JP2762430B2 - Preparation of aralkylaminopyrimidines - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a process for producing aralkylaminopyrimidines useful as fungicides.

[0002]

2. Description of the Prior Art Aralkylaminopyrimidines can be produced by combining a halopyrimidine and an aralkylamine in a non-polar solvent (eg, benzene, toluene, etc.) in the presence of an organic base (eg, triethylamine, pyridine, etc.). A method of reacting by heating and stirring (JP-A-59-36666) is known. However, the method has a problem that it is not suitable as an industrial method for producing aralkylaminopyrimidines because the reaction time is long and the yield is not satisfactory.

[0003]

It is an object of the present invention to provide an industrial process for producing aralkylaminopyrimidines.

[0004]

Means for Solving the Problems The inventors of the present invention have made intensive studies to solve the above-mentioned problems, and as a result, by reacting pyrimidines and aralkylamines in an alcohol solvent in the presence of a base, the object has been achieved. The compound aralkylaminopyrimidines can be synthesized in a short time,
The inventors have found that they can be obtained at a high yield, and have completed the present invention.

That is, the present invention provides a compound A represented by the following formula:

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Wherein R ¹ represents a halogen atom, an alkyl group or a hydrogen atom; R ² represents an alkyl group or a halogen atom; or R ¹ and R ² represent a carbon atom to which they are bonded. Together with a pyrimidine ring to form a saturated or unsaturated 5 or 6 which may have one sulfur atom.
R ³ represents a hydrogen atom, an alkyl group, a cycloalkyl group, an alkylthio group or an amino group which may be substituted by an alkyl group; and X represents a leaving group. ) And pyrimidines

Compound B of the following formula:

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(Wherein, R ⁴ represents an alkyl group, a haloalkyl group, a cycloalkyl group, or a hydrogen atom; R ⁵ represents a halogen atom or a hydrogen atom; R ⁶ represents a hydrogen atom, an alkyl group, a halogen atom, a lower alkoxy group) N represents 1 or 2; the carbon atom marked with * is an asymmetric carbon atom.) With an aralkylamine in an alcohol solvent.

Compound C of the following formula:

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Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
R ⁶ and n are as defined above. The present invention relates to a method for producing aralkylaminopyrimidines represented by the formula (1).

Hereinafter, the present invention will be described in detail. In the aralkylaminopyrimidines (compound C), which is the target compound, pyrimidines (compound A) and aralkylamines (compound B), which are raw materials for producing the same,

Examples of R ¹ include a halogen atom (eg, a chlorine atom, an iodine atom, a bromine atom, a fluorine atom, etc.) and an alkyl group (eg, a linear or branched one). But preferably a linear or branched one having 1 to 8 carbon atoms; more preferably a linear one having 1 to 4 carbon atoms), and a hydrogen atom. But preferably a halogen atom; more preferably a chlorine atom,
A bromine atom or the like is preferred; a chlorine atom is more preferred.

As R ² , an alkyl group (for example, a linear or branched one) can be used, and a halogen atom (for example, the halogen atoms described above can be used; preferably, chlorine is used). An alkyl group is preferable; a linear or branched alkyl group having 1 to 8 carbon atoms is more preferable; and an alkyl group having 1 to 4 carbon atoms is more preferable. A linear alkyl group is preferred.

Alternatively, R ² and R ³ are fused together with the carbon atom to which they are bonded to a pyrimidine ring to form a saturated or unsaturated 5- or 6-membered ring optionally having one sulfur atom. May be formed; preferably a benzene ring,
It may form a thiophene ring or cyclopentane.

As R ³ , a hydrogen atom or an alkyl group (for example, a linear or branched one can be mentioned; preferably, a linear or branched one having 1 to 8 carbon atoms is preferred. More preferably a linear group having 1 to 4 carbon atoms, and a cycloalkyl group (for example, a group having 3 to 6 carbon atoms can be mentioned; preferably a cyclopropyl group). ), Alkylthio groups (for example, straight-chain or branched ones can be mentioned;
It is preferably a linear or branched one having 1 to 8 carbon atoms; more preferably a linear one having 1 to 4 carbon atoms. ), An amino group which may be substituted with an alkyl group (for example, a linear or branched one may be mentioned; a linear or branched one having 1 to 8 carbon atoms is preferred.) More preferably 1 to 4 carbon atoms
Is preferred. Further, the amino group optionally substituted with an alkyl group is preferably an amino group substituted with an alkyl group. ) And the like; preferably a hydrogen atom.

