JPH1149759A - Production of 4-(2-(4-(trifluoromethoxy)phenyl) ethylamino)pyrimidine derivative, production intermediate and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new production intermediate enabling the industrial production of a pyrimidine derivative useful as pharmaceuticals, agrochemicals, etc., by reacting a specific pyrimidine derivative with carbon disulfide and an alkylation agent. SOLUTION: The objective compound of formula I (R<1> is H, a halogen or OH; R<2> is a 1-4C alkyl.) [e.g. (±)-5-chloro-6-(1-fluoroethyl)-4-[2-(4-(methylthio thiocarbonyloxy)phenyl)ethy]aminolpyrimidine] is produced by reacting a 4-[2-(4- hydroxyphenyl)ethylaminolpyrimidine derivative of formula II with carbon disulfide and an alkylation agent expressed by the formula R<2> -X (X is a halogen or a sulfuric acid ester residue) (e.g. methyl iodide). Preferably, the compound of formula I is made to react with hydrogen fluoride.pyridine in the presence of 1,3-dibromo-5,5-dimethylhydantoin to obtain a 4-[2-(4-(trifluoromethoxy) phenyl) ethylamino]pyrimidine derivative of formula III.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to an industrial method for producing a 4- [2- (4- (trifluoromethoxy) phenyl) ethylamino] pyrimidine derivative which is useful as a medicine, a pesticide and the like.

[0002]

2. Description of the Related Art A 4- [2- (4- (trifluoromethoxy) phenyl) ethylamino] pyrimidine derivative produced by the present invention is useful as an insecticide, acaricide, fungicide, nematicide and the like. It is known that there are some cases (for example, JP-A-7-258223 and JP-A-8-291149). In these production methods, a 4-halogeno-5-chloro-6- (1-substituted ethyl) pyrimidine derivative,
By using [4- (trifluoromethoxy) phenyl] ethylamine as a production intermediate, 4- [2- (4- (trifluoromethoxy)
Phenyl) ethylamino] pyrimidine derivatives. However, the production process of 2- [4- (trifluoromethoxy) phenyl] ethylamine is complicated, and expensive and hardly available trifluoromethoxy-substituted benzenes are used as production intermediates. It must be used as a raw material for production. Moreover, even if it purchases, it becomes expensive. Therefore, the disclosed process using 2- [4- (trifluoromethoxy) phenyl] ethylamine as a production intermediate is not an industrial process.

[0003]

DISCLOSURE OF THE INVENTION The present invention relates to an industrial process for producing 4- [2- (4- (trifluoromethoxy) phenyl) ethylamino] pyrimidine derivatives useful as pharmaceuticals and agricultural chemicals, and intermediates for producing the same. And to provide a manufacturing method.

[0004]

Means for Solving the Problems The present inventors have conducted studies to solve the above-mentioned problems, and as a result, have found that hydrogen fluoride / pyridine and a compound which is a novel production intermediate obtained by a novel production method can be used as a compound. [2- (4- (alkylthiothiocarbonyloxy) phenyl) ethylamino] pyrimidine derivative,
By reacting in the presence of 1,3-dibromo-5,5-dimethylhydantoin, a 4- [2- (4- (trifluoromethoxy) phenyl) ethylamino] pyrimidine derivative useful as a pharmaceutical or agrochemical is industrially produced. The present inventors have found a method for producing the same, and have completed the present invention. That is, the present invention is as follows. According to a first aspect, the following formula (1):

[0005]

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(Wherein R ¹ represents a hydrogen atom, a halogen atom or a hydroxyl group; R ² represents an alkyl group having 1 to 4 carbon atoms.) 4- [2- (4- (alkylthio) Thiocarbonyloxy) phenyl) ethylamino]
It relates to a pyrimidine derivative. The second invention is
The following equation (2):

[0007]

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(Wherein R ¹ has the same meaning as described above), carbon disulfide and a 4- [2- (4-hydroxyphenyl) ethylamino] pyrimidine derivative represented by the following formula (3):

[0009]

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Wherein R ² is as defined above; X is a halogen atom or a sulfate residue (—O—SO ₂ —O—
R ² ). 4- [2] represented by the above formula (1),
The present invention relates to a method for producing a-(4- (alkylthiothiocarbonyloxy) phenyl) ethylamino] pyrimidine derivative. According to a third aspect of the invention, 4- [2- (4- (alkylthiothiocarbonyloxy) phenyl) ethylamino] pyrimidine derivative represented by the above formula (1) and hydrogen fluoride / pyridine are combined with 1,3-dibromo Wherein the reaction is carried out in the presence of -5,5-dimethylhydantoin;

