WO2009054210A1

WO2009054210A1 - Process for producing toluidine compound

Info

Publication number: WO2009054210A1
Application number: PCT/JP2008/066797
Authority: WO
Inventors: Shigeo Murai; Hiroshi Yoshizawa; Takeshi Ohshima; Katsuyoshi Murakami; Takayoshi Ando; Tadashi Nakamura; Norio Adachi; Akihiko Isogai
Original assignee: Ishihara Sangyo Kaisha, Ltd.
Priority date: 2007-10-24
Filing date: 2008-09-10
Publication date: 2009-04-30
Also published as: CL2008003130A1; TW200922923A; JP2009242370A; AR068733A1

Abstract

ABSTRACT Because fluazinam is excellent as an active ingredient of pesticides and highly useful, it is desired to produce it efficiently in a proper form with simple operations at low cost in an environmentally friendly manner. The desired product is obtained in good yields with simple operations by using industrially advantageous reaction systems by a process comprising (1) a step of reacting ACTF and DCDNBTF in the presence of an alkali component, a solvent selected from the group consisting of ethers, nitriles and esters, (2) a step of neutralizing or acidifying the reaction mixture with an acid and (3) a step of removing the solvent by distillation from the mixture containing fluazinam as the reaction product and the solvent to precipitate crystals of the product.

Description

DESCRIPTION PROCESS FOR PRODUCING TOLUIDINE COMPOUND

BACKGROUND OF THE INVENTION TECHNICAL FIELD

The present invention relates to a process for producing 3-chloro-N- (3-chloro-5-trifluoromethyl-2 - pyridyl) -α,α,α-trifluoro-2, 6-dinitro-p-toluidine as an active ingredient of pesticides (common name: fluazinam) .

BACKGROUND ART

USP 4,331,670 (Patent Document 1) discloses a process for producing 3-chloro-N- (3-chloro-5- trifluoromethyl -2 -pyridyl) -α, a, α-trifluoro-2 , 6-dinitro-p- toluidine which comprises reacting 2-amino-3-chloro-5- trifluoromethylpyridine and 2 , 4-dichloro-3 , 5- dinitrobenzotrifluoride in the presence of a base and a solvent and discloses alkali metal hydroxides, carbonates and hydrides or alkaline earth metal hydroxides and carbonates as examples of the base and aprotic polar solvents such as dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, sulfolane and dioxane as examples of the solvent .

WO 2007/060662 (Patent Document 2) discloses the use of methyl isobutyl ketone (MIBK) as the solvent in the above-mentioned process disclosed in USP 4,331,670 (Patent Document 1) . Patent Document 2 discloses that a higher yield is attained when the presence of water, which is hardly miscible with MIBK, in the reaction is minimized to decrease the hydrolysis by-product and that the presence of a high concentration of water resulting from the reaction or attributed to the reagents increases the hydrolysis by-product and thereby decreases the yield. Patent Document 2 also discloses that the ratio of the solvent to the reactant should be larger than about 10%w/v and that the solvent is preferably pure MIBK (for example, with a purity of about 98%) or recycled MIBK with a water content of less than 2%, and that in the production of fluazinam as the desired product described in Example 2, the reaction was carried out by adding solid KOH (3.5 mol eq.) to a mixture of 2-amino-3- chloro-5-trifluoromethylpyridine, 2 , 4-dichloro-3 , 5- dinitrobenzotrifluoride and a MIBK azeotrope containing 1.6% water. However, use of MIBK has a problem of formation of bad- smelling components at the time of the reaction. Patent Document 1: USP 4,331,670 Patent Document 2: WO 2007/060662

DISCLOSURE OF THE INVENTION

Because fluazinam is excellent as an active ingredient of pesticides and highly useful, it is desired to produce fluazinam efficiently in a proper form with simple operations at low cost in an environmentally friendly manner. Especially, there is a demand for processes preferable from the viewpoints of the cost for industrial production, simplicity of reaction procedures and safety. Through their extensive research on the reaction conditions and reaction procedures for more efficient and industrially advantageous production of 3-chloro-N- (3- chloro-5-trifluoromethyl-2-pyridyl) -α, a, α-trifluoro-2 , 6- dinitro-p-toluidine, the present inventors found that use of a particular solvent carries various advantages, allows a high yield of the desired product and is favorable for post-reaction operations such as isolation, purification and recovery of the product and accomplished the present invention on the basis of these discoveries. Namely, the present invention provides the following.

