JP2015083541A - Method of producing symmetric 4,6-bis(aryloxy) pyrimidine compound - Google Patents

Abstract

[Problem] To provide a method capable of producing a target 4,6-bis [4-fluoro-3- (trifluoromethyl) phenoxy] pyrimidine with high purity and high yield, which can be produced very advantageously industrially. To do. A 1,4-diazabicyclo [2.2.2] octane compound, quinuclidine is used as a catalyst when reacting 4,6-dichloropyrimidine with 4-fluoro-3- (trifluoromethyl) phenol. A compound or an N-methylpyrrolidine compound or a salt thereof is used. [Selection figure] None

Description

  The present invention relates to a method for producing a symmetrical 4,6-bis (aryloxy) pyrimidine compound. In particular, the present invention relates to a novel process for preparing the pesticidal agent 4,6-bis [4-fluoro-3- (trifluoromethyl) phenoxy] pyrimidine.

  A method for producing a symmetric 4,6-bis (aryloxy) pyrimidine compound is described in Patent Document 1. Here, symmetry means that the substituents of the 4- and 6-position pyrimidines are the same. In Patent Document 1, in particular, Example No. 27 in Table I describes 4,6-bis [4-fluoro-3- (trifluoromethyl) phenoxy] pyrimidine having a boiling point of 200 ° C./0.6 mmHg. In Example 3, which is another compound, there is a description of a method for producing 4,6-bis (4-chloro-3-trifluoromethylphenoxy) pyrimidine. However, in patent document 1, there is no description using a catalyst.

In Patent Document 1 (Example 3), column chromatography is used as a purification method, which is unsuitable as a purification method for industrial production. 4,6-Bis [4-chloro-3- (trifluoromethyl) phenoxy] pyrimidine The melting point of this compound is 111 ° C., and its crystallinity is good and easy to handle. However, since the melting point of 4,6-bis [4-fluoro-3- (trifluoromethyl) phenoxy] pyrimidine of the present invention is as low as 66 to 67 ° C., when the purity is low, it is obtained as a lower melting point or an oily substance. It will be. In addition, when the compound is used as a solid in the formulation process, particularly when a granular wettable powder or flowable agent (sol) is used, a high-pure compound must be used as a solid to produce a good formulation. There was a problem.
In addition, the raw material 4-fluoro-3- (trifluoromethyl) phenol has an irritating odor and is desired to be removed as much as possible so that it is not contained in the active ingredient. High purity was demanded.
On the other hand, methods for producing asymmetric 4,6-bis (aryloxy) pyrimidines using a catalyst are known (Patent Documents 2 to 6).

WO94 / 02470 WO2001 / 0772719 WO2006 / 114572 WO2008 / 043977 WO2008 / 043978 WO2008 / 075341

  Accordingly, an object of the present invention is to provide a novel method that can be produced very advantageously industrially and that can produce 4,6-bis (aryloxy) pyrimidine with high purity and high yield.

  As a result of intensive studies to solve the above problems, the present inventor has obtained 4,6-dichloropyrimidine and 4-fluoro-3- (trifluoro) in the presence of a catalyst and further in the presence of a solvent and a base. In the method for producing 4,6-bis [4-fluoro-3- (trifluoromethyl) phenoxy] pyrimidine by reacting with (methyl) phenol, the catalyst is used in an amount of 0.5 to 4,6-dichloropyrimidine. By using the following compounds in an amount of from 05 to 40 mol%, the desired symmetrical 4,6-bis (aryloxy) pyrimidine compound is obtained in a solid state having a high melting point and a melting point of 60 ° C. or higher. The present invention has been achieved.

で表される化合物又はその塩、又は
(ii)以下の式(II)：

で表されるＮ-メチルピロリジン化合物又はその塩。 (i) The following formula (I):

Or a salt thereof, or
(ii) The following formula (II):

Or an N-methylpyrrolidine compound or a salt thereof.

