WO1998003272A1

WO1998003272A1 - Processes for the preparation of 4-amino-5-chloro-6-(1-fluoroethyl)pyrimidine compounds

Info

Publication number: WO1998003272A1
Application number: PCT/JP1997/002475
Authority: WO
Inventors: Katsutoshi Fujii; Yoshinori Yamanaka; Yasushi Nakamoto
Original assignee: Ube Industries, Ltd.
Priority date: 1996-07-19
Filing date: 1997-07-17
Publication date: 1998-01-29
Also published as: JPH1036355A

Abstract

4-Amino-5-chloro-6-(1-fluoroethyl)pyrimidine compounds of general formula (1) useful as pest-controlling agents for agricultural and horticultural use can be prepared industrially by reacting 5-chloro-6-(1-chloroethyl)-4-(2-phenylethylamino)pyrimidine with potassium fluoride in the presence of n-tetrabutylammonium bromide, or by reacting 5-chloro-6-(1-bromoethyl)-4-(2-phenylethylamino)pyrimidine with potassium fluoride.

Description

Specification

4-Amino-5-chloro-6- (1-year-old rotyl) Pyrimidine compound manufacturing method

The present invention relates to a method for producing a 4-amino-5-chloro-6-O-fluroyl pyrimidine compound which is useful as a medicament or a drug, and more particularly, to an industrially advantageous method for producing this compound. About. Background art

Numerous compounds are known as the 4-amino-5-chloro-6- (1-1 full-year-old rotyl) pyrimidine compound produced by the present invention, and insecticides, acaricides, and? It is also known to be useful as an S fungicide, a nematicide, etc. (for example, Japanese Patent Application Laid-Open Nos. 5-194417, 5-23036, Japanese Unexamined Patent Publication No. Hei 6—2,5187, Japanese Unexamined Patent Publication No. Hei 6-116,247, Japanese Unexamined Patent Publication No. Hei 6-247939, Japanese Unexamined Patent Publication No. Hei 7-258,223, Japanese Patent Application Laid-Open No. H08-113135, etc.).

However, these prior art processes require industrially complex processes because the reaction steps are complicated and expensive raw materials must be used, the reaction intermediates are unstable, and the yield is poor. It is hard to say the law.

That is, in these prior arts, the following production methods (1) to (3) are known, but they have various problems and cannot be said to be industrially useful methods.

(1) Manufacturing method 1

The following equation (5)

(Five)

Where X represents an octogen atom,

4-octane-5-chloro-6- (1-one-year-old roethyl) pyrimidine compound represented by the following formula (6):

H ₂ NA (6)

In the formula, A represents an alkyl group, an aralkyl group, a cycloalkyl group, or the like, and is a method of reacting with various amines represented by.

The reaction intermediate, 4-halogeno 5-chloro-6- (1-1 full-year rotyl) pyrimidine, is disclosed in JP-A-5-194417.

(Five)

Where X represents an octogen atom,

It can be manufactured by the method shown in FIG.

However, this production method has problems that the reaction step is complicated and expensive raw materials have to be used, and that the compound (5) is unstable.

Therefore, this manufacturing method cannot be called an industrial manufacturing method.

(2) Manufacturing method 2 The following equation (8):

Wherein A is as defined above,

4-amino-5-chloro-6- (1-chloroethyl) pyrimidine compound represented by

The following equation (9):

H-R ² (9)

Wherein R ² represents a lower acyl group;

After reacting with lower fatty acids shown in

The following equation (10):

M-OH (10)

In the formula, M represents an alkali metal,

With an inorganic base represented by

The following equation (11):

^2H 5 \

— SF ₃

2H5

The target compound can be produced by a method of reacting a fluorinating agent represented by

However, in this production method, the reaction step is complicated, and an expensive fluorinating agent (compound (11)) must be used.

Therefore, this production method cannot be said to be an industrial production method.

(3) Manufacturing method 3

A 4-amino-5-chloro-6- (1-chloroethyl) pyrimidine compound represented by the formula (8), and a compound represented by the following formula (13): M—F (1 3)

Where M represents alkali gold アルカリ

The target compound can be produced by a method of reacting with an alkali gold fluorine compound represented by the following formula.

However, this method uses N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), 1,3-dimethyl-2-imidazolidone, dimethylsulfoxide, sulfolane and mixtures thereof as solvents. However, high reaction temperature and long reaction time are required, and the yield is poor.

Therefore, this manufacturing method is also not an industrial manufacturing method.

An object of the present invention is to provide an industrial production method of a 4-amino-5-chloro-6- (1 -full-year-old rotyl) pyrimidine compound useful as a medicine and a pesticide. Disclosure of the invention

Means for Solving the Problems As a result of studying to solve the above problems, the present inventors have found a method for industrially producing a 4-amino-5-chloro-6- (1-full-age lotyl) pyrimidine compound. It was completed.

That is, the present invention is as follows.

The following equation (1A):

In the formula, R is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a halogen atom, an unsubstituted or halogen atom, a carbon atom having 1 to 4 alkyl groups, An alkoxy group having 1 to 4 carbon atoms, a benzoyl group having at least one of haloalkyl groups having 1 to 4 carbon atoms as a substituent, a haloalkyl group having 1 to 4 carbon atoms, Octoalkoxy, halo with 2 to 5 carbon atoms Alkylcarbonyl group, alkylsulfonyloxy group having 1 to 4 carbon atoms, haloalkylsulfonyloxy group having 1 to 4 carbon atoms, (alkoxy group having 1 to 4 carbon atoms) iminobenzyl group, 2-phenyl At least one of a 1,3-dioxolanyl group, an unsubstituted or halogen atom, a benzyl group having at least one hydroxyl group as a substituent, an unsubstituted or halogen atom, and a haloalkyl group having 1 to 4 carbon atoms. A phenoxy group having one as a substituent, a haloalkenyloxy group having 2 to 5 carbon atoms, an alkenyloxy group having 2 to 5 carbon atoms, tri (alkyl having 1 to 4 carbon atoms) silylalkoxy group, carbon A pyridyl group having 1 to 4 alkyl groups, a hydroxyl group, an unsubstituted or halogen atom, a pyridyl group having at least one of haloalkyl groups having 1 to 4 carbon atoms as a substituent, 1 to 4 carbon atoms Alkylsulfonyl group, alkylsulfinyl group having 1 to 4 carbon atoms, haloalkylsulfinyl group having 1 to 4 carbon atoms, haloalkylthio group having 1 to 4 carbon atoms, alkylcarbonyl group having 1 to 4 carbon atoms Represents an alkynyl group having 2 to 5 carbon atoms, or a nitro group, and π represents an integer of up to 5,

4-Amino-5-chloro-6- (1-chloroethyl) pyrimidine compound represented by

The following equation (2):

-F (2)

In the formula, M represents an alkali metal,

And alkali metal fluorine compounds represented by

The following equation (3):

(R ¹ ) ₄ NX (3)

In the formula, R ¹ represents an alkyl group having 4 to 4 carbon atoms, a benzyl group or a phenyl group, and X is as defined above.

