JP3007258B2 - Synthetic method of benzyl alcohols - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

An object of the present invention is to provide a method for producing a fungicidally active compound for medical use or agriculture and horticulture with higher yield and advantage.

[0002]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel method for producing a novel or known azole compound having excellent bactericidal activity.

[0003]

2. Description of the Related Art Some of the compounds represented by the following general formula (III) are disclosed in JP-A-5-222060 (Japanese Patent Application No.
No. 267234), which are novel compounds described as agricultural and horticultural and medical fungicides.

Some of the compounds represented by the general formula (III) are known compounds described in JP-B-3-45065 as agents for controlling phytopathogenic fungi.

[0005]

In producing the object of the present invention represented by the general formula (III), the compound of the following general formula (I) is used as a starting material and the compound of the following general formula (II) is used. When the usual Grignard reaction, that is, the reaction is carried out in an ether solvent in the absence of a Lewis acid, compound (III) can be obtained only in a low yield.

The inventors of the present invention have conducted various studies on the reactants, solvent, reaction time, reaction temperature and other conditions with respect to the process for producing the target compound of the present invention, and found that the reaction was carried out in the presence of a Lewis acid. The present inventors have found that the desired product can be obtained in a higher yield as compared with known production methods, and completed the present invention.

[0007]

Configuration of the Invention

[0008]

The present invention provides a compound represented by the general formula (I):

[0009]

Embedded image

Wherein A represents N or CH, n is 0,
1, 2 or 3 (when n is 2 or 3, each X
May be different from each other), X is a halogen atom, a phenyl group, an alkyl group having 1 to 6 carbon atoms which may be substituted with 1 to 3 identical or different halogens, or an 1 to 6 identical or different An alkoxy group having 1 to 6 carbon atoms which may be substituted by three halogens (when two alkoxy groups are adjacent to each other, a 5- or 6-membered dioxolano or Which may form a dioxano heterocycle). A compound represented by the general formula (II):

[0011]

Embedded image R ¹ MgZ (II) [wherein, R ¹ is 1 to 6 alkyl groups having a carbon number, cycloalkyl group which may be substituted by an alkyl group having 1 to 3 carbon atoms, 1 to carbon atoms A cycloalkylalkyl group optionally substituted by three alkyl groups or a compound of the formula R ² R ³ R ⁴ Si (C
A group represented by H ₂ ) _m — (wherein R ² is a group having 1 to 4 carbon atoms)
Represents an alkyl group or a phenyl group which may be substituted with the same or different 1 to 3 halogen atoms, R ³ and R ⁴ represent an alkyl group having 1 to 4 carbon atoms, and m represents 1, 2 or 3 is indicated. ) And Z represents a halogen atom. Wherein the compound represented by the general formula (III) is reacted in the presence of a Lewis acid.

[0012]

Embedded image

Wherein A, n, X and R ¹ are as defined above. ] The production method of the compound represented by this.

The "halogen atom" in the above definition of X and Z is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a chlorine atom, a bromine atom or an iodine atom.

The "alkyl group having 1 to 6 carbon atoms" in the above definition of X and R ¹ includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl , N-pentyl, isopentyl,
2-methylbutyl, neopentyl, 1-ethylpropyl, n-
Hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, A straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms such as 1,3-dimethylbutyl, 2,3-dimethylbutyl and 2-ethylbutyl, preferably a straight-chained alkyl group having 1 to 4 carbon atoms. Or a branched alkyl group, more preferably a methyl, ethyl, propyl or butyl group.

In the above definition of X, “an alkyl group having 1 to 6 carbon atoms which may be substituted by 1 to 3 identical or different halogens” refers to the unsubstituted “alkyl group having 1 to 6 carbon atoms”. Other alkyl groups '', for example, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, chloromethyl, bromomethyl, iodomethyl, 2,2,2-trichloroethyl, 2,2,2- Trifluoroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2,2-dibromoethyl, 3-chloropropyl, 3,3,3-trifluoropropyl, 4-fluorobutyl, 5,5,5- Trichloropentyl, 6,
It is a group in which the same or different 1 to 3 halogen atoms are substituted for the “alkyl group having 1 to 6 carbon atoms”, such as 6,6-trifluorohexyl. At this time, the lower alkyl group substituted with the same or different 1 to 3 halogens is preferably a linear or branched alkyl group having 1 to 3 carbon atoms in which the same halogen atom has 1 to 3 halogen atoms. It is a substituted group, more preferably a methyl or ethyl group substituted with 1 to 3 fluorine atoms or chlorine atoms, and most preferably a trifluoromethyl group.

In the above definition of X, “C 1 to C 6”
Examples of the `` alkoxy group '' include, for example, methoxy, ethoxy,
n-propoxy, isopropoxy, n-butoxy, isobutoxy, s-butoxy, t-butoxy, n-pentyloxy, isopentyloxy, 2-methylbutoxy, neopentyloxy, 1-ethylpropoxy, n-hexyloxy, 4 -Methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy , 1,3-dimethylbutoxy,
A linear or branched alkoxy group having 1 to 6 carbon atoms such as 2,3-dimethylbutoxy and 2-ethylbutoxy, preferably a linear or branched alkoxy group having 1 to 4 carbon atoms And more preferably a methoxy or ethoxy group.

