KR0134838B1 - Process for preparing 2,3-dihydro-2-methyl-2-alkylbengofuran - Google Patents

Abstract

The present invention relates to a method for preparing a 2,3-dihydro-2-methyl-2-alkylbenzofuran derivative represented by the following structural formula (I) which is useful as an intermediate of agrochemicals and medicines.

Wherein, X is an alkyl group of a hydrogen atom, a halogen atom, a hydroxy group, an aldehyde group or a C ₁ ~ C _6, R is an alkyl group of C ₁ ~ C _6.

Description

Method for preparing 2,3-dihydro-2-methyl-2-alkylbenzofuran derivative

The present invention relates to a method for preparing a 2,3-dihydro-2-methyl-2-alkylbenzofuran derivative represented by the following structural formula (I) which is useful as an intermediate of agrochemicals and medicines.

Wherein, X is an alkyl group of a hydrogen atom, a halogen atom, a hydroxy group, an aldehyde group or a C ₁ ~ C _6, R is an alkyl group of C ₁ ~ C _6.

The 2,3-dihydro-2-methyl-2-alkylbenzofuran derivative represented by the above structural formula (I) is well known as an intermediate compound of pesticides and pharmaceuticals including pesticides, in particular 2,3-dihydro-2 2,3-dihydro-2,2-dimethyl-7-hydroxybenzofuranyl methylcarbamate, which is widely known as a pesticide, is highly regarded as a pesticide. It is a useful intermediate.

As a conventional method for preparing the carbofuran phenol, 2-metalyloxyphenol is synthesized by alkylation of catechol and metalyl halide, and then cyclized at a high temperature of 100 to 200 ° C. under a strong acid or Lewis acid catalyst. Manufacturing method (US Patent No. 4,380,654; Japanese Patent Publication No. 60-100,569; European Patent Publication No. 115,837 (1984); Japanese Patent Publication No. 58-174,375; Japanese Patent Publication No. Hei 5-835,180; Japanese Patent Publication) 5-839,679 and Japanese Patent Application Laid-Open No. 58-21,676), and 2-metalloxyphenol were synthesized by catechol by Claisen rearrangement, and then 100-200 under strong or Lewis acid catalyst. Method for producing by cyclization reaction at high temperature of ℃ [Patent No. 62-178,580; Brazilian Patent Application 8301,980 and German Patent Publication No. 3,027,335 (1981).

In addition to the carbofuran phenols exemplified above, 2,3-dihydro-2,2-dimethylbenzofuran aldehyde derivatives are known as useful intermediates for the preparation of pyrethroid derivatives, which are widely known as insecticides (Japanese Patent 402,753 A1; European Patent 0473, 041 A1; German Patent 2108,932 and European Patent 0271,170.

As a result, the inventors of the present invention have tried to develop a novel preparation method for more easily preparing a 2,3-dihydro-2-methyl-2-alkylbenzofuran derivative having a wide range of use as described above. and (β-alkylallyl) oxybenzene derivatives were synthesized by 2- (β-alkylallyl) phenol and 2- (2-alkylpropenyl) phenol isomers by the Klysene potential, and then the catalytic amount in an inert organic solvent was added. The present invention was completed by adding iodine to cyclization reaction at room temperature to prepare a 2,3-dihydro-2-methyl-2-alkylbenzofuran derivative.

It is an object of the present invention to provide a novel process for producing 2,3-dihydro-2-methyl-2-alkylbenzofuran derivatives useful as agrochemicals and pharmaceutical intermediates in high yields in a short time.

Hereinafter, the present invention will be described in detail.

The present invention relates to a method for preparing a 2,3-dihydro-2,2-dimethylbenzofuran derivative using (β-alkylallyl) oxybenzene derivative as a starting material, wherein (β- represented by the following structural formula (II) It is characterized in that the alkylallyl) oxybenzene derivative is prepared by isomeric compound represented by the following structural formulas (III-1) and (III-2) by means of the Klysene potential and cyclized at room temperature by adding a catalytic amount of iodine thereto. It relates to a method for producing a 2,3-dihydro-2-methyl-2-alkylbenzofuran derivative.

Wherein X and R are as defined above.

Referring to the present invention in more detail as follows.

The present invention is represented by the above-mentioned structural formula (I), which is well known as 2,3-dihydro-2,2-dimethyl-7-hydroxybenzofuranylmethyl carbamate or an intermediate for preparing pyrethroids, which are widely used as pesticides and medicines, in particular pesticides. It relates to a method for producing a 2,3-dihydro-2-methyl-2-alkylbenzofuran derivative, which is shown in the following scheme.