Characterized by reacting in the presence of a quaternary ammonium salt represented by

The following equation (4 A): (4A)

Wherein R and n are as defined above,

The present invention relates to a method for producing a 4-amino-5-chloro-6- (1-fluoroethyl) pyrimidine compound represented by the formula:

The invention further provides:

The following equation (I B):

In the formula, R ′ is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a halogen atom, a haloalkyl group having 1 to 4 carbon atoms, and a carbon atom having 1 to 4 carbon atoms. A 4-amino-5-chloro- (1-promoethyl) pyrimidine compound represented by the formula, which represents four octaalkoxy groups and a dihydroxy group, and the above formula (2):

M- F (2)

In the formula, M represents an alkali metal,

And reacting it with formaldehyde, N-methylformamide, or a mixture of formamide or N-methylformamide with 3-dimethyl-21-imidazolidinone as a solvent. Equation (4B): (4B)

Wherein R ′ is as defined above,

The present invention relates to a method for producing a 4-amino-5-chloro- (11-full-year rotyl) pyrimidine compound represented by the formula: BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail.

The target compound, 4-amino-5-chloro-6- (1-fluoroethyl) pyrimidine (compounds (4A) and (4B)) and its production raw materials (compound (1A),

(1 B), R expressed in (2) and (3)), M, R 1, R ' and X are as follows.

(R)

R represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a halogen atom, a benzoyl group, a haloalkyl group having 1 to 4 carbon atoms, a carbon atom of 1 to 4 carbon atoms. Haloalkoxy groups, haloalkylcarbonyl groups having 2 to 5 carbon atoms, alkylsulfonyl groups having 1 to 4 carbon atoms, haloalkylsulfonyl groups having 1 to 4 carbon atoms, iminobenzyl groups, 2 —Phenyl-1,3-dioxolanyl group, benzyl group, phenoxy group, haloalkenyl group having 2 to 5 carbon atoms, alkenyl group having 2 to 5 carbon atoms, tri 1 to 4 alkyl) silylalkoxy group, C1 to C4 alkyl group, hydroxyl group, pyridyl group, C4 to C4 alkylsulfonyl group, C1 to C4 alkylsulfonyl group Finyl group, carbon number 1-4 Haloalkylsulfinyl group, haloalkyl group having 1 to 4 carbon atoms, alkylcarbonyl group having 1 to 4 carbon atoms, alkynyl group having 2 to 5 carbon atoms, nitro group, etc. . The substitution position of R is not particularly limited; however, 2-position, 3-position and 4-position are preferred.

Examples of the alkyl group include a linear or branched alkyl group; preferably an alkyl group having 1 to 4 carbon atoms; and more preferably CH ₃ and t-C ₄ H ₉ .

Alkoxy groups include linear or branched ones; preferably those having 1 to 4 carbon atoms; more preferably —OCH ₃ and 1 OC ₂ H ₅ .

Examples of the halogen atom include a fluorine atom, a chlorine atom, an iodine atom and an iodine atom; preferred are a fluorine atom and a chlorine atom.

Examples of the benzoyl group include unsubstituted and substituted groups. Examples of the S-substituent include a halogen) atom, an alkyl group having 4 to 4 carbon atoms, an alkoxy group having 4 to 4 carbon atoms, and a haloalkyl group having 1 to 4 carbon atoms. it can.

The position of the substituent in the benzoyl group is not particularly limited; however, the 3_ position or the 4 position is preferable.

Substituted halogen atoms in the benzoyl group include fluorine, chlorine, bromine and iodine; fluorine and chlorine are preferred.

The dialkyl group in the benzoyl group may be linear or branched; preferably it has 1 to 4 carbon atoms; and more preferably CH ₃ .

Examples of the substituted alkoxy group in the benzoyl group include straight-chain or branched ones; preferably one having 1 to 4 carbon atoms; more preferably —OCH ₃ T.

As the haloalkyl group in the benzoyl group, alkyl has 1 to 4 carbon atoms. Examples thereof include linear or branched ones having a halogen atom such as a fluorine atom, a chlorine atom, a bromine urine, and an iodine atom; preferably, CF ₃ is used. Examples of the haloalkyl group include those in which alkyl is linear or branched having 1 to 4 carbon atoms and has a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. ; it is preferably CF _3.

Examples of the haloalkoxy group include those in which alkoxy is straight or branched having 4 to 4 carbon atoms and having a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; preferably an _{_{OC F 3, -OCH F 2,}} - O CH 2 CF 3, -OC F 2 CHFCF 3, -OCH FCH F 2, - a OC F ₂ CH FC I and single OC B r F _2.

Examples of the haloalkylcarbonyl group include those in which alkyl is linear or branched having 1 to 4 carbon atoms and having an octagen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; preferably an COC F _3. Examples of the alkylsulfonyl group include those having a linear or branched alkyl group; preferably, it is OS ₂ CH ₃ .

Examples of the haloalkylsulfonyloxy group include those in which the alkyl is linear or branched having 1 to 4 carbon atoms and has a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. But preferably one OS 0 ₂ CF ₃ .

Examples of the iminobenzyl group include those having an alkoxy group having 1 to 4 carbon atoms. And, as this alkoxy group, preferably one OCH

There are 3 ゝ.

Examples of the 2-phenyl-3-dioxolanyl group include unsubstituted and those having a halogen atom as a substituent.

The position of the substituent in the 2-phenyl 1,3-dioxolanyl group is not particularly limited; however, the 4-position of the phenyl moiety is preferred. Examples of the substituted halogen atom in the 2-phenyl-1,3-dioxolanyl group include a fluorine atom, a chlorine atom, an iodine atom and an iodine atom; a chlorine atom is preferred.

Examples of the benzyl group include unsubstituted and substituted ones. The substituent includes a halogen atom and a hydroxyl group. The position of the substituent in the benzyl group is not particularly limited; the α-position is preferred.