In the above definition of X, the term "alkoxy group having 1 to 6 carbon atoms which may be substituted by 1 to 3 identical or different halogens" refers to the unsubstituted "alkoxy group having 1 to 6 carbon atoms". Other alkoxy groups '', for example, trifluoromethoxy, trichloromethoxy, difluoromethoxy, dichloromethoxy, dibromomethoxy, fluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, 2,2,2-trichloroethoxy, 2,2, 2-trifluoroethoxy, 2-bromoethoxy, 2-chloroethoxy,
2-fluoroethoxy, 2,2-dibromoethoxy, 3-chloropropoxy, 3,3,3-trifluoropropoxy, 4-fluorobutoxy, 5,5,5-trichloropentyloxy, 6,6,6-
It is a group in which the same or different 1 to 3 halogen atoms are substituted for the above “C1 to C6 alkoxy group” such as trifluorohexyloxy. At this time, as the lower alkoxy group substituted with the same or different 1 to 3 halogens, preferably, the same halogen atom as the 1 to 3 carbon atoms in the straight or branched chain alkoxy group has 1 to 3 halogen atoms.
It is a substituted group, more preferably a methoxy or ethoxy group substituted with 1 to 3 fluorine atoms or chlorine atoms, and most preferably a trifluoromethoxy group.

The "5- or 6-membered dioxolano or dioxano heterocycle formed by two adjacent alkoxy groups" in the above definition of X is a dioxolane ring or a dioxane ring, preferably a 5-membered dioxolane ring. is there.

"Cycloalkyl group which may be substituted by an alkyl group having 1 to 3 carbon atoms" in the above definition of R ¹
Is, for example, cyclopropyl, 1-methylcyclopropyl, 2-methylcyclopropyl, 2,2-dimethylcyclopropyl, 2,3-methylcyclopropyl, cyclobutyl, 1-methylcyclobutyl, 2-methylcyclobutyl, 3 -Methylcyclobutyl, 1,2-dimethylcyclobutyl, 2,3-dimethylcyclobutyl, 3,3-dimethylcyclobutyl, cyclopentyl, 1-methylcyclopentyl, 2-methylcyclopentyl, 3-methylcyclopentyl, 2,3- Dimethylcyclopentyl, 3,3-dimethylcyclopentyl, 3,4-dimethylcyclopentyl, cyclohexyl, 1-methylcyclohexyl, 2-methylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, 1,3-dimethylcyclohexyl, 2,4- Alkyl having 1 to 3 carbon atoms such as dimethylcyclohexyl and 4,4-dimethylcyclohexyl. A cycloalkyl group of groups 3 to 6-membered ring may be substituted, preferably cyclopropyl, cyclobutyl, cyclopentyl.

The “cycloalkylalkyl group which may be substituted by an alkyl group having 1 to 3 carbon atoms” in the above definition of R ¹ is cyclopropylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl, 1-cyclopropylpropyl, 2-cyclopropylpropyl, 3-cyclopropylpropyl, 1-cyclopropylbutyl, 2-cyclopropylbutyl, 3-cyclopropylbutyl, 4-cyclopropylbutyl, 1-methyl-2-cyclopropyl Such as ethyl, cyclobutylmethyl, 2-cyclobutylmethyl, 3-cyclobutylmethyl, 1-cyclopentylethyl, 2-cyclopentylethyl, 1-cyclohexylethyl, 2-cyclohexylethyl, The “cycloalkyl group which may be substituted by an alkyl group” is described below in “C1 to C4.
And substituted with “alkyl groups”, preferably cyclopropylmethyl, 1-cyclopropylethyl, 1-cyclopentylethyl.

In the above definition of R ² , R ³ and R ⁴ , “alkyl group having 1 to 4 carbon atoms” means methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, preferably methyl, ethyl, t-butyl.

The "phenyl group optionally substituted by 1 to 3 identical or different halogen atoms" in the above definition of R ² includes a phenyl group and, for example, 2-phenyl
Chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-bromophenyl, 2,4-difluorophenyl, 2,
1 such as 6-difluorophenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 2-chloro-4-fluorophenyl, 2,4,6-trifluorophenyl, 2,4,6-trochlorophenyl And phenyl in which arbitrary positions are substituted with one to three of the above “halogen atoms”.

The general formula (I) produced by the method of the present invention
Representative compounds represented by II) include, for example, the compounds described in Table 1 below, but the present invention is not limited to these compounds.

[0025]

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[0026]

