JPH04235976A - Production of aralkylaminopyrimidine compounds - Google Patents

Abstract

PURPOSE:To profitably produce an aralkylaminopyrimidine compound useful as an antimicrobial agent by reacting a pyrimidine compound with an aralkylamine compound in an alcoholic solvent. CONSTITUTION:A compound of formula I (R<1> is halogen, alkyl, H; R<2> is alkyl, halogen, or R<1> and R<2> may be condensed with the pyrimidine ring with the carbon atoms bonded to the R<1> and R<2>, respectively, to form a saturated or unsaturated five or six-membered ring which may contain a sulfur atom; R<3> is H, alkyl, etc.; X is a releasable group) is reacted with a compound of formula II (R<4> is alkyl, haloalkyl, H, etc.; R<5> is halogen, H; R<6> is H, alkyl, halogen, etc.; n is 1,2) preferably in a ratio of 1:0.5-1.5 in the presence of a base in an alcoholic solvent such as methanol preferably at 70-14 deg.C for 1-4hr, followed b by purifying the solution product by various chromatographic methods to provide the objective compound of formula III.

Description

[Detailed description of the invention]

0001

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing aralkylaminopyrimidines useful as fungicides.

0002

[Description of the prior art] A method for producing aralkylaminopyrimidines involves combining halopyrimidines and aralkylamines in a nonpolar solvent (e.g., benzene, toluene, etc.) in the presence of an organic base (e.g., triethylamine, pyridine, etc.). A method of reacting by heating and stirring (Japanese Unexamined Patent Publication No. 59-36666) is known. However, this method requires a long reaction time and does not give a satisfactory yield, so it is not suitable as an industrial method for producing aralkylaminopyrimidines.

0003

SUMMARY OF THE INVENTION An object of the present invention is to provide an industrial method for producing aralkylaminopyrimidines.

0004

[Means for Solving the Problems] As a result of intensive research in order to solve the above problems, the present inventors have achieved the objective by reacting pyrimidines and aralkylamines in an alcohol solvent in the presence of a base. Aralkylaminopyrimidine compounds can be synthesized in a short time,
The present inventors have discovered that it can be obtained in high yield and have completed the present invention.

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

[C4
]

(In the formula, R1 represents a halogen atom, an alkyl group, or a hydrogen atom; R2 represents an alkyl group or a halogen atom; or R1 and R2 together with the carbon atom to which they are bonded form a pyrimidine ring. Saturated or unsaturated 5 or 6 which may be condensed and have one sulfur atom
It may form a membered ring; R3 represents a hydrogen atom, an alkyl group, a cycloalkyl group, an alkylthio group, or an amino group which may be substituted with an alkyl group; X represents a leaving group; ) and pyrimidines represented by

Compound B of the following formula:

[C5]

(In the formula, R4 represents an alkyl group, a haloalkyl group, a cycloalkyl group, or a hydrogen atom; R5 represents a halogen atom or a hydrogen atom; R6 represents a hydrogen atom, an alkyl group, a halogen atom, a lower alkoxy group, a halo Represents an alkoxy group; n represents 1 or 2; carbon atoms marked with * are asymmetric carbon atoms) are reacted in an alcohol solvent.

Compound C of the following formula:

[C6]

(In the formula, R1, R2, R3, R4, R5,
R6 and n are as defined above. ) The present invention relates to a method for producing aralkylaminopyrimidines represented by the following.

The present invention will be explained in detail below. Aralkylaminopyrimidines which are the target compounds mentioned above [
Compound C], its manufacturing raw materials pyrimidines [Compound A] and aralkylamines [Compound B],

0
[012] As R1, a halogen atom (for example, a chlorine atom, an iodine atom, a bromine atom, a fluorine atom, etc.), an alkyl group (for example, a linear or branched one can be mentioned), (preferably linear or branched ones having 1 to 8 carbon atoms; more preferably linear ones having 1 to 4 carbon atoms), hydrogen atoms, etc. Preferably a halogen atom; More preferably a chlorine atom, a bromine atom, etc.; Even more preferably a chlorine atom.

