JP2003089691A - 6-(1-fluoroethyl)pyrimidine compound and method for producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new 6-(1-fluoroethyl)pyrimidine compound which is useful as an intermediate for medicines, agrochemicals, and the like. SOLUTION: The new 6-(1-fluoroethyl)pyrimidine compounds are represented by formula (1) to (3) (R is a 1 to 4C alkyl; X is H or a halogen atom; * is an asymmetric carbon atom) and are useful as intermediates for medicines, agrochemicals and the like. A method for synthesizing the new 6-(1-fluoroethyl) pyrimidine compounds represented by formulas (1) to (3) is also provided.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention
The present invention relates to novel 6- (1-fluoroethyl) pyrimidines useful as intermediates for medicines and agricultural chemicals described in JP-A-201999, JP-A-6-116247 and the like.

[0002]

2. Description of the Related Art 6-Useful as an intermediate for medicines and agricultural chemicals
(1-Fluoroethyl) pyrimidines are disclosed in, for example, Japanese Patent Application Laid-Open No. 5-320141. However, the disclosure of 6- (1-fluoroethyl) pyrimidines in which the 2-position of the pyrimidine ring is substituted with a mercapto group and a lower alkylthio group as in the present invention is not recognized.

[0003]

An object of the present invention is to provide a novel 6- (1-fluoroethyl) pyrimidine useful as an intermediate for medicines and agricultural chemicals.

[0004]

Means for Solving the Problems As a result of studies to solve the above-mentioned problems, the present inventors have found a method for synthesizing a novel 6- (1-fluoroethyl) pyrimidine, and completed the present invention. . That is, the present invention is as follows.

The first aspect of the present invention is 2-
It relates to alkylthio-4-chloro-6- (1-fluoroethyl) pyrimidines.

[Chemical 5] (In the formula, R represents an alkyl group having 1 to 4 carbon atoms, X represents a hydrogen atom or a halogen atom, and * represents an asymmetric carbon atom.)

A second aspect of the present invention is the 2-indicated by the following equation (2):
It relates to alkylthio-6- (1-fluoroethyl) -4-hydroxypyrimidines.

[Chemical 6] (In the formula, R, X and * are as defined above.)

A third aspect of the present invention is 6-indicated by the following equation (3).
It relates to (1-fluoroethyl) -2-mercapto-4-hydroxypyrimidine.

[Chemical 7] (In the formula, * has the same meaning as above.)

A fourth invention is 6- (1-
It relates to a method for producing fluoroethyl) pyrimidines.

[Chemical 8] (In the formula, X ¹ and X ² represent a halogen atom, and R and * have the same meanings as described above.)

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below. The various substituents represented by the above compounds are as follows. R is a linear or branched carbon atom number 1 to 4
Although an alkyl group can be mentioned, a methyl group is preferable. Examples of the halogen atom in X, X ¹ and X ² include a chlorine atom, an iodine atom, a bromine atom and a fluorine atom, and a chlorine atom is preferable. Since the compounds (1), (2) and (3) of the present invention contain an asymmetric carbon atom represented by *, any of the individual optical isomers derived therefrom, racemates, or a mixture thereof are included in the present invention. include.

The synthetic method of the compounds (1), (2) and (3) of the present invention will be described in more detail. (Synthesis Method 1) The synthesis method 1 comprises the compound (4) and the compound (5).
And is reacted in the presence of a base in a solvent to obtain the compound (3).

As the type of solvent, one having 1 to 4 carbon atoms such as methanol, ethanol, propanol and butanol is used.
Examples of alcohols include methanol,
Ethanol is preferred. The amount of the solvent used is the compound (4)
Can be used in an amount of 5 to 80% by weight, preferably 10 to 70% by weight. Examples of the base include inorganic bases such as alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and metal alcoholates such as sodium methoxide and sodium ethoxide, but metal alcoholates are preferable. Further, sodium methoxide and sodium ethoxide are preferable. The amount of the base used is 1 to 5 times mol, but preferably 1.2 to 3 times mol, of the compound (4). The reaction temperature is not particularly limited, but is within a temperature range from room temperature to the boiling point of the solvent used, or 50 to 100.
C is preferred. The reaction time is 2 to 8 hours, though it varies depending on the concentration and temperature. The compound (4) used in the present invention can be produced by a method represented by the following formula according to the method described in JP-A No. 11-171834.

[0012]

[Chemical 9]

As the compound (5) used in the synthesis of the compound (3), a commercially available product can be used.

