JP2977591B2 - Method for producing benzene derivative - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a novel method for producing a benzene derivative useful as an intermediate for the synthesis of certain herbicides.

Conventional technology General formula (V) (Wherein, R ¹ and R ² represent alkyl groups). A method for producing 2-methoxycarbonyl-3-hydroxyacetophenone in 6 steps from 3-nitrophthalic anhydride is known as a method for producing a benzene derivative represented by the formula: (Pharmaceutical Magazine Vol. 74, page 466). However, this has a problem in that the reaction rate is too low or a large amount of by-products are produced depending on the process, so that the final yield decreases and the operation of separating the by-products becomes complicated.

Further, a compound of the general formula (IV) as a precursor of the benzene derivative of the general formula (V) (Wherein R, R ¹ , and R ² represent alkyl groups). A method for obtaining 2-methoxycarbonyl-3-methoxyacetophenone from 3-methoxyacetophenone ethylene acetal is known (Journal). Of Organic Chemistry (Journal of Organic Chemistry), Vol. 48, No. 14
Issue, p. 2349 (1983)]. However, this method has low regioselectivity due to steric hindrance, and methoxycarbonyl groups are introduced at the 2- and 4-positions. The overall yield is low, and a large amount of chromium carbonate is required as a catalyst. I cannot help being disadvantaged.

The present invention overcomes the drawbacks of the conventional methods and provides a novel method for selectively producing the benzene derivative in a simple and short process with a good yield. It is done for the purpose of.

Means for Solving the Problems The present inventors have conducted various studies to develop a method for producing the benzene derivative having the above-mentioned preferable characteristics, and as a result, have found that a 3-substituted oxy group such as 3-benzyloxyacetophenone ethylene acetal can be obtained. It has been found that by reacting phenyl ketone ethylene acetal with carbon dioxide or haloformate, a carboxylic acid or a derivative thereof can be introduced into the 2-position of a benzene derivative with good selectivity and good yield. The invention has been completed.

That is, the present invention relates to the general formula Wherein R is an alkyl group, an aralkyl group or an alkoxyalkyl group, and R ′ is an alkyl group or an aralkyl group, wherein carbon dioxide is reacted in the presence of a base. formula Wherein R and R ′ have the same meanings as described above, and a general formula (Wherein R is an alkyl group, an aralkyl group or an alkoxyalkyl group, and R ′ is an alkyl group or an aralkyl group) in a compound represented by the general formula XCOOR ″ (where R ″ is an alkyl group) in the presence of a base. Or an aralkyl group, wherein X is a halogen atom). (Wherein R, R ′ and R ″ have the same meaning as described above).

The benzene derivatives of the formulas (II) and (III) obtained by the method of the present invention are useful as synthetic intermediates for 2-substituted pyrimidinyloxy-6-alkoxykiminoalkylbenzoic acid-based herbicides as described below. .

A flowchart of an example of a method for producing various benzene derivatives of a raw material system or an induced product system in several steps before and after the novel production method of the present invention and the production process is shown below.

In the chart, R represents an alkyl group, an aralkyl group or an alkoxyalkyl group, R 'represents an alkyl group or an aralkyl group, and R "represents an alkyl group or an aralkyl group.

The target compound (II) in the present invention can be obtained by reacting the compound (I) with carbon dioxide such as dry ice in the presence of a base. The amount of carbon dioxide to be used is selected in the range of 2 to 5 moles based on the compound (I). As the base, for example, n-butyllithium, phenyllithium, phenylsodium and the like are used. The amount to be used is selected in the range of 1 to 1.2 moles based on Compound (I). Further, an inert solvent may be used for the reaction. For example, n-hexane, diethyl ether,
Tetrahydrofuran, toluene and the like are used.

In the present invention, the target compound (III) is
It is obtained by reacting the compound (I) with a haloformate in the presence of a base. As the base, for example, n
-Butyl lithium, phenyl lithium, phenyl sodium and the like are used. The amount to be used is selected in the range of 1 to 1.2 moles based on Compound (I). Examples of the haloformate include methyl chloroformate and ethyl chloroformate. The amount to be used is selected in the range of 1 to 1.2 moles based on Compound (I). Further, an inert solvent may be used for the reaction. For example, n-hexane, diethyl ether, benzene, toluene and the like are used.

