 degreeC, Preferably it is -20 degreeC-50 degreeC. The cyclization reaction time is about 0.1 to 48 hours, preferably about 0.5 to 24 hours.

In addition, the present invention also includes a method for producing a salt compound of 4,5-dihydrooxazol-2-ylbenzene derivative represented by the formula (1) as a scope.

The salt compound in the present invention mainly includes a pharmaceutically or agrochemically acceptable salt, and the method for preparing the salt compound can be carried out by a conventional method. In the present invention, pharmaceutically or agrochemically acceptable salts include, for example, metal salts, salts with organic bases, salts with inorganic acids, salts with organic acids, basic or acidic amino acids, and the like. May be included. Suitable metal salts include, for example, alkali metal salts such as sodium salts, potassium salts and the like; Alkaline earth metal salts such as calcium salts, magnesium salts, barium salts and the like; Aluminum salts and the like. Salts with organic bases include, for example, salts with organic bases such as trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N , N -dibenzylethylenediamine , and the like. Salts with inorganic acids may include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Salts with organic acids may include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid and the like . Salts with basic amino acids may include salts with, for example, arginine, lysine, ornithine, and the like. Salts with acidic amino acids may include salts with, for example, aspartic acid, glutamic acid and the like.

On the other hand, the compound represented by the formula (2) used as a raw material in the cyclization reaction according to the present invention may exist isomers such as optical isomers, geometric isomers as a compound containing activated carbon. Therefore, according to the three-dimensional structure of the compound represented by the formula (2) used as a raw material in the cyclization reaction according to the present invention, the compound represented by the formula (1) prepared is each isomer compound, a mixture of these isomers, or racemic Can be prepared as a sieve.

The compound represented by the formula (2) can be synthesized by a known method known.

A typical method for preparing a compound represented by Chemical Formula 2 is shown in Scheme 3 below.

Scheme 3

(In Reaction Scheme 3, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and R ₆ are each as defined above.)

According to Scheme 3, the 8-methyl- 4H -benzo [ d ] [1,3] oxazin-4-one derivative represented by Formula 3 is reacted with the hydroxyalkylamine compound represented by Formula 4 It can manufacture. The preparation method according to Scheme 3 may be performed at room temperature by mixing the amino alcohol of Formula 3 and Formula 4 in a solvent that does not participate in the reaction, such as tetrahydrofuran.

In addition, the compound represented by Formula 3 or 4 used as a raw material in the production method according to Scheme 3 is a known compound, can be prepared and used through a known production method. The preparation method of 8-methyl- 4H -benzo [ d ] [1,3] oxazin-4-one derivative represented by Chemical Formula 3 is disclosed in WO 2004/011447, 2004/033468, and 2004/111030. And 2006/068669.

The present invention as described above is explained in more detail based on the following examples, but the present invention is not limited to these examples.

[Example]

Example 1. 3-Bromo- N- (4-chloro-2- (2-hydroxyethylcarbamoyl) -6-methylphenyl) -1- (3-chloropyridin-2-yl) -1 H -pyra Synthesis of Sol-5-Carboxamide (Compound 2)

In a 250 mL flask containing 100 mL of anhydrous tetrahydrofuran, 2- (3-bromo-1- (3-chloropyridin-2-yl) -1 H -pyrazol-5-yl) -6-chloro under nitrogen -8-methyl- 4H -benzo [ d ] [1,3] oxazin-4-one (8 g, 17.7 mmol) was added thereto, and 2-aminoethanol (1.3 g, 21.2 mol) was slowly dropped while stirring. After stirring for 1 hour at room temperature, acidified with 1 N HCl and extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, distilled under reduced pressure and washed with ethyl ether to give 8.26 g (yield 91%) of the title compound.

¹ H NMR (300 MHz, acetone- d ₆ , ppm) δ 2.24 (s, 3H), 3.47 (t, J = 5.7 Hz, 2H), 3.64 (t, J = 5.7 Hz, 2H), 7.38 (s, 1H), 7.41 (d, J = 1.8 Hz, 1H), 7.52 (d, J = 2.7 Hz, 1H), 7.62 (dd, J = 8.1 Hz, J = 4.8 Hz, 1H), 8.1 (dd, J = 8.1 Hz, J = 1.5 Hz, 1H), 8.52 (dd, J = 4.8 Hz, J = 1.5 Hz, 1H)