First, an isomeric mixture represented by the above-mentioned formulas (III-1) and (III-2) is prepared by a (c) -alkylallyl) oxybenzene derivative represented by the above formula (II) by chrysene rearrangement. At this time, the rearrangement may proceed without a solvent or in the presence of a high boiling point solvent. Suitable solvents include N, N-dimethylaniline, 2,6-xyldine, 2,6-xyleneol or dode Cells and the like can be used, and a suitable reaction temperature is 180 to 250 ° C, preferably 210 to 220 ° C.

The isomeric mixture prepared above is a 2- (β-alkylallyl) phenol derivative represented by the above formula (III-1) and 2- (2-alkyl represented by the above formula (III-2) by a conventional separation method. Each of these compounds was identified by nuclear magnetic resonance spectroscopy ( ¹ H-NMR), ultraviolet absorption spectroscopy (IR) and mass spectrometry.

Subsequently, the isomeric mixture or a single compound separated from each of these isomeric mixtures was subjected to cyclization reaction at room temperature for 30 minutes to 4 hours by adding a catalytic amount of iodine under an organic solvent to give 2,3-dihydro- which is the target compound of the present invention. Prepare 2-methyl-2-alkylbenzofuran derivatives.

Since the iodine used in the cyclization reaction acts as a catalyst, the amount of iodine used does not significantly affect the reaction, but 0.1 to 1 equivalent is used for the compounds represented by the structural formulas (III-1) and (III-2). It is preferable to use 0.2 equivalents more preferably. As the organic solvent suitable for the cyclization reaction, a hydrocarbon solvent such as dichloromethane, chloroform, carbon tetrachloride, toluene, and xylene may be used.

In the case of the preparation method according to the present invention, the iodide ring reaction (Tetrahedron, Vol. 46, pp. 3321-3408 (1990)) by the reaction of 2-metallphenol or 2-isobutenylphenol and iodine does not occur very much. There is an advantage to obtain a 2,3-dihydro-2-methyl-2-alkylbenzofuran derivative in high yield under mild conditions.

Hereinafter, the present invention will be described in detail with reference to the following Examples, but the present invention is not limited by the Examples.

Example 1

Preparation of 2,3-dihydro-2,2-dimethyl-7-hydroxybenzofuran

22 g (0.2 mole) of catechol is added to a mixed solvent of 120 ml of acetone and 30 ml of dimethylformamide, and 14 g (0.1 mole) of anhydrous K ₂ CO ₃ and 20 ml (0.2 mole) of metalyl chloride are added under stirring, followed by stirring for 18 hours. The reaction mixture is cooled to room temperature, the solid is filtered off, and the solvent is concentrated by distillation under reduced pressure. 100 ml of 2N aqueous hydrochloric acid solution was added to the residue, followed by extraction with hexane (50 ml x 3) and ethyl acetate (50 ml x 3), respectively. After extracting the organic layer with 20% NaOH (50ml × 3 times), the base layer was acidified with concentrated hydrochloric acid and extracted with hexane. The extracted portion with hexane was dried over anhydrous MgSO ₄ and then distilled under reduced pressure to remove the solvent. The residue was separated by short silica gel column chromatography to give 17.8 g of pure 2-metalyloxyphenol.

Boiling Point: 78 ~ 80 ℃ / 0.05torr

¹ H NMR (CDCl ₃ ): δ1.8 (s, 3H), 4.46 (s, 2H), 4.95 (s, 1H), 5.05 (s, 1H), 5.68 (br, 1H), 6.76 ~ 6.95 (m , 4H).

The mixture obtained by mixing 15.95 g of 2-metalloxyphenol and 30 g of N, N-dimethylaniline obtained above is stirred at 200 ° C. for 1 hour, and then cooled to room temperature. 100 ml of 2N aqueous hydrochloric acid solution was added to the reaction mixture, followed by extraction with hexane, followed by extraction with ethyl acetate (50 ml × 4). The ethyl acetate layer was dried over anhydrous MgSO ₄ and then distilled under reduced pressure to remove the solvent. The residue was distilled by a high vacuum pump to give 11.6 g (yield 73%) of a mixture of 2-metall catechol and 2-isobutenyl catechol in a 3: 1 ratio (NMR spectrum analysis) of yellow oil.

Boiling Point of Mixture: 104 ℃ / 0.05torr

2-metall catechol

¹ H NMR (CDCl ₃ ): δ 1.7 (s, 3H), 3.35 (s, 2H), 4.85 (dd, 2H), 5.7 (br, 2H), 6.76 (m, 4H).

