JPH04360847A - Stereo-specific synthesis of benzyl alcohol compounds - Google Patents

Abstract

PURPOSE:To produce the erythro isomer of a benzyl alcohol compound useful as an antibacterial agent, antibiotic or their intermediate for drugs or agricultural chemicals more preferentially (stereo-selectively) than the threo isomer thereof. CONSTITUTION:A compound of formula I [A is halogen, aryl capable of having one to three substituents (halogen or lover alkyl), 5-6 membered heterocyclic group capable of containing one to three N atoms and zero to two S or O atoms and further having the substituents; R<1> to R<3> are H, halogen, lower alkyl or lower alkoxy which may be substituted with one to three halogen atoms, aryl or aryloxy capable of having one to three substituents (halogen or lower alkyl)] is reacted with a compound of formula II (R<4> is lower alkyl; R<5> is H, lower alkyl; M is MgX, tri-lower alkylsilyl, tri-lower alkyl stannyl; X is halogen) in the presence of a Lewis acid catalyst to preferentially produce the erythro isomer [(2R*, 3S*) isomer] of a compound of formula III among the two diastereoisomers thereof at the 2- and 3-positioned asymmetric carbons of the compound of formula III.

Description

[Detailed description of the invention]

0001

[Purpose of the invention]

0002

[Industrial Application Field] The present invention is an agricultural fungicide or a pharmaceutical antibacterial agent having bactericidal or antibacterial activity.
The present invention also relates to a method for stereoselective synthesis of compounds useful as intermediates for triazole derivatives having bactericidal or antibacterial activity.

[0003] For details, the following general formula (III)

0004
]

[C4]

[In the formula, A is a halogen atom, an aryl group (
The aryl group may be substituted with 1 to 3 halogen atoms or lower alkyl groups. ) or a 5- to 6-membered heterocyclic group (the heterocyclic group contains 1 to 3 nitrogen atoms or 0 or 1 sulfur or oxygen atom, and is substituted with 1 to 3 lower alkyl groups or halogen atoms) ), and R1, R2, and R3 are the same or different from each other and each represents a hydrogen atom, a halogen atom, a lower alkyl group, or a lower alkoxy group (the lower alkyl group or lower alkoxy group may contain 1 to 3 ), an aryl group or an aryloxy group (the aryl group or aryloxy group may be substituted with 1 to 3 halogen atoms or a lower alkyl group).
, R4 represents a lower alkyl group, and R5 represents a hydrogen atom or a lower alkyl group. The present invention relates to a method for preferentially producing the erythro form [(2R*, 3S*) form] of the two diastereomers at the asymmetric carbons at the 2- and 3-positions of the compound represented by the following.

Among the compounds represented by the above general formula (III), for example, the compound of formula (IV)

[0007]

[C5]

[0008] is known as a fungicide for medical, veterinary or agricultural use in Japanese Patent Application Laid-Open No. 60-36468. Accordingly, the present invention provides a method for preferentially producing one diastereomer of a fungicidal compound for medical, veterinary or agricultural use.

[0009]

[Prior Art] Japanese Patent Application Laid-open No. 60-36468 discloses a method for producing the compound of the above formula (IV), which specifically includes the following steps (in the formula, all stereos are relative stereos). (indicates coordination).

0010

[C6]

In step A, crotyl Grignard obtained from crotyl bromide and metallic magnesium is added to the ketone (V) to form chlorohydrin (VIa) and (V
This is the step of obtaining Ib). Step B involves using chlorohydrin (
This is a step of converting VIa) and (VIb) into epoxides (VIIa) and (VIIb) by intramolecular substitution reaction. Step D is epoxide (VIIa) and (VIIb
) by nucleophilic addition of triazole to (IVa)
and (IVb).

[0012] Steps B and D are stereospecific reaction steps, and the stereochemistry of the final target products (IVa) and (IVb) directly reflects the stereochemistry of (VIa) and (VIb), respectively. Therefore, whether either the erythro form (IVa) or the threo form (IVb) of the final target compound is preferentially obtained depends on the stereoselectivity of Step A in the reaction of ketone (V) and crotyl Grignard. Dependent. However, the method disclosed in JP-A-60-36468, that is, the reaction in step A, is stereononselective, and the erythro form (VIa) and the threo form (VIb) are produced in a ratio of approximately 1:1. . Moreover, the above general formula (III
) can also be produced by the same method, but (I
As in the case of V), neither the erythro form nor the threo form can be preferentially obtained.