In which R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are independently hydrogen, fluorine, methyl, methoxy, methylene or cyano, or independently R ¹ and R ² , R ³ and R ⁴ , R ⁵ and R ⁶ together form ═O or ═S;
R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are independently hydrogen, hydroxyl group, halogen, alkyl, alkenyl, alkynyl, alkylcarbonyl, formyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, Dialkylaminocarbonyl, aryl, alkoxy, cycloalkyloxy, aryloxy, alkylcarbonyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, heterocyclyl, cycloalkyl or optionally substituted silyloxy, or independently with R ⁷ R ⁸ , R ⁹ and R ¹⁰ , and R ¹¹ and R ¹² together form ═O or ═S;
A is N or C—R ¹³ , and R ¹³ is hydrogen, hydroxyl group, halogen, alkyl, alkenyl, alkynyl, alkylcarbonyl, formyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aryl, alkoxy , Cycloalkyloxy, aryloxy, alkylcarbonyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, heterocyclyl or cycloalkyl; and R ¹⁴ is hydrogen, hydroxyl or C _1-4 linear or branched alkyl.

  It is surprising that this reaction can give excellent yields of 0.05-40 mol% of the above catalyst. This is confirmed by comparative experiments (Examples 1, 5, 6, 7 and 8) in which this reaction was performed without adding the catalyst, as will be described later. Without such a catalyst, the product is only isolated in low yield and low purity.

  As described above, in the present invention, the target symmetrical 4,6-bis [4-fluoro-3- (trifluoromethyl) phenoxy] pyrimidine can be obtained with a specific catalyst in a high yield and high purity. It was found. Further, as a purification method, unreacted 4-fluoro-3- (trifluoromethyl) phenol can be removed into the filtrate by washing with water on the neutral to alkaline side at pH 7 or higher in the collection step. Moreover, the irritating odor of 4-fluoro-3- (trifluoromethyl) phenol can be removed by drying under reduced pressure in the drying step (specifically, by GC analysis less than 0.1%). Therefore, an excellent effect that a purification step such as recrystallization can be omitted is exhibited. In addition, the reaction solvent can be recovered without using an excessive amount of 4-fluoro-3- (trifluoromethyl) phenol. In particular, recycling can be facilitated by using methyl isobutyl ketone (MIBK). Has many advantages.

In the following, the present invention will be described in more detail.
The present invention is carried out in the presence of a solvent and a base.
Preferred solvents include the following.
Aliphatic, alicyclic or aromatic hydrocarbons such as petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin; halogenated hydrocarbons such as chlorobenzene, dichlorobenzene, dichloromethane, chloroform , Carbon tetrachloride, dichloroethane or trichloroethane; ethers such as diethyl ether, diisopropyl ether, methyl t-butyl ether, methyl t-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane or anisole Ketones such as acetone, butanone, methyl isobutyl ketone or cyclohexanone; nitriles such as acetonitrile, propionitrile, n- or i-butyronitrile or benzonitrile; tertiary amines such as N, N-di-isopropylethylamine (Hunig base), N, N-dimethylaniline, triethylamine, t-butyldimethyl-amine, N, N-diisopropylmethylamine N, N-diisopropylisobutylamine, N, N-diisopropyl-2-ethylbutylamine, tri-n-butylamine, N, N-dicyclohexylmethylamine, N, N-dicyclohexylethyl-amine, N-tert-butylcyclohexylamine N, N-dimethylcyclohexylamine, 1,5-diazabicyclo [4.3.0] -non-5-ene, 1,8-diazabicyclo [5.4.0] undec-7-ene or 2-dimethylamino Pyridines; amides such as N, N-dimethylformanilide, N, N-dimethylacetamide N-methylformanilide, N-methylpyrrolidone or hexamethylphosphate triamide; esters such as methyl acetate, ethyl acetate, isopropyl acetate or butyl acetate; sulfoxides such as dimethyl sulfoxide; phosphones such as sulfolane; or water and those Mixture of.
In particular, it is preferable to use methyl isobutyl ketone (MIBK) or a mixture thereof with water.

Preferred bases include the following.
Alkaline earth or alkali metal hydroxides, acetates, carbonates or bicarbonates such as sodium hydroxide, potassium hydroxide, sodium acetate, potassium acetate, sodium carbonate, potassium carbonate, potassium bicarbonate or sodium bicarbonate And alkaline earth metal or alkali metal hydrides such as calcium hydride, sodium hydride or potassium hydride.
In particular, sodium hydroxide, potassium hydroxide, potassium carbonate or sodium carbonate is preferably used.

  In the present invention, the reaction temperature can be varied within a relatively wide range. In general, the reaction is carried out at temperatures between -20 ° C and 140 ° C, preferably between 0 ° C and 120 ° C, in particular between 10 ° C and 80 ° C.