[1] A process for producing 3-chloro-N- (3-chloro-5- trifluoromethyl-2-pyridyl) -α, α, α-trifluoro-2 , 6-dinitro-p- toluidine, which comprises (1) a step of reacting 2- amino-3-chloro-5-trifluoromethylpyridine (ACTF) and 2,4- dichloro-3,5-dinitrobenzotrifluoride (DCDNBTF) in the presence of an alkali component and at least one member selected from the group consisting of ethers, nitriles and esters as a solvent, (2) a step of neutralizing or acidifying the reaction mixture with an acid and (3) a step of removing the solvent from a mixture containing 3- chloro-N- (3-chloro-5-trifluoromethyl-2-pyridyl) -α, α,α- trifluoro-2, 6-dinitro-p-toluidine as the reaction product and the reaction solvent by distillation to precipitate crystals of the product .

[2] The process according to [1] , wherein the alkali component is selected from alkali metals, hydrides, hydroxides and carbonates of alkali metals and hydroxides and carbonates of alkaline earth metals . [3] The process according to [1] or [2] , wherein the solvent is at least one member selected from the group consisting of ethers and esters.

[4] The process according to [3] , wherein the solvent is cyclopentyl methyl ether, methyl tert-butyl ether, 1,2- dimethoxyethane , 1, 2-diethoxyethane, tetrahydropyran, methyl acetate, ethyl acetate, propyl acetate or butyl acetate.

[5] The process according to any one of [1] to [4] , wherein in the step (1), at least 2 mol , preferably from 3 to 10 mol, particularly preferably from 4 to 10 mol, of the alkali component is present in relation to 1 mol of 2-amino-3-chloro-5-trifluoromethylpyridine .

[6] The process according to any one of [1] to [5] , wherein in the step (1), 2 , 4-dichloro-3 , 5- dinitrobenzotrifluoride is used in an amount of from 0.8 to 1.2 mol, preferably from 1 to 1.05 mol, in relation to 1 mol of 2-amino-3-chloro-5-trifluoromethylpyridine . [7] The process according to any one of [1] to [6] , wherein in the step (1) , the solvent is used in an amount of from 50 to 1000 g, preferably from 100 to 700 g, in relation to 100 g of 2-amino-3-chloro-5- trifluoromethylpyridine .

[8] The process according to any one of [1] to [4] , wherein in the step (2), water is added to the reaction mixture, and the reaction mixture is separated, and the organic phase is neutralized or acidified with the acid. [9] The process according to any one of [1] to [4] , wherein in the step (3) , the mixture containing 3-chloro- N- (3 -chloro-5-trifluoromethyl-2-pyridyl) -α, α, α-trifluoro- 2 , 6-dinitro-p-toluidine as the reaction product and the solvent is mixed with water and then the solvent is removed by distillation to precipitate crystals of the product in water. [10] The process according to any one of [1] to [4] and [9], wherein in the step (3), the crystals are precipitated in the presence of α-crystals of the reaction product as a seed. [11] A process for producing 3-chloro-N- (3-chloro-5- trifluoromethyl-2-pyridyl) -α, α, α-trifluoro-2 , 6-dinitro-p- toluidine or a salt thereof, which comprises reacting 2- amino-3-chloro-5-trifluoromethylpyridine and 2,4- dichloro-3 , 5-dinitrobenzotrifluoride in the presence of an alkali component and at least one member selected from the group consisting of ethers, nitriles and esters as a solvent . EFFECT OF THE INVENTION