2-isobutenylcatechol

¹ H NMR (CDCl ₃ ): δ 1.68 (s, 3H), 1.90 (s, 3H), 4.72 (dd, 2H), 5.7 (br, 2H), 6.76 (m, 3H).

7.75 g of the mixture of 2-metall catechol and 2-isobutenyl catechol obtained above was dissolved in carbon tetrachloride (50 ml), 2.4 g (0.2 equivalent) of iodine (I ₂ ) was added thereto, followed by stirring at room temperature for 30 minutes. Saturated aqueous NaS ₂ O ₅ solution is added and the organic layer is separated. The water layer is extracted with dichloromethane (20 ml × 2 times), the organic layers are collected, dehydrated with anhydrous MgSO ₄ , filtered, and the solvent is removed under reduced pressure to obtain a residue. The residue was separated by column chromatography to give 6.5 g (yield 84%) of 2,3-dihydro-2,2-dimethyl-7-hydroxybenzofuran.

Boiling Point: 84 ~ 85 ℃ / 0.002torr

¹ H NMR (CDCl ₃ ): δ 1.45 (s, 3H), 3.0 (s, 2H), 5.42 (s, 1H), 5.7 (br, 2H), 6.7 (m, 3H).

Example 2

Preparation of 2,3-dihydro-2,2-dimethylbenzofuran-5-aldehyde

61 ml (0.5 M) of 4-hydroxybenzaldehyde is added to a mixed solvent of 150 ml of acetone and 25 ml of dimethylformamide, and 51 g of anhydrous K ₂ CO ₃ and 63 ml (0.75 M) of metall chloride are added with stirring, followed by stirring under reflux for 18 hours. The reaction mixture is cooled to room temperature, the solid is filtered off, and the solvent is concentrated by distillation under reduced pressure. The residue was dissolved in 100 ml of ethyl ether and washed successively with water, 20% aqueous sodium hydroxide solution and brine. The organic layer is dried over anhydrous MgSO ₄ and then distilled under reduced pressure to remove the solvent. The residue was separated by short silica gel column chromatography to give 76.5 g (86.8%) of colorless 4-metalyloxybenzaldehyde.

Boiling Point: 95 ℃ / 0.001torr

¹ H NMR (CDCl ₃ ): δ 1.80 (s, 3H), 4.45 (s, 2H), 4.98 (dd, 1H), 5.15 (d, 1H), 6.70 (d, 1H), 7.50 (dd, 2H ), 9.7 (s, 1 H).

The mixture obtained by mixing 57 g (0.33 M) of 4-metalloxybenzaldehyde and 50 g of N, N-dimethylaniline obtained above was heated and stirred at 210 ° C. for 1 hour and then cooled to room temperature. The reaction mixture is diluted with 50 ml of hexane, extracted with chrysene alkali (50 ml x 2) and washed once with hexane. The alkali layer was cooled to 0 ° C., neutralized with concentrated hydrochloric acid, and extracted with ethyl ether (30 ml × 3). The organic layer is dried over anhydrous MgSO ₄ and then distilled under reduced pressure to remove the solvent. The residue was separated by column chromatography to give 36 g (yield 63%) of 2-metalylphenol-4-aldehyde as a yellow oil.

¹ H NMR (CDCl ₃ ): δ1.74 (s, 3H), 3.38 (s, 2H), 4.70 (s, 1H), 4.84 (s, 1H), 5.69 (br, 1H), 6.70 (d, 1H ), 7.50 (dd, 2H), 9.7 (s, 1H).

27.5 g of 2-methylphenol-4-aldehyde and 2-isobutenylphenol-4-aldehyde obtained above were dissolved in dichloromethane (160 ml), 6.0 g (0.2 equivalent) of iodine was added thereto, followed by stirring at room temperature for 2 hours. 10% NaS ₂ O ₅ aqueous solution is added and the organic layer is separated.

The water layer is extracted with dichloromethane (30 ml × 2 times), the organic layers are collected, dehydrated with anhydrous MgSO ₄ , filtered, and the solvent is removed under reduced pressure to obtain a residue. The residue was separated by column chromatography to give 20.3 g (74% yield) of 2,3-dihydro-2,2-dimethylbenzofuran-5-aldehyde.

¹ H NMR (CDCl ₃ ): δ 1.48 (s, 3H), 3.00 (s, 2H), 6.70 (d, 1H), 7.50 (dd, 2H), 9.7 (s, 1H).