The compound (III) can also be obtained by esterifying the compound (II) by reacting the compound (II) with an alkylating agent or an aralkylating agent in the presence of a base. As the base, for example, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydride, alcoholate and the like are used. The amount used is 1 based on the compound (II).
It is selected in the range of ~ 1.5 times mol. As the alkylating agent or the aralkylating agent, for example, halides such as methyl iodide and benzyl bromide, and sulfates such as methyl sulfate are used. The amount of use is selected in the range of 1 to 1.5 moles based on the compound (II). Also,
An inert solvent may be used for the reaction. For example, acetonitrile, acetone, dimethylformamide and the like are used.

The starting compound (I) of the present invention is, for example, the compound (V
It is obtained by dehydrating I) and ethylene glycol in the presence of an acid. In this case, the amount of ethylene glycol to be used is selected in the range of 5 to 10 moles based on the compound (VI). As the acid, for example, p-trienesulfonic acid, sulfuric acid, boron trifluoride-diethyl ether complex and the like are used. The amount used is 0.05 to 0.1 based on the compound (VI).
It is selected in the range of double amount. Further, an inert solvent may be used for the reaction. For example, benzene, toluene, xylene, 1,2-dichloroethane and the like are used. The compound represented by the general formula (VI) is described in, for example, "Journal
Of Agricultural Food Chemistry (Jo
urnal of Agricultural Food Chemistry), Vol. 19, No. 3, page 439 (1971) "and the like.

Further, from the target compound (III) of the present invention, as shown in the above chart, acylated benzene derivatives of the formulas (IV) and (V) are obtained as follows.

That is, the compound (IV) is the compound (III)
Is selectively hydrolyzed in the presence of a mineral acid. As the mineral acid, for example, hydrochloric acid, sulfuric acid and the like are used. The amount to be used is 0.5-based on the compound (III).
It is selected in the range of 1.5 times mol. Further, an inert solvent may be used for the reaction. For example, methanol, ethanol, tetrahydrofuran and the like are used.

Next, the compound (V) is obtained by a selective elimination reaction of R of the compound (IV). The elimination reaction is, when R is an aralkyl group such as a benzyl group, reductive dearalkylation by hydrogenation or selective hydrolysis with a Lewis acid such as hydrobromic acid, and R is an alkyl group or an alkoxy group. In the case of an alkyl group, elimination by an acid is required. In the hydrogenation reaction, palladium carbon, platinum oxide or the like is used as a catalyst. The amount used is based on compound (IV)
It is selected in the range of 0.03 to 0.3 times, preferably about 0.2 times. Further, an inert solvent may be used for the reaction. For example, methanol, ethanol, ethyl acetate, tetrahydrofuran and the like are used. In the elimination reaction using an acid, boron tribromide, hydrobromic acid, or the like is used as the acid. The amount used is 1.1 to 2.0 based on the compound (IV).
It is selected in the range of 2 moles. Further, an inert solvent may be used for the reaction. For example, dichloromethane, chloroform and the like are used.

In the case where R is an aralkyl group such as a benzyl group, compound (V) is obtained by simultaneously performing reductive dearalkylation and acetal elimination by hydrogenation on compound (III) in the presence of a mineral acid. Can also be obtained by In this reaction, palladium carbon, platinum oxide or the like is used as a catalyst. The amount used is 0.03 to 0.3 based on the compound (III).
The amount is selected in the range of double, preferably about 0.2 times. As the mineral acid, for example, hydrochloric acid, sulfuric acid and the like are used. The amount to be used is selected in the range of 0.5 to 1.5 times the amount of the compound (III). Further, an inert solvent may be used for the reaction. For example, methanol, ethanol, ethyl acetate, tetrahydrofuran and the like are used.

Next, examples of the starting compound and the target compound in the production method of the present invention are shown in the following table.

Next, from the compound (V), 2-substituted pyrimidinyloxy-6-alkoxyiminoalkylbenzoic acids such as 2-[(4,6-dimethoxypyrimidin-2-yl) oxy] -6- [1 -(Methoxyimino)
Ethyl] methyl benzoate is prepared as shown in the following reaction scheme.

This first-stage reaction is carried out in the presence of a base such as potassium carbonate or sodium hydride in an inert solvent such as acetonitrile, tetrahydrofuran, or dimethylformamide at room temperature to 100 ° C., and the second-stage reaction is performed using potassium acetate. And in an inert solvent such as methanol in the presence of a base such as at room temperature to reflux temperature.