  In the present invention, generally 1.8 to 3.0 mol, preferably 1.9 to 2.1 mol of 4-fluoro-3- (trifluoromethyl) phenol is used per mol of 4,6-dichloropyrimidine.

  In the present invention, the catalyst is used in an amount of 0.05 to 40 mol%, preferably 1 to 20 mol% per mol of 4,6-dichloropyrimidine.

In the present invention, for example, a catalyst can be mixed with a solvent and a base together with 4-fluoro-3- (trifluoromethyl) phenol. 4,6-dichloropyrimidine is then added to the mixture and the mixture is stirred at an elevated temperature if appropriate. After the reaction has ended, the reaction mixture is worked up in the usual manner. The reactants may be formulated in the reverse order.
The present invention can also be carried out as a one-pot reaction.
In the present invention, high purity, particularly 4,6-bis [4-fluoro-3- (trifluoromethyl) phenoxy] pyrimidine is obtained. Depending on the content of impurities, the melting point of the obtained 4,6-bis [4-fluoro-3- (trifluoromethyl) phenoxy] pyrimidine generally decreases and cannot be obtained in the solid state. In the present invention, for example, 4,6-bis [4-fluoro-3- (trifluoromethyl) phenoxy] pyrimidine having a melting point of 55 ° C. or higher, preferably 60 ° C. or higher is obtained.

Hereinafter, the present invention will be specifically described with reference to examples. However, the scope of the present invention is not limited by these examples.
In the following examples, the following alphabetic symbols have the following meanings.
TEDA: 1,4-diazabicyclo [2.2.2] octane MIBK: methyl isobutyl ketone.

Example 1
Process for producing 4,6-bis [4-fluoro-3- (trifluoromethyl) phenoxy] pyrimidine
To a solution of sodium carbonate (13.3 g) and 4-fluoro-3- (trifluoromethyl) phenol (18.1 g, 0.10 mol) in MIBK (60 ml) was added 4,6-dichloropyrimidine (7.45 g, 0.05 mol). ) And heated to reflux (115 ° C.) under nitrogen. After 2 hours, TEDA (0.30 g) was added, and the mixture was further heated to reflux for 1 hour. After returning to room temperature, water (60 ml) was poured into this mixture, and MIBK was distilled off under reduced pressure using a rotary evaporator. Thereafter, 120 ml of water was added and collected in a state of pH 10-12, washed with water (100 ml), and dried under reduced pressure to obtain 21.5 g of odorless product (99% yield).
Melting point 66.5-67.5 ℃ Purity 99.0% or more (GC)
¹ H NMR (CDCl ₃ ): δ 6.50 (1H, d), 7.25-7.44 (6H, m), 8.39 (1H, d)
At this time, the content of 4-fluoro-3- (trifluoromethyl) phenol was less than 0.1%.

Comparative Experiment Example 1
The reaction was carried out under the same conditions as in Example 1 except that TEDA was not added. In the reaction at 115 ° C. for 3 hours, the product in MIBK was only 55% (GC) produced as analyzed by gas chromatography.

Example 2
The reaction was performed under the same conditions as in Example 1 except that 0.15 g of 3-quinuclidinol was added instead of TEDA.
The product in MIBK was 99.0% or more (GC) as a result of analysis by gas chromatography.
Example 3
The reaction was carried out under the same conditions as in Example 1 except that 0.15 g of quinuclidine hydrochloride was added instead of TEDA.
The product in MIBK was 99.0% as a result of analysis by gas chromatography.
Example 4
The reaction was conducted under the same conditions as in Example 1 except that 0.15 g of 3-quinuclidinone hydrochloride was added instead of TEDA.
The product in MIBK was 99.0% (GC) as a result of analysis by gas chromatography.

Example 5
Preparation of 4,6-bis [4-fluoro-3- (trifluoromethyl) phenoxy] pyrimidine 4-Fluoro-3- (trifluoromethyl) phenol (18.1 g, 0.10 mol) with MIBK (60 ml) Sodium carbonate (13.3 g) was added to a mixed solution with water (30 ml) and stirred. Thereafter, TEDA (0.20 g) and 4,6-dichloropyrimidine (7.45 g, 0.05 mol) were added and heated (85 ° C.) for 3 hours under nitrogen. After returning to room temperature, MIBK was distilled off under reduced pressure using a rotary evaporator. Thereafter, 120 ml of water was added, and the mixture was collected in a pH of 10 to 12, washed with water (100 ml) and dried under reduced pressure to obtain 21.4 g of odorless product (yield 98%).
Melting point 66.5-67.5 ℃ Purity 99.0% or more (GC)
At this time, the content of 4-fluoro-3- (trifluoromethyl) phenol was less than 0.1%.