According to the present invention, in production of 3-chloro-N- (3-chloro~5-trifluoromethyl-2-pyridyl) -α,α,α- trifluoro-2 , 6-dinitro-p-toluidine by reacting 2-amino-3- chloro-5-trifluoromethylpyridine and 2 , 4-dichloro-3 , 5- dinitrobenzotrifluoride, it is possible not only to obtain the desired product in excellent yields by using industrially advantageous reaction systems through simple procedures, but also to isolate and purify the desired product efficiently and industrially advantageously. The process of the present invention gives a high yield of the desired product and is therefore advantageous over conventional processes in industrial applicability. Further, it is an extremely excellent industrial process from the viewpoints of cost, operations and safety.

Other objects, features, advantages and aspects of the present invention would be clear to a person skilled in the art from the following description. However, it should be understood that the following description and specific examples in the present specification illustrate preferable embodiments of the present invention just for the sake of explanation. From the teachings of the following description and the rest of the present specification, a person skilled in the art would readily understand various possible changes and/or revisions (modifications) within the intention in the present invention and the scope of the present invention disclosed in the present specification. All the patent documents and reference documents referred to in the present specification are referred to for the sake of explanation, and their contents should be understood to be incorporated in the present specification as part of the present specification.

BEST MODE FOR CARRYING OUT THE INVENTION

In the step (1), from 0.8 to 1.2 mol of 2,4- dichloro-3, 5-dinitrobenzotrifluoride may be used in relation to 1 mol of 2-amino-3-chloro-5- trifluoromethylpyridine. Preferably, from 1 to 1.05 mol of 2 ,4-dichloro-3, 5-dinitrobenzotrifluoride may be used in relation to 1 mol of 2-amino-3-chloro-5- trifluoromethylpyridine. The reaction (1) is a condensation reaction between 2-amino-3-chloro-5- trifluoromethylpyridine and 2, 4 -dichloro-3 , 5- dinitrobenzotrifluoride, and the two starting materials are preferably used in a ratio within the above-mentioned range by allowing for slight loss of the latter, though they are used in equimolar amounts in theory. Nevertheless, their ratio may fall outside the above- mentioned range.

In the step (1) , from 50 to 1000 g, preferably from 100 to 700 g, of a solvent may be used in relation to 100 g of 2-amino-3-chloro-5-trifluoromethylpyridine. The solvent used in the process of the present invention is an ether, nitrile or ester, specifically at least one member selected from the group consisting of ethers such as diethyl ether, diisopropyl ether, dioxane, cyclopentyl methyl ether, methyl tert-butyl ether, 1,2- dimethoxyethane , 1, 2-diethoxyethane, tetrahydrofuran and tetrahydropyran, nitriles such as acetonitrile and esters such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl acetates. The use of such a solvent is not only suitable for attaining a higher yield in the reaction (1) but also greatly simplifies the operations up to recovery of the desired product in the process of the present invention because they do not form bad-smelling components at the time of the reaction and environmentally advantageous. Such a solvent is miscible with water or forms a low-boiling azeotrope with water.