[0013] As R2, an alkyl group (for example, a linear or branched one can be mentioned), a halogen atom (for example, the above-mentioned halogen atom can be mentioned; preferably a chlorine atom) preferred are alkyl groups; more preferably linear or branched alkyl groups having 1 to 8 carbon atoms; even more preferred are linear or branched alkyl groups having 1 to 4 carbon atoms. A chain alkyl group is preferable.

Alternatively, R2 and R3 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 which may have one sulfur atom. Preferably a benzene ring,
It may form a thiophene ring or cyclopentane.

R3 is a hydrogen atom or an alkyl group (for example, a linear or branched group; preferably a linear or branched group having 1 to 8 carbon atoms; More preferably, a linear one having 1 to 4 carbon atoms is preferable.), a cycloalkyl group (for example, one having 3 to 6 carbon atoms is preferable; a cyclopropyl group is preferable). , alkylthio group (for example, straight-chain or branched ones; preferably straight-chain or branched ones having 1 to 8 carbon atoms; more preferably 1 to 4 carbon atoms) ), an amino group which may be substituted with an alkyl group (for example, a straight chain or branched one; preferably a straight chain having 1 to 8 carbon atoms) A chain or branched one is preferable; a straight chain one having 1 to 4 carbon atoms is more preferable.In addition, for an amino group which may be substituted with an alkyl group, it is preferable to use an amino group substituted with an alkyl group. Preferably, a hydrogen atom is used.

R4 is an alkyl group or a haloalkyl group (for example, a linear or branched group; preferably a linear or branched group having 1 to 8 carbon atoms; More preferably, a straight-chain one having 1 to 4 carbon atoms is preferable.The halogen atom is preferably a fluorine atom. (preferably a cyclopropyl group), a hydrogen atom, etc.; preferably an alkyl group (for example, a linear or branched group; preferably a carbon Straight chain or branched ones having 1 to 8 atoms are preferable; straight chain ones having 1 to 4 carbon atoms are more preferable.), and cycloalkyl groups are preferable.

Examples of R5 include halogen atoms (for example, the halogen atoms described above; preferably fluorine atoms and bromine atoms), hydrogen atoms, etc.; preferably hydrogen atoms. Good.

R6 is a hydrogen atom or an alkyl group (for example, a linear or branched group; preferably a linear or branched group having 1 to 8 carbon atoms; More preferably, a linear one having 1 to 4 carbon atoms is preferable.), a halogen atom (for example, the halogen atoms described above can be mentioned; chlorine atoms and fluorine atoms are preferable), Alkoxy groups (for example, linear or branched ones can be mentioned;
Preferably, it is a straight chain or branched chain having 1 to 8 carbon atoms; more preferably a straight chain having 1 to 4 carbon atoms. ), haloalkoxy groups (for example, straight-chain or branched ones; preferably straight-chain or branched ones having 1 to 8 carbon atoms; more preferably 1 carbon atom) A straight-chain one of 4 to 4 is preferable.Also, as the halogen atom, a fluorine atom is preferable.Although, a hydrogen atom is preferable.

[0019] As n, an integer of 1 or 2 can be listed.

[0020] X is not particularly limited, and includes, for example, a halogen atom (for example, chlorine, bromine, or iodine),
Alkylthio groups (e.g., methylthio, ethylthio, propylthio, butylthio, etc.), alkanesulfonyloxy groups optionally substituted with halogen (e.g., methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy, etc.), arylsulfonyloxy groups ( For example, benzenesulfonyloxy, p
-toluenesulfonyloxy, etc.), hydroxyl group, etc., preferably a halogen atom, and more preferably a chlorine atom.