[Table 1] 化合物 Compound number A (X) _n R ¹ ( (Example number) ──────────────────────────────────── 1 NH CH ₃ 2 N 4-Cl _{CH 3 3 (14) N 4} -F CH 3 4 (1) N 4-F CH 2 CH 3 5 N 4-Cl CH 2 CH 3 6 N 2,4-F 2 CH 2 CH 3 7 CH 2,4 -Cl ₂ CH ₂ CH ₃ 8 N 2,4-Cl ₂ CH ₂ CH ₃ 9 N 4-F CH ₂ CH ₂ CH ₃ 10 N 4-Cl CH (CH ₃ ) ₂ 11 (7) NH CH ₂ CH ₂ CH ₂ CH ₃ 12 (8) N 4-F CH ₂ CH ₂ CH ₂ CH ₃ 13 N 4-Cl CH ₂ CH ₂ CH ₂ CH ₃ 14 CH 2,4-Cl ₂ CH ₂ CH ₂ CH ₂ CH ₃ 15 (13) N 2,4-Cl ₂ CH ₂ CH ₂ CH ₂ CH ₃ 16 N 2-Cl, 4-F CH ₂ CH ₂ CH ₂ CH ₃ 17 (11) N 4-CH ₃ CH ₂ CH ₂ CH ₂ CH ₃ 18 (12) N 4-OCH ₃ CH ₂ CH ₂ CH ₂ CH ₃ 19 N 4-CF ₃ CH ₂ CH ₂ CH ₂ CH ₃ 20 N 4-OCF ₃ CH ₂ CH ₂ CH ₂ CH ₃ 21 N 4-Ph CH ₂ CH ₂ CH ₂ CH ₃ 22 N 2,4,6 _{-F 3 CH 2 CH 2 CH 2} CH 3 23 N 4-F CH (CH 3) CH 2 CH 3 24 (21) N 4-F C (CH 3) 3 25 N 2,4-F 2 CH 2 CH ₂ CH ₂ CH ₂ CH ₃ 26 N 2,4-Cl ₂ CH (CH ₃ ) CH ₂ CH ₂ CH ₃ 27 NH CH ₂ CH (CH ₃ ) CH ₂ CH ₃ 28 N 4-F CH ₂ CH ₂ CH _{(CH 3) 2 29 (23} N H CH 2 C (CH 3) 3 30 (15) N 4-F CH 2 C (CH 3) 3 31 (17) N 4-Cl CH 2 C (CH 3) 3 32 (16) N 2,4-F 2 CH 2 C (CH 3) 3 33 (18) N 2,4-Cl 2 CH 2 C (CH 3) 3 34 N 2,4,6-F 3 CH 2 _{C (CH 3) 3 35 CH} 4-F CH 2 C (CH 3) 3 36 N 4-F CH 2 CH 2 CH 2 CH 2 CH 3 37 N 4-Cl cyclo-Propyl 38 N 2,4-F 2 1-CH ₃ -cyclo-Propyl 39 (22) N 4-F cyclo-Butyl 40N H cyclo-Pentyl 41 N 4-F cyc _{lo-Hexyl 42 N H CH 2} - (cyclo-Propyl) 43 N H CH (CH 3) - (cyclo-Propyl) 44 N 4-F CH (CH 3) - (cyclo-Propyl) 45 N 4-Cl CH (CH ₃ )-(cyclo-Propyl) 46 N 2,4-F ₂ CH (CH ₃ )-(cyclo-Propyl) 47 CH 2,4-Cl ₂ CH (CH ₃ )-(cyclo-Propyl) 48 N _{2,4-Cl 2 CH (CH 3} ) - (cyclo-Propyl) 49 N 4-CH 2 CH 3 CH (CH 3) - (cyclo-Propyl) 50 N 4-OCH (CH 3) 2 CH (CH 3 ) - (cyclo-Propyl) 51 N 4-CF 2 Cl CH (CH 3) - (cyclo-Propyl) 52 N 4-Ph CH (CH 3) - (cyclo-Propyl) 53 N H CH 2 - (cyclo- Butyl) 54 N 4-F CH _2- (cyclo-Pentyl) 55 N 4-Cl CH (CH ₃ )-(cyclo-Pentyl) 56 N 2,4-F ₂ CH _2- (cyclo-Hexyl) 57 CH H _{CH 2 Si (CH 3) 3} 58 N H CH 2 Si (CH 3) 3 59 CH 4-F CH 2 Si (CH 3) 3 60 N 4-F CH 2 Si (CH 3) 3 (2-6, 9,10,24,25) 61 CH 4-Cl CH ₂ Si (CH ₃ ) ₃ 62 N 4-Cl CH ₂ Si _{(CH 3) 3 63 N 4} -Br CH 2 Si (CH 3) 3 64 N 4-CH 3 CH 2 Si (CH 3) 3 65 N 4-CF 3 CH 2 Si (CH 3) 3 66 N 4- _{OCH 3 CH 2 Si (CH 3} ) 3 67 N 4-OCF 3 CH 2 Si (CH 3) 3 68 N 4-CH 2 CH 3 CH 2 Si (CH 3) 3 69 N 4-CH (CH 3) 2 _{CH 2 Si (CH 3) 3} 70 N 4-Ph CH 2 Si (CH 3) 3 71 N 2,4-F 2 CH 2 Si (CH 3) 3 72 CH 2,4-Cl 2 CH 2 Si (CH _{3) 3 73 N 2,4-Cl} 2 CH 2 Si (CH 3) 3 74 N 2-Cl, 4-F CH 2 Si (CH 3) 3 75 N 2,4,6-F 3 CH 2 Si ( _{CH 3) 3 76 N 2,4,6-} Cl 3 CH 2 Si (CH 3) 3 77 N 4-CH (CH 3) 2 CH 2 Si (CH 3) 2 Ph 78 N 4-F CH 2 Si ( CH ₃ ) ₂ CH ₂ CH ₃ 79 N 4-Cl CH ₂ Si (CH ₂ CH ₃ ) ₂ (p-Cl-Ph) 80 NH CH ₂ CH ₂ Si (CH ₃ ) ₃ 81 N 4-F CH ₂ CH ₂ CH ₂ Si (CH ₃ ) ₃ 82 N 2,4-F ₂ CH ₂ CH ₂ CH ₂ CH ₃ 83 (19) N 4-F CH ₂ CH (CH ₃ ) ₂ 84 (20) N 4-Cl CH ₂ CH (CH ₃ ) ₂ ───────────────────────中 In the table, Ph represents a phenyl group.