Examples of the substituted halogen atom in the benzyl group include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; a fluorine atom and a chlorine atom are preferred.

Examples of phenoxy groups include unsubstituted and substituted groups. Examples of the substituent include a halogen atom and a haloalkyl group having 1 to 4 carbon atoms.

Substituted halogen atoms in the phenoxy group include fluorine, chlorine, bromine and iodine; fluorine and chlorine are preferred.

Examples of the haloalkyl group in the phenoxy group include those in which the alkyl is a linear or branched alkyl group having 1 to 4 carbon atoms and has a halogen atom such as a fluorine atom, a chlorine atom, an iodine atom and an iodine atom. Although it is; Ru preferably CF ₃ der.

Examples of the haloalkenyl group include linear or branched groups having a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; CH = CH F _2, a _{_{_{-OCH 2 CH 2 CF = CF 2}}} .

Alkenyloxy groups include straight-chain or branched ones; preferably -OCH ₂ CH = CH ₂ . Examples of the tri (C 4 alkyl) silylalkoxy group include those in which the alkyl and alkoxy groups are linear or branched; preferably, the alkyl and alkoxy have carbon atoms! And more preferably 4 CH ₂ S i (CH ₃ ) ₃ .

Examples of the alkylthio group having 1 to 4 carbon atoms include those having a linear or branched alkyl group; one SCH ₃ is preferable.

Examples of the pyridyl group include unsubstituted and substituted groups. Examples of the substituent include a halogen atom and a haloalkyl group having 1 to 4 carbon atoms.

Examples of the substituted halogen atom in the pyridyloxy group include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; a fluorine atom is preferred.

Examples of the substituted haloalkyl group in the pyridyloxy group include those in which the alkyl is linear or branched having 1 to 4 carbon atoms and having a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. But preferably CF3.

Preferred pyridyl radicals include pyridine-12-yl and pyridine-13-yl, and most preferably pyridine-12-isole.

The position of the substituent in the pyridyloxy group is not particularly limited; however, the 3-position and the 5-position are preferred.

Examples of the alkylsulfonyl group include those having a linear or branched alkyl group; preferably, one is SO ₂ CH ₃ .

The alkylsulfinyl group, there may be mentioned also have a linear or branched alkyl group; preferably an S 0 CH _3.

As the haloalkylsulfinyl group, alkyl is a straight-chain or

Π Is branched and includes those having a halogen atom such as a fluorine atom, a chlorine atom, an iodine atom and an iodine atom; preferably, 1 S CH ₂ F. Examples of the haloalkylthio group include those in which alkyl is linear or branched having 4 to 4 carbon atoms and having a halogen atom such as a fluorine atom, a chlorine atom, an iodine atom and an iodine atom. Preferably one SCH ₂ CF ₃ .

Alkylcarbonyl groups include straight or branched ones having 2 to 5 carbon atoms; preferably one COCH ₃ .

The alkynyloxy group may be a straight-chain or branched one having 2 to 5 carbon atoms; preferably one OCH ₂ C≡CH.

(n)

n represents an integer of 1 to 5, preferably 1, 2 or 3.

(*)

* Represents an asymmetric carbon atom.

(M)

Examples of M include alkali metals such as sodium, potassium, and cesium; potassium or cesium is preferred.

(R,)

R ′ is hydrogen atom, alkyl group having 1 to 4 carbon atoms, alkoxy group having 1 to 4 carbon atoms, halogen atom, number of haloalkyl groups having up to 4 carbon atoms, number of carbon atoms Examples thereof include 1 to 4 haloalkoxy groups and a nitro group.

Examples of the alkyl group include linear or branched ones having 1 to 4 carbon atoms; preferably, a methyl group and an ethyl group.

Examples of the alkoxy group include straight or branched ones having 1 to 4 carbon atoms; preferably, a methoxy group or an ethoxy group.

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; preferably, a fluorine atom and a chlorine atom. Examples of the octaalkyl group include those in which the alkyl is a straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms and having a halogen atom such as poly, a fluorine atom, a chlorine atom, an iodine atom and an iodine atom. it can but; is preferably an CF _3.

Examples of the haloalkoxy group include those in which alkoxy has a straight or branched chain having 1 to 4 atoms, and has a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. But preferably with one OCF ₃ , one OCH F ₂ , —OCH ₂ CF ₃ , —OC F ₂ CH FC F ₃ , one OCH FCHF ₂ , —OCF ₂ CH FC I and one OC B r F ₂ Yes; more preferably one OCF ₃ and one CH ₂ CF ₃ .

(R,)

Examples of R ¹ include an alkyl group having 1 to 4 carbon atoms, a benzyl group and a phenyl group; an alkyl group having 1 to 4 carbon atoms; and an n-butyl group is more preferable.

(X)

X is an octogen atom, and may include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; and preferably a chlorine atom and a bromine atom.

Specific examples of alkali metal fluorine compound MF; compound (2) include sodium fluoride, potassium fluoride, and cesium fluoride, with preference given to fluorinated lithium.

Specific examples of the phase transfer catalyst (R ¹ ), ΝΧ; compound (3) include triethyl benzylammonium chloride, tetramethylammonium chloride, triethylbenzylammonium bromide, tributylbenzylammonium chloride, Trimethylbenzylammonium chloride, trimethylphenylammonium bromide, tetramethylammonium bromide, tetraethylammonium bromide, tetra-bromoammonium bromide, tetramethylammonium iodide, tetramethylammonium iodide, tetra-bromoiodide -Petit ammonium.

The compound (1) used in the present invention is disclosed in Compound (7) and compound (12) can be produced by reacting compound (7) with compound (12) in the presence or absence of a solvent in the same manner as described in JP-A-8223.

In the formula, R, X and n are as defined above.

As the compound (2) and the compound (3) used in the present invention, commercially available products can be suitably used.

The present invention relates to a method for producing a compound (1A) and a compound (2) by reacting the compound (1A) and the compound (2) in the absence of a solvent or in a solvent in the presence of a phase transfer catalyst (R ¹ ) ₄ NX; Can be.

The compound (2) can be used in an amount of 1 to 10 moles per mole of the compound (1A); preferably 3 to 5 moles.

The compound (3) can be used in an amount of 0.01 to 2 times mol of the compound (1A); preferably 0.3 to 0 times mol.