However, it is well known that triazole derivatives having bactericidal or antibacterial activity have different biological activities depending on their steric configuration. For example, on page 9 of the abstracts of the 8th Medicinal Symposium, there are compounds of the general formula (VIIIa) and (VIIIb) that are thought to have the same activity as the compound represented by the general formula (III).

[0014]

[C7]

[In the formula, X1 represents a fluorine atom or a chlorine atom, and R6 represents an alkylsulfide group, an alkylsulfoxy group, or an alkylsulfonyl group. ], and in this case (VI
The one having the relative stereochemistry represented by IIa) is (V
It is stated that the activity is higher than that of the compound having the relative stereochemistry represented by IIIb). Therefore, the general formula (
Regarding the compound represented by III), it is necessary to selectively produce one of the two diastereomers, erythro form or threo form.
The method disclosed in Japanese Patent No. 36468 could not achieve any of the objectives.

[0016]

[Problem to be solved by the invention] Therefore, the general formula (I
One of the two diastereomers of the compound represented by II), particularly the erythro form [(2R*,3S*) form] having the same stereochemistry as (VIIIa), is used in the present invention.
The purpose is to obtain it preferentially.

[0017]

[Structure of the invention]

[0018]

[Means for Solving the Problems] That is, the present invention has the general formula (I)

[0019]

[Chemical formula 8]

[In the formula, A is a halogen atom, an aryl group (
The aryl group may be substituted with 1 to 3 halogen atoms or lower alkyl groups. ) or a 5- to 6-membered heterocyclic group (the heterocyclic group contains 1 to 3 nitrogen atoms or 0 or 1 sulfur or oxygen atom, and is substituted with 1 to 3 lower alkyl groups or halogen atoms) ), and R1, R2, and R3 are the same or different from each other and each represents a hydrogen atom, a halogen atom, a lower alkyl group, or a lower alkoxy group (the lower alkyl group or lower alkoxy group may contain 1 to 3 ), an aryl group or an aryloxy group (the aryl group or aryloxy group may be substituted with 1 to 3 halogen atoms or a lower alkyl group).
shows. ] and general formula (II)

00
21]

[Chemical formula 9] R4 CH=CHCHR5 M
(II) [In the formula, R4 represents a lower alkyl group, R
5 represents a hydrogen atom or a lower alkyl group, M is MgX
group (X represents a halogen atom), a tri-lower alkylsilyl group, or a tri-lower alkylstannyl group. ] in the presence of a Lewis acid,
General formula (III)

[0022]

[Chemical formula 10]

[In the formula, A is a halogen atom, an aryl group (
The aryl group may be substituted with 1 to 3 halogen atoms or lower alkyl groups. ) or a 5- to 6-membered heterocyclic group (the heterocyclic group contains 1 to 3 nitrogen atoms or 0 or 1 sulfur or oxygen atom, and is substituted with 1 to 3 lower alkyl groups or halogen atoms) ), and R1, R2, and R3 are the same or different from each other and each represents a hydrogen atom, a halogen atom, a lower alkyl group, or a lower alkoxy group (the lower alkyl group or lower alkoxy group may contain 1 to 3 ), an aryl group or an aryloxy group (the aryl group or aryloxy group may be substituted with 1 to 3 halogen atoms or a lower alkyl group).
, R4 represents a lower alkyl group, and R5 represents a hydrogen atom or a lower alkyl group. This is a method for preferentially producing the erythro form [(2R*, 3S*) form] of the two diastereomers at the asymmetric carbons at the 2- and 3-positions of the compound represented by the following.

The "halogen atom" in the definitions of A, R1, R2, R3 and X is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom,
It is a chlorine atom or a bromine atom, and more preferably a chlorine atom.

"Aryl" in the definition of A, R1, R2 and R3 means, for example, phenyl, indenyl,
It is an aromatic hydrocarbon group having 5 to 14 carbon atoms, such as naphthyl, phenanthrenyl, anthracenyl, and preferably a phenyl group.

"Aryloxy" in the definition of R1, R2 and R3 is a group in which an oxygen atom is bonded to the above "aryl".

"5- to 6-membered heterocyclic group" in the definition of A
is a 5- to 6-membered heterocyclic group containing 1 to 3 nitrogen atoms or 0 or 1 sulfur or oxygen atom, such as pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl,
moieties or moieties corresponding to aromatic heterocyclic groups such as pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and aromatic heterocyclic groups such as morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl; A completely reduced type group, preferably a 5- to 6-membered heterocyclic group containing 1 to 3 nitrogen atoms and no oxygen or sulfur atoms, such as pyrrolyl, azepinyl, pyrazolyl, imidazolyl, triazolyl, Partially or fully reduced forms corresponding to aromatic heterocyclic groups such as tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and aromatic heterocyclic groups such as pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl More preferably, it is imidazolyl, triazolyl, and partially or completely reduced groups corresponding to these groups.

