JP2013032336A - Method for producing 3-trifluoromethylpyridine n-oxide - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing 3-trifluoromethylpyridine N-oxide useful as intermediates of pharmaceuticals and agricultural chemicals by a simple operation at a high generation rate and in a high yield.SOLUTION: The method for producing 3-trifluoromethylpyridine N-oxide is characterized by bringing 3-trifluoromethylpyridine and a hydrogen peroxide solution into oxidation reaction in the presence of at least one catalyst selected from the group consisting of tungstic acid, alkali metal salts of tungstic acid, alkaline earth metal salts of tungstic acid, molybdenum oxide and ammonium molybdate.

Description

  The present invention relates to a method for producing 3-trifluoromethylpyridine N-oxide useful as an intermediate for pharmaceuticals and agricultural chemicals.

Patent Document 1 discloses a method for producing N-oxide derivatives of pyridines by maintaining pyridines and hydrogen peroxide water at pH 3-9 in the presence of a catalyst containing a tungstic acid compound and / or a molybdate compound. Is described. However, 3-trifluoromethylpyridine is not described as a specific example of pyridines.
Non-Patent Document 1 describes a method for producing 3-trifluoromethylpyridine N-oxide by oxidizing 3-trifluoromethylpyridine in the presence of acetic acid and hydrogen peroxide. However, it does not describe a method for performing an oxidation reaction using a tungstic acid compound and / or a molybdate compound as a catalyst. In the method described in Non-Patent Document 1, since an acetic acid solvent is used, acetic acid is distilled off after completion of the reaction, and the residue is neutralized with sodium carbonate and then extracted with methylene chloride. Is complicated, and is not always satisfactory in terms of the production rate of 3-trifluoromethylpyridine N-oxide 3-ethoxycarbonylpyridine N-oxide.

Japanese Patent Laid-Open No. 10-324678

Chem. Pharm. Bull., 17 (3), 2244-2247, 1969

  Provided is a method for producing 3-trifluoromethylpyridine N-oxide by a simple operation with high production rate and high yield.

As a result of various studies to solve the above-mentioned problems, as a result of oxidation reaction of 3-trifluoromethylpyridine and hydrogen peroxide water in the presence of tungstic acid compound and / or molybdic acid compound as catalysts, The present inventors have found a method for producing 3-trifluoromethylpyridine N-oxide with a high yield and high yield.
That is, according to the present invention, 3-trifluoromethylpyridine and hydrogen peroxide water are subjected to an oxidation reaction in the presence of a tungstic acid compound and / or molybdate compound as a catalyst. The present invention relates to a method for producing oxide.

  According to the production method of the present invention, 3-trifluoromethylpyridine N-oxide can be produced with a high production rate and a high yield by a simple operation. Further, since the catalyst can be recycled, the target product can be produced economically.

  3-trifluoromethylpyridine N-oxide can be produced by subjecting 3-trifluoromethylpyridine and aqueous hydrogen peroxide to an oxidation reaction in the presence of a tungstic acid compound and / or molybdate compound as a catalyst.

  As the catalyst, a tungstic acid compound and / or a molybdate compound can be used. Examples of the tungstic acid compound include tungstic acid; alkali metal salts of tungstic acid such as lithium tungstate, sodium tungstate, and potassium tungstate; alkalis of tungstic acid such as magnesium tungstate, calcium tungstate, and barium tungstate. Earth metal salts; and the like. Examples of molybdate compounds include molybdenum oxide and ammonium molybdate. Among these, tungstic acid, sodium tungstate, molybdenum oxide, and ammonium molybdate are desirable from the viewpoint of production rate and yield in producing 3-trifluoromethylpyridine N-oxide.

  The oxidation reaction is performed by reacting 3-trifluoromethylpyridine with hydrogen peroxide. The hydrogen peroxide solution can be used at a normal hydrogen peroxide concentration, preferably 5 to 90% by weight, more preferably 10 to 60% by weight. In addition to the hydrogen peroxide solution, the reaction may be carried out by further adding water as a solvent.

  The hydrogen peroxide solution is usually used in an amount of 1 to 10 moles, preferably 1 to 3 moles per mole of 3-trifluoromethylpyridine as hydrogen peroxide. However, depending on the reaction conditions, an amount outside this range can be used.

  The reaction temperature is usually about 0 to 100 ° C, preferably about 10 to 90 ° C, more preferably about 60 to 90 ° C, and the reaction time is usually about 0.1 to 24 hours, preferably 0.5 to 3 hours. It is about time.