As the Lewis acid used in the present invention, any ordinary Lewis acid can be used, but preferably a dry one is preferred. Such Lewis acids include, for example, lithium chloride and lithium bromide. , Lithium iodide,
Lithium perchlorate, magnesium fluoride, magnesium chloride, magnesium bromide, magnesium bromide-diethyl ether complex, magnesium iodide, magnesium perchlorate, boron trifluoride-diethyl ether complex, boron trichloride, boron tribromide , Aluminum chloride, diethylaluminum chloride, ethylaluminum dichloride, chlorotrimethylsilane, trimethylsilyltrifluoromethanesulfonate, t-butyldimethylsilyltrifluoromethanesulfonate, calcium chloride, titanium trichloride, titanium tetrachloride, titanium tetraisopropoxy , Titanium dichloride diisopropoxide, titanocene dichloride, zinc chloride, zinc bromide, zinc iodide, yttrium chloride, zirconocene dichloride, palladium chloride, palladium acetate, sulfur dichloride , Tin (II) trifluoromethane sulfonate, tin tetrachloride, cerium chloride, lanthanum chloride,
Lanthanide trichloride and the like, and more preferably, lithium perchlorate, magnesium chloride, magnesium bromide, magnesium bromide-diethyl ether complex, and magnesium iodide.

The Lewis acid to be used may be a commercially available reagent, or may be synthesized immediately before in a reaction vessel according to a well-known method and used for the reaction without isolation. For example, as such an example, the magnesium bromide-diethyl ether complex may be synthesized from metal magnesium and ethylene dibromide or bromine in an inert solvent containing diethyl ether and used for the reaction without isolation. Can be.

The amount of the Lewis acid used is not particularly limited.
It is preferably 1 to 10 equivalents, more preferably 1 to 3 equivalents.

The amount of the organomagnesium reagent represented by the formula (II) used in the method of the present invention is not particularly limited as long as it is at least stoichiometric with respect to the compound of the formula (I). Is 1 to 10 equivalents, more preferably 1 to 3 equivalents.

The organomagnesium reactant of the formula (II) used in the method of the present invention is usually prepared in an ether solvent or, if necessary, in another ether solvent or a mixed solvent with another solvent.

Examples of the ether-based solvent include diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether and the like, with diethyl ether and diisopropyl ether being preferred.

The process of the present invention is carried out in the above ether solvent used for preparing the organomagnesium reactant of the formula (II) and, if necessary, another ether solvent.
Alternatively, the reaction is performed in a mixed solvent of these and another solvent, preferably performed in a mixed solvent, more preferably a mixed solvent of diethyl ether and toluene or a mixed solvent of diethyl ether and dichloromethane.

The other solvent is not particularly limited as long as it is a solvent inert to the reaction. Examples thereof include hydrocarbons such as hexane, pentane, cyclohexane, benzene and toluene, and halogens such as dichloromethane, dichloroethane and tetrachloroethane. Amides such as fluorinated hydrocarbons, dimethylformamide, dimethylacetamide, hexamethylphosphoramide, and mixtures thereof, and benzene, toluene and dichloromethane are preferred.

In the method of the present invention, the reaction temperature is not particularly limited, but is preferably from -100 ° C to 100 ° C, more preferably from -50 ° C to 60 ° C.

The reaction time mainly depends on the reaction temperature, the starting compound,
Depending on the type of reaction reagent or solvent used,
It is usually from 2 minutes to 24 hours, preferably from 5 minutes to 5 hours.

After the reaction, the compound of formula (II)
The compound of I) can be obtained. When the reaction does not proceed quantitatively, the mixture becomes a mixture with the raw material (I). However, a higher purity (III) can be obtained by ordinary purification methods such as chromatography and recrystallization. Further, since the raw material (I) has high water solubility in an acidic state, (III) can be easily made high in purity by a liquid separation operation. (I) dissolved in the aqueous layer can be recovered in high yield by neutralization with sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate and the like followed by extraction.

The method of the present invention will be described in more detail with reference to Examples and Reference Examples.

[0039]

【Example】

[0040]

Example 1 2- (4-fluorophenyl) -1- (1,2,4-tri
Azol -1-yl) -2-butanol magnesium bromide-diethyl ether complex (526 mg)
Of α- (1,2,4-triazol-1-yl) -4 in an ether-dichloromethane (1: 1, 5 ml) solution.
-A solution of fluoroacetophenone (207 mg) in dichloromethane (10 ml) was added at room temperature, and the mixture was stirred for 20 minutes.
To this was added a 1.8 M solution of ethyl magnesium bromide in ether (1.2 ml) diluted with dichloromethane (3 ml). After the reaction mixture was stirred for 2 hours, the mixture was poured into an aqueous layer and extracted with ethyl acetate. The extract layer was dried and concentrated to obtain a white powder (220 mg). This was purified by silica gel column chromatography to obtain the desired compound (1).
68 mg). Yield 70% MASS (M / z): 235 (M ⁺ ), 206,164,153,149,135,123,115,10
9,95,91,83.NMR (270MHz) δ (CDCl ₃ ) ppm: 0.80 (3H, t, J = 7.6Hz), 1.75
(1H, dt, J = 14.3Hz, J = 7.6Hz), 1.90 (1H, dt, J = 14.3Hz, J = 7.
6Hz), 4.41 (2H, s), 7.00 (2H, dd, J = 8.7Hz, J = 8.7Hz), 7.2
8 (2H, dd, J = 8.7Hz, J = 5.3Hz), 7.84 (1H, s), 7.88 (1H, s).