The solvent is preferably at least one member selected from the group consisting of nitriles such as acetonitrile; ethers such as cyclopentyl methyl ether, methyl tert-butyl ether, 1, 2 -dimethoxyethane, 1,2- diethoxyethane, tetrahydrofuran and tetrahydropyran; and esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and tert-butyl acetate. As the solvent, particularly preferred is cyclopentyl methyl ether, 1,2- dimethoxyethane, 1 , 2-diethoxyethane, tetrahydropyran, methyl acetate, ethyl acetate, propyl acetate or butyl acetate. As the basic substance, alkali components such as alkali metals, hydrides, hydroxides and carbonates of alkali metals, hydroxides and carbonates of alkaline earth metals may be mentioned, and specifically, metallic sodium, metallic potassium, sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, calcium hydroxides, magnesium hydroxide, calcium carbonate and magnesium carbonate may be mentioned. Metallic sodium, sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide and magnesium hydroxide are preferably mentioned. An alkali selected from the group consisting of sodium hydroxide and potassium hydroxide is preferred for industrial use. For simplicity, the present invention will be described in reference to sodium hydroxide or potassium hydroxide as a typical example of the basic substance, although other basic substances may be used instead of sodium hydroxide or potassium hydroxide. It is necessary to carry out the above-mentioned step (1) at a sufficient alkali concentration, unless an alkali metal or the hydride of an alkali metal is used as the alkali. A sufficient amount of an alkali means that an alkali is used in an amount more than stoichiometrically required for the reaction. Use of a theoretically excessive amount of an alkali has the advantages of a greater reaction rate and suppression of formation of by- products. In the step (1), at least 2 mol, preferably from 3 to 10 mol, particularly preferably from 4 to 10 mol, of an alkali is used in relation to 1 mol of 2- amino-3-chloro-5-trifluoromethylpyridine . The reaction procedure in the step (1) such as the order in which the starting materials and the solvent are fed into the reactor is determined considering that the reaction is exothermic and that 2 , 4-dichloro-3 , 5- dinitrobenzotrifluoride is susceptible to hydrolysis. The best procedure comprises firstly feeding 2-amino-3- chloro-5-trifluoromethylpyridine and a given amount of a solvent into the reactor, mixing them, then feeding an alkali, mixing the resulting solution, cooling the resulting mixture to 5-30⁰C for a while and feeding 2,4- dichloro-3 , 5-dinitrobenzotrifluoride dissolved in the solvent. The procedure may be appropriately modified in view of the prices of the starting reaction materials to be used and the reaction conditions.

The reaction temperature for the reaction is from 10 to 40⁰C, preferably from 15 to 35°C. The reaction time is about from 0.5 to 5 hours, preferably about from 1.0 to 3.5 hours. The reaction may be carried out under an atmosphere of an inert gas such as nitrogen or argon. The progress and completion of the reaction can be monitored by instrumental analysis such as HPLC. After completion of the reaction, the reaction mixture is neutralized or acidified with an acid in order to inactivate the excess base in the reaction mixture and liberate the free reaction product from its salt with an alkali such as sodium or potassium.

In the step (2) , an acid is used to neutralize or acidify the reaction mixture obtained after completion of the reaction (1) . The acid is preferably hydrochloric acid or sulfuric acid in view of their industrial availability, though any acid at any concentration may be used as long as it can neutralize or acidify the reaction mixture after completion of the reaction (1) . The acid is used in such an amount that it can neutralize or acidify the reaction mixture. When the acid is used at a high concentration, water may be added to the reactor in advance. For example, in the step (2), the reaction mixture obtained after the step (1) may be adjusted to pH 2-7, preferably pH 5-6.

Further, in the step (2) , the reaction mixture obtained after the step (1) may be neutralized or acidified directly, or the organic phase separated from the reaction mixture mixed with water may be neutralized or acidified. In the process of the present invention, because the reaction product is formed in the form of an alkali salt such as a sodium or potassium salt and migrates into the organic phase, there is no loss of the product at the time of separation of the reaction mixture after the reaction and addition of water. The liquid- liquid separation in this step removes the excess alkali and the salt resulting from the reaction such as sodium or potassium chloride and is favorably keeps down the ^■ volume of the reaction system at the time of the subsequent neutralization or acidification of the organic phase .

In the step (3), 3-chloro-N- (3-chloro-5- trifluoromethyl-2-pyridyl) -α, α, α-trifluoro-2 , 6-dinitro-p- toluidine as the reaction product crystallizes upon removal of the solvent by distillation from the organic phase neutralized or acidified in the step (2), i.e., a mixture containing it and the solvent. Specifically speaking, 3-chloro-N- (3-chloro-5-trifluoromethyl-2- pyridyl) -a, α, α-trifluoro-2, 6-dinitro-p-toluidine as the reaction product crystallizes in water upon removal of the solvent by distillation followed by addition of water from the mixture containing the reaction product and the solvent mixed with water.