[0011]

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(Wherein R ¹ has the same meaning as described above.) The present invention relates to a method for producing a 4- [2- (4- (trifluoromethoxy) phenyl) ethylamino] pyrimidine derivative represented by the formula:

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail. 4- [2- (4- (trifluoromethoxy) phenyl) ethylamino] pyrimidine derivative [compound (4)] which is the target compound, a production intermediate thereof, and raw materials [compounds (1) to (3)] R ¹ , R ² and X are as follows.

R ¹ is a hydrogen atom, a halogen atom,
A hydroxyl group can be mentioned. As a halogen atom,
Examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. R ² has 1 to 4 carbon atoms
Linear or branched alkyl groups. X represents a halogen atom, a sulfate ester residue (−
^{_{O-SO 2 -O-R 2}} ) can be exemplified.

In the present invention, the target compound (4) is a compound (1) and hydrogen fluoride / pyridine as shown below.
It can be produced by reacting in a solvent in the presence of 1,3-dibromo-5,5-dimethylhydantoin.

[0016]

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(In the formula, R ¹ and R ² have the same meanings as described above.) Hydrogen fluoride / pyridine preferably has a composition of about 70% hydrogen fluoride and about 30% pyridine. .
The type of the solvent is not particularly limited as long as it does not participate in the present reaction. Chlorinated or non-chlorinated aromatic, aliphatic and cycloaliphatic hydrocarbons such as trichloroethylene, cyclohexane I); ethers such as diethyl ether, tetrahydrofuran, dioxane and the like and mixtures of said solvents are preferred; Preferred is methylene chloride.

The amount of the solvent used is such that the compound (1) is 5-80.
Weight percent can be used; however, 10
~ 50% by weight is preferred. As the compound (4) used in the present invention, an easily available and inexpensive commercial product can be used. The amount of compound (4) to be used can be 1 to 10 times mol with respect to compound (1); preferably 2 to 5 times mol. Reaction temperature is -100 ° C
From within the temperature range of the boiling point of the solvent used or less;
80 ° C. to room temperature is preferred. The reaction time varies depending on the above concentration and temperature; it can be usually carried out for 1 to 3 hours.

After completion of the reaction, the target compound (4) produced as described above is subjected to ordinary post-treatments such as extraction, concentration, filtration and the like, and if necessary, recrystallization, various chromatography and the like. Can be appropriately purified by the above-mentioned means.
The novel compound (1), which is a production intermediate, can be obtained by a novel production method of reacting compound (2), carbon disulfide, and compound (3) in a solvent in the presence of a base, as shown below. Can be.

[0020]

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(Wherein R ¹ and R ² have the same meanings as described above). As an alkylating agent for the compound (3), methyl iodide,
Examples thereof include ethyl iodide, propyl iodide, dimethyl sulfate, and diethyl sulfate; preferably, methyl iodide and dimethyl sulfate.

The type of the solvent is not particularly limited as long as it does not participate in the present reaction. Examples thereof include benzene, toluene, xylene, methylnaphthalene, petroleum ether, ligroin, hexane, chlorobenzene, dichlorobenzene, methylene chloride, and chloroform. Aromatic or aliphatic, cycloaliphatic hydrocarbons, chlorinated or not, such as, dichloroethane, trichloroethylene, cyclohexane;
Ethers such as diethyl ether, tetrahydrofuran, dioxane and the like and mixtures of the above solvents are preferred; more preferred are methylene chloride and tetrahydrofuran.

The amount of the solvent used is such that the compound (2)
Weight percent can be used; however, 10
~ 50% by weight is preferred. The compound (3) can be used in an amount of 1 to 10 moles compared to the compound (2); preferably 1 to 3 moles. The reaction temperature is in the temperature range from 0 ° C. to the boiling point of the solvent to be used, but preferably from 0 ° C. to room temperature. The reaction time varies depending on the above concentration and temperature; it can be usually carried out for 2 to 3 hours.