[0041]

Example 2 2- (4-fluorophenyl) -1- (1,2,4-tri
Azol-1-yl) -3-trimethylsilyl-2-p
Lopanol magnesium bromide-diethyl ether complex (566 m
g) in ether-toluene (1: 1, 5 ml) solution
α- (1,2,4-triazol-1-yl) -4-fluoroacetophenone (220 mg) in toluene (15 m
l) The solution was added at room temperature and stirred for 30 minutes. Here,
An ether solution (1.3 ml) of 1.637M-trimethylsilylmethylmagnesium chloride was dissolved in toluene (13 m
Diluted in 1) and added. After stirring the reaction mixture for 2.5 hours, 3% hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated, and the obtained residue was purified by silica gel column chromatography to obtain the desired compound (138 m
g) was obtained. Yield 44% Melting point 118-119 ° C NMR (270 MHz) δ (CDCl ₃ ) ppm: -0.18 (9H, s), 1.16 (1H, d, J
= 14.5Hz), 1.33 (1H, d, J = 14.5Hz), 4.36 (1H, d, J = 14.0H
z), 4.43 (1H, d, J = 14.0Hz), 6.93-7.01 (2H, m), 7.26-7.3
1 (2H, m), 7.91 (1H, s), 7.99 (1H, s)

[0042]

Example 3 2- (4-fluorophenyl) -1- (1,2,4-tri
Azol-1-yl) -3-trimethylsilyl-2-p
Lopanol (i) ether of magnesium (26.4 g) (30 m
l) Add chloromethyltrimethylsilane (150 m
About 10 ml of a solution of l) in ether (70 ml) was added and the mixture was vigorously stirred. After the reaction was started, the mixture was diluted with ether (100 ml), and the remaining ether solution of chloromethyltrimethylsilane was added dropwise over 3 hours while adding ether (300 ml) in three portions. After dripping 2
After heating under reflux for an hour, the mixture was allowed to stand at room temperature overnight. The obtained trimethylsilylmethylmagnesium chloride was diluted with dichloromethane (400 ml) immediately before use.

(Ii) To a suspension of magnesium (26.5 g) in ether (130 ml) was added about 20 ml of a solution of 1,2-dibromoethane (93 ml) in ether (170 ml) with vigorous stirring. After the start of the reaction, the remaining ether solution of 1,2-dibromoethane was added dropwise over 2 hours while adding ether (about 1.5 liters) so as to maintain a two-layer separation state in the system. After completion of the dropwise addition, the mixture was further stirred for 2 hours, and then dichloromethane (1.5 liter) was added to obtain a solution. To this was added a solution of α- (1,2,4-triazol-1-yl) -4-fluoroacetophenone (100 g) in dichloromethane (600 ml), and the mixture was stirred for 1 hour.

(Iii) An ether-dichloromethane solution of trimethylsilylmagnesium chloride obtained in the above (i) was added to the suspension obtained in the above (ii) at 15-22 ° C. with vigorous stirring, followed by stirring for 1 hour. The reaction mixture was poured into ice water (3 liters), hexane (2 liters),
Dilute hydrochloric acid (600 ml of concentrated hydrochloric acid diluted with 1.4 liter of water) was added, and the mixture was shaken well and then separated. The organic layer (upper layer) was washed twice with 10% hydrochloric acid (1 liter) and then with saturated saline (400 ml). The washing waters were combined and extracted with dichloromethane-hexane (1: 1, 1 liter), and the aqueous layer was further extracted using the organic layer.
The organic layer was washed twice with 10% hydrochloric acid (500 ml) and then with saturated saline (200 ml). The organic layers were combined, dried over anhydrous sodium sulfate and a small amount of water, and concentrated to obtain the desired compound (65 g). Yield 45%.

The aqueous layer and the washing water were neutralized with sodium carbonate, the pH was adjusted to about 8 to 9, and extracted twice with ethyl acetate (1.25 liter). The extract layers were combined, dried over anhydrous sodium sulfate, and concentrated to recover a raw material (53 g).
96% recovery rate

[0046]

Example 4 2- (4-fluorophenyl) -1- (1,2,4-tri
Azol-1-yl) -3-trimethylsilyl-2-p
Lopanol (i) A three-necked flask (10 m) equipped with a Dimroth condenser and a dropping funnel was charged with 237 mg of magnesium and 1 ml of ether.
l) and stirred at room temperature under a stream of nitrogen gas. Here, 1.3 ml of chloromethyltrimethylsilane and ether 3.
3 ml of the mixture was added dropwise and the mixture was stirred until the exotherm stopped and magnesium was almost gone.

(Ii) Magnesium 237 mg and ether 5
ml was placed in a three-necked flask (50 ml) equipped with a Dimroth condenser and a dropping funnel, and stirred at room temperature under a nitrogen gas stream. To this was added dropwise a solution of 0.84 ml of dibromoethane and 5 ml of ether. As the reaction proceeded, ether was distilled off, so ether was added as needed. Stirring was continued until the magnesium was almost gone.

(Iii) From the suspension obtained in the above (ii),
The ether was distilled off under reduced pressure to obtain MgBr ₂ · OEt ₂ white crystals. To this, 3.3 ml of toluene was added and stirred vigorously to form a suspension. Next, 1 g of α- (1,2,4-triazol-1-yl) -4-fluoroacetophenone ground in a mortar
Was added and stirred for 1 hour. To this suspension was added the ether solution of trimethylsilylmagnesium chloride obtained in (i) above, and the mixture was stirred for 3 hours. Thereafter, ethyl acetate and saturated aqueous NH ₄ Cl were added to the reaction system, followed by stirring. The mixture was separated with a separating funnel, and the aqueous layer was further extracted twice with ethyl acetate. The separated ethyl acetate layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1.37 g of a crude product. This was dissolved in toluene and separated with 10% HCl, and the toluene layer was washed with water, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 854 mg (yield: 63%) of the desired product. Neutralize the 10% HCl aqueous layer and extract with ethyl acetate.
After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure, and the raw material α-
370 mg (100% recovery) of (1,2,4-triazol-1-yl) -4-fluoroacetophenone was obtained.