Further, the order of the first-stage reaction and the second-stage reaction can be reversed.

According to the method of the present invention, the compound represented by the formula (II) or (III) can be selectively prepared in a simple and short process with a good yield.
A benzene derivative having a carboxyl group and an ester at the 2-position can be produced.

These target compounds of the present invention are useful as synthetic intermediates for synthesizing specific substituted benzoic acid herbicides.

Further, according to the method of the present invention, the number of steps for the total synthesis of the compound represented by the general formula (V) for the herbicide can be reduced, and the total yield can be improved. When the compound of the general formula (IV) is produced from the compound of the formula (I) via the compounds of the general formulas (II) and (III), the reaction temperature, the selectivity and the yield are higher than those of the prior art. It has a remarkable effect of being excellent in terms of efficiency and no catalyst.

EXAMPLES Next, the present invention will be described in more detail with reference to examples.

Reference Example 1 45.2 g (0.2 mol) of 3-benzyloxyacetophenone, 49.6 (0.8 mol) of ethylene glycol and a catalytic amount of p-toluenesulfonic acid in 500 ml of toluene using a Dean-Stark moisture meter to decompose water produced.
The mixture was refluxed for 15 hours. After cooling, 200 ml of water was added, extracted with ether, washed with water and dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure, and the obtained mixture was separated by column (Wakogel C-300, eluent: n-hexane / ethyl acetate = 15 /
1) Then, 43.5 g of 3-benzyloxyacetophenone ethylene acetal was obtained as a colorless oil.

80.5% yield, ▲ n ²⁰ _D ▼ 1.5583 Example 1 3-benzyloxy-acetophenone ethylene acetal 4.05g of (0.015 mol) was dissolved in n- liquid oxygen 80 ml, under nitrogen flow 1.55 M n- butyllithium in n- hexane 1
After 0.6 ml (0.0165 mol) was added dropwise under ice cooling, the mixture was stirred at room temperature for 2 hours. The obtained mixture was poured into excess dry ice suspended in 60 ml of n-hexane, and 100 ml of water was added at 0 ° C.
And extracted with ether. The aqueous layer was separated, made acidic with a 10% aqueous hydrochloric acid solution, extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting crystals were washed with isopropyl ether to give 3-benzyloxy-2
-3.54 g of carboxyacetophenone ethylene acetal
Was obtained as colorless crystals.

Yield 75.1%, melting point 115-118 ° C Reference Example 2 0.47 g (0.0015 mol) of 3-benzyloxy-2-carboxyacetophenone ethylene acetal, 0.23 g (0.00165 mol) of methyl iodide and 0.23 g (0.001 mol) of potassium carbonate
(65 mol) in 80 ml of acetonitrile under reflux for 3 hours. After distilling off the solvent under reduced pressure, 50 ml of water was added, extracted with ether, washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the generated crystals were washed with n-hexane.
0.48 g of -benzyloxy-2-methoxycarbonylacetophenone ethylene acetal was obtained as colorless crystals.

Yield 98.0% Example 2 3-benzyloxyacetophenone ethylene acetal (5.40 g, 0.02 mol) was dissolved in n-hexane (100 ml) and n-hexane solution of 1.55 M n-butyllithium (1) was added under a nitrogen stream.
After 4.0 ml (0.022 mol) was added dropwise under ice cooling, the mixture was stirred at room temperature for 2 hours. Then, to this, methyl chlorodiate 2.08 g
(0.022 mol) of an n-hexane solution (2 ml) was added dropwise under ice-cooling.
After stirring at room temperature for 2 hours, 100 ml of water was added, extracted with ether, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting crystals were recrystallized from isopropyl ether / n-hexane to obtain 4.94 g of 3-benzyloxy-2-methoxycarbonylacetophenone ethylene acetal as colorless crystals.

Yield 75.3%, melting point 92-95 ° C Reference Example 3 0.13 g (0.0004 mol) of 3-benzyloxy-2-methoxycarbonylacetophenone ethylene acetal was dissolved in 10 ml of methanol, and 2 ml of a 10% aqueous hydrochloric acid solution was added.
Stir for hours. The solvent was distilled off under reduced pressure, 10 ml of water was added, the mixture was extracted with ether, washed with saturated saline, and dried over anhydrous magnesium sulfate. After dissolution and evaporation, the residue was dissolved in 10 ml of tetrahydrofuran, 0.02 g of 10% palladium carbon was added, and hydrogenation was performed for 3 hours. After filtering off the catalyst, the solvent was distilled off, and the resulting crystals were washed with isopropyl ether, and 0.07 g of 3-hydroxy-2-methoxycarbonitoacetophenone was added.
Was obtained as colorless crystals.