The desired compound (3) produced as described above is subjected to usual post-treatments such as extraction, concentration and filtration after completion of the reaction, and if necessary, distillation, recrystallization and various chromatographies. It can be appropriately purified by a known means such as.

(Synthesis Method 2) In Synthesis Method 2, compound (3) and compound (6) are reacted in a solvent in the presence of a base to give compound (2-1) (X in compound (2)). Is a hydrogen atom). Examples of the solvent include nitriles such as acetonitrile and propionitrile, ketones having 1 to 4 carbon atoms such as acetone and methyl ethyl ketone, N, N-dimethylformamide, dimethyl sulfoxide, sulfolane, N, There may be mentioned aprotic polar solvents such as N-dimethylimidazolidinone, N-methylpyrrolidone and the like, or mixtures of said solvents, but aprotic polar solvents are preferred,
Furthermore, N, N-dimethylformamide is preferable. The amount of the solvent used may be 5 to 80% by weight of the compound (3), but 10 to 70% by weight is preferable.

Examples of the compound (6) include commercially available alkyl halides having 1 to 4 carbon atoms such as methyl iodide, ethyl iodide, propyl bromide, butyl bromide and the like. Is alkyl iodide,
Further, methyl iodide is preferable. The amount of the compound (6) used is 1.0 to 5 times the molar amount of the compound (3),
1.0 to 1.2 times mol is preferable

Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, inorganic bases such as alkali metal carbonates such as sodium carbonate and potassium carbonate, sodium methoxide, sodium ethoxide and the like. The above-mentioned metal alcoholates can be mentioned, but they are usually inorganic bases, alkali metal carbonates are preferable, and potassium carbonate is more preferable. The amount of the base used is 1 to 5 times, and preferably 1 to 1.2 times the mol of the compound (3). The reaction temperature is not particularly limited, but is within a temperature range from 0 ° C. to the boiling point of the solvent used, and 0 ° C. to room temperature is preferable. The reaction time is 0.5 to 8 hours, though it varies depending on the above-mentioned concentration and temperature.

The desired compound (2-1) produced as described above is subjected to usual post-treatments such as extraction, concentration and filtration after completion of the reaction, and if necessary distilled, recrystallized and various other treatments. It can be appropriately purified by a known means such as chromatography.

(Synthesis Method 3) The synthesis method 3 is the same as compound (2-
1) and the compound (7) are reacted in a solvent to obtain a compound (2-2) (wherein in the compound (2), X is a halogen atom). The type of solvent is not particularly limited as long as it is not directly involved in this reaction, and for example, benzene, toluene, xylene, methylnaphthalene, petroleum ether, ligroin, hexane, chlorobenzene, dichlorobenzene, chloroform, dichloromethane, Chlorinated or unchlorinated aromatics such as dichloroethane, trichloroethylene, aliphatic, alicyclic hydrocarbons, ethers such as tetrahydrofuran, dioxane, diethyl ether, etc., or a mixture of the above solvents, etc. However, chlorinated aliphatic hydrocarbons such as chloroform, dichloromethane, dichloroethane are preferred.

The amount of the solvent used is such that the compound (2-1) is 5 to 5.
It can be used by adjusting it to 80% by weight.
10 to 70% by weight is preferable. The reaction temperature is not particularly limited, but is within a temperature range from room temperature to the boiling point of the solvent used or less, and preferably 10 to 40 ° C. The reaction time varies depending on the above-mentioned concentration and temperature, but is usually 0.5 to 5 hours. Examples of the compound (7) include commercially available sulfuryl chloride, halogenated sulfuryl such as bromide, and the like, and sulfuryl chloride is preferable. The amount of compound (7) used is 1 with respect to compound (2-1).
˜5 times mol, but preferably 1.0 to 1.3 times mol. The desired compound (2-
After completion of the reaction, 2) can be subjected to usual post-treatments such as extraction, concentration, filtration, etc., and if necessary, can be appropriately purified by known means such as distillation, recrystallization, various chromatography and the like.

(Synthesis Method 4) The synthesis method 4 is the same as compound (2-
1) or compound (2-2) and thionyl chloride (8) are reacted in the presence of N, N-dimethylformamide in a solvent to give compound (1-1) (in compound (1), X is a hydrogen atom). Thing) or (1-2) (X in compound (1)
Is a halogen atom). Solvent types include benzene, toluene, xylene, methylnaphthalene, petroleum ether, ligroin, hexane, chlorobenzene, dichlorobenzene, chloroform, dichloromethane, dichloroethane, trichlorethylene and unchlorinated aromatics. , Aliphatic, alicyclic hydrocarbons, ethers such as tetrahydrofuran, sioxane, diethyl ether, etc., esters such as methyl acetate, ethyl acetate, or a mixture of the above solvents, but the esters Of ethyl acetate are preferred. The amount of the solvent used is the compound (2-1) or the compound (2
-2) can be used in an amount of 5 to 80% by weight, preferably 10 to 70% by weight.