[0049]

Example 5 2- (4-Fluorophenyl) -1- (1,2,4-tri
Azol-1-yl) -3-trimethylsilyl-2-p
Adding about 5ml of a mixed solution of propanol (i) magnesium 3.65g of ether 10ml suspension chloromethyltrimethylsilane ether 18.4 g (15 ml) and toluene (50ml) was stirred vigorously. After the start of the reaction, the remaining solution
The mixture was added dropwise little by little so as not to exceed 0 ° C., and stirring was continued until magnesium was almost dissolved, and the mixture was left at room temperature.

(Ii) Bromine (24 g) was added dropwise to a mixture of magnesium (3.65 g), ether (35 ml) and toluene (35 ml) over 1.5 hours so that the internal temperature did not exceed 27 ° C. . Here, α- (1,2,4-triazol-1-yl) -4-fluoroacetophenone (2
4.6 g), and toluene (20 ml) was further added dropwise.
Stirred at room temperature for 1 hour.

(Iii) The suspension obtained in the above (ii) is cooled to an internal temperature of 10 ° C. or less, and vigorously stirred at 18 ° C. or less at a temperature of 18 ° C. or less in the ether-toluene solution of trimethylsilylmagnesium chloride obtained in the above (i) Was added and stirred for 1 hour. The reaction mixture was cooled to an internal temperature of 20 ° C. or lower, a 20% aqueous NH ₄ Cl solution (200 ml) was added, and the mixture was stirred for 30 minutes. Then, ethyl acetate (200 ml) was added, and the mixture was shaken well with a separating funnel and then separated. The organic layer was washed with a saturated saline solution (200 ml). The organic layer was further separated with 10% HCl (200 ml).
This aqueous layer was neutralized with a 10% aqueous NaOH solution, and ethyl acetate (2%) was added.
00 ml), and the ethyl acetate layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated, and the raw material (9.
15 g) were collected. Recovery rate 67.4%.

The organic layer obtained when the solution was separated with 10% HCl was washed with saturated saline solution (200 ml × 2), dried over anhydrous sodium sulfate and concentrated to obtain the desired product (16.7 g). (Crude yield 47.4%). Add water (150ml)
After heating and stirring at 40 ° C. for 30 minutes, the mixture was allowed to cool, collected by filtration, and dried to obtain the desired product (15.8 g). Yield 44.8%.

[0053]

Example 6 2- (4-fluorophenyl) -1- (1,2,4-tri
Azol-1-yl) -3-trimethylsilyl-2-p
Lopanol (i) A solution of 6.2 ml of chloromethyltrimethylsilane in 20 ml of ether was added dropwise with stirring to a mixture of 1.2 g of magnesium and 5 ml of ether at room temperature under a nitrogen gas stream, and the mixture was stirred until magnesium was almost completely dissolved.

(Ii) 2.4 g of magnesium and 5 of toluene
5 ml of bromine was slowly added dropwise to a mixture of 0 ml and 25 ml of ether while stirring at room temperature under a nitrogen gas stream so that the internal temperature would not rise too much.

(Iii) The suspension obtained in the above (ii) was added with α-
10 g of (1,2,4-triazol-1-yl) -4-fluoroacetophenone were added with vigorous stirring. At this time, the reaction vessel was cooled with a water bath so that the internal temperature did not rise.
After stirring for another 5 minutes, the ether solution of trimethylsilylmagnesium chloride obtained in (i) above was added with stirring. After allowing to stand at room temperature for 2 hours, the reaction solution was treated in the same manner as in Example 4, and 8.57 g (yield: 62%) of the desired product and α-
3.56 g (recovery 93.7%) of (1,2,4-triazol-1-yl) -4-fluoroacetophenone was obtained.

[0056]

Example 24 2- (4-Fluorophenyl) -1- (1,2,4-tri
Azol-1-yl) -3-trimethylsilyl-2-p
Dry THF (15 ml) was added to lopanol anhydrous cerium chloride (999.7 mg) at 0 ° C. with vigorous stirring, and the mixture was added at room temperature to 14 ml.
Stirred for hours. Here, under ice-cooling, a THF solution of 1.07N-trimethylsilylmagnesium chloride (3.8 ml) was added.
Was added and stirred at the same temperature for 4.5 hours. Here, α-
(1,2,4-Triazol-1-yl) -4-fluoroacetophenone (549.3 mg) in THF (10 m
l) The solution was added dropwise and stirred for 1.5 hours. This is 0.1
The mixture was poured into normal hydrochloric acid, and sodium carbonate (about 2 g) was added thereto. The mixture was filtered and washed with ethyl acetate. The organic layer of the filtrate was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, and concentrated to obtain 630 mg of a mixture of a raw material and a target compound. The ratio of the starting material to the target compound was measured by ¹ H-NMR and found to be 66:34 (yield 34%).

[0057]

[Comparative example]

[0058]

Comparative Example 1 2- (4-fluorophenyl) -1- (1,2,4-tri
1.8 M-bromide in a solution of azol-1-yl) -2-butanol α- (1,2,4-triazol-1-yl) -4-fluoroacetophenone (219.8 mg) in tetrahydrofuran (10 ml) at room temperature at room temperature. An ether solution of ethyl magnesium (1.20 ml) was added,
Stir for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried and concentrated, and a white powder (22
3.2 mg). When this was analyzed by NMR,
The target compound, 1- (4-fluorophenyl) -2- (1,
It was a 2: 1: 12 mixture of 2,4-triazol-1-yl) ethanol (reduced form) and raw materials. 13% yield of the target compound.