The type of the solvent is not particularly limited as long as it does not directly participate in the reaction, and examples thereof include benzene, toluene, xylene, methylnaphthalene, petroleum ether, ligroin, hexane, chlorobenzene, dichlorobenzene, and methylene chloride. , Chlorinated or non-chlorinated aromatic, aliphatic, and lipophilic hydrocarbons, such as chloroform, dichloroethane, trichloroethylene, and cyclohexane; such as getyl ether, tetrahydrofuran, and dichlorohexane. Ethers; acetate N, N-dimethylformamide (DMF), N, N-dimethylacetamide, 1,3-dimethyl-2-^^ midazolidone (DMI) Amides such as dimethyl sulfoxide and a mixture of the above-mentioned solvents; and N, N-dimethylformamide (DMF);

Amides such as 1,3-dimethyl-2-imidazolidone (DMI) are preferred.

The amount of the solvent to be used may be such that the amount of the compound (3) is 5 to 100% by weight; it is preferably 10 to 50% by weight.

The reaction temperature is in the temperature range from room temperature to the boiling point of the solvent to be used, but it is preferably from 110 to 130 ° C.

The reaction time varies depending on the concentration and temperature described above; it can be usually carried out for 2 to 5 hours.

After completion of the reaction, the target compound (1A) produced as described above is subjected to ordinary post-treatments such as extraction, concentration, filtration, etc., and, if necessary, recrystallization and various chromatographic methods. It can be appropriately purified by known means such as.

The compound (1B) used in the present invention is obtained by dissolving the compound (14) and the compound (15) in the presence of a base in the same manner as described in JP-A-7-258223, as shown below. It can be easily produced by reacting in a medium or a solvent. '

In the formula, X and R ′ are as defined above.

As the compound (1B), for example, the compound shown in Table 3 synthesized by the method shown in the below-mentioned reference example can be mentioned.

The compound (2) used in the present invention is the same as described above, and a commercially available product (for example, spray-dried potassium difluoride) can be used.

In the present invention, the target compound (4B) can be produced by reacting the compound (1B) with the compound (2) in a solvent.

Examples of the type of the solvent include formamide, N-methylformamide, or a mixture of formamide or N-methylformamide and 1,3-dimethyl-2-imidazolidone (DMI).

The amount of the solvent to be used may be such that the amount of the compound (1B) is 5 to 80% by weight; however, it is preferably 0 to 50% by weight.

The compound (2) can be used in such an amount that it is used in an amount of up to 10-fold the molar amount of the compound (1B); preferably a 2- to 5-fold molar amount.

The reaction temperature is within the temperature range from room temperature to the boiling point of the solvent used or less; preferably 50 to 10 CTC.

The reaction time varies depending on the degree of rheology and the degree of the above; it can be generally carried out for about 1 to 3 hours.

After completion of the reaction, the target compound (4B) produced as described above is subjected to ordinary post-treatments such as extraction, concentration, and oxidation, and, if necessary, recrystallization and various chromatographies. It can be appropriately purified by known means such as. Example

Hereinafter, the present invention will be described specifically with reference to Examples. Note that these examples do not limit the scope of the present invention.

Example 1 (Synthesis of Compound (4)) (1) Synthesis of 5-chloro-6- (1-year-old roethyl) 1-41- (2-phenylethylamino) pyrimidine (compound 1)

Heat n-butylammonium bromide (2.7 g) and spray-dried potassium fluoride (3.9 g) to 115 ° C to 12 CTC, stir, and knead well. In this state, add 5-chloro-6- (1-chloroethyl) -141- (2-phenylethylamino) pyrimidine (5.0 g) and stir at the same temperature for 2 hours. After completion of the reaction, water (30 ml) was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate, and ethyl acetate was distilled off under reduced pressure. The resulting oil was purified by column chromatography (Co-gel C-200, toluene: ethyl acetate = 9: 1 elution). ) To give 3.0 g (63.7%) of the target product as colorless powdery crystals.

(2) Synthesis of compound 1

Add 5- (1-chloroethyl) 1-4-1 (2-phenylethylamino) pyrimidine (5.0 g) to anhydrous 1,3-dimethyl-2-imidazolidone (8 ml). Dissolve in water, add tetra-n-butylammonium bromide (2.1 g) and spray-dried potassium fluoride (3.0 g), and stir at 110 ° C to 115 ° C for 4 hours. Reacted.

After completion of the reaction, the mixture was cooled to room temperature, water (30 ml) and St-ethyl (30 ml) were added, and the mixture was stirred, and then the ethyl acetate layer was separated. The aqueous layer was extracted once with ethyl acetate, washed with the ethyl acetate layer, dried over anhydrous sodium sulfate, and then ethyl acetate was distilled off under reduced pressure.The resulting oil was subjected to column chromatography. 3.3 g (70.0%) of the desired product as colorless powdery crystals was obtained by chromatography (ヮ -gel C-200, elution with toluene: ethyl 6ΐ = 9: 1).

(3) Synthesis of 5-chloro-6- (1-furethyl) -141 [2- (4-methylphenyl) ethylamino] pyrimidine (Compound 2)

5-chloro-6- (1-chloroethyl) 1-41 [2- (4-methylphenyl) Ethilamino] Bilimidine (3.1 g) was dissolved in anhydrous 1,3-dimethyl-2-imidazolidone (5 ml) by heating, and the solution was sprayed on an Oka Tetra n-butylammonium (1.3 g) and spray-dried. Potassium fluoride (1.8 g) was added, and the mixture was stirred and reacted at 110 to 115 for 4 hours.

After completion of the reaction, the mixture was cooled to room temperature, water (20 ml) and ethyl acetate (20 ml) were added, and the mixture was stirred, and the ethyl acetate layer was separated. The water was extracted again with ethyl acetate, combined with the previous ethyl acetate layer, washed with water, dried over anhydrous sodium sulfate, and ft-ethyl acetate was distilled off under reduced pressure. The resulting oil was purified by column chromatography (ヮ CO One gel C-200, elution with toluene: ethyl acetate = 9: 1) yielded 2.0 g (68.1%) of the target compound as colorless powdery crystals.

(4) Synthesis of 5-chloro-6- (1 -year-old rotyl) -4- [2- (4-methoxyphenyl) ethylamino] pyrimidine (Compound 3)

5-Chloro-6- (1-Chloroethyl) 1-41 [2- (4-Methoxyphenyl) ethylamino] Pyrimidine (3.3 g) is converted to anhydrous N, N-dimethyl-wood lumamide (5 ml) Then, add tetra-n-butylammonium bromide (1.3 g) and spray-dried potassium fluoride (1.8 g), and stir at 110 ° C to 115 for 4 hours. did.