  After completion of the reaction, the reaction solution is cooled to precipitate a catalyst, which is separated into solid and liquid by a separation operation such as filtration, and the used catalyst can be recovered. Alternatively, the reaction product is recovered from the reaction solution by solvent extraction, and then the aqueous solution is treated with a reducing agent such as sodium sulfite and acidified with a dilute acid such as dilute sulfuric acid to precipitate the catalyst. This can be separated into solid and liquid by a separation operation such as filtration, and the used catalyst can be recovered. The recovered catalyst can be used again in the oxidation reaction of the production method of the present invention, whether it is used after drying or not.

  In order to describe the present invention in more detail, examples are described below, but the present invention is not construed as being limited thereto.

Example 1
In a four-necked flask equipped with a stirrer, a thermometer, and a condenser tube, 220.65 g of 3-trifluoromethylpyridine and 15.0 g of tungstic acid were charged. Thereto, 182.1 g of 35% hydrogen peroxide solution was added dropwise at 75 to 85 ° C. over 1 hour and reacted at the same temperature for 2 hours.
After cooling the reaction solution, 30 g of 20% aqueous sodium hydroxide solution was added at 30 ° C. or lower, and the mixture was stirred for 15 minutes, and further 47.3 g of 20% sodium sulfite was added. After the addition, the mixture was stirred at the same temperature for 15 minutes, and it was confirmed with potassium iodide starch paper that the treatment of excess hydrogen peroxide in the reaction solution was completed. Extraction was performed twice with dichloromethane (745 ml, 496 ml) to obtain 1863 g of a dichloromethane solution containing 3-trifluoromethylpyridine N-oxide.
The dichloromethane solution was heated under normal pressure until the internal temperature reached 50 ° C. to distill off the dichloromethane, and the water in the system was removed to obtain 977 g of a dichloromethane solution containing 3-trifluoromethylpyridine N-oxide. As a result of analysis by liquid chromatography, the yield was almost quantitative.
To the aqueous layer from which 3-trifluoromethylpyridine was removed by solvent extraction, 66.0 g of 20% sulfuric acid was added to acidify to pH 1.5 to precipitate crystals. After stirring for 3 hours, the white slurry was filtered. did. The crystals were dried at 45 ° C. for 14 hours to recover 12.4 g of catalyst.
The oxidation reaction was performed again using the recovered catalyst. In a four-necked flask equipped with a stirrer, a thermometer and a condenser tube, 77.4 g of 3-trifluoromethylpyridine and 6.25 g of a recovered catalyst were charged. Thereto, 63.9 g of 35% aqueous hydrogen peroxide was added dropwise at 75 to 85 ° C. over 1 hour and reacted at the same temperature for 3 hours.
After cooling the reaction solution, 10 g of a 20% aqueous sodium hydroxide solution was added at 30 ° C. or lower and stirred for 15 minutes, and then 15.8 g of 20% sodium sulfite was further added. After the addition, the mixture was stirred at the same temperature for 15 minutes, and it was confirmed with potassium iodide starch paper that the treatment of excess hydrogen peroxide in the reaction solution was completed. Extraction with dichloromethane was performed twice in total (248 ml, 165 ml), concentrated and vacuum-dried to obtain 79.9 g of 3-trifluoromethylpyridine N-oxide crystals.
To the aqueous layer from which 3-trifluoromethylpyridine was removed by solvent extraction, 23.0 g of 20% sulfuric acid was added to acidify to pH 1.5 to precipitate crystals. After stirring for 3 hours, the white slurry was filtered. did. The wet crystals were dried at 45 ° C. for 14 hours to recover 5.1 g of catalyst.

Example 2
In a four-necked flask equipped with a stirrer, a thermometer, and a condenser tube, 29.4 g of 3-trifluoromethylpyridine and 1.50 g of tungstic acid were charged. Thereto, 29.1 g of 35% hydrogen peroxide solution was added dropwise at 75 to 85 ° C. over 1 hour and reacted at the same temperature for 3 hours. When the reaction solution was analyzed by liquid chromatography, it was confirmed that it contained 0.57% of 3-trifluoromethylpyridine and 98.85% of 3-trifluoromethylpyridine N-oxide.
The reaction solution was cooled to 10 ° C., and the slurry solution was filtered with Nutsche to recover 2.34 g of wet crystal catalyst.
The oxidation reaction was carried out again using the entire amount of the recovered catalyst. In a four-necked flask equipped with a stirrer, a thermometer, and a condenser tube, 29.4 g of 3-trifluoromethylpyridine and 2.34 g of a recovered catalyst were charged. Thereto, 29.1 g of 35% hydrogen peroxide solution was added dropwise at 75 to 85 ° C. over 1 hour and reacted at the same temperature for 1 hour. The reaction was further continued for 3 hours by adding 0.5 g of tungstic acid. When the reaction solution was analyzed by liquid chromatography, it was confirmed that it contained 0.53% of 3-trifluoromethylpyridine and 98.80% of 3-trifluoromethylpyridine N-oxide.