Example 2. 3-Bromo- N- (4-chloro-2- (4,5-dihydrooxazol-2-yl) -6-methylphenyl) -1- (3-chloropyridin-2-yl) -1 H - pyrazole-5-carboxamide synthesis of (compound 1)

Manufacturing method using DAST :

In a 50 mL flask containing 10 mL of anhydrous acetonitrile, 3-bromo- N- (4-chloro-2- (2-hydroxyethylcarbamoyl) -6-methylphenyl) -1- (3-chloropyridine-2- Ill) -1 H -pyrazole-5-carboxamide (500 mg, 0.97 mmol) was added and (diethylamino) sulfur trifluoride (DAST; 0.2 mL, 46 mmol) with stirring at 0 ° C. under a nitrogen atmosphere. Dropped slowly. After stirring for 30 minutes, the temperature was raised to room temperature and stirred for 16 hours. The mixture was evaporated under reduced pressure and purified by column chromatography (hexane / ethyl acetate = 1/1) to give 450 mg (yield 93%) of the title compound.

¹ H NMR (300 MHz, acetone- d ₆ , ppm) δ 2.20 (s, 3H), 4.19 (t, J = 9.3 Hz, 2H), 4.49 (t, J = 9.3 Hz, 2H), 7.31 (s, 1H), 7.47 (d, J = 1.5 Hz), 7.61 (dd, J = 8.1 Hz, J = 4.8 Hz, 1H), 7.74 (d, J = 1.8 Hz), 8.11 (dd, J = 8.1 Hz, J = 1.5 Hz, 1H), 8.52 (dd, J = 4.5 Hz, J = 1.2 Hz, 1H), 11.20 (br s, 1H)

Example 2-1.

The reaction was carried out under the same conditions as in Example 2, except that 400 mg (yield 83%) of the title compound was obtained using tetrahydrofuran instead of acetonitrile as a reaction solvent.

Example 2-2.

The reaction was carried out under the same conditions as in Example 2 except that 340 mg (yield 71%) of the title compound was obtained using methylene glolide instead of acetonitrile as a reaction solvent.

Example 3. 3-Bromo- N- (4-chloro-2- (4,5-dihydrooxazol-2-yl) -6-methylphenyl) -1- (3-chloropyridin-2-yl) -1 H - pyrazole-5-carboxamide synthesis of (compound 1)

Preparation method using paratoluene sulfonyl chloride :

3-bromo- N- (4-chloro-2- (2-hydroxyethylcarbamoyl) -6-methylphenyl) -1- (3-chloropyridin-2-yl) -1 H -pyrazole-5- Carboxamide (500 mg, 0.97 mmol) was added to 10 mL of dichloromethane, and paratoluene sulfonyl chloride (241 mg, 0.97 mmol) was added while stirring, and triethylamine (0.14 mL, 0.97 mmol) was slowly dropped at room temperature. It was stirred for 16 hours at room temperature. The mixture was evaporated under reduced pressure and purified by column chromatography (hexane / ethyl acetate = 1/1) to give 150 mg (yield 32%) of the title compound.

Example 4. 3-Bromo- N- (4-chloro-2- (1-hydroxypropan-2-yl-carbamoyl) -6-methylphenyl) -1- (3-chloropyridin-2-yl pyrazole-5-carboxamide (formula 2 compound) -) -1 H

2- (3-bromo-1- (3-chloropyridin-2-yl) -1 H -pyrazol-5-yl) -6-chloro-8-methyl-4 H -benzo [ d ] [1, 3] Oxazin-4-one (8 g, 17.7 mmol) was added to a 250 mL flask containing 100 mL of anhydrous tetrahydrofuran and slowly dropped 2-aminopropan-1-ol (1.6 g, 21.2 mol) while stirring. . After stirring for 30 minutes at room temperature, acidified with 1 N HCl, extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, distilled under reduced pressure and washed with ethyl ether to give 8.4 g (yield 90%) of the title compound as a white solid. .