As R ⁴ , an alkyl group or a haloalkyl group (for example, a linear or branched one can be mentioned; preferably, a linear or branched one having 1 to 8 carbon atoms is preferred. More preferably a linear one having 1 to 4 carbon atoms, and a halogen atom is preferably a fluorine atom; a cycloalkyl group (for example, one having 3 to 6 carbon atoms); But preferably a cyclopropyl group), a hydrogen atom and the like; preferably an alkyl group (for example, a linear or branched one; preferably) A linear or branched one having 1 to 8 carbon atoms is preferred; a linear one having 1 to 4 carbon atoms is more preferred), and a cycloalkyl group is preferred.

As R ⁵ , a halogen atom (for example, the halogen atoms described above can be mentioned; preferably a fluorine atom and a bromine atom are preferable), a hydrogen atom and the like can be mentioned; Atoms are good.

As R ⁶ , a hydrogen atom or an alkyl group (for example, a linear or branched one can be mentioned; preferably, a linear or branched one having 1 to 8 carbon atoms is preferred. More preferably a linear one having 1 to 4 carbon atoms) and a halogen atom (for example, the halogen atoms described above can be mentioned; preferably a chlorine atom and a fluorine atom are preferable). , An alkoxy group (for example, a linear or branched one can be mentioned; preferably a linear or branched one having 1 to 8 carbon atoms; more preferably 1 to 4 carbon atoms) And a haloalkoxy group (for example, a linear or branched one may be mentioned; preferably a linear or branched one having 1 to 8 carbon atoms). Often;
More preferably, it is a linear one having 1 to 4 carbon atoms. Further, as the halogen atom, a fluorine atom is preferable. ) And the like; preferably a hydrogen atom.

As n, an integer of 1 or 2 can be mentioned.

X is not particularly restricted but includes, for example, halogen atoms (eg, chlorine, bromine or iodine),
An alkylthio group (eg, methylthio, ethylthio, propylthio, butylthio, etc.), an alkanesulfonyloxy group optionally substituted by halogen (eg, methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy, etc.), an arylsulfonyloxy group ( For example, benzenesulfonyloxy, p
-Toluenesulfonyloxy), a hydroxyl group and the like, preferably a halogen atom, more preferably a chlorine atom.

The substitution position of the substituent --OCF ₂ R ⁵ includes the 3-position and 4-position.

The position of the substituent-(R ⁶ ) _n is as follows:
The 2-position, 3-position, 4-position and 5-position can be mentioned, but the 2-position, 3-position and 5-position are preferred. Since the target compound [compound (3)] has an amino group, it can easily form an acid addition salt.

Examples of the acid forming an acid addition salt include, for example,
Inorganic acids (hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.), carboxylic acids (formic acid, oxalic acid, fumaric acid, adipic acid, stearic acid, oleic acid, aconitic acid, etc.), organic sulfonic acids (methanesulfone, etc.) Acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.) and saccharin.

When the carbon atom indicated by * is an asymmetric carbon atom in the starting compound B, the obtained target compound C includes individual optical isomers, racemic compounds or mixtures thereof.

The synthesis of the compound C of the present invention can be generally carried out by reacting the compound A and the compound B as starting materials with heating in an alcohol solvent. Compound A used in the present invention can be obtained, for example, from Journal of Chemical Society (J. Chem. Soc.), 3478-34.
According to the method described on page 81 (1955), it can be easily produced by performing the following formula.

[0026]

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(In the formula, R ¹ , R ² and R ³ have the same meanings as described above.) As the compound A, for example, Tables 1 to 8
Each compound consisting of the type of each substituent corresponding to the compound numbers _{1 to 61} shown therein (referred to as compounds A _{1 to} A ₆₁ )
[For example, compound A of compound number ₁ is referred to as compound A1. The compound A ₁ means that R ^{1 in the} formula represented by the compound A is a chlorine atom, R ² is an ethyl group, and R ³ is a hydrogen atom. In addition,
X is a leaving group, here a chlorine atom. ].

Compound B used in the present invention is described in, for example, Journal of American Chemical Society (J. Amer. Chem. Soc.), Vol. 79, Vol.
According to the method described on page 55 (1957) and the like, the production can be easily carried out as shown in the following formula.