After the completion of the reaction, the reaction mixture was cooled to room temperature, water (20 ml) and acetic acid ethyl (20 ml) were added, and the mixture was stirred. The aqueous layer was extracted again with ethyl sulphate, combined with the ethyl sulphate ring, washed with water, dried over anhydrous sodium sulfate, and the ethyl sulphate was distilled off under reduced pressure, and the resulting oil was subjected to column chromatography. By chromatography (グラフィー -gel C-200, elution with toluene: ethyl ethyl acetate = 9: 1), 2.0 g (64.6%) of the target compound as colorless powdery crystals was obtained.

(5) Synthesis of 5-chloro-6- (1-flurocetyl) 1-41 [2- [4-1 (triflume-l-methoxy) phenyl] ethylamino] pyrimidine (compound 14)

5—Chloro 6— (1—Chloroethyl) 1 4 1 (2— [4 1 Xy) phenyl] ethylamino] pyrimidine (20.0 g) is dissolved in anhydrous 3-dimethyl-2-imidazolidone (20 ml) by heating, and sprayed with tetra-n-butylammonium bromide (8.6 g) Dry potassium fluoride (12.2 g) was added, and the mixture was stirred at 110 to 115 for 4 hours.

After the reaction was completed, the reaction mixture was cooled to room temperature, added with water (20 ml) and ethyl acetate (20 ml), stirred, and the ethyl acetate layer was separated. The aqueous layer was extracted again with ethyl acetate and combined with the previous ethyl acetate layer. After washing with water and drying over anhydrous sodium sulfate, ethyl acetate is distilled off under reduced pressure, and the resulting oil is subjected to column chromatography (ヮ -gel C-200, toluene: ethyl acetate = 9: 1 elution). The above yielded 14.0 g (73.2%) of the desired product as colorless powdery crystals.

(6) Synthesis of compound (4) in Table 1

Other compounds (4) in Table 1 were synthesized according to the methods described in the above (0) to (5).

Table 1 shows the compounds synthesized as described above and their physical properties.

table 1

Table 1 (continued)

Table 1 (continued)

. ^ Table 1 (continued)

Further, for 'Η-NMR (CDC I ₃ ) <5 ppm, it is as follows. (Compound 1)

1.59 to 1.72 (dd, 3H), 2.84 to 2.95 (t, 2H), 3.7 "! To 3.79 (q, 2H), 5.48 to 5, 60 (m, 1 H), 5.73 to 6.01 (m, 1 H), 7.1 1 to 7.36 (m, 5 H), 8.52 (s, 1 H)

(Compound 14)

1.62 ~ 1.73 (dd, 3 H), 2.92 ~ 3.01 (t, 2 H), 3.76 ~ 3.85 (m, 2 H), 5.46 ~ 5.62 ( m, 1 H), 5.78 to 6.04 (dq, 1 H), 7.1 1 to 7.20 (d, 2 H), 7.22 to 7.28 (d, 2 H), 8 . 59 (s, 1 H)

(Compound 36)

1.60 to 1.73 (dd, 3H), 2.73 (s, 3H), 3.00 to 3.05 (m, 2H), 3.81 to 3.84 (m, 2H) , 5.48 to 5.65 (m, 1 H), 5.81 to 5.96 (dq, 2 H), 7.38 to 7.41 (d, 2 H), 7.60 to 7. 63 (d, 2 H), 8.56 (s, 1 H) Example 2 (Synthesis of Compound (4B))

(1) (Sat) 5-—Mouth—6 -— (1—one-year-old roetil) 1-41 (2-Phenylethyl amino) Synthesis of pyrimidine (Compound 1)

6- (1-Bromoethyl) -1-5-chloro-4-1 (2-phenylethylamino) pyrimidine (1.0 g) was added to formamide (2mI) and 1,3-dimethyl-2-imidazolidinone (DMI) (DMI) ( 2 ml), mixed with spray-dried potassium fluoride (0.5 g), and stirred in an oil bath at 80 for 3 hours.

After completion of the reaction, water (1 OmI) was added, extracted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate.

Ethyl acetate was distilled off under reduced pressure, and the obtained oil was purified by column chromatography. (ヮ Kokesole C-200, toluene: ethyl ethyl sulphate = 20: 1 to 5: 1 elution) gave 0.56 g (68.3%) of the target compound as colorless powdery crystals.

• ¹ H-NMR (CDC I ₃ ) <5 p pm

2.00 to 2.02 (q, 3H), 2.92 to 2.97 (t, 2H),

3.75 to 3.82 (q, 2H), 5.38 to 5.45 (q, 1H),

5.5 5 (s, 1 H), 7.2 2 to 7.36 (m, 5 H),

8.54 (s, 1 H)

(2) (Ch) Synthesis of 5-chloro-6- (1-fluoroethyl) 1-41- [2- (4-methylphenyl) ethylamino] pyrimidine (Compound 2)

6— (1-Promoethyl) 1-5-Chloro4-1- [2- (4-Methylphenylethylamino) pyrimidine (1.0 g) is added to formamide (2 ml) and 1,3-dimethyl-2-imidazolidinone (DM I ) Dissolve in the mixed solvent of (2mI), add spray-dried potassium fluoride (0.5 g), and in an oil bath. The mixture was stirred at C for 3 hours.

After completion of the reaction, water (1 OmI) was added, extracted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The ethyl acetate was distilled off under reduced pressure, and the obtained oil was purified by column chromatography (co-gel C—200, toluene: ethyl acetate = 20: ■! To 5: 1 elution) to give a colorless powder. 0.58 g (70.0%) of the desired product as a state crystal was obtained.

(3) (Sat) Synthesis of 5-chloro-6- (1-full-year roethyl) 1-41- [2- (4-methoxyphenyl) ethylamino] pyrimidine (Compound 3)

6- (1-Promoethyl) 15-Chloro-4-1 [2- (4-Methoxyphenylethylamino) pyrimidine (1.0 g) is combined with formamide (2mI) and 1,3-dimethyl-2-imidazolidinone ( DMI) (2 ml) was dissolved in a mixed solvent, and spray-dried potassium fluoride (0.5 g) was added, followed by stirring in an oil bath at 80 ^ for 3 hours. After completion of the reaction, water (1 OmI) was added, extracted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate.