Comparative Experiment Example 2
The reaction was performed under the same conditions as in Example 5 except that TEDA was not added. The product in MIBK was analyzed by gas chromatography and found to be 10% (GC).

Example 6
Process for producing 4,6-bis [4-fluoro-3- (trifluoromethyl) phenoxy] pyrimidine Flaked sodium hydroxide (98%, 4.2 g) and 4-fluoro-3- (trifluoromethyl) phenol Add TEDA (0.30 g) and 4,6-dichloropyrimidine (7.45 g, 0.05 mol) to a MIBK (60 ml) solution of (18.1 g, 0.10 mol) under nitrogen and heat for 2 hours (60 ° C.) did. After returning to room temperature, water (60 ml) was poured into this mixture, and MIBK was distilled off under reduced pressure using a rotary evaporator. Thereafter, 120 ml of water was added and collected in a pH of 10 to 12, washed with water (100 ml), and dried under reduced pressure to obtain 21.5 g of odorless product (99% yield).
Melting point 66.5-67.5 ℃ Purity 99.0% or more (GC)
At this time, the content of 4-fluoro-3- (trifluoromethyl) phenol was less than 0.1%.

Comparative Experiment Example 3
The reaction was performed under the same conditions as in Example 6 except that TEDA was not added. The product in MIBK was analyzed by gas chromatography. As a result, it was found to be 79.9% (GC). The intermediate 4-chloro-6- [4-fluoro-3- (trifluoromethyl) phenoxy] pyrimidine remained 20.1% (GC).

Example 7
Method for producing 4,6-bis [4-fluoro-3- (trifluoromethyl) phenoxy] pyrimidine 4-fluoro-3- (trifluoromethyl) phenol (18.1 g, 0.10 mol), potassium carbonate (17.2 g) ) And TEDA (0.30 g) were added to a mixed solution of MIBK (150 ml), and 4,6-dichloropyrimidine (7.45 g, 0.05 mol) was added at room temperature (28 ° C.). After stirring this mixture at room temperature overnight (16 hours), water (60 ml) was poured into this mixture, and MIBK was distilled off under reduced pressure using a rotary evaporator. Thereafter, 120 ml of water was added and collected at a pH of 10 to 12, washed with water (100 ml), and dried under reduced pressure to obtain 21.4 g of odorless product (yield 98%).
Melting point 66.5-67.5 ℃ Purity 99.0% or more (GC)
At this time, the content of 4-fluoro-3- (trifluoromethyl) phenol was less than 0.1%.

Comparative Experiment Example 4
The reaction was carried out under the same conditions as in Example 7 except that TEDA was not added. The product in MIBK was analyzed by gas chromatography and found to be 20% (GC). 80% of the intermediate 4-chloro-6- [4-fluoro-3- (trifluoromethyl) phenoxy] pyrimidine remained.

Example 8
Method for producing 4,6-bis [4-fluoro-3- (trifluoromethyl) phenoxy] pyrimidine 48% aqueous sodium hydroxide (8.4 g) and 4-fluoro-3- (trifluoromethyl) phenol (18.1 g) , 0.1 mol) in a MIBK (60 ml) solution were added TEDA (0.30 g) and 4,6-dichloropyrimidine (7.45 g, 0.05 mol) under nitrogen and heated (60 ° C.) for 2 hours. After returning to room temperature, water (60 ml) was poured into this mixture, and MIBK was distilled off under reduced pressure using a rotary evaporator. Thereafter, 120 ml of water was added, and the mixture was collected at a pH of 10 to 12, washed with water (100 ml), and dried under reduced pressure to obtain 21.4 g of odorless product (yield 98%).
Melting point 66.5-67.5 ℃ Purity 99.0% or more (GC)
At this time, the content of 4-fluoro-3- (trifluoromethyl) phenol was less than 0.1%.