When water is added in the step (3) , the amount of water does not influence the procedure in the step (3) in a strict sense. However, use of an excessively small or large amount of water makes inefficient recovery of the precipitated crystals by filtration. After addition of a given amount of water to the organic phase, the product remains dissolved in the solvent, and as the solvent is removed by distillation, the product crystallizes in water.

The solvent in the step (3) is the same solvent as used in the step (1) . The solvent may be removed by- distillation at a temperature of from 10 to 65°C, optionally under reduced pressure. The removed solvent is typically recovered as the water azeotrope and may be recycled in the process of the present invention.

Crystals of the desired product obtained in the present invention such as crystals of 3-chloro-N- (3- chloro-5-trifluoromethyl-2-pyridyl) -a, a, α-trifluoro-2, 6- dinitro-p-toluidine (common name: fluazinam) which precipitate in the step (3) are a known compound disclosed in The Pesticide Manual Thirteenth Edition and the like and are light yellow crystals having a melting point of 115-117°C, called α-crystals. A different form of crystals having a lower melting point is called β- crystals. Stable production of α-crystals is demanded from the viewpoint of manufacturing control .

In the step (3) , crystallization may be carried out in the presence of α-crystals of the product as a seed. In this case, the solvent may be distilled off in two steps by removing about from 50 to 95% of the solvent, feeding a seed and then removing the rest of the solvent.

The crystals precipitated in water in the step (3) can be recovered easily by ordinary filtration.

The crystals of 3-chloro-N- (3-chloro-5- trifluoromethyl-2-pyridyl) -α, α, α-trifluoro-2 , 6-dinitro-p- toluidine which precipitate in the step (3) may be purified by washing with hydrous isopropanol . In the purification method by washing, the starting material may preliminarily be washed with water before washed with hydrous isopropanol. The water content of the hydrous isopropanol used for the washing may be appropriately selected so as not to substantially dissolve the desired crystals of 3-chloro-N- (3-chloro-5-trifluoromethyl-2- pyridyl) -ex, a, α-trifluoro-2 , 6-dinitro-p-toluidine . Isopropanol (IPA) with a low water content unfavorably dissolves the desired crystals of 3-chloro-N- (3 -chloro-5- trifluoromethyl-2-pyridyl) -α, α, α-trifluoro-2 , 6-dinitro-p- toluidine. Typically, at most 90% aqueous isopropanol, preferably at most 85% aqueous isopropanol, is used. The hydrous isopropanol is used in an amount of from 50 to 500 g, preferably from 100 to 200 g, in relation to 100 g of crystals of the desired product as the starting material .

The results of washing of the crystals of 3-chloro- N- (3-chloro-5-trifluoromethyl-2-pyridyl) -α, α, α-trifluoro- 2 , 6-dinitro-p-toluidine which precipitate in the step (3) with hydrous isopropanol are described below. When the starting crystals (PhOH derivative, 0.25; impurity 1, 0.63; impurity 2, 0.80; other impurities, 2.27; the desired product, 96.05) were washed with 85% aqueous isopropanol, crystals (PhOH derivative, 0; impurity 1, 0; impurity 2, 0; other impurities, 0.74; the desired product, 99.26) were obtained after the washing. The PhOH derivative means a decomposition product of 2,4- dichloro-3, 5-dinitrobenzotrifluoride (DCDNBTF), impurity

1 means 2-amino-3-chloro-5-trifluoromethylpyridine (ACTF) , impurity 2 means DCDNBTF, and the desired product means 3-chloro-N- (3 -chloro-5-trifluoromethyl -2 -pyridyl) - α, α, α-trifluoro-2 , 6-dinitro-p-toluidine .