Ethyl acetate was distilled off under reduced pressure, and the obtained oil was subjected to column chromatography (ヮ co-gel C-200, toluene: ethyl acetate = 20: 1-5: 1) to give colorless powdery crystals. 0.60 g (72.1%) of the desired product was obtained.

(4) (Sat) 5-Chloro-6— (1 一 1-year-old roethyl) 1-41 [2- (4-Trifluoromethoxyphenyl) ethylamino] pyrimidine (Compound 14)

6— (1—Bromoethyl) —5—Chloro—4— [2— (4-Trifluoromethyl kiphenylethylamino) Pyrimidine (1.0 g) is added to formamide (2 ml) and 1,3-dimethyl-2 —Dissolved in a mixed solvent of imidazolidinone (DMI) (2 ml), added spray-dried potassium fluoride (0.5 g), and stirred in an oil bath at 80 ° C for 3 hours.

Ethyl acetate was distilled off under reduced pressure, and the obtained oil was subjected to column chromatography (Ecogel C-200, toluene: ethyl ether = 20: 1 to 5: 1) to give colorless powdery crystals. 0.60 g (69.8%) of the desired product was obtained.

^-1 H-NM R (C DC I ₃ ) <5 p pm

2.0 1 to 2.03 (d, 3H), 2.93 to 2.98 (t, 2H),

3.75 to 3.82 (q, 2H), 5.38 to 5.46 (q, 1H),

5.55 (s, 1Η), 7.16 to 7.27 (m, 5 H),

8.54 (s, 1 H)

(5) (Sat) Synthesis of 5-chloro-6- (1-fluoroethyl) 1-41 [2- (4-trifluoromethoxyphenyl) ethylamino] pyrimidine (Compound 14)

6— (1—Promoethyl) —5—Black mouth_4—1—2— (4—Trifluorome kiphenylethylamino) Birimidine (1.Og) to N-methylformamide (2 ml), spray-dried potassium fluoride (0.5 g) was added, and the mixture was stirred in an oil bath at 80 80 for 3 hours.

The ethyl sulphate was distilled off under reduced pressure, and the resulting oil was colorless powdered by column chromatography (ヮ 200, C-1 gel, eluting with toluene: ethyl acetate = 20: 1-5: 1). 0.58 g (67.5%) of the desired product as crystals was obtained.

(6) Synthesis of other compounds (3) in Table 2

Other compounds (3) in Table 2 were synthesized according to the methods described in the above (1) to (5).

Table 2 shows the compounds synthesized as described above and their physical properties.

Table 2

Comparative example

Hereinafter, comparative examples (described in JP-A-7-258223) corresponding to the examples of the present invention will be described.

Comparative Example 1 (Synthesis of Compound (4))

(1) Synthesis of 5-chloro-6- (1-full-year roethyl) -4-1- (2-phenylethylamino) pyrimidine (compound 1)

2-Phenylethylamine (1.2 g) and triethylamine (1.2 g) were dissolved in toluene (3 OmI), and 4,5-dichloro-6- (1 G) Pyrimidine (2.0 g) was added, and the mixture was heated for 4 hours.

After completion of the reaction, water was added, and the mixture was extracted with toluene. The extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting oil was purified by column chromatography (Pecogel C-200, toluene: ethyl ethyl sulphate = 1). (0: 1 elution) to give 2.3 g (82.3%) of the desired product as colorless powdery crystals.

(2) Synthesis of 5-chloro-6- (1-fluoroethyl) -4- (2- (4-methylphenyl) ethylamino) pyrimidine (Compound 2)

2- (4-Methylphenyl) ethylamine (4.1 g) and triethylamine (5.0 g) are dissolved in toluene (100 ml), and 4,5-dichloro-6- (1-chloroethyl) pyrimidine (6 3 g) was added, and the mixture was heated and passed for 3 hours. After completion of the reaction, water was added, and the mixture was extracted with toluene. The extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting oil was purified by column chromatography (P-gel C-200, toluene: ethyl acetate = 10%). : 1 elution) to obtain 8.4 g (90.3%) of colorless powdery crystals of 5-chloro-6- (1-1-chloroethyl) 1-41- [2- (4-methylphenyl) ethylamino] pyrimidine. Dissolve the obtained 5-chloro-6- (1-chloroethyl) 144- [2- (4-methylphenyl) ethylamino] pyrimidine (3.5 g) in N, N-dimethylformamide (50 ml). Then, potassium drunkate (1.4 g) and potassium carbonate (1.6 g) were added, and the mixture was heated and flowed for 3 hours.

After the reaction was completed, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting oil was purified by column chromatography (ヮ co-gel C-200, toluene: ethyl acetate = 4: 1). (Elution), which is a colorless oily liquid 5-chloro-6-

(4-Monophenyl) ethylamino] pyrimidine (2.0 g, 53.1%) was obtained.

The obtained 5-black mouth 6- (1-acetoxyshethyl) 1-41 [2- (4-me Thiphenyl) ethylamino] pyrimidine (2.3 g) in ethanol (25m

I), add a 1N aqueous solution of sodium hydroxide (13 ml), and heat at about 60 ° C.

The mixture was heated and stirred for 1 hour.

After the completion of the reaction, water was added, and the mixture was extracted with ethyl sulphate. The extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting oil was purified by column chromatography (ヮ 200, C-100 gel, toluene: ethyl acetate = 4). : A colorless oily liquid depending on the "I-elution". 5—Black mouth— 6— (1-Hydroxyethyl) 1-41 [2—

(4-Monophenyl) ethylamino] pyrimidine (2.0 g, quantitative) was obtained. The obtained 5-chloro-6- (1-hydroxyethyl) 1.41- [2- (4-methylphenyl) ethylamino] pyrimidine (1.5 g) was treated with methylene chloride (30m2).

I), and then, while cooling and stirring, getylaminosulfur trifluoride (DAST) (0.8 g) was added dropwise, followed by stirring at room temperature for 1 hour.

After completion of the reaction, water was slowly added under cooling and stirring, and the organic layer was separated. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained oil was purified by column chromatography (ヮ co-gel C-200, toluene: ethyl acetate = 10: 1 eluted) ) Gave 1.0 g (66.7%) of the desired product as a pale yellow oily liquid.

The total yield of all steps is 31.9%.