[0021] Examples of the substitution position of the substituent -OCF2R5 include the 3-position and the 4-position.

The substitution position of the substituent -(R6)n is as follows:
Examples include the 2-position, 3-position, 4-position, and 5-position, but preferably the 2-position, 3-position, and 5-position. Since the target compound [compound (3)] has an amino group, it can easily form an acid addition salt.

Examples of acids that form acid addition salts include:
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 (methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.), saccharin, etc. be able to.

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

Compound C of the present invention can usually be synthesized by heating and reacting raw materials Compound A and Compound B in an alcohol solvent. Compound A used in the present invention is described, for example, in Journal of Chemical Society (J.Chem.Soc.), 3478-34.
It can be easily produced according to the method described on page 81 (1955) as shown in the following formula.

[0026]

[C7]

(In the formula, R1, R2 and R3 have the same meanings as described above.) As the compound A, for example, Tables 1 to 8
Compounds consisting of the types of substituents corresponding to compound numbers 1 to 61 shown therein (referred to as compounds A1 to A61).
For example, compound A with compound number 1 is referred to as compound A1. Compound A1 means that in the formula represented by compound A, R1 is a chlorine atom, R2 is an ethyl group, and R3 is a hydrogen atom. In addition,
X is a leaving group, here a chlorine atom. ].

Compound B used in the present invention is described, for example, in the Journal of the American Chemical Society (
J. Amer. Chem. Soc. ), vol. 79, 145
It can be easily produced by following the method shown in the following formula, in accordance with the method described in, for example, p. 5 (1957).

[0029]

[Chemical formula 8]

(In the formula, R4, R5, R6 and n have the same meanings as described above.) As compound B, for example, Table 1
Compounds (referred to as compounds B1 to B61) consisting of the types of substituents corresponding to compound numbers 1 to 61 shown in ~8 can be mentioned [for example, compound B of compound number 1 can be referred to as compound B1]. It is called. This compound B1 is defined by the formula represented by compound B, in which R4 is an ethyl group and R5 is
means that is a fluorine atom and (R6)n is a hydrogen atom. ].

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

[0032] 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, etc. or their hydrates; mixtures of the above solvents;
Can list things. The amount of the solvent to be used can be such that the concentration of compound B is in the range of 5 to 80% by weight, but preferably the concentration of compound B is in the range of 10 to 70% by weight. It is better to use it.

[0033] Regarding the amount of the raw material compound to be used, Compound B can be used in an amount of 0.3 to 2 times the mole of Compound A, preferably 0.5 to 1.5 times in mole. .

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

The reaction time varies depending on the concentration of the above-mentioned raw material 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 chromatography. The acid addition salt thereof can be easily obtained, for example, by introducing an acid into the reaction solution after the reaction is completed, and then removing the solvent.

[0037] Examples of the compound C include compounds (referred to as compounds C1 to C61) having the types of substituents corresponding to compound numbers 1 to 61 shown in Tables 1 to 8. For example, compound C with compound number 1 is referred to as compound C1. This compound C1 is defined by the formula represented by compound C, in which R1 is a chlorine atom, R2 is an ethyl group, R3 is a hydrogen atom, R4 is an ethyl group, R5 is a fluorine atom, and (R6)n is a hydrogen atom. means. ].

[0038]

[Examples] Examples of the present invention will be explained in detail 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]

[Example] ■ 4, which is the raw material compound A4,
5-dichloro-6-methylpyrimidine 1.6g (10m
mol), dl-α-ethyl- which is the raw material compound B4
2.4 g (12
mmol) and triethylamine 1.8 g (18 mmol)
1) 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.
The target compound C4 was extracted twice and quantified by gas chromatography internal standard method (1,2-dichlorobenzene was used as an internal standard substance), and the yield was 90%.