¹ H NMR (300 MHz, acetone- d ₆ , ppm) δ 1.2 (d, J = 6.6 Hz, 3H), 2.24 (s, 3H), 3.57 (d, J = 5.7 Hz, 2H), 4.13 (m, 1H), 7.35 (s, 1H), 7.41 (d, J = 1.8 Hz, 1H), 7.49 (s, 1H), 7.62 (dd, J = 8.1 Hz, J = 4.8 Hz, 1H), 8.1 (dd, J = 8.1 Hz, J = 1.5 Hz, 1H), 8.52 (dd, J = 4.8 Hz, J = 1.5 Hz, 1H), 10.28 (br s, 1H)

Example 5. 3-Bromo- N- (4-chloro-2-methyl-6- (4-methyl-4,5-hydrooxazol-2-yl) phenyl) -1- (3-chloropyridine- Synthesis of 2-yl) -1 H -pyrazole-5-carboxamide (Compound 2)

Manufacturing method using DAST :

3-bromo- N- (4-chloro-2- (1-hydroxypropan-2-yl-carbamoyl) -6-methylphenyl) -1- (3-chloropyridin-2-yl) -1 H -Pyrazole-5-carboxamide (500 mg, 0.948 mmol) was placed in a 50 mL flask containing acetonitrile (10 mL), and slowly DAST (0.2 mL, 46 mmol) was stirred at 0 ° C. and anhydrous conditions. After dropping, the mixture was stirred at room temperature for 16 hours. The mixture was evaporated under reduced pressure and purified by column chromatography (hexane / ethyl acetate = 1/1) to give 434 mg (yield 90%) of the title compound.

^OneH NMR (300 MHz, acetone-d ₆, ppm) δ 1.37 (d, 6.6 Hz, 3H), 2.24 (s, 3H), 4.01 (t,J= 6.6 Hz, 1H), 4.54-4.64 (m, 2H), 7.33 (s, 1H), 7.47 (d,J= 1.5 Hz, 1H), 7.63 (dd,J= 8.1 Hz,J= 4.8 Hz, 1H), 7.69 (d,J= 1.8 Hz, 1H), 8.11 (dd,J= 8.1 Hz,J= 1.5 Hz, 1H), 8.52 (dd,J= 4.5 Hz,J= 1.2 Hz, 1 H), 11.25 (br s, 1 H).

Example 5-1.

The reaction was carried out under the same conditions as in Example 5 except that 386 mg (yield 80%) of the title compound was obtained using tetrahydrofuran instead of acetonitrile as a reaction solvent.

Example 5-2.

The reaction was carried out under the same conditions as in Example 5, except that 318 mg (yield 66%) of the title compound was obtained using tetrahydrofuran instead of acetonitrile as a reaction solvent.

Example 6. 3-Bromo- N- (4-chloro-2-methyl-6- (4-methyl-4,5-hydrooxazol-2-yl) phenyl) -1- (3-chloropyridine- Synthesis of 2-yl) -1 H -pyrazole-5-carboxamide (Compound 2)

Preparation method using paratoluene sulfonyl chloride :

3-bromo- N- (4-chloro-2-methyl-6- (4-methyl-4,5-hydrooxazol-2-yl) phenyl) -1- (3-chloropyridin-2-yl) -1 H -pyrazole-5-carboxamide (500 mg, 0.948 mmol) was added to dichloromethane (10 mL), followed by stirring with paratoluene sulfonylchloride (241 mg, 0.97 mmol) and triethylamine (0.14 mL). , 0.97 mmol) was slowly dropped from room temperature and then stirred at room temperature for 16 hours. The mixture was distilled under reduced pressure and purified by column chromatography (hexane / ethyl acetate = 1/1) to give 230 mg (yield 48) of the title compound.

Based on the preparation method illustrated in the above examples, 4,5-dihydrooxazol-2-ylbenzene derivative represented by Chemical Formula 1 was prepared.

The chemical structure and yield of each compound prepared are summarized in Table 1 below, and the structural confirmation data of the prepared compounds are shown in Table 2 below.

compound
number R ₁ R ₂ R ₃ R ₄ R ₅ R ₆ solid
Orientation yield
(%) One H Cl H H H H 93 2 Br Cl Me H H H 90 3 Br Cl Me Me H H 75 4 Br Br Me H H H 95 5 Br Br Me Me H H 80 6 Br Cl H H Me H 85 7 Br CN Me H H H 88 8 Br CN Me Me H H 80 9 Br Cl Me H H H (S) 92 10 Br Cl Me H H H (R) 90 11 CF ₃ Cl Me H H H 95 12 CF ₃ Cl Me Me H H 85 13 CF ₃ Br Me H H H 95 14 CF ₃ Br Me Me H H 80