[0029]

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(Wherein R ⁴ , R ⁵ , R ⁶ and n have the same meanings as described above).
Examples of the compounds (referred to as Compounds B _{1 to} B ₆₁ ) consisting of the types of the substituents corresponding to Compound Nos. _{1 to 61} shown in Compound Nos. _{1 to 61} [for example, compound B of Compound No. 1 is a compound B ₁ and referred to. And this compound B ₁
Means that R ^{4 in the} formula represented by compound B is an ethyl group,
⁵ means a fluorine atom, and (R ⁶ ) _n means a hydrogen atom. ].

In the present invention, it is preferable to use a base since hydrogen halide is generated. And, as such a base, for example, triethylamine, pyridine,
Organic bases such as N, N-dimethylaniline; alkali metal alkoxides such as sodium methoxide, sodium ethoxide; sodium amide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydride, etc. And the like.

As the alcohol solvent in the present invention,
For example, methanol, ethanol, n-propanol,
i-propanol, n-butanol, t-butanol,
Alcohols such as ethylene glycol monomethyl ether, methylene glycol monoethyl ether, diethylene glycol and the like or hydrates thereof;
Things and the like. The amount of the solvent can be used such that the concentration of the compound B is in the range of 5 to 80% by weight, and preferably the concentration of the compound B is 10 to 70% by weight. Good to use.

With respect to the amount of the starting compound, the compound B can be used in a molar amount of 0.3 to 2 times, preferably 0.5 to 1.5 times the molar amount of the compound A. .

The reaction temperature is preferably from 60 to 200 ° C., more preferably from 70 to 140 ° C.

The reaction time varies depending on the concentration of the above-mentioned starting compounds and the reaction temperature, but it can usually be carried out for 1 to 4 hours.

The target compound C produced as described above can be appropriately purified by known means such as recrystallization and various types of chromatography. The acid addition salt can be easily obtained, for example, by introducing an acid into the reaction solution after the reaction and then removing the solvent.

As the compound C, for example, there can be mentioned compounds (referred to as compounds C _{1 to} C ₆₁ ) each having the kind of each substituent corresponding to the compound numbers ₁ to ₆₁ shown in Tables 1 to 8. [For example, Compound C of Compound No. ₁ is referred to as Compound C1. The compound C ₁ is a compound represented by the formula C wherein R ¹ is a chlorine atom, R ² is an ethyl group, R ³ is a hydrogen atom, R ⁴ is an ethyl group, R ⁵ is a fluorine atom, and (R ⁶ ) _n Is a hydrogen atom. ].

[0038]

DESCRIPTION OF THE PREFERRED EMBODIMENTS Embodiments of the present invention will be specifically described below.
Note that these examples do not limit the scope of the present invention.

Example 1 [Synthesis of 5-chloro-6-methyl-4- (α-ethyl-4-difluoromethoxybenzylamino) pyrimidine]

[0040] EXAMPLES 4 is a compound _{A 4} ingredients,
1.6 g of 5-dichloro-6-methylpyrimidine (10 m
mol), dl-α- ethyl compounds _{B 4} ingredients -
2.4 g of 4-difluoromethoxybenzylamine (12
mmol) and 1.8 g of triethylamine (18 mmol)
l) was dissolved in 4.8 ml of ethanol and heated under reflux for 7 hours. After the reaction, the reaction mixture was diluted with 30 ml of toluene.
Extracting times, the result of quantification of compound C ₄ object by gas chromatography internal standard method (as an internal standard, using 1,2-dichlorobenzene.), The yield was 90%.

[0041] In the above, the compound _{B 4} 2.2 g
(11 mmol) and 1.5 g of triethylamine (15
mmol), results ethanol synthesized all with the to compound _{C 4} similar except for using 10 ml, and the yield 9
It was 0%. FIG. 1 shows the change over time of the reaction in this synthesis method.

[0042] In the above, the compound _{B 4} 2.0 g
All except that the (10 mmol) and the results obtained by combining the Compound _{C 4} in the same manner, with a yield of 86%.

Comparative Example In the above, compound B ₄
2.2 g (11 mmol) and triethylamine in 1.
And 5 g (15 mmol), result toluene to synthesize a compound _{C 4} in the same manner as all except that 10ml used in place of ethanol, a yield of 69%. FIG. 1 shows the change over time of the reaction in this synthesis method.