The reaction temperature is not particularly limited, but it is within the temperature range from room temperature to the boiling point of the solvent to be used, 50 to
100 ° C. is preferred. The reaction time is 0.5 to 8 hours, although it varies depending on the concentration and temperature. As the thionyl chloride (8), a commercially available product can be used. The amount of thionyl chloride (8) used is the compound (2-1) or the compound (2
-2), but 1 to 5 times mol, but 1.0 to 1.
A 3-fold molar amount is preferred. The addition amount of N, N-dimethylformamide is 0.05 to 1.0 times mol of the compound (2-1) or the compound (2-2), but 0.1 to 0.
A 5-fold molar amount is preferred. The desired compound (1-1) or compound (1-2) produced as described above is subjected to usual post-treatments such as extraction, concentration and filtration after completion of the reaction, and if necessary, distilled, various It can be appropriately purified by a known means such as chromatography.

The compound of the present invention can be prepared by the method represented by the following formula: JP-A-5-201999 and JP-A-6-116247.
It is an important compound derived from the intermediate (13) for producing the compound (14) useful as a pesticide described in Japanese Patent Publication No.

[0024]

[Chemical 10] (In the formula, R, X and * have the same meanings as described above. R ¹ represents a lower alkyl group, a hydrogen atom or the like, R ² represents a lower haloalkoxy group, a hydrogen atom or the like, and n is 1 to 5 Represents the integer of.)

[0025]

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

Example (1) 6- (1-Fluoroethyl) -2-mercapto-
Synthesis of 4-hydroxypyrimidine (Compound 3) 4-Fluoro-3-oxopentanoic acid ethyl ester 8
1.1 g of thiourea and 38.1 g of ethanol 500 m
In addition to 1, 101.5 g of 28 wt% sodium methoxide (methanol solution) was added with stirring at room temperature, and the mixture was heated under reflux for 7 hours. After completion of the reaction, the reaction mixture was allowed to cool, ethanol was distilled off under reduced pressure, and the residue was dissolved in 300 ml of water. The crystals which were made weakly acidic with hydrochloric acid under ice-cooling stirring were collected by filtration, washed with water and dried to obtain 58.0 g of the target compound as colorless powdery crystals. m. p. 196-198 ° C Mass Spectrometry CI-MS m / e = 175 (m + 1)

(2) 6- (1-fluoroethyl) -2-
Methylthio-4-hydroxypyrimidine (Compound 2-
Synthesis of 1) 6- (1-fluoroethyl) -2-mercapto-4-hydroxypyrimidine 16.0 g was dissolved in N, N-dimethylformamide 150 ml and potassium carbonate 13.4 g
Was added and stirred for 30 minutes at room temperature. Then, 13.8 g of methyl iodide was added dropwise, and the mixture was further stirred for 3 hours at room temperature. Cold water was added to the reaction mixture, which was made weakly acidic with hydrochloric acid, and the precipitated crystals were separated by filtration, washed with water, and dried to obtain 12.0 g of the target compound as colorless powdery crystals. m. p. 167.6-168.3 [deg.] C. mass spectrometry CI-MS m / e = 189 (m + 1)

(3) Synthesis of 5-chloro-6- (1-fluoroethyl) -2-methylthio-4-hydroxypyrimidine (Compound 2-2) 6- (1-Fluoroethyl) -2-methylthio-4- 13.2 g of hydroxypyrimidine was dissolved in 69 ml of acetic acid, 3.7 ml of acetic anhydride was added, and the mixture was heated with stirring at about 60 ° C. for 4 hours. After completion of the reaction, water was added to the reaction mixture, and the precipitated crystals were collected by filtration and dried to obtain 12.7 g of the target compound as colorless powdery crystals.

M. p. 193.2-194.5 ° C Mass spectrometry CI-MS m / e = 223 (m + 1)

(4) Synthesis of 4-chloro-6- (1-fluoroethyl) -2-methylthiopyrimidine (Compound 1-1) 6- (1-Fluoroethyl) -2-methylthio-4-hydroxypyrimidine 18. 8 g was suspended in 88 ml of ethyl acetate, 0.8 g of N, N-dimethylformamide was added, and the mixture was heated and stirred at about 70 ° C. Then thionyl chloride 1
3.3 ml was slowly added dropwise, and after the addition, the mixture was stirred for 3 hours. After completion of the reaction, the reaction mixture was added to crushed ice water and neutralized with a 20 wt% sodium hydroxide aqueous solution. The oily substance that separated was extracted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was filtered off, ethyl acetate was distilled off under reduced pressure, and the obtained oily substance was purified by distillation under reduced pressure to obtain the target compound 1 as a colorless oily liquid.
6.0 g was obtained. b. p. 102 ℃ / 6.7mmHg mass spectrometry ^{CI-MS m / e = 207} (m + 1) 1 H-NMR (CDCl 3, δppm) 1.60~1.73 (3H, m), 2.55 (3H,
s), 5.40 to 5.63 (1H, dq), 7.6 (1H,
s)

(5) 4,5-Dichloro-6- (1-fluoroethyl) -2-methylthiopyrimidine (Compound 1-
Synthesis of 2) 5-Chloro-6- (1-fluoroethyl) -2-methylthio-4-hydroxypyrimidine (6.67 g) was suspended in ethyl acetate (27 ml), and N, N-dimethylformamide (0.23 g) was added. The mixture was heated and stirred at 70 ° C. Then
Thionyl chloride (4 ml) was slowly added dropwise, and after the addition, the mixture was stirred for 2 hours. After completion of the reaction, the reaction mixture was added to crushed ice water and neutralized with a 20 wt% sodium hydroxide aqueous solution. The oily substance that separated was extracted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. After filtering off anhydrous sodium sulfate,
Ethyl acetate was distilled off under reduced pressure, and the obtained oily substance was purified by Karaku chromatography (Wakogel C-200, developing solvent; n-hexane: ethyl acetate = 3: 1) to give a colorless oily liquid. Target compound 7.3
g was obtained.

¹ H-NMR (CDCl ₃ , δppm) 1.59 to 1.71 (3H, m), 2.49 (3H,
s), 5.39 to 5.62 (1H, dq),

Reference Example (1) Synthesis of 6- (1-fluoroethyl) -4-hydroxypyrimidine (Compound 11) 12.2 g of 6- (1-fluoroethyl) -2-mercapto-4-hydroxypyrimidine was added to water. 240 ml and 28
To a mixed solution of 12% by weight ammonia water, 20 g of developed Raney nickel was added, and the mixture was stirred under reflux for 3 hours. After completion of the reaction, nickel was removed by hot filtration, the filtrate was concentrated under reduced pressure, and the obtained crystals were dried to obtain 8.8 g of the desired product as pale bluish white powdery crystals. m. p. 170-172 ° C

(2) Synthesis of 5-chloro-6- (1-fluoroethyl) -4-hydroxypyrimidine (Compound 12) 5-chloro-6- (1-fluoroethyl) -2-methylthio-4-hydroxypyrimidine 11.2 g of water 18
Add to a mixture of 0 ml and 9 ml of 28 wt% ammonia water,
15 g of developed Raney nickel was added, and the mixture was stirred under reflux for 3 hours. After completion of the reaction, nickel was removed by hot filtration, the filtrate was concentrated under reduced pressure, and the obtained crystals were dried to obtain 9.8 g of the desired product as white powdery crystals. m. p. 190-191 ° C

[0035]

INDUSTRIAL APPLICABILITY The present invention can provide a novel 6- (1-fluoroethyl) pyrimidine useful as an intermediate for medicines and agricultural chemicals.

Claims (4)

[Claims] 1. A 2-alkylthio-group represented by the following formula (1):
4-chloro-6- (1-fluoroethyl) pyrimidines. [Chemical 1] (In the formula, R represents an alkyl group having 1 to 4 carbon atoms, X represents a hydrogen atom or a halogen atom, and * represents an asymmetric carbon atom.) 2. A 2-alkylthio- represented by the following formula (2):
6- (1-Fluoroethyl) -4-hydroxypyrimidines. [Chemical 2] (In the formula, R, X and * are as defined above.) 3. A 6- (1-fluoroethyl) -2-mercapto-4-hydroxypyrimidine represented by the following formula (3). [Chemical 3] (In the formula, * has the same meaning as above.) 4. A process for producing 6- (1-fluoroethyl) pyrimidines according to claim 1, 2 or 3 represented by the following formula. [Chemical 4] (In the formula, X ¹ and X ² represent a halogen atom, and R and * have the same meanings as described above.)