compound
number ¹ H NMR (300 MHz, acetone- d ₆ , ppm) δ One 2.20 (s, 3H), 4.19 (t, J = 9.3 Hz, 2H), 4.49 (t, J = 9.3 Hz, 2H), 7.31 (s, 1H), 7.47 (d, J = 1.5 Hz), 7.61 (dd, J = 8.1 Hz, J = 4.8 Hz, 1H), 7.74 (d, J = 1.8 Hz), 8.11 (dd, J = 8.1 Hz, J = 1.5 Hz, 1H), 8.52 (dd, J = 4.5 Hz, J = 1.2 Hz, 1H), 11.20 (br s, 1H) 2 1.37 (d, 6.6 Hz, 3H), 2.24 (s, 3H), 4.01 (t, J = 6.6 Hz, 1H), 4.54-4.64 (m, 2H), 7.33 (s, 1H), 7.47 (d, J = 1.5 Hz, 1H), 7.63 (dd, J = 8.1 Hz, J = 4.8 Hz, 1H), 7.69 (d, J = 1.8 Hz, 1H), 8.11 (dd, J = 8.1 Hz, J = 1.5 Hz, 1H), 8.52 (dd, J = 4.5 Hz, J = 1.2 Hz, 1H), 11.25 (br s, 1H) 3 1.42 (s, 6H), 2.25 (s, 3H), 4.21 (s, 2H), 7.37 (s, 1H), 7.47 (d, J = 1.5 Hz), 7.63 (dd, J = 8.1 Hz, J = 4.8 Hz, 1H), 7.69 (d, J = 1.8 Hz, 1H), 8.11 (dd, J = 8.1 Hz, J = 1.5 Hz, 1H), 8.54 (dd, J = 4.5 Hz, J = 1.2 Hz, 1H), 11.36 (br s, 1H) 4 1.37 (d, 6.3 Hz, 3H), 2.24 (s, 3H), 4.01 (t, J = 6.6 Hz, 1H), 4.54-4.64 (m, 2H), 7.35 (s, 1H), 7.61-7.66 (m, 2H), 7.83 (d, J = 2.4 Hz), 8.11 (dd, J = 8.1 Hz, J = 1.5 Hz, 1H), 8.53 (dd, J = 4.5 Hz, J = 1.2 Hz, 1H), 11.32 (br s, 1H) 5 1.42 (s, 6H), 2.24 (s, 3H), 4.20 (s, 2H), 7.36 (s, 1H), 7.60-7.65 (m, 2H), 7.82 (d, J = 2.4 Hz), 8.1 (dd, J = 8.1 Hz, J = 1.5 Hz, 1H), 8.54 (dd, J = 4.5 Hz, J = 1.2 Hz, 1H), 11.37 (br s, 1H) 6 1.27 (d, 6.3 Hz, 3H), 2.08 (s, 3H), 3.6 (dd, J = 15 Hz, J = 7.5 Hz, 1H), 4.14 (dd, J = 14.7 Hz, J = 9.3 Hz, 1H), 4.758-4.833 (m, 1H), 7.16 (s, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.48 (d, J = 7.8 Hz, J = 4.5 Hz, 1H), 7.55 (d, J = 2.4 Hz), 8.11 (dd, J = 8.1 Hz, J = 1.5 Hz, 1H), 8.53 (dd, J = 4.5 Hz, J = 1.2 Hz, 1H), 11.11 (br s, 1H) 7 1.39 (d, 6.0 Hz, 3H), 2.29 (s, 3H), 4.06 (t, J = 6.6 Hz, 1H), 4.59-4.66 (m, 2H), 7.37 (s, 1H), 7.65 (dd, J = 8.1 Hz, J = 4.8 Hz, 1H), 7.84 (s, 1H), 8.06 (s, 3H), 8.13 (d, J = 8.1 Hz, 1H), 8.54 (d, J = 4.5 Hz, 1H), 11.89 (br s, 1H) 8 1.44 (s, 6H), 2.29 (s, 3H), 4.26 (s, 2H), 7.39 (s, 1H), 7.65 (dd, J = 8.1 Hz, J = 4.8 Hz, 1H), 7.85 (s, 1H), 8.09 (s, 1H), 8.13 (d, 8.1 Hz, 1H), 8.54 (d, J = 4.5 Hz, 1H), 11.92 (br s, 1H) 9 1.37 (d, 6.6 Hz, 3H), 2.24 (s, 3H), 4.01 (t, J = 6.6 Hz, 1H), 4.54-4.64 (m, 2H), 7.33 (s, 1H), 7.47 (d, J = 1.5 Hz, 1H), 7.63 (dd, J = 8.1 Hz, J = 4.8 Hz, 1H), 7.69 (d, J = 1.8 Hz, 1H), 8.11 (dd, J = 8.1 Hz, J = 1.5 Hz, 1H), 8.52 (dd, J = 4.5 Hz, J = 1.2 Hz, 1 H), 11.25 (br s, 1 H). 10 1.37 (d, 6.6 Hz, 3H), 2.24 (s, 3H), 4.01 (t, J = 6.6 Hz, 1H), 4.54-4.64 (m, 2H), 7.33 (s, 1H), 7.47 (d, J = 1.5 Hz, 1H), 7.63 (dd, J = 8.1 Hz, J = 4.8 Hz, 1H), 7.69 (d, J = 1.8 Hz, 1H), 8.11 (dd, J = 8.1 Hz, J = 1.5 Hz, 1H), 8.52 (dd, J = 4.5 Hz, J = 1.2 Hz, 1H), 11.25 (br s, 1H) 11 1.36 (d, 6.3 Hz, 3H), 2.26 (s, 3H), 4.01 (t, J = 6.6 Hz, 1H), 4.54-4.64 (m, 2H), 7.50 (s, 1H), 7.67-7.72 (m, 2H), 8.17 (dd, J = 8.1 Hz, J = 1.5 Hz, 1H), 8.52 (dd, J = 4.5 Hz, J = 1.2 Hz, 1H), 11.38 (br s, 1H) 12 1.40 (s, 6H), 2.26 (s, 3H), 4.21 (s, 2H), 7.49 (d, J = 2.1 Hz, 1H), 7.67-7.72 (m, 3H), 8.16 (dd, J = 8.1 Hz, J = 1.5 Hz, 1H), 8.58 (dd, J = 4.5 Hz, J = 1.2 Hz, 1H), 11.43 (br s, 1H) 13 1.35 (d, 6.3 Hz, 3H), 2.26 (s, 3H), 4.01 (t, J = 6.6 Hz, 1H), 4.54-4.64 (m, 2H), 7.63-7.72 (m, 3H), 7.84 (d, J = 2.4 Hz), 1H), 8.17 (dd, J = 8.1 Hz, J = 1.5 Hz, 1H), 8.58 (dd, J = 4.5 Hz, J = 1.2 Hz, 1H), 11.39 (br s, 1H) 14 1.40 (s, 6H), 2.26 (s, 3H), 4.20 (s, 2H), 7.62 (d, J = 2.4 Hz, 1H), 7.67-7.70 (m, 2H), 7.84 (d, J = 2.4 Hz, 1H), 8.14 (dd, J = 8.1 Hz, J = 1.5 Hz, 1H), 8.58 (dd, J = 4.5 Hz, J = 1.2 Hz, 1H), 11.48 (br s, 1H)