(3) Synthesis of 5-chloro-6- (1-fluoroethyl) -1 4- [2- (4-methoxyphenyl) ethylamino] pyrimidine (Compound 3)

5-Chloro-6- (1-Chloroethyl) 1-41 [2- (4-Methoxyphenyl) ethylamino] Pyrimidine (Ί.5 g) is dissolved in anhydrous N, N-dimethylformamide (30 ml) Then, cesium fluoride (1.5 g) was added, and the mixture was stirred at 120 ° C. to 140 for 12 hours.

After the completion of the reaction, the mixture was cooled to room temperature, water (20 ml) and ethyl acetate (20 ml) were added, and the mixture was stirred. Extract the aqueous layer again with ethyl acetate, After washing with water and drying over anhydrous sodium sulfate, the ethyl acetate was distilled off under reduced pressure, and the resulting oil was subjected to column chromatography (ヮ co-gel C-200, toluene: St-ethyl = 9). 0.5 g (35.1%) of the target compound as colorless powdery crystals.

(4) Synthesis of 5-chloro-6- (1-fluoroethylene) 1-41 [2- [4-1 (trifluoromethoxy) phenyl] ethylamino] pyrimidine (compound 14) 2- [4- (trifluoromethyl) Xy) phenyl] ethylamine (2.05 g) and triethylamine (3.0 g) were dissolved in toluene (20 ml), and the mixture was dissolved in 4,5-dichloro-6- (1-one-year-old roethyl) pyrimidine (2.0). g) and stirred at about 60 for 4 hours.

After the reaction was completed, water was added, and the mixture was extracted with toluene. The extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting oil was purified by column chromatography (Co-gel C-200, toluene: acid ethyl = (10: 1)) to obtain 2.6 g (71.5%) of the desired product as pale yellow powdery crystals.

Table 3 below shows a comparison of the production results of the compound (4) in the present invention and Comparative Examples.

Three

Reference example

Hereinafter, a method for synthesizing the starting compound (5) used in Comparative Examples (described in JP-A-7-258223) (described in JP-A-5-194417 and JP-A-5-320141) Is shown.

Reference Example 1 (Synthesis of Compound (5))

(1) Synthesis of 4,5-dichloro-6- (1-one-year-old rotyl) pyrimidine

6— (1-Chloroethyl) 1,4,5-Dichloropyrimidine (10.2 g) is dissolved in N, N-dimethylformamide (150 ml), and potassium acetate (10.2 g) and carbonic acid are dissolved. Potassium (12.0 g) was added, and the mixture was stirred at about 60 ° C for 3 hours. Water (200 ml) was added to the reaction solution, and the separated oil was extracted with toluene, washed with water, and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained oil was purified by column chromatography (ヮ -gel C-200, toluene: ethyl acetate = 10: 1 elution) to give a pale yellow liquid. 5.2 g (45.9%) of 5-dichloro-6- (1-acetoxicetyl) pyrimidine was obtained.

Dissolve 4,5-dichloro-6- (1-acetoxitytyl) pyrimidine (4.O g) in tetrahydrofuran (50 ml) and slowly add 1N-aqueous sodium hydroxide solution (30 ml) with stirring. It was dropped. After the dropwise addition, the mixture was further stirred at room temperature for 1 hour to complete the reaction. Then, the solvent was distilled off under reduced pressure, and the resulting oil was subjected to column chromatography (クロ co-gel C-200, toluene: ethyl acetate = 5: 1 elution) to give a pale yellow liquid 4,5. —Dichloro-6— (1-hydroxyethyl) pyrimidine (2.8 g, 85.4%) was obtained.

The obtained 4,5-dichloro-6- (1-hydroxyethyl) pyrimidine (2.1 g) was dissolved in dichloromethane (15 ml), and cooled and stirred, and getylaminosulfur trifluoride (2.0 g) was added thereto. The mixture was added dropwise and further stirred at room temperature for 1 hour to complete the reaction. Cold water (20 ml) was added to the reaction solution, dichloromethane was separated, washed with water, and dried over anhydrous sodium sulfate. Next, the solvent is distilled off under reduced pressure. The obtained oil was subjected to column chromatography (Pelcogel C-200, elution with chloroform) to give 1.3 g (61.3%) of the target compound as a pale yellow liquid.

The total yield of all steps is 24.0%.

Reference Example 2 (Synthesis of Compound (7))

(2) Synthesis of 6- (1-chloroethyl) -1,4,5-dichropyrimidine

4,5-Dichloro-6-ethylpyrimidine (270 g) was dissolved in dichloromethane (750 ml), heated at 30 to 35, and blown with chlorine gas for 2 hours with stirring. After completion of the reaction, nitrogen gas was blown into the reaction solution to remove excessively dissolved chlorine gas. Then, dichloromethane was distilled off under reduced pressure, and the obtained oil was distilled under reduced pressure to obtain 240 g of the target substance as a pale yellow liquid.

Reference Example 3 (Synthesis of Compound (1B))

(1) (Sat) Synthesis of 6- (1-bromoethyl) -1-5-chloro-4-1 (2-phenylethylamino) pyrimidine (Compound 1-1)

2-Phenylethylamine (1.2 g) and triethylamine (1.2 g) were dissolved in toluene (30 ml), and then 4-promo 6- (1-promoethyl) -15-chloropyrimidine (3.0 g) and stirred at about 40 for 4 hours.

After completion of the reaction, water was added, and the mixture was extracted with toluene.

The extract is washed with water, dried over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure, and the obtained oil is subjected to column chromatography (ヮ co-gel C-200, toluene: ethyl acetate = 10: 1 elution). 2.9 g (85.

3%).

• m.p.Ί 03〜 05 ° C

(2) (Sat) Synthesis of 6- (1-promoethyl) -1-5-chloro-4- [2- (4-trifluromethyoxyphenyl) ethylamino] pyrimidine (compounds 1-7)

2- (4-triflurescent romoxyphenyl) ethylamine (3.0 g) Dissolve ethylethylamine (3.0 g) in toluene (50 ml), add 4-bromo-6- (1-promoethyl) -15-chloropyrimidine (4.5 g), and add it at about 40 ° C for 3 hours. Stirred.

After completion of the reaction, water was added, and the mixture was extracted with toluene. The extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained oil was purified by column chromatography (Cocogel C-200, toluene: ethyl acetate = (10: 1 elution) to give 5.9 g (92.7%) of the target compound as colorless powdery crystals.