After completion of the reaction, the target compound (1) produced as described above is subjected to ordinary post-treatments such as extraction, concentration, filtration and the like, and if necessary, recrystallization, various chromatography, etc. Can be appropriately purified by the above-mentioned means.
Compound (2) was prepared as described below in JP-A-7-1177.
The compound (5) and the compound (6) can be easily produced by reacting the compound (5) with the compound (6) in the presence of a base without a solvent or in a solvent by the method described in Japanese Patent Publication No.

[0025]

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(In the formula, R ¹ and X have the same meanings as described above.) As the compound (6), an easily available and inexpensive commercial product can be used.

[0027]

EXAMPLES The present invention will be specifically described below with reference examples and examples. Note that these examples do not limit the scope of the present invention.

Reference Example 1 [Synthesis of Compound (2)] (1) (±) 5-Chloro-6-ethyl-4- [2- (4
-Hydroxyphenyl) ethylamino] pyrimidine
[Compound (2-1)] Synthesis Tyramine (1.4 g) and triethylamine (1.2 g)
Was dissolved in toluene (30 ml) and 4,5-dichloro-
6-ethylpyrimidine (1.8 g) was added, and the mixture was stirred at about 40 ° C for 4 hours. After completion of the reaction, water was added, and the mixture was extracted with toluene. After washing the extract with water and drying over anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure, and the obtained oil was subjected to column chromatography (Wakogel C-200, elution with toluene: ethyl acetate = 3: 1) to obtain 2.3 g of the target compound as colorless powdery crystals.

M. p. 191 to 193 ° C. ¹ H-NMR (CDCl ₃ ) δ ppm 1.21 to 1.20 (t, 3H), 2.71 to 2.77
(Q, 2H), 2.79 to 2.84 (t, 2H), 3.
62 to 3.70 (m, 2H), 5.98 to 6.15
(M, 1H), 6.74-6.78 (d, 2H), 7.
03 to 7.05 (d, 2H), 8.35 (s, 1H),
8.83 (s, 1H)

(2) (±) 5-chloro-6- (1-fluoroethyl) -4- [2- (4-hydroxyphenyl)
Synthesis of ethylamino] pyrimidine [compound (2-5)] Tyramine (1.4 g) and triethylamine (1.2 g)
Was dissolved in toluene (30 ml) and 4,5-dichloro-
6- (1-Fluoroethyl) pyrimidine (2.0 g) was added, and the mixture was stirred at about 40 ° C for 4 hours. After completion of the reaction, water was added, and the mixture was extracted with toluene. After the extract was washed with water and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting oil was subjected to column chromatography (Wakogel C-20).
0, toluene: ethyl acetate = 3: 1) to give 2.5 g of the desired product as colorless powdery crystals.

M. p. 172-174 ° C. ¹ H-NMR (CDCl ₃ ) δ ppm 1.59-1.70 (dd, 3H), 2.81-2.
87 (t, 2H), 3.67 to 3.74 (m, 2H),
5.74 to 6.00 (dq, 1H), 6.12 to 6.
28 (m, 1H), 6.77 to 6.80 (d, 2H),
7.01 to 7.07 (d, 2H), 8.49 (s, 1
H), 8.78 (s, 1H)

(3) Synthesis of Other Compound (2) in Table 1 According to the method described in the above (1) or (2), other compound (2) in Table 1 was synthesized. Table 1 shows the compounds synthesized as described above and their physical properties.

[0033]

[Table 1]

Example 1 [Synthesis of Compound (4)] (1) (±) 5-chloro-6- (1-fluoroethyl)
Synthesis of -4- [2- (4-trifluoromethoxyphenyl) ethylamino] pyrimidine [compound (5-5)] 1,3-Dibromo-5,5-dimethylhydantoin (2.3 g) was treated with methylene chloride (10 ml). )
The mixture was cooled and stirred at −78 ° C. in an ethanol / dry ice bath, and hydrogen fluoride / pyridine (5 ml) was added. Then, 5-chloro-6- (1-fluoroethyl) -4-
A solution of [2- (4- (methylthiothiocarbonyloxy) phenyl) ethylamino] pyrimidine (1.0 g) in methylene chloride (5 ml) was added dropwise. After dropping, 0 ° C
And the stirring was continued for 1 hour. After completion of the reaction, a solution of sodium bicarbonate (10 g) in water (50 ml) was slowly added, and the mixture was extracted with methylene chloride. Wash the extract with water,
After drying over anhydrous sodium sulfate, ethyl acetate was distilled off under reduced pressure. The obtained oil was subjected to column chromatography (Wakogel C-200, toluene: ethyl acetate = 9:
1 elution) to give 0.67 of the target compound as colorless powdery crystals.
g was obtained.