The product, 3-chloro-N- (3 -chloro-5 -trifluoromethyl - 2 -pyridyl) -α, a, α-trifluoro-2 , 6-dinitro-p-toluidine, obtained is suitably dried under a reduced pressure to give a highly pure dry product . In the method for drying a product, optimum conditions can be selected appropriately from conditions which do not cause decomposition of the desired product, and for example, the drying may be carried out under a reduced pressure of at most 300 mmHg, or a reduced pressure of at most 200 mmHg. In the drying method, the product may be dried, for example, at a temperature of 115°C or below, or at a temperature of 70⁰C or below. The drying method can efficiently provide a stable preparation of the pesticide active ingredient with a good purity. The crystals thus obtained are formulated with various adjuvants into products in the forms of powders, wettable powders, suspensions.

Now, the present invention will be described in detail with reference to Examples. However, these Examples are mere concrete embodiments for the sake of explanation and by no means limit or restrict the scope of the present invention. It should be understood that the present invention can be carried out in various modes on the basis of the concept in the present specification.

All the Examples were carried out or can be carried out by standard techniques common and conventional to a person skilled in the art.

In each Example, eq, vol and wt in parentheses represent equivalent ratio, volume ratio and weight ratio in relation to 1 equivalent, volume and weight of ACTF, respectively. And PA% represents peak area %. EXAMPLE 1

ACTF (1.5 g, 7.6 mmol, purity = 99.5%) , DCDNBTF (2.5 g, 8.0 mmol, purity = 98.9%), KOH (2.1 g, 4 eq, purity = 85%) and dimethoxymethane (10 mL) were fed into a 50 mL flask and reacted at 25-30⁰C while stirred with a magnetic stirrer. After about 8 hours, the reaction solution was analyzed by HPLC, and the content of 3- chloro-N- (3-chloro-5-trifluoromethyl-2-pyridyl) -α,α,α- trifluoro-2 , 6-dinitro-p-toluidine as the, desired product was 95.2%. Similar experiments were carried out using cyclopentyl methyl ether (CPME) , methyl tert-butyl ether (MTBE) , diethoxyethane (DEE) , tetrahydropyran (THP) , ethyl acetate (AcOEt) or tetrahydrofuran (THF) as the solvent. The results are shown in Table 1, together with the result of the above experiment with dimethoxyethane (DME) .

The amount of potassium hydroxide in relation to ACTF as the starting material and the reaction time are also shown in the table. TABLE 1

EXAMPLE 2

ACTF (1.5 g, 7.6 mmol , purity = 99.5%) , DCDNBTF (2.5 g, 8.0 mmol, purity = 98.9%), NaOH (1.24 g, 4 eq, purity = 98.5%) and DME (10 mL) were fed into a 50 mL flask and reacted at 25-30°C while stirred with a magnetic stirrer. 0 After about 3 hours, the reaction solution was analyzed by HPLC, and the content of 3-chloro-N- (3-chloro-5- trifluoromethyl-2-pyridyl) -α, α, α-trifluoro-2 , 6-dinitro-p- toluidine as the desired product was 95.8%. Similar experiments were carried out using cyclopentyl methyl ether (CPME) , methyl tert-butyl ether (MTBE) , diethoxyethane (DEE) , tetrahydropyran (THP) , ethyl acetate (AcOEt) or tetrahydrofuran (THF) as the solvent. The results are shown in Table 2, together with the result of the above experiment with dimethoxyethane (DME) .