Comparative Experiment Example 5
The reaction was performed under the same conditions as in Example 8 except that TEDA was not added. Although the reaction was carried out at 60 ° C. for 5 hours, the target product in MIBK was analyzed by gas chromatography. As a result, the reaction was not completed at 75% (GC). 25% of the intermediate 4-chloro-6- [4-fluoro-3- (trifluoromethyl) phenoxy] pyrimidine remained.

  Although the present invention has been described with reference to preferred embodiments and examples, the scope of the present invention is not limited only to these embodiments and examples. It will be apparent to those skilled in the art that changes and modifications may be made to the invention as described without departing from the spirit and scope of the invention as defined and limited by the appended claims. All publications cited herein are incorporated by reference to the same extent as if each publication was specifically and individually incorporated for all purposes.

Claims (9)

In the presence of a solvent and a base and in the presence of a catalyst, 4,6-dichloropyrimidine is reacted with 4-fluoro-3- (trifluoromethyl) phenol to give 4,6-bis [4-fluoro. In the method for producing -3- (trifluoromethyl) phenoxy] pyrimidine, 0.05 to 40 mol% of the following compound is used as the catalyst with respect to 4,6-dichloropyrimidine. Method.
(i) The following formula (I):

Or a salt thereof, or
(ii) The following formula (II):

Or an N-methylpyrrolidine compound or a salt thereof.
In which R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are independently hydrogen, fluorine, methyl, methoxy, methylene or cyano, or independently R ¹ and R ² , R ³ and R ⁴ , R ⁵ and R ⁶ together form ═O or ═S;
R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are independently hydrogen, hydroxyl group, halogen, alkyl, alkenyl, alkynyl, alkylcarbonyl, formyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, Dialkylaminocarbonyl, aryl, alkoxy, cycloalkyloxy, aryloxy, alkylcarbonyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, heterocyclyl, cycloalkyl or optionally substituted silyloxy, or independently with R ⁷ R ⁸ , R ⁹ and R ¹⁰ , and R ¹¹ and R ¹² together form ═O or ═S;
A is N or C—R ¹³ , and R ¹³ is hydrogen, hydroxyl group, halogen, alkyl, alkenyl, alkynyl, alkylcarbonyl, formyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aryl, alkoxy , Cycloalkyloxy, aryloxy, alkylcarbonyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, heterocyclyl or cycloalkyl; and R ¹⁴ is hydrogen, hydroxyl or C _1-4 linear or branched alkyl. The catalyst is 1,4-diazabicyclo [2.2.2] octane, quinuclidine, quinuclidinol, or quinuclidinone, or the formula (I) [wherein R ^{1 to} R ⁶ and R ^{9 to} R ¹³ are Hydrogen, and
(i) R ⁷ is hydrogen and R ⁸ is halogen, alkyl, alkenyl, alkynyl, alkylcarbonyl, formyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aryl, alkoxy, cycloalkyloxy, aryl Is oxy, alkylcarbonyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, heterocyclyl or cycloalkyl, or
(ii) R ⁸ is hydrogen and R ⁷ is halogen, alkyl, alkenyl, alkynyl, alkylcarbonyl, formyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aryl, alkoxy, cycloalkyloxy, aryl Oxy, alkylcarbonyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, heterocyclyl or cycloalkyl. ]
The method of Claim 1 which is a compound represented by these, or its salt.   The process according to claim 2, wherein the catalyst is 1,4-diazabicyclo [2.2.2] octane, quinuclidine, 3-quinuclidinol, 3-quinuclidinone or N-methylpyrrolidine, or a salt thereof.   The method according to claim 1, wherein the salt is hydrochloride.   The method according to any one of claims 1 to 4, wherein the catalyst is in an amount of 0.1 to 20 mol% relative to 4,6-dichloropyrimidine.   The process according to claim 1, wherein the solvent is methyl isobutyl ketone, cyclohexanone, N, N-diisopropylethylamine, isopropyl acetate, N, N-dimethylformamide or a mixture thereof with water.   The method of claim 1, wherein the base is potassium carbonate, sodium carbonate, sodium hydroxide or potassium hydroxide.   The method according to any one of claims 1 to 7, which is carried out at a temperature of 0 to 120 ° C.   The process according to claim 1, wherein 4,6-bis [4-fluoro-3- (trifluoromethyl) phenoxy] pyrimidine is obtained in solid form with a melting point of 55 ° C or higher.