Yield: 91% Reference Example 4 0.33 g (0.001 mol) of 3-benzyloxy-2-methoxycarbonylacetophenone ethylene acetal was dissolved in 20 ml of methanol, and 0.2 ml (0.0005 mol) of a 10% aqueous hydrochloric acid solution was added thereto. g was added and hydrogenation was carried out for 2 hours. After filtering off the catalyst, the solvent was distilled off, and 10 ml of water was added.
And extracted with ether, washed with water and dried over anhydrous magnesium sulfate. After the solvent was removed, the resulting crystals were recrystallized from isopropyl ether / hexane to give 3-hydroxy-2.
0.135 g of -methoxycarbonylacetophenone was obtained as colorless crystals.

Yield 71.0% Example 3 3-methoxyacetophenone ethylene acetal 1.36
g (7 mmol) was dissolved in 15 ml of dry ether and cooled to ０0 ° C. in an ice bath under a nitrogen atmosphere. 1.6M (15
%) A solution of n-butyllithium in n-hexane (6 ml, 10 mmol) was added dropwise, followed by stirring at the same temperature for 30 minutes.
The ice bath was replaced with a dry ice-acetone bath and cooled to -78 ° C. Approximately 5 g of finely crushed dry ice was added little by little, stirred, and allowed to return to room temperature. 20 ml of water
The aqueous layer was separated by a liquid separation operation, and the obtained colorless aqueous layer was subjected to acid precipitation with a dilute acid, filtered, dried, and then dried to give the desired 3-methoxy-2-carboxyacetophenone ethylene acetal 0.83 g. I got

Yield 50.0%, melting point 140-141 ° C Reference Example 5 3-methoxy-2-carboxyacetophenone ethylene acetal 2.38 g (10 mmol), potassium carbonate 1.22 g
(10 mmol) and dimethylformamide (20 ml) were mixed, and the mixture was stirred at room temperature. Then, 1.42 g (10 mmol) of methyl iodide was added dropwise, and the mixture was stirred at 80 ° C. for about 1 hour. The reaction solution was poured into water, the oily substance was separated with ethyl acetate, washed with water, dried and concentrated, and purified by silica gel chromatography (n-hexane: ethyl acetate = 10: 1) to give 3-methoxy-
2.12 g of 2-methoxycarbonylacetophenone ethylene acetal was obtained as a colorless transparent liquid.

Yield: 85.0%, (n ²⁰ _D) = 1.5331 Example 4 3-methoxyacetophenone ethylene acetal 1.36
g (7 mmol) was dissolved in 15 ml of dry toluene and cooled to 〜0 ° C. in an ice bath under a nitrogen atmosphere. 1.6M (15
%) N-butyllithium solution (6 ml, 10 mmol) in n-hexane was added dropwise, followed by stirring at room temperature for 2 hours. Then, the mixture was cooled to 〜0 ° C. once in an ice bath, and a solution of 0.94 g (10 mmol) of methyl chloroformate dissolved in 5 ml of n-hexane was added dropwise at 5 ° C. or lower, followed by stirring at room temperature for 2 hours. The reaction solution was poured into ice water, the n-hexane layer was separated by adding 30 ml of ethyl acetate, washed with water, dried and concentrated, and purified by silica gel chromatography (n-hexane: ethyl acetate = 10: 1) to give 3 1.31 g of -methoxy-2-methoxycarbonylacetophenone ethylene acetal was obtained as a colorless transparent liquid.

75.0% yield, ▲ n ²⁰ _D ▼ = 1.5331 dissolved Example 5 3-methoxymethoxy acetophenone ethylene acetal 1.56g (7 mmol) in dry ether 15 ml, under nitrogen atmosphere and cooled to ~0 ° C. in an ice bath. to this,
1.6M (15%) n-butyllithium n-hexane solution 6m
After l (10 mmol) was added dropwise, the mixture was stirred at the same temperature for 30 minutes. Replace the ice bath with a dry ice-acetone bath, ~
Cooled to -78 ° C. Approximately 5 g of finely crushed dry ice was added little by little, stirred, and allowed to return to room temperature. Hydrolysis with 20 ml of water, the aqueous layer was separated by a liquid separation operation, and the obtained colorless aqueous layer was precipitated with dilute acid, filtered, dried,
1.22 g of the desired 3-methoxymethoxy-2-carboxyacetophenone ethylene acetal was obtained.