• m.p. 9 1 to 9 1.5 ° C

(3) (Sat) Synthesis of 6- (1-promoethyl) -1-5-clo-4-1- [2-((412-phenyl) ethylamino] pyrimidine (Compounds 1-10)

2- (4-N-phenyl phenyl) ethylamine hydrochloride (3.0 g) is suspended in toluene (50 ml), and triethylamine (3.0 g) and 6- (1-promoethyl) are added. , 5-Dichrolic pyrimidine (3.8 g) was added, and the mixture was stirred at about 50 ° C for 5 hours.

After completion of the reaction, water was added, and the mixture was extracted with toluene. The extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting oil was purified by column chromatography (P-gel C-200, toluene: ethyl acetate = 10%). : 1 elution) to give 5.1 g (88.2%) of the target compound as colorless powdery crystals.

• m.p. 1 1 4 to 1 16 * C

(4) Synthesis of other compounds (1 B) in Table 4

Other compounds (1B) in Table 4 were synthesized according to the methods described in the above) to (3).

Table 4 shows the compounds synthesized as described above and their physical properties. Table 4

Industrial applicability

According to the present invention, it is possible to provide an industrial process for producing 4-amino-5-chloro-6- (11-full-year-old rotyl) pyrimidine compound useful as a medicament, a pesticide for agricultural and horticultural use, and the like.

Claims

Range of claim: A)

In the formula, R is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a halogen atom, a non-S-substituted or halogen atom, and a carbon number! Up to 4 alkyl groups, up to 4 carbon alkoxy groups, 1 to 4 haloalkyl groups as substituents, benzoyl group having 1 to 4 carbon atoms, 1 to 4 carbon haloalkyl groups A haloalkoxy group having 1 to 4 carbon atoms, a haloalkylcarbonyl group having 2 to 5 carbon atoms, an alkylsulfonyloxy group having 4 to 4 carbon atoms, an octaalkylsulfonyloxy group having 4 to 4 carbon atoms , (Alkoxy group having 1 to 4 carbon atoms) iminobenzyl group, 2-phenyl-2-oxolanyl group, unsubstituted or benzyl group having at least one of a halogen atom and a hydroxyl group as a substituent , No S or halogen urine, phenoxy group having at least one of octaalkyl group having 4 to 4 carbon atoms as a substituent, haloalkenyl group having 2 to 5 carbon atoms, 2 carbon atoms ~ 5 alkenyls , Tri (alkyl having 1 to 4 carbon atoms) at least one of a silylalkoxy group, an alkylthio group having 1 to 4 carbon atoms, a hydroxyl group, a substituted or halogen atom, and a haloalkyl group having 1 to 4 carbon atoms A pyridyl group having 1 to 4 carbon atoms, an alkylsulfonyl group having 1 to 4 carbon atoms, an alkylsulfinyl group having 1 to 4 carbon atoms, an octaalkylsulfinyl group having 1 to 4 carbon atoms, 1 to 4 carbon atoms Represents a haloalkyl group, an alkylcarbonyl group having 1 to 4 carbon atoms, an alkynyl group having 2 to 5 carbon atoms, or a nitro group, and n represents an integer of〗 to 5, 4-Amino-5-chloro-6- (1-chloroethyl) pyrimidine compound represented by

The following equation (2):

-F (2)

In the formula, M represents an alkali metal,

With alkali gold-fluorine compounds represented by

The following equation (3):

(R,) ₄ NX (3)

In the formula, R ¹ represents an alkyl group having 1 to 4 carbon atoms, a benzyl group or a phenyl group. X represents a halogen atom,

Wherein the reaction is carried out in the presence of a quaternary ammonium salt represented by the following formula (4A):

Wherein R and n are as defined above,

A method for producing 4-amino-5-chloro-6- (1-full-year rotyl) pyrimidine compound.

2. The process according to claim 1, wherein the reaction is carried out for 2 to 5 hours in a temperature range from room temperature to the boiling point of the solvent to be used or lower.

3. The reaction temperature is 1 1 0〗 30 ^e C in preparation ranging first claim of claim is.

4. The compound represented by the formula (3) is obtained by converting triethylbenzylammonium chloride, tetramethylammonium chloride, triethylbenzylammonium bromide, Butylbenzylammonium, Trimethylbenzylammonium chloride, Trimethylphenylammonium iodide, Tetramethylammonium bromide, Tetraethylammonium iodide, Tetramethylammonium iodide, Tetramethylammonium iodide, 2. The process according to claim 1, wherein the process is selected from the group consisting of: and tetra-n-butylammonium iodide.

5. The method according to claim 1, wherein the compound represented by the formula (2) is spray-dried potassium fluoride.

6. Compound (2) is used in an amount of 1 to 10 times the molar amount of compound (1A), and compound (3) is used in an amount of 0.01 to 2 times the molar amount of compound (1A). The production method according to claim 1.

7. The compound (2) is used in an amount of 3 to 5 times the molar amount of the compound (1 A), and the compound (3) is used in an amount of 0.3 to 1.0 times the molar amount of the compound (1 A). The production method according to claim 1.

The following equation (1B):

In the formula, R ′ is a hydrogen atom, an alkyl group having 4 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a halogen atom, a haloalkyl group having 1 to 4 carbon atoms, and a carbon atom having 1 to 4 carbon atoms. And a 4-amino-5-chloro-6- (1-promoethyl) pyrimidine compound represented by The following equation (2):

M—F (2)

In the formula, M represents an alkali metal,

And an alkali metal fluorine compound represented by

Characterized by reacting formamide, N-methylformamide, or a mixture of formamide or N-methylformamide with 1,3-dimethyl-2-imidazolidinone as a solvent

The following equation (4B):

Wherein R is as defined above,

A method for producing 4-amino-5-chloro-6- (1-fluroletyl) pyrimidine compound represented by the formula:

9. The process according to claim 8, wherein the reaction is carried out for 1 to 3 hours in a temperature range from room temperature to the boiling point of the solvent to be used.

10. The process according to claim 8, wherein the reaction temperature is 50 to 100.

1 1. The process according to claim 8, wherein the compound represented by the formula (2) is spray-dried potassium fluoride.

12. The process according to claim 8, wherein the compound (2) is used in an amount of 1 to 10 moles per mole of the compound (1B).

13. The process according to claim 8, wherein the compound (2) is used in an amount of 2 to 5 moles per mole of the compound (1B).

14. The process according to claim 8, wherein the solvent is used in an amount such that the amount of the compound (1B) is 5 to 80% by weight.

1 5. The process according to claim 8, wherein the solvent is used in such an amount that the compound (1B) becomes 10 to 50% by weight.