Claims (4)

Preparing a 4,5-dihydrooxazol-2-ylbenzene compound represented by the following Chemical Formula 1 by cyclizing the hydroxyalkyl benzamide compound represented by the following Chemical Formula 2;
Method for producing a 4,5-dihydrooxazol-2-ylbenzene compound or a salt thereof comprising a.
(2)

[Chemical Formula 1]

In Formula 1 or 2, R ₁ is a halogen atom or a C ₁ -C ₄ haloalkyl group substituted with 1 to 8 halogen atoms; R ₂ represents a halogen atom or a cyano group; R ₃ , R ₄ , R ₅ , and R ₆ are the same or different from each other and are a hydrogen atom or a C ₁ -C ₄ alkyl group.
The method according to claim 1,
The cyclization reaction is carried out in the presence of (diethylamino) sulfur trifluoride (DAST), or para-toluenesulfonate (TsOH), 4,5-dihydrooxazol-2-ylbenzene compound Or a method for preparing a salt thereof.
The method according to claim 1,
The cyclization reaction is carried out in the presence of a tri (C ₁ -C ₆ ) alkylamine and a base selected from the group consisting of hydroxides, hydrides and C ₁ -C ₆ alkoxides of alkali or alkaline earth metals. Method for the preparation of, 5-dihydrooxazol-2-ylbenzene compound or salt thereof.
The method according to claim 3,
4,5 characterized in that the base is selected from the group consisting of trimethylamine, triethylamine, diethylisopropylamine, lithium hydroxide, sodium hydroxide, calcium hydroxide, sodium hydride, potassium hydride, sodium methoxide, and potassium methoxide A process for preparing a dihydrooxazol-2-ylbenzene compound or a salt thereof.