Yield 65.0%, melting point 132-134 ° C. Reference Example 6 2.38 g (10 mmol) of 3-methoxymethoxy-2-carboxyacetophenone ethylene acetal, 1.22 g (10 mmol) of potassium carbonate and 20 m of dimethylformamide
After adding l and stirring at room temperature, methyl iodide 1.42 g
(10 mmol) was added dropwise and stirred at 80 ° C. for about 1 hour.
The reaction solution was poured into water, the oily substance was separated with ethyl acetate, washed with water, dried and concentrated, and then subjected to silica gel chromatography (n
-Hexane: ethyl acetate = 10: 1) to give 2.44 g of 3-methoxymethoxy-2-methoxycarbonylacetophenone ethylene acetal as a colorless transparent liquid.

85.9% yield, ▲ n ²⁰ _D ▼ = 1.5394 dissolved Example 6 3-Methoxy-methoxyacetophenone ethylene acetal 1.56g (7 mmol) in dry triene 15 ml, under nitrogen atmosphere and cooled to ~0 ° C. in an ice bath. to this,
1.6M (15%) n-butyllithium n-hexane solution 6m
After l (10 mmol) was added dropwise, the mixture was stirred at room temperature for 2 hours. Then, the mixture was cooled to 〜0 ° C. once in an ice bath, and a solution of 0.94 g (10 mmol) of methyl chloroformate dissolved in 5 ml of n-hexane was added dropwise at 5 ° C. or lower, followed by stirring at room temperature for 2 hours. The reaction solution was poured into ice water, and the n-hexane layer was ethyl acetate.
30 ml was added, fractionated, washed with water, dried and concentrated, and then subjected to silica gel chromatography (n-hexane: ethyl acetate = 10: 10).
Purification was performed in 1) to obtain 2.08 g of 3-methoxymethoxy-2-methoxycarbonylacetophenone ethylene acetal as a colorless transparent liquid.

Yield _{^{73.0%, ▲ n 20 D ▼}} = 1.5394 Reference Example 7 3-hydroxy-2-methoxycarbonyl-acetophenone 10.0 g, 4,6-dimethoxypyrimidin-2-yl methyl sulfone 9.6g and dimethylformamide 50ml potassium carbonate 7.2g The mixture was stirred at 100 ° C for 1 hour to give 10.0 g of methyl 2-[(4,6-dimethoxypyrimidin-2-yl) oxy] -6-acetylbenzoate.

Then 3.3 g of this compound, 4.1 g of methoxyamine hydrochloride
And 4.9 g of potassium acetate in 50 ml of methanol at reflux temperature.
Stir with time, 2-[(4,6-dimethoxypyrimidine-
3.2 g of methyl 2-yl) oxy] -6- [1- (methoxyimino) ethyl] benzoate were obtained.

────────────────────────────────────────────────── ─── Continued on the front page (72) Shigehiko Tachikawa, Inventor 3-57, Anzai, Shizuoka City, Shizuoka Prefecture (72) Ryo Yoshida 3353, Kamo, Kikugawa-cho, Ogasa-gun, Shizuoka Prefecture (56) References Org. Chem. (1983), 48 (14), pages 2349-2356 Tetrahedron (1985), 41 (24), pabes 5771-5778 (58) Fields investigated (Int. Cl. ⁶ , DB name) C07D 317/00-317/72 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] (1) General formula (Wherein R is an alkyl group, an aralkyl group or an alkoxyalkyl group, and R ′ is an alkyl group or an aralkyl group), wherein carbon dioxide is reacted in the presence of a base. General formula (Wherein, R and R ′ have the same meanings as described above). 2. The general formula (Wherein R is an alkyl group, an aralkyl group or an alkoxyalkyl group, and R ′ is an alkyl group or an aralkyl group) in a compound represented by the general formula XCOOR ″ (where R ″ is an alkyl group) in the presence of a base. Or an aralkyl group, wherein X is a halogen atom). (Wherein R, R ′ and R ″ have the same meaning as described above).