Example 3
In a four-necked flask equipped with a stirrer, a thermometer and a condenser, 30.2 g of 3-trifluoromethylpyridine, 2.6 g of sodium tungstate dihydrate and 0.8 g of concentrated sulfuric acid were charged. Thereto, 182.1 g of 35% aqueous hydrogen peroxide was added dropwise at 75 to 85 ° C. over 1 hour and 10 minutes, and reacted at the same temperature for 4 hours. After cooling the reaction solution, 75.6 g of 10% sodium sulfite was added at 30 ° C. or lower. After the addition, the mixture was stirred at the same temperature for 15 minutes, and it was confirmed with potassium iodide starch paper that the treatment of excess hydrogen peroxide in the reaction solution was completed. Extraction with 75 g of dichloromethane was performed three times, the solvent was distilled off under reduced pressure, and vacuum drying was performed to obtain 20.4 g of 3-trifluoromethylpyridine-N-oxide crystals.

Example 4
In a four-necked flask equipped with a stirrer, a thermometer and a condenser tube, 73.55 g of 3-trifluoromethylpyridine and 2.16 g of molybdenum oxide were charged. Thereto, 72.86 g of 35% hydrogen peroxide solution was added at 75 to 85 ° C. over about 1 hour, and reacted for 3 hours under the same temperature condition.
After cooling the reaction solution, 17.38 g of sodium sulfite was added at 30 ° C. or lower. After the addition, the mixture was stirred at 30 to 40 ° C. for about 1 hour, and it was confirmed by potassium iodide starch paper that the treatment of excess hydrogen peroxide in the reaction solution was completed. 36 ml of water was added thereto, and then extraction with 147.1 ml of dichloromethane was repeated three times.
The extracted dichloromethane solution was concentrated at normal pressure and then subjected to azeotropic dehydration under reflux to obtain 145.4 g of a dichloromethane solution containing 80.16 g of 3-trifluoromethylpyridine N-oxide.

Example 5
A four-necked flask equipped with a stirrer, a thermometer, and a condenser tube was charged with 44.13 g of 3-trifluoromethylpyridine, 18.54 g of 6-ammonium 7-molybdate, and 90.0 g of water. Thereto, 98.79 g of 35% aqueous hydrogen peroxide was added at 75 to 85 ° C. over about 1 hour, and reacted for 1 hour under the same temperature condition.
After cooling the reaction solution, 37.82 g of sodium sulfite was added at 30 ° C. or lower. After the addition, the mixture was stirred at 30 to 40 ° C. for about 1 hour, and it was confirmed by potassium iodide starch paper that the treatment of excess hydrogen peroxide in the reaction solution was completed. When the reaction solution was analyzed by liquid chromatography, it was confirmed that it contained 0.25% 3-trifluoromethylpyridine and 99.39% 3-trifluoromethylpyridine N-oxide.

Claims (6)

  A method for producing 3-trifluoromethylpyridine N-oxide, comprising subjecting 3-trifluoromethylpyridine and hydrogen peroxide water to an oxidation reaction in the presence of a tungstic acid compound and / or molybdate compound as a catalyst.   The method according to claim 1, wherein the tungstic acid compound is at least one selected from the group consisting of tungstic acid, alkali metal salts of tungstic acid, and alkaline earth metal salts of tungstic acid.   The method according to claim 1, wherein the molybdate compound is molybdenum oxide and / or ammonium molybdate.   The process according to claim 1, wherein the catalyst is at least one selected from the group consisting of tungstic acid, alkali metal salts of tungstic acid, alkaline earth metal salts of tungstic acid, molybdenum oxide and ammonium molybdate.   The method according to claim 1, wherein 1 to 10 moles of hydrogen peroxide are used per mole of 3-trifluoromethylpyridine.   The process of claim 1, wherein the oxidation reaction is carried out at a reaction temperature of 0 to 100 ° C.