The amount of sodium hydroxide in relation to ACTF as the starting material and the reaction time are also

10 shown in the table. TABLE 2

EXAMPLE 3

ACTF (19.7 g, 0.1 mol, purity = 99.5%) , DCDNBTF (32.5 g, 0.105 mol, purity = 98.5%), NaOH (16.2 g, 4 eq, purity = 98.5%) and DME (118 mL, 6 vol) were fed into a 300 mL four-neck flask equipped with a thermometer and a starrer and reacted at 25-30°C with stirring. After about 3 hours, the reaction solution was analyzed by HPLC to confirm disappearance of the starting material. Water (49 mL, 2.5 wt) was added to the reaction mixture while the temperature was kept at 30⁰C or below, and the aqueous layer was removed. The organic layer was mixed with water (49 mL, 2.5 wt) and adjusted to pH 5-6 with 70% sulfuric acid while the temperature was kept at 5O⁰C or below. The aqueous layer was removed to obtain a DME solution of 3-chloro-N- (3-chloro-5-trifluoromethyl-2- pyridyl) -ex, α, α-trifluoro-2 , 6-dinitro-p-toluidine as the reaction product.

After addition of water (39 mL, 2 wt) to the DME solution, DME was removed by distillation under a reduced pressure (150 mmHg) until the internal temperature reached 46°C. After addition of 0.04 g of α-crystals as a seed at 46°C, water (59 mL, 3 wt) was added dropwise to precipitate crystals. DME was further removed by distillation under a reduced pressure (150 mmHg) until the internal temperature reached 6O⁰C. After removal of DME by distillation, the crystals were dispersed in water (39 mL, 2 wt) and then cooled to 25°C or below. The resulting slurry was filtered under a reduced pressure, and the resulting cake was washed with water (78 inL, 4 wt) and 63 g of 85% isopropanol aq. The resulting yellow crystals were dried at 55°C to give 44.6 g of 3-chloro-N- (3-chloro-5-trifluoromethyl-2-pyridyl) - α,α,α-trifluoro-2, 6-dinitro-p-toluidine (crude yield =

95.8%, HPLCPA% = 99.1%, m.p. = 114.0-117.8⁰C) . EXAMPLE 4

ACTF (19.7 g, 0.1 mol , purity = 99.5%), DCDNBTF (32.5 g, 0.105 mol, purity = 98.5%) , NaOH (16.2 g, 4 eq, purity = 98.5%) and THP (118 mL, 6 vol) were fed into a 300 mL four-neck flask equipped with a thermometer and a stirrer and reacted at 25-30⁰C with stirring. After about 9 hours, the reaction solution was analyzed by HPLC to confirm disappearance of the starting material. Water (49 mL, 2.5 wt) was added to the reaction mixture while the temperature was kept at 30°C or below, and the aqueous layer was removed. The organic layer was mixed with water (49 mL, 2.5 wt) and adjusted to pH 5-6 with 70% sulfuric acid while the temperature was kept at 50⁰C or below. The aqueous layer was removed to obtain a THP solution of 3-chloro-N- (3-chloro-5-trifluoromethyl-2- pyridyl) -α, α, α-trifluoro-2 , 6-dinitro-p~toluidine as the reaction product. After addition of water (39 mL, 2 wt) to the THP solution, THP was removed by distillation under a reduced pressure (150 mmHg) until the internal temperature reached 43°C. After addition of 0.04 g of α-crystals as a seed at 43°C, water (59 mL, 3 wt) was added dropwise to precipitate crystals. THP was further removed by distillation under a reduced pressure (150 mmHg) until the internal temperature reached 60°C. After removal of THP by distillation, the crystals were dispersed in water (39 mL, 2 wt) and then cooled to 25°C or below.

The resulting slurry was filtered under a reduced pressure, and the resulting cake was washed with water (78 mL, 4 wt) and 63 g of 85% isopropanol aq. The resulting yellow crystals were dried at 55°C to give 44.9 g of 3-chloro-N- (3-chloro-5-trifluoromethyl-2-pyridyl) - α, α, α-trifluoro-2 , 6-dinitro-p-toluidine (crude yield = 96.4%, HPLCPA% = 98.4%, m.p. = 113.1-116.3°C) .

INDUSTRIAL APPLICABILITY

The present invention makes it possible to efficiently obtain a highly pure preparation of a pesticide active ingredient, fluazinam, in good yields and in an industrially advantageous manner and makes it possible to isolate and purify the desired product from the reaction system for its synthesis and obtain a dry preparation of the desired product efficiently at low cost with simple operations. Therefore, the process of the present invention is an industrially excellent process .