M. p. 95-97 ° C. ¹ H-NMR (CDCl ₃ ) δ ppm 2.01-2.03 (d, 3H), 2.93-2.98
(T, 2H), 3.75-3.82 (q, 2H), 5.
38 to 5.46 (q, 1H), 5.55 (s, 1H),
7.16 to 7.27 (m, 5H), 8.54 (s, 1
H)

(2) Synthesis of other compound (4) in Table 2 According to the method described in the above (1), other compound (4) in Table 2 was synthesized. Table 2 shows the compounds synthesized as described above and their physical properties.

[0037]

[Table 2]

Example 2 [Synthesis of Compound (1)] (1) (±) 5-chloro-6- (1-fluoroethyl)
Synthesis of 4- [2- (4- (methylthiothiocarbonyloxy) phenyl) ethylamino] pyrimidine 5-chloro-6- (1-fluoroethyl) -4- [2-
(4-Hydroxyphenyl) ethylamino] pyrimidine (2.1 g) and tetra-n-butylammonium hydrogensulfate were dissolved in a solution of methylene chloride (20 ml) and tetrahydrofuran (10 ml), and a 50% aqueous sodium hydroxide solution (20 g) was used. ) Was added. With vigorous stirring at room temperature, carbon disulfide (1.2 g) and methyl iodide (1.3
g) was added all at once. After the addition, stirring was continued for 3 hours.
After the reaction was completed, a water (50 ml) solution was added, and the mixture was extracted with methylene chloride. The extract was washed with water and dried over anhydrous sodium sulfate, and ethyl acetate was distilled off under reduced pressure. The obtained oil was subjected to column chromatography (Wakogel C-200,
(Toluene: ethyl acetate = 9: 1 elution) to obtain 2.2 g of the target compound as pale yellow powdery crystals.

.M. p. 72-74 ° C. ¹ H-NMR (CDCl ₃ ) δ ppm 1.61-1.72 (dd, 3H), 2.67 (s,
2H), 2.94-2.99 (t, 2H), 3.77-
3.85 (m, 2H), 5.51-5.59 (m, 1
H), 5.76-6.02 (dq, 1H), 7.05.
-7.08 (d, 2H), 7.26-7.29 (d, 2
H), 8.55 (s, 1H)

(2) Synthesis of other compound (1) in Table 3 According to the method described in the above (1), other compound (1) in Table 3 was synthesized.

[0041]

[Table 3]

[0042]

EFFECT OF THE INVENTION According to the present invention, 5-chloro-6- (1-substituted ethyl) -4 which is useful as a medicine, a pesticide and the like.
-[2- (4- (Trifluoromethoxy) phenyl) ethylamino] pyrimidine derivative can be industrially produced.

Claims (3)

[Claims] 1. The following formula (1): (In the formula, R ¹ represents a hydrogen atom, a halogen atom or a hydroxyl group; R ² represents an alkyl group having 1 to 4 carbon atoms.)
A 4- [2- (4- (alkylthiothiocarbonyloxy) phenyl) ethylamino] pyrimidine derivative represented by the formula: 2. The following formula (2): (Wherein R ¹ has the same meaning as in claim 1), carbon disulfide and a 4- [2- (4-hydroxyphenyl) ethylamino] pyrimidine derivative represented by the following formula (3): 3] Wherein R ² is as defined in claim 1; X is a halogen atom or a sulfate residue (—O—SO ₂ —O—R
² ). Wherein the alkylating agent represented by the formula (1) is reacted with the alkylating agent represented by the formula (1).
Method for producing [2- (4- (alkylthiothiocarbonyloxy) phenyl) ethylamino] pyrimidine derivative. 3. The method according to claim 1, wherein 4- [2]
-(4- (alkylthiothiocarbonyloxy) phenyl) ethylamino] pyrimidine derivative and hydrogen fluoride
Reacting pyridine with 1,3-dibromo-5,5-dimethylhydantoin in the following formula (4): (Wherein R ¹ has the same meaning as described in claim 1). A method for producing a 4- [2- (4- (trifluoromethoxy) phenyl) ethylamino] pyrimidine derivative represented by the formula: