JPH05320141A - 4,5-dihalogeno-6-@(3754/24)alpha-substituted-ethyl)pyrimidine and its production - Google Patents

Abstract

PURPOSE:To provide a new 4,5-dihalogeno-6-(alpha-substituted-ethyl)pyrimidine useful as a synthetic intermediate for pharmaceuticals, agricultural chemicals, etc. CONSTITUTION:The compound of formula I (R is lower acyloxy or OH), e.g. 6-(alpha-acetoxyethyl)-4,5-dichloropyrimidine. The compound of formula I wherein R is lower acyloxy can be produced by reacting a pyrimidine compound of formula II with a lower aliphatic carboxylic acid of formula III (R' is lower alkyl) preferably in the presence of a base in a solvent. The obtained compound can be converted to another compound of formula I wherein R is OH by reacting with an inorganic salt of the formula M-OH (M is alkali metal).

Description

Detailed Description of the Invention

[0001]

The present invention relates to a novel 4,5-dihalogeno-6-, which is useful as a synthetic intermediate for medicines and agricultural chemicals.
It relates to (α-substituted ethyl) pyrimidine.

[0002]

Description of the Prior Art Many halogenopyrimidine compounds useful as synthetic intermediates for medicines and agricultural chemicals are known (for example, JP-A-59-89670). However, 4,5-dihalogeno-6-like compounds of the present invention which are useful as raw materials for the synthesis of pyrimidine derivatives having insecticidal, acaricidal and bactericidal activities (for example, the compounds described in Japanese Patent Application No. 3-354223). (Α-substituted ethyl)
Reports on pyrimidines are not accepted.

[0003]

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a novel 4,5-dihalogeno-6- (α-substituted ethyl) pyrimidine which is useful as a synthetic intermediate for medicines and agricultural chemicals.

[0004]

Means for Solving the Problems The inventors of the present invention have conducted extensive studies to solve the above problems, and as a result, novel 4,5-
The inventors have found a method for synthesizing dihalogeno-6- (α-substituted ethyl) pyrimidine and completed the present invention. That is,
The present invention is as follows. The first invention is represented by the following formula (I):

[0005]

[Chemical 6]

(In the formula, R represents a lower acyloxy group or a hydroxyl group), and 4,5-dihalogeno-6- (α
-Substituted ethyl) pyrimidine. The second invention is represented by the following formula (II):

[0007]

[Chemical 7]

A pyrimidine compound represented by the following formula (II)
I):

[0009]

[Chemical 8]

(In the formula, R'represents a lower alkyl group.)
The present invention relates to a process for producing a pyrimidine compound represented by the above formula (I), wherein R represents a lower acyloxy group, which is characterized by reacting with a lower aliphatic carboxylic acid represented by The third invention is the following formula (I-1):

[0011]

[Chemical 9]

(Wherein R'is as defined above) and a pyrimidine compound represented by the following formula (IV):

[0013]

[Chemical 10]

A method for producing a pyrimidine compound represented by the above formula (I), wherein R represents a hydroxyl group, characterized by reacting with an inorganic salt represented by the formula (M represents an alkali metal) Is. Hereinafter, the present invention will be described in detail. The novel 4, which is the above-mentioned target compound
5-dihalogeno-6- (α-substituted ethyl) pyrimidine [compound (I) {compound (I-1), compound (I-
2)}], its raw material [compound (II), compound (I
II), inorganic salts], R, R'and M are as follows.

Examples of R include a lower acyloxy group and a hydroxyl group. The lower acyloxy group in R is preferably a linear or branched one having 1 to 4 carbon atoms (eg, acetyloxy group, n-propionyloxy group, i-propionyloxy group, n-butyroyloxy group). , I-butyroyloxy group, t-butyroyloxy group, etc.), and more preferably acetyloxy group. M represents an alkali metal.

The compound (I) of the present invention can be synthesized by the following synthetic method 1 or 2. (Synthesis Method 1) Synthesis of 4,5-dihalogeno-6- (α-lower acyloxyethyl) pyrimidine [Compound (I-1)] in which R is a lower acyloxy group in Compound (I) is shown below. Thus, compound (II) and compound (I
It can be carried out by reacting with II) in a solvent or without a solvent; it is preferable to react in a solvent in the presence of a base.

[0017]

[Chemical 11]

(In the formula, R'has the same meaning as described above.) 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 and petroleum. Chlorinated or unchlorinated aromatic, aliphatic or alicyclic hydrocarbons such as ether, ligroin, hexane, chlorobenzene, dichlorobenzene, methylene chloride, chloroform, dichloroethane, trichloroethylene; diethyl ether,
Ethers such as tetrahydrofuran, dioxane; ketones such as acetone, methyl ethyl ketone; amides such as N, N-dimethylformamide, N, N-dimethylacetamide; acetonitrile,
Nitriles such as propionitrile; organic bases such as triethylamine, pyridine, N, N-dimethylaniline; 1,3-dimethyl-2-imidazolinone; dimethyl sulfoxide; acetic acid, propionic acid, etc. Aliphatic carboxylic acids; a mixture of the above solvents, and the like can be mentioned.

Of the above solvents, N, N are preferred.
-It is preferable to use dimethylformamide or the same aliphatic carboxylic acid as the acyloxy group to be introduced. The amount of the solvent used may be such that the concentration of the compound (II) is in the concentration range of 5 to 80% by weight, but the pus degree of the compound (II) is preferably 10 to 50% by weight. It is good to use in this way.

The base is not particularly limited and includes, for example,
Organic bases (eg triethylamine, pyridine, N,
N-dimethylaniline, DBU, etc.) and inorganic bases (eg, sodium hydride, sodium amide, sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, sodium carbonate, potassium carbonate, etc.) can be mentioned; A good base. The amount of the base used can be 1 to 5 times the molar amount of the compound (II), but preferably 1.2 to 2 times the molar amount.

The reaction temperature is not particularly limited, but is within a temperature range from room temperature to the boiling point of the solvent to be used, 40 ° C.
-80 degreeC is preferable. The reaction time varies depending on the above-mentioned concentration and temperature, but can be usually 1 to 10 hours.

The desired compound (I-1) produced as described above is subjected to usual post-treatments such as extraction, concentration and filtration after the completion of the reaction, and if necessary, recrystallization, various chromatographies and the like. It can be appropriately purified by a known method. Examples of the compound (I-1) include the compounds (I) shown in Table 1 below [for example, compounds 1 to 3 and the like. And the compound 1 means that R in the formula represented by the compound (I) is -OCOCH ₃ . ] Can be mentioned.

[0023]

[Table 1]

(Synthesis Method 2) Synthesis of 4,5-dihalogeno-6- (α-hydroxyethyl) pyrimidine [Compound (I-2)] in which R is a hydroxyl group in Compound (I) is shown below. Thus, the compound (I-1) and the inorganic salt [compound (IV)] can be reacted in a solvent.

[0025]

[Chemical formula 12]

(In the formula, R ′ and M have the same meanings as described above.) The solvent is not particularly limited as long as it does not directly participate in this reaction, and for example, the ethers described in Synthesis Method 1 , Solvents such as ketones and amides; alcohols (eg, methanol, ethanol, propanol,
Butanol, etc.); water; a mixture of the above solvents, and the like.

Among the above solvents, a mixture of ethers such as tetrahydrofuran and dioxane and water is preferable. The amount of the solvent used is the compound (I-1)
The compound (I-1) can be used in a concentration range of 5 to 80% by weight, preferably the compound (I-1) concentration is 10 to 70% by weight.

Examples of the inorganic salts [compound (IV)] include the inorganic bases described in Synthesis Method 1; sodium hydroxide and potassium hydroxide are preferable. The amount of the inorganic base used is 1 with respect to the compound (I-1).
~ 5 times the molar amount can be used, but preferably 2 ~
5 times mole is good.

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, or from room temperature to
50 ° C is preferred. The reaction time varies depending on the above-mentioned concentration and temperature, but can usually be 0.5 to 1 hour. The desired compound (I-
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 a known means such as recrystallization or various chromatography. The physical properties of the compound (I-2) are shown in Table 1 above.

The compound (I) thus obtained is
For example, as shown below, it is useful as a raw material for synthesizing an aralkylaminopyrimidine derivative having excellent insecticidal, acaricidal and bactericidal activity as described in Japanese Patent Application No. 3-354223.

[0031]

[Chemical 13]

(Wherein R has the same meaning as described above; R
¹ represents a hydrogen atom or an alkyl group; R ² represents a lower haloalkoxy group, a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower haloalkyl group, a nitro group or a halogen atom; and n represents an integer of 1 to 5. .. )

[0033]

EXAMPLES The present invention will be specifically described below with reference to examples. It should be noted that these examples do not limit the scope of the present invention. Reference Example 1 [Synthesis of Compound (II)] Synthesis of 6- (α-chloroethyl) -4,5-dichloropyrimidine 4,5-Dichloro-6-ethylpyrimidine (270 g)
Is dissolved in dichloromethane (750 ml), 30-35
Chlorine gas was blown in for 2 hours while being heated to ℃ and stirred. After completion of the reaction, nitrogen gas was blown into the reaction solution to remove excessive dissolved chlorine gas. Then, dichloromethane was distilled off under reduced pressure, and the obtained oily substance was distilled under reduced pressure to obtain 240 g of a target product which was a pale yellow liquid.

(Physical properties) b. p. ^{110~113 ℃ / 7mmHg · 1 H-} NMR (CDCl 3) δppm 1.90 (d, 3H), 5.50 (q, 1H), 8.9
0 (s, 1H)

Example 1 [Synthesis of Compound (1)] (1) Synthesis of 6- (α-acetoxyethyl) -4,5-dichloropyrimidine (Compound 1) 4,5-Dichloro-6-ethylpyrimidine (10) .2
g) was dissolved in N, N-dimethylformamide (150 ml), potassium acetate (12.0 g) and potassium carbonate (3.0 g) were added, and the mixture was stirred at about 60 ° C. for 3 hr. Water (200 ml) was added to the reaction solution, the separated oily substance 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 residue was purified by column chromatography (Wakogel C-200, toluene: ethyl acetate = 10: 1 elution) to give the desired product as a pale yellow liquid. Obtained 5.2 g.

(Physical properties) ¹ H-NMR (CDCl ₃ ) δppm 1.55 to 1.62 (d, 3H), 2.15 (s, 3)
H), 6.00 to 6.12 (q, 1H), 8.84
(S, 1H)

(2) Synthesis of 4,5-dichloro-6- (α-hydroxyethyl) pyrimidine (Compound 4) 6- (α-acetoxyethyl) -4,5-dichloropyrimidine (4.0 g) was added to tetrahydrofuran ( 50 ml)
Dissolved in 1N-sodium hydroxide aqueous solution (3
0 ml) was slowly added dropwise. After the dropping, the reaction was completed by further stirring for 1 hour at room temperature. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (Wakogel C-200, toluene: ethyl acetate = 5: 1 elution) to give the desired product as a pale yellow liquid. 2.8 g was obtained.

(Physical properties) ¹ H-NMR (CDCl ₃ ) δppm 1.47 to 1.52 (d, 3H), 3.76 to 3.85
(D, 1H), 5.17 to 5.25 (m, 1H), 8.
88 (s, 1H)

(3) Synthesis of Other Compounds in Table 1 According to the method described in (1) above, 4,5-dihalogeno-6- (α-lower acyloxyethyl) as described in Table 1 Pyrimidine was synthesized.

[0040]

The novel 4,5-dihalogeno-6 of the present invention
-(Α-Substituted ethyl) pyrimidine is useful as a synthetic intermediate for medicines and agricultural chemicals.

Claims (3)

[Claims] 1. The following formula: (In the formula, R represents a lower acyloxy group or a hydroxyl group.)
The 4,5-dihalogeno-6- (α-substituted ethyl) pyrimidine represented by: 2. The following formula: And a pyrimidine compound represented by the following formula: (In the formula, R'represents a lower alkyl group.) A lower aliphatic carboxylic acid represented by the formula (I) is reacted with R in the formula (I). Process for producing pyrimidine compound. 3. The following formula: (In the formula, R ′ has the same meaning as described in claim 1.) and a pyrimidine compound represented by the following formula: (In the formula, M represents an alkali metal.) An inorganic salt represented by the formula is reacted to produce a pyrimidine compound represented by formula (I) in which R is a hydroxyl group.