[0044] In the above, the compound _{B 4} 2.2 g
(11 mmol) and 8.4 g of triethylamine (84 g).
mmol) and then, all except that heating and stirring at 90 to 98 ° C. without ethanol and result of combining to give compound C ₄ Similarly, a yield of 46%.

Example 2 Synthesis of 5-chloro-6-methyl-4- (α-methyl-4-difluoromethoxybenzylamino) pyrimidine

[0046] is a compound _{A 23} of EXAMPLES material 4,5-dichloro-6-methylpyrimidine 1.6 g (1
0mmol), dl-α- methyl-4-difluoromethoxy-benzyl amine 2g is a compound _{B 23} of the raw material (1
1 mmol) and 1.5 g of triethylamine (15 mm
ol) was dissolved in 10 ml of ethanol and heated under reflux for 3 hours. After the reaction, the reaction mixture was diluted with 40 ml of toluene.
Extracting times, the results of quantification of the compound C ₂₃ of interest by gas chromatography internal standard method (as an internal standard, using 1,2-dichlorobenzene.), The yield was 91%.

[0047] [Comparative Example] The results obtained by combining the Compound C ₂₃ in the same manner as all but using toluene in place of ethanol, a yield of 55%.

Example 3 [Synthesis of 5-chloro-6-ethyl-4- (α-ethyl-4-difluoromethoxybenzylamino) pyrimidine]

[0049] EXAMPLES 4 is a compound _{A 3} of the raw material,
1.8 g of 5-dichloro-6-ethylpyrimidine (10 m
mol), dl-α- ethyl is a compound _{B 3} of the raw material -
2.2 g of 4-difluoromethoxybenzylamine (11
mmol) and 1.5 g of triethylamine (15 mmol
l) was dissolved in 10 ml of ethanol and heated under reflux for 3 hours. After the reaction, the reaction mixture was extracted 3 times with toluene 40 ml, the compound C ₃ object as a quantitative result (internal standard substance by gas chromatography internal standard method,
1,2-Dichlorobenzene was used. ), With a yield of 8
8%.

[0050] [Comparative Example] The results obtained by combining the Compound C ₃ in the same manner as all but using toluene in place of ethanol, a yield of 40%.

[0051]

According to the present invention, the desired aralkylaminopyrimidines can be synthesized in a short time,
And it can be obtained in high yield.

[Brief description of the drawings]

FIG. 1 is an explanatory diagram showing a change over time in a synthesis reaction of alkylaminopyrimidine in Example 1. In addition, ●
-● indicates the conversion rate (%) of pyrimidine (A) in Examples, and… indicates the conversion rate (%) of pyrimidine (A) in Comparative Examples.

[Table 1]

[Table 2]

[Table 3]

[Table 4]

[Table 5]

[Table 6]

[Table 7]

[Table 8]

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI C07D 239/95 C07D 239/95 513/04 351 513/04 351 381 381 // A01N 43/54 A01N 43/54 Z (58) Surveyed fields (Int.Cl. ⁶ , DB name) C07D 239/42 C07D 239/47 C07D 239/48 C07D 239/70 C07D 239/94 C07D 239/95 C07D 513/04 351 C07D 513/04 381 A01N 43 / 54 CA (STN) REGISTRY (STN) WPIDS (STN)

Claims (1)

(57) [Claims] (1) The following formula: (Wherein, R ¹ represents a halogen atom, an alkyl group or a hydrogen atom; R ² represents an alkyl group or a halogen atom; or R ¹ and R ² represent a pyrimidine ring together with the carbon atom to which they are bonded) To form a saturated or unsaturated 5- or 6-membered ring which may have one sulfur atom; R ³ represents a hydrogen atom, an alkyl group, a cycloalkyl group, an alkylthio group or X represents an amino group which may be substituted with an alkyl group; X represents a leaving group) and a pyrimidine represented by the following formula: (Wherein, R ⁴ represents an alkyl group, a haloalkyl group, a cycloalkyl group, or a hydrogen atom; R ⁵ represents a halogen atom or a hydrogen atom; R ⁶ represents a hydrogen atom, an alkyl group, a halogen atom, an alkoxy group, a haloalkoxy) N represents 1 or 2), and is reacted with an aralkylamine represented by the following formula in an alcoholic solvent: (Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and n have the same meanings as described above).