When this reaction is similarly carried out with an ether solvent, the target compound, 1- (4-fluorophenyl) -2-
It was a 5: 1: 23 mixture of (1,2,4-triazol-1-yl) ethanol (reduced form) and raw materials. 17% yield of the target compound.

[0060]

Comparative Example 2 2- (4-fluorophenyl) -1- (1,2,4-tri
Azol-1-yl) -3-trimethylsilyl-2-p
Lopanol (method according to Method A described in Japanese Patent Application No. 4-267234) Ether of α- (1,2,4-triazol-1-yl) -4-fluoroacetophenone (205 mg) (20 m
l) To the suspension was added an ether solution (10 ml) of 1M trimethylsilylmethylmagnesium chloride at room temperature, and the mixture was stirred for 6 hours. Pour the reaction mixture into aqueous ammonium chloride,
Extracted with ethyl acetate. The extract layer was dried and concentrated, and the obtained residue was purified by silica gel column chromatography to obtain the desired compound (20 mg). Yield 7%.

Examples 1, 2, 3, 4, 5, 6, and 24,
Table 2 shows Examples 7 to 23 and 26 performed according to Example 1, and Example 25 performed according to Example 24.
Table 3 shows Comparative Examples 1 and 2, and Comparative Examples 3 to 17 performed in accordance with Comparative Example 1. The yield in the table is
It shows the value obtained from the isolation yield or the integration ratio of NMR.

[0062]

Embedded image

[0063]

[Table 2]

[0064]

[Table 3] In the table, Et ₂ O indicates diethyl ether, ⁱ Pr ₂ O indicates diisopropyl ether, and THF indicates tetrahydrofuran.

Table 4 shows NMR and MASS spectrum data of each compound of the formula (III) obtained in Table 2.

[0066]

[Table 4]

[0067]

As is apparent from the above Examples and Comparative Examples, according to the present invention, it is possible to provide a method which can produce a compound of the formula (III) in a high yield and advantageously in industrial practice. .

[0068]

Reference Example Hereinafter, the formula (II) produced by the present invention will be described.
The biological effects of the compounds of I) are shown as reference examples.

[0069]

[Reference Example 1] Rice blast control test (therapeutic effect) Rice blast fungus (Pyric) was applied to 4-5 leaf stage rice seedlings (cultivar: Kofu).
conical spore suspension of E. ularia oryzae). After inoculation, place rice seedlings in a room at a temperature of 20-22 ° C and a relative humidity of 100% for 24 hours.
Sprayed at a rate of ml. Subsequently, the rice seedlings were placed in the same room for 6 days to cause disease, and the control efficacy was investigated based on the number of lesions formed on the top two leaves. Table 5 shows the results.

The controlling effect was indicated by the following criteria by observing the degree of disease development of the test plant with the naked eye (the same applies to the following Reference Examples).

5: No onset is observed. 4: Disease onset is 10% or less of the untreated plot (the same applies if no test compound is used). 3: Disease incidence is 10% or more and 30% or less of the untreated area. 2: Disease incidence is 30% or more and 50% or less of the untreated area. 1: Disease incidence is 50% or more and 70% or less of the untreated area. 0: The disease incidence was 70% or more of the untreated plot, and no difference was observed from the untreated plot.

[0072]

[Reference Example 2] Test for controlling rice sheath blight (preventive effect) 100% of test compound was applied to rice seedlings (variety: Nipponbare) at the 4-5 leaf stage.
The ppm solution was sprayed at a rate of 30 ml per 3 pots. Twenty-four hours after spraying the drug solution, rice sheath blight fungus (Rhizoctoniasolani)
Oat kernels cultured with 4-5 seedlings are placed beside the rice seedlings.
The disease was left in a room at 25-27 ° C and 100% relative humidity for 5 days. The control effect was investigated based on the height of the lesion formed on the leaf sheath. Table 5 shows the results.

[0073]

[Reference Example 3] Rice sheath blight control test (therapeutic effect) 4-5 Oat grains previously cultured with rice sheath blight fungus (Rhizoctonia solani) were cultivated in the vicinity of a rice seedling (variety: Nipponbare) at the leaf stage. -Five
Grains were placed and inoculated. After inoculation, the rice seedlings are placed in a room at a temperature of 25-27 ° C and a relative humidity of 100% for 24 hours.
The pm solution was sprayed at a rate of 30 ml per 3 pots. Subsequently, the rice seedlings were placed in the same room for 5 days to cause disease, and the control efficacy was examined based on the height of the lesion formed on the leaf sheath. Table 5 shows the results.

[0074]

[Reference Example 4] Rice sheath blight control test (water surface application) 3-4 leaf stage rice seedlings grown in pots (variety: Nipponbare)
Was maintained in a flooded state at a depth of 1 cm, and the test compound was applied to the pot so that the amount of the active ingredient was 100 g / 10a. After placing the rice seedlings in the glass greenhouse for 7 days,
zoctonia solani)
4-5 pellets were inoculated. After the disease was left in a room at a temperature of 25-27 ° C. and a relative humidity of 100% for 5 days, the controlling effect was examined based on the height of the lesion formed on the leaf sheath. Table 5 shows the results.