Example 3

Preparation of 2,3-dihydro-2,2-dimethylbenzofuran-7-aldehyde

36.6 g (0.3 M) of salicylaldehyde was added to a mixed solvent of 150 ml of acetone and 25 ml of dimethylformamide, and 31 g (0.2 M) of anhydrous K ₂ CO ₃ and 44.4 ml (0.45 M) of metalyl chloride were added under reflux for 18 hours while stirring. Stir. The reaction mixture is cooled to room temperature, the solid is filtered off, and the solvent is concentrated by distillation under reduced pressure. 100 ml of 2N aqueous hydrochloric acid solution was added to the residue, followed by extraction with 25% benzene (50 ml × 3 times) diluted with hexane, followed by washing the organic layer successively with 20% NaOH (50 ml × 3 times) and brine. The organic layer is dried over anhydrous MgSO ₄ and then distilled under reduced pressure to remove the solvent. The residue was distilled with a high vacuum pump to give 47 g (yield 90%) of 2-metalloxybenzaldehyde as a yellow oil.

Boiling Point: 84 ℃ / 0.005torr

¹ H NMR (CDCl ₃ ): δ 1.8 (s, 3H), 4.32 (s, 2H), 4.97 (d, 1H), 6.72 ~ 7.2 (m, 4H), 11.5 (m, 4H).

The mixed solution of 36.6 g of 2-metalloxybenzaldehyde obtained above and 40 g of N, N-dimethylaniline is heated and stirred at 170 to 175 ° C for 1 hour, and then cooled to room temperature. The reaction mixture is diluted with 50 ml of hexane, extracted with chrysene alkali (25 ml x 3) and washed once with hexane. The alkaline layer was cooled to 0 ° C., neutralized with concentrated hydrochloric acid and extracted with ethyl ether. The organic layer is dried over anhydrous MgSO ₄ and then distilled under reduced pressure to remove the solvent. The residue was separated by silica gel column chromatography to give 23.53 g of 2-metalylphenol-7-aldehyde as a yellow oil.

¹ H NMR (CDCl ₃ ): δ 1.68 (s, 3H), 3.31 (s, 2H), 4.66 (d, 2H), 5.6 (br, 1H), 6.5 ~ 7.2 (m, 3H), 9.62 (s , 1H).

In the above, 7.04 g of 2-metallphenol-7-aldehyde was dissolved in dichloromethane (60 ml), 2.1 g (0.2 equivalents) of iodine was added thereto, stirred at room temperature for 3 hours, and then an aqueous 5% NaS ₂ O ₅ solution was added thereto. Isolate. The water layer was extracted with dichloromethane (30 ml × 2 times), and the organic layers were collected, dehydrated with MgSO ₄ , filtered, and the solvent was removed under reduced pressure to obtain a residue. The residue was separated by column chromatography to give 4.43 g (63% yield) of 2,3-dihydro-2,2-dimethylbenzofuran-7-aldehyde.

Boiling Point: 81 ~ 82 ℃

¹ H NMR (CDCl ₃ ): δ 1.49 (s, 6H), 3.00 (s, 2H), 6.60 to 7.75 (m, 3H), 10.05 (s, 1H).

[Examples 4 to 13]

2,3-dihydro-2-methyl-2-alkylbenzofuran was prepared by the same method as in Examples 1 to 3, except that the isomeric mixture was separated from each isomer by fractional distillation under reduced pressure. Compounds were separated and cyclized under the reaction conditions of Table 1 or Table 2 below.

The physical constants and instrumental analysis data of 2,3-dihydro-2,2-dimethylbenzofuran derivatives prepared in Example 4-13 were consistent with those of known literature (see Heterocycles, 1993, Vol. 36, pp. 497-505).

Claims (2)

In the method for producing a 2,3-dihydro-2,2-dimethylbenzofuran derivative using (β-alkylallyl) oxybenzene derivative as a starting material, (β-alkylallyl) represented by the following structural formula (II) 2, characterized in that to prepare an isomeric compound represented by the following structural formulas (III-1) and (III-2) by the oxybenzene derivatives by the Klysene potential and cyclization reaction at room temperature by adding a catalytic amount of iodine; Method for preparing 3-dihydro-2-methyl-alkylbenzofuran derivative. Wherein, X is an alkyl group of a hydrogen atom, a halogen atom, a hydroxy group, an aldehyde group or a C ₁ ~ C _6, R is an alkyl group of C ₁ ~ C _6. The isomer compound according to claim 1, wherein each of the isomeric compounds is (β-alkylallyl) phenol represented by the structural formula (III-1) and 2- (2-alkylpropenyl) phenol represented by the structural formula (III-2), respectively. A process for producing a 2,3-dihydro-2-methyl-2-alkylbenzofuran derivative characterized by using an isolated state or a mixture thereof.