■ In the above ■, 2.2 g of compound B4
(11 mmol), triethylamine 1.5 g (15
mmol), all except 10 ml of ethanol■
As a result of synthesizing compound C4 in the same manner as above, the yield was 9
It was 0%. Figure 1 shows the time course of the reaction in this synthetic method.

■ In the above ■, 2.0 g of compound B4
Compound C4 was synthesized in the same manner as in (2) except that the amount was changed to (10 mmol), and the yield was 86%.

[Comparative example] ■ In the above ■, compound B4
2.2g (11mmol) of triethylamine and 1.2g (11mmol) of triethylamine.
Compound C4 was synthesized in the same manner as in (2) except that the amount was 5 g (15 mmol) and 10 ml of toluene was used instead of ethanol, and the yield was 69%. Figure 1 shows the time course of the reaction in this synthetic method.

■ In the above ■, 2.2 g of compound B4
(11 mmol), 8.4 g (84 mmol) of triethylamine
Compound C4 was synthesized in the same manner as in (2) except that the compound C4 was heated and stirred at 90 to 98° C. without using ethanol, and the yield was 46%.

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

[Example] ■ 4 which is the raw material compound A23
,5-dichloro-6-methylpyrimidine 1.6g (10
mmol), 2 g of dl-α-methyl-4-difluoromethoxybenzylamine (11
mmol) and triethylamine 1.5 g (15 mmol)
1) was dissolved in 10 ml of ethanol and heated under reflux for 3 hours. After the reaction, the reaction mixture was extracted three times with 40 ml of toluene, and the target compound C23 was quantified by gas chromatography internal standard method (1,2-dichlorobenzene was used as the internal standard substance). The rate was 91%.

[Comparative Example] ■ Compound C23 was synthesized in the same manner as in ■ above except that toluene was used instead of ethanol, and the yield was 55%.

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

[Example] ■ 4, which is the raw material compound A3,
5-dichloro-6-ethylpyrimidine 1.8g (10m
mol), dl-α-ethyl- which is the raw material compound B3
2.2 g of 4-difluoromethoxybenzylamine (11
mmol) and triethylamine 1.5 g (15 mmol)
1) was dissolved in 10 ml of ethanol and heated under reflux for 3 hours. After the reaction, this reaction mixture was extracted three times with 40 ml of toluene, and the target compound C3 was quantified by gas chromatography internal standard method (as an internal standard substance,
1,2-dichlorobenzene was used. ), the yield is 8
It was 8%.

[Comparative Example] ■Compound C3 was synthesized in the same manner as in ■, except that toluene was used instead of ethanol, and the yield was 40%.

[0051]

[Effect of the invention] According to the present invention, the target aralkylaminopyrimidines can be synthesized in a short time.
and can be obtained in high yield.

[Brief explanation of the drawing]

FIG. 1 is an explanatory diagram showing changes over time in the synthesis reaction of alkylaminopyrimidine in Example 1. In addition,●
−● is the conversion rate (%) of pyrimidine (A) in Example ■
), ○...○ indicates pyrimidine (A) in comparative example ■
The conversion rate (%) is shown.

[Table 1]

[Table 2]

[Table 3]

[Table 4]

[Table 5]

[Table 6]

[Table 7]

[Table 8]

Claims (1)

[Claims] Claim 1: The following formula: [Formula 1] (In the formula, R1 represents a halogen atom, an alkyl group, or a hydrogen atom; R2 represents an alkyl group or a halogen atom; or R1 and R2 are bonded together. may be fused to the pyrimidine ring with the carbon atom of represents a cycloalkyl group, an alkylthio group, or an amino group which may be substituted with an alkyl group; X represents a leaving group) and the pyrimidines represented by the following formula: R5 represents a halogen atom or a hydrogen atom; R6 represents a hydrogen atom, an alkyl group, a halogen atom, an alkoxy group, a haloalkoxy group; n represents 1 or 2; ) is reacted with an aralkylamine represented by the following formula in an alcohol solvent: Synonymous with ).