[0075]

Reference Example 5 Wheat Rust Control Test (Therapeutic Effect) Spores of wheat leaf rust (Puccinia recondita) were sprinkled on 1.5-leaf stage wheat seedlings (variety: Norin 61) and inoculated.
After inoculation, leave the wheat seedlings in a room at a temperature of 20-22 ° C and a relative humidity of 100% for 24 hours, then transfer them to a glasshouse at 15-20 ° C, and two days later, 3 pots of 3 ppm solution of the test compound 30 per
Sprayed at a rate of ml. Subsequently, the wheat seedlings were placed in a glass greenhouse for 10 days to cause disease, and the control efficacy was investigated based on the area of the lesion formed on the first leaf. Table 5 shows the results.

[0076]

[Reference Example 6] Barley powdery mildew control test (Therapeutic effect) Barley powdery mildew was added to 1-leaf barley seedlings (cultivar: Akagiri).
Hordei (Erysiphe graminis f.sp.hordei) was sprinkled and inoculated. After the inoculation, the barley seedlings are placed in a glass greenhouse at a temperature of 15 to 20 ° C for 24 hours, and 3 ppm of the test compound is added to the solution.
Sprayed at a rate of 30 ml per pot. Subsequently, the barley seedlings were placed in a glass greenhouse for 10 days to cause disease, and the control efficacy was examined based on the area of the lesion formed on the first leaf. Table 5 shows the results.

Note that "-" in the table indicates that the test has not been performed. The compounds used for comparison are as follows.

Comparative compound 1 4- (4-chlorophenyl) -4-hydroxy-5-
(1,2,4-triazol-1-yl) -3-trimethylsilyl-1-pentene {JF. Chollet et al . (Pestic. Sci., 29 , 427-435)
(1990) one optical isomer of compound XX} comparative compound 24- (4-chlorophenyl) -4-hydroxy-5-
(1,2,4-triazol-1-yl) -3-trimethylsilyl-1-pentene {JF. Chollet et al . (Pestic. Sci., 29 , 427-435)
(1990) one optical isomer of compound XX-a diastereomer of comparative compound 1> comparative compound 3 3-tert-butyl-3-hydroxy-4- (1,2,4-
Triazol-1-yl) -1-trimethylsilyl-1
-Pentine {Isomer A of Example 11 of JP-A-61-257975} Comparative compound 4 3- (2,4-dichlorophenyl) -3-hydroxy-
4- (1,2,4-triazol-1-yl) -1-trimethylsilyl-1-butyne {JF. Chollet et al . (Pestic. Sci., 29 , 427-435)
(1990) and the intermediate of Example 4 of GB2224278} Comparative compound 5 4- (4-chlorophenyl) -4-hydroxy-5-
(1,2,4-triazol-1-yl) -1-trimethylsilyl-1-pentene {JF. Chollet et al . (Pestic. Sci., 29 , 427-435)
(1990) Compound XXIII} Comparative compound 6 3- (2,4-dichlorophenyl) -3-hydroxy-
4- (1,2,4-triazol-1-yl) -1-trimethylsilyl-1-butene {Example 4, compound number 13 of GB222278}

[0079]

[Table 5]

Continuation of the front page (51) Int.Cl. ⁷ Identification code FI A01N 43/653 A01N 43/653 C 55/00 55/00 C C07B 61/00 300 C07B 61/00 300 (56) Reference JP-A-250847 (JP, A) JP-A-54-160372 (JP, A) JP-A-56-12372 (JP, A) JP-A-57-81469 (JP, A) (58) Field surveyed (Int. Cl. ⁷ , DB name) CA (STN)

Claims (2)

(57) [Claims] 1. A compound of the general formula (I) Wherein A represents N or CH, and n represents 0, 1, 2, or 3.
(When n is 2 or 3, each X may be different), and X is a halogen atom, a phenyl group, or a carbon number which may be substituted with the same or different 1 to 3 halogens. 1 to 6 alkyl groups or an alkoxy group having 1 to 6 carbon atoms which may be substituted with 1 to 3 same or different halogens (when two alkoxy groups are adjacent to each other, Carbon atoms may form a 5- or 6-membered dioxolano or dioxano heterocycle). And a compound represented by the general formula (II): R ¹ MgZ (II) wherein R ¹ is an alkyl group having 1 to 6 carbon atoms, and an alkyl group having 1 to 3 carbon atoms is substituted. Or a cycloalkyl group which may be substituted by an alkyl group having 1 to 3 carbon atoms, or a group represented by the formula R ² R ³ R ⁴ Si (C
H ₂ ) _m — wherein R ² represents an alkyl group having 1 to 4 carbon atoms or a phenyl group which may be substituted with the same or different 1 to 3 halogen atoms;
R ³ and R ⁴ each represent an alkyl group having 1 to 4 carbon atoms;
m represents 1, 2 or 3. ) And Z represents a halogen atom. In the presence of a Lewis acid
Reacting in a mixed solvent of an ether solvent and another solvent , characterized by the general formula (III): [Wherein, A, n, X and R ¹ have the same meaning as described above. ] The production method of the compound represented by this. 2. A compound of the general formula (I) Wherein A represents N, n represents 1, and X represents a halogen atom. And a compound (CH ₃ ) ₃
SiCH ₂ MgCl is reacted in a mixed solvent of diethyl ether and toluene or dichloromethane in the presence of a magnesium bromide-diethyl ether complex, characterized by the general formula (III): [Wherein, A, n and X have the same meanings as described above, and R ¹ represents (CH ₃ ) ₃ SiCH ₂ . ] The production method of the compound represented by this.