JP4587202B2 - Process for producing phenyloxadiazoles - Google Patents

Description

  The present invention relates to a process for producing phenyloxadiazoles useful as an intermediate for medicines and agricultural chemicals.

Phenyloxadiazoles are useful compounds as intermediates for medicines and agrochemicals. Known synthesis methods include benzamide oximes in the presence of boron trifluoride ether complex and ethyl orthoformate as a solvent and reaction substrate. (Patent Document 1).

However, in the method described in Patent Document 1, since ethyl orthoformate is used as a reaction substrate and solvent, a large amount of ethyl orthoformate is required, and the yield of the target product, phenyloxadiazoles, is 80%. A method for producing phenyloxadiazoles in a high yield and industrially advantageously has been desired.

JP 51-105067

The present invention provides a method for industrially advantageously producing phenyloxadiazoles useful as a pharmaceutical and agrochemical intermediate in a high yield.

（式中、Ｘは水素原子、ハロゲン原子、アルキル基、アルコキシ基、フェニル基、トリフルオロメチル基、ニトロ基、アルキルチオ基、またはジアルキルアミノ基を表す。）で示されるベンズアミドオキシム類をアルコール類および酸触媒存在下、オルト蟻酸エステルと反応させた場合においてのみ







式（２）

（式中、Ｘは、前記と同じ意味を表わす。）で示されるフェニルオキサジアゾール類が
高収率で工業的に有利に得られることを見い出し、本発明を完成させた。 In order to solve the above problems, the present inventors have focused on the reaction conditions, particularly the solvent used during the reaction, to produce phenyloxadiazoles from benzamide oximes in an industrially advantageous manner in a high yield. As a result of various investigations on ketones such as methyl ethyl ketone and methyl isobutyl ketone, esters such as ethyl acetate and butyl acetate, alcohols such as methyl alcohol, ethyl alcohol and isopropyl alcohol,
Formula (1)

(Wherein, X represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, a phenyl group, a trifluoromethyl group, a nitro group, an alkylthio group, or a dialkylamino group) a benzamide oxime represented by an alcohol and Only when reacted with orthoformate in the presence of acid catalyst







Formula (2)

It was found that phenyloxadiazoles represented by the formula (wherein X represents the same meaning as described above) can be obtained industrially advantageously in a high yield, and the present invention was completed.

Hereinafter, the present invention will be described in more detail.
In the present invention, examples of the benzamide oxime represented by the formula (1) include nitrobenzamide oxime and chlorobenzamide oxime.

Examples of the orthoformate ester in the present invention include methyl orthoformate, ethyl orthoformate, isopropyl orthoformate and the like. The amount of orthoformate used is usually in the range of 1 to 20 mol, preferably in the range of 2 to 10 mol, per mol of the benzamide oxime represented by the formula (1). If the amount of orthoformate used is less than 1 mol, the yield of the product is lowered, which is not preferred, and if it exceeds 20 mol, the productivity is lowered, which is not preferred as an industrial production method.

  The alcohol used in the present invention is not particularly limited as long as it does not inhibit the reaction of the present invention, and examples thereof include methanol, ethanol, propanol, isopropanol, butanol, isobutanol, and t-butanol. Among these, propanol, isopropanol, butanol, isobutanol, and t-butanol are preferable, and isopropanol is more preferable, and each can be used alone or in combination of two or more. The amount of the solvent used is usually in the range of 10 to 2000 parts, preferably in the range of 100 to 1000 parts, more preferably 100 parts by weight of the benzamide oxime represented by the formula (1). , 200 parts to 500 parts.

As the acid catalyst used in the present invention, both inorganic acids and organic acids can be used. Examples of inorganic acids include mineral acids such as hydrochloric acid, phosphoric acid and sulfuric acid, and examples of organic acids include formic acid and paratoluenesulfonic acid. Among them, sulfuric acid, hydrochloric acid, phosphoric acid and the like can be mentioned. Mineral acids are preferred, and each can be used alone or in combination of two or more.
The amount of the acid catalyst used is not particularly limited, but is 0.1 to 50% by weight, preferably 1 to 20% by weight, based on the benzamide oxime represented by the formula (1).

  Although the reaction temperature in this invention changes with the usage-amounts of a raw material, a solvent, etc., it is normally performed in the temperature range of 0 degreeC-100 degreeC, Preferably, it is a temperature range of 20 degreeC-60 degreeC.

Although the reaction time in this invention changes with reaction conditions, such as the usage-amounts of a raw material, a solvent, etc., it is normally performed in the range of 1 to 20 hours.

By the method of the present invention, phenyloxadiazoles useful as an intermediate for medicines and agricultural chemicals can be produced industrially advantageously in higher yields.

Next, although the detail of this invention is shown in the following examples, this invention is not limited to these.