It is clear that the present invention can be practiced in other modes than those described herein or in the Examples. In view of the teachings herein, many- revisions and/or variations on the present invention are possible and fall within the scope of the claims attached hereto.

The entire disclosures of Japanese Patent Application No. 2007-276855 filed on October 24, 2007 and Japanese Patent Application No. 2008-062682 filed on March 12, 2008 including specifications, claims and summaries are incorporated herein by reference in their entireties.

Claims

1. A process for producing 3-chloro-N- (3-chloro-5- trifluoromethyl-2-pyridyl) -α, α, α-trifluoro-2 , 6-dinitro-p- toluidine, which comprises (1) a step of reacting 2- amino-S-chloro-S-trifluoromethylpyridine and 2,4- dichloro-3, 5-dinitrobenzotrifluoride in the presence of an alkali component and at least one member selected from the group consisting of ethers, nitriles and esters as a solvent, (2) a step of neutralizing or acidifying the reaction mixture with an acid and (3) a step of removing the solvent from a mixture containing 3-chloro-N- (3- chloro-5-trifluoromethyl-2-pyridyl) -α, α, α-trifluoro-2 , 6- dinitro-p-toluidine as the reaction product and the reaction solvent by distillation to precipitate crystals of the product .

2. The process according to Claim 1, wherein the alkali component is selected from alkali metals, hydrides, hydroxides and carbonates of alkali metals and hydroxides and carbonates of alkaline earth metals.

3. The process according to Claim 1, wherein the solvent is at least one member selected from the group consisting of ethers and esters.

4. The process according to Claim 3 , wherein the solvent is cyclopentyl methyl ether, methyl tert-butyl ether, 1, 2-dimethoxyethane, 1, 2-diethoxyethane, tetrahydropyran, methyl acetate, ethyl acetate, propyl acetate or butyl acetate.

5. The process according to Claim 1, wherein in the step (1) , at least 2 mol of an alkali component is present in relation to 1 mol of 2-amino-3-chloro-5- trifluoromethylpyridine .

6. The process according to Claim 5, wherein from 4 to 10 mol of the alkali component is present in relation to 1 mol of 2-amino-3-chloro-5-trifluoromethylpyridine .

7. The process according to Claim 1, wherein in the step (1) , 2 , 4-dichloro-3 , 5-dinitrobenzotrifluoride is used in an amount of from 0.8 to 1.2 mol in relation to 1 mol of 2 -amino-3-chloro-5-trifluoromethylpyridine .

8. The process according to Claim 1, wherein in the step (1) , the solvent is used in an amount of from 50 to 1000 g in relation to 100 g of 2-amino-3-chloro-5- trifluoromethylpyridine .

9. The process according to Claim 1, wherein in the step (2) , water is added to the reaction mixture, and the reaction mixture is separated, and the organic phase is neutralized or acidified with the acid.

10. The process according to Claim 1, wherein in the step (3) , the mixture containing 3-chloro-N- (3-chloro-5- trifluoromethyl-2-pyridyl) -a, α, α-trifluoro-2 , 6-dinitro-p- toluidine as the reaction product and the solvent is mixed with water and then the solvent is removed by distillation to precipitate crystals of the product in water.

11. The process according to Claim 1, wherein in the step (3) , the crystals are precipitated in the presence of α-crystals of the reaction product as a seed.

12. A process for producing 3-chloro-N- (3-chloro-5- trifluoromethyl-2-pyridyl) -α, α, α-trifluoro-2 , 6-dinitro-p- toluidine or a salt thereof, which comprises reacting 2- amino-3-chloro-5-trifluoromethylpyridine and 2,4- dichloro-3 , 5-dinitrobenzotrifluoride in the presence of an alkali component and at least one member selected from the group consisting of ethers, nitriles and esters as a solvent.