10.0 g (0.055 mol) of p-nitrobenzamide oxime, 16.4 g (0.11 mol) of ethyl orthoformate and 50 g of isopropanol were mixed, and 1.1 g of 98% sulfuric acid was added dropwise at 20 ° C to 30 ° C. After completion of the dropwise addition, the reaction solution was heated to 45-50 ° C. and reacted with stirring for 2 hours. When analyzed by LC after completion of the reaction, the peak of the starting material p-nitrobenzamide oxime disappeared. After completion of the reaction, the reaction mixture was cooled to 5 ° C. and the precipitated white crystals were collected by filtration to obtain 10.13 g of 3- (4-nitrophenyl) -1,2,4-oxadiazole having a purity of 99.9 wt%. It was. The yield was 96.1%.

10.0 g (0.055 mol) of p-nitrobenzamide oxime, 32.7 g (0.22 mol) of ethyl orthoformate and 32.8 g of methanol were mixed, and 1.1 g of 98% sulfuric acid was added dropwise at 20 ° C to 30 ° C. After completion of the dropwise addition, the reaction solution was heated to 45-50 ° C. and reacted at the same temperature with stirring for 5 hours. When analyzed by LC after completion of the reaction, the peak of the starting material p-nitrobenzamide oxime disappeared. After completion of the reaction, the mixture was cooled to 5 ° C. and the precipitated white crystals were collected by filtration to obtain 9.70 g of 9 (9-wt%) 3- (4-nitrophenyl) -1,2,4-oxadiazole. It was. The yield was 91.9%.

20 g (0.11 mol) of p-nitrobenzamide oxime, 81.9 g (0.55 mol) of ethyl orthoformate and 4.1 g of ethanol were mixed, and 2.2 g of 98% sulfuric acid was added dropwise at 20 ° C to 30 ° C. After completion of the dropwise addition, the reaction solution was heated to 30 ° C. and reacted at the same temperature with stirring for 12 hours. When analyzed by LC after completion of the reaction, the peak of the starting material p-nitrobenzamide oxime disappeared. After completion of the reaction, the mixture was cooled to 5 ° C., and the precipitated white crystals were collected by filtration to obtain 18.65 g of 9 (wt) -nitro (4-nitrophenyl) -1,2,4-oxadiazole having a purity of 99.8 wt%. It was. The yield was 88.4%.

(Comparative Example 1)
25.3 g (0.14 mol) of p-nitrobenzamide oxime is mixed with 166.6 g (1.12 mol) of ethyl orthoformate, and 2 ml of boron trifluoride ether complex compound is added to this solution. The resulting mixture was reacted with stirring at room temperature for 12 hours. When analyzed by LC after completion of the reaction, the peak of the starting material p-nitrobenzamide oxime disappeared. After completion of the reaction, the reaction mixture was cooled to 5 ° C., and the produced white crystals were collected by filtration and dried to obtain 21. 3- (4-nitrophenyl) -1,2,4-oxadiazole having a purity of 99.5 wt%. 0 g was obtained. The yield was 78.5%.

(Comparative Example 2)
20.0 g (0.11 mol) of p-nitrobenzamide oxime, 32.8 g (0.22 mol) of ethyl orthoformate and 100 g of ethyl acetate were mixed, and 8 g of 98% sulfuric acid was added dropwise at 20 ° C to 30 ° C. After completion of dropping, the reaction solution was stirred at the same temperature, whereby the reaction solution was solidified. Thereafter, an additional 100 g of ethyl acetate was added and reacted for 12 hours. Analysis by LC after completion of the reaction revealed that 47% of the charged amount of the starting material p-nitrobenzamide oxime remained as the starting material.

(Comparative Example 3)
20.0 g (0.11 mmol) of p-nitrobenzamide oxime, 32.8 g (0.22 mol) of ethyl orthoformate and 100 g of methyl isobutyl ketone were mixed, and 8 g of 98% sulfuric acid was added dropwise at 20 ° C to 30 ° C. After completion of dropping, the reaction solution was reacted at the same temperature for 12 hours. When analyzed by LC after completion of the reaction, 99% of the charged amount of p-nitrobenzamide oxime as a raw material remained as the raw material.

Claims (3)

Formula (1)
[Chemical 1]

(Wherein, X represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, a phenyl group, a trifluoromethyl group, a nitro group, an alkylthio group or a dialkylamino group,.) Methanol benzamide oximes represented by ethanol , Propanol, isopropanol, butanol, isobutanol, t-butanol and at least one selected from the group consisting of alcohols and an orthoformate in the presence of an acid catalyst (2)
[Chemical 2]

(Wherein X represents the same meaning as described above) 2. The method for producing phenyloxadiazoles according to claim 1, wherein the orthoformate is ethyl orthoformate and the alcohol is isopropyl alcohol. The method for producing phenyloxadiazoles according to claim 1, wherein the acid catalyst is a mineral acid.