A, R1, R2, R3, R4, R
"Lower alkyl" in the definitions of 5 and M means, 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-
Straight chain or branched carbon atoms having 1 to 6 carbon atoms, such as dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl It is a chain alkyl, preferably a straight or branched chain alkyl having 1 to 4 carbon atoms.

"Lower alkoxy" in the definition of R1, R2 and R3 is a group in which an oxygen atom is bonded to the above "lower alkyl".

"Tri-lower alkylsilyl" in the definition of M is a group in which three of the above "lower alkyls" are bonded to silicon atoms, such as trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, t- A group such as butyldimethylsilyl, preferably trimethylsilyl or t-butyldimethylsilyl.

"Tri-lower alkylstannyl" in the definition of M is a group in which three of the above "lower alkyls" are bonded to tin atoms, such as trimethylstannyl and triethylstannyl. These include tripropylstannyl, triisopropylstanyl, tributylstannyl, and triisobutylstannyl, and preferably groups such as trimethylstannyl, triethylstannyl, and tributylstannyl.

The "Lewis acid" used in this reaction refers to all those commonly called Lewis acids, but preferably those that can be dried, such as lithium chloride, lithium bromide,
Magnesium chloride, magnesium bromide-diethyl ether complex, boron trifluoride-diethyl ether complex, boron trichloride, boron tribromide, aluminum chloride, diethylaluminium chloride, chlorotrimethylsilane, trimethylsilyl trifluoromethanesulfonate, t-butyl Dimethylsilyl trifluoromethanesulfonate, titanium tetrachloride, titanium trichloride, titanocene dichloride, zinc chloride, zinc bromide, zinc iodide, yttrium chloride, zirconocene dichloride, tin dichloride, tin tetrachloride, lanthanum chloride, lanthanoid trichloride More preferred are boron trifluoride-diethyl ether complex, titanium tetrachloride, zinc chloride, and zinc bromide.

In the production method of the present invention, the addition reaction of the organometallic compound of formula (II) to the carbonyl group of the compound of formula (I) is carried out in an erythro-selective manner by coexisting a Lewis acid, and Of the two diastereomers of the compound, the erythro form [(2R*,3S*)
body].

[0034] In the present invention, the mark "*" indicates a racemate. In other words, the expression (2R*, 3S*) is (2R*, 3S*).
, 3S) and (2S, 3R), which has the same meaning as (2S*, 3R*). On the other hand, the expression (2R*, 3R*) is (
It means a 1:1 mixture of the isomers 2R, 3R) and (2S, 3S), which has the same meaning as (2S*, 3S*).

As an erythro-selective addition reaction to carbonyl compounds, a method using an organic tin compound in the presence of a Lewis acid is known (Aldrichimica et al.
Acta Vol. 20, No. 2 (1987), Section 45. , Te
trahedron Lett. Volume 25 (1984)
No. 18, Section 1879. ). However, the carbonyl compounds used in these methods are all examples of aldehydes, and it is generally known that when these reaction conditions are applied to ketones, the selectivity of the reaction decreases. In addition, the toxicity of organic tin compounds used as nucleophilic reagents has recently become a problem, and they are expensive.

The present inventors overcame these drawbacks of the above-mentioned reaction and investigated the possibility of erythroselectively synthesizing the compound of general formula (III) more generally, more advantageously, and on an industrial level. . In JP-A-60-36468, a compound of formula (III) is obtained, although non-selectively, by using an organomagnesium reagent, that is, a Grignard reagent, as an organometallic compound for introducing an α-methylallyl group. There is. Literature (Comprehensive O
rganometallicchemistry
According to Vol. 1, p. 173), the Grignard reagent represented by (IIa) is an equilibrium mixture with the Grignard reagent represented by (IIb), and the equilibrium is (II
It is known that 80 to 90% or more is tilted toward a).

[0037]

[Chemical formula 11]

(In the formula, Y represents a halogen atom.) Also, from this form, this Grignard reagent (IIa) reacts at the γ position from the carbon to which magnesium is bonded. From the above findings, it can be seen that the reactivity of allyl Grignards is similar to that of allylstananes and allylsilanes. Therefore, we focused on the fact that a Lewis acid is used in the method using an organotin compound, and investigated carrying out the reaction between the ketone (I) and the Grignard reagent (IIa) in the presence of a Lewis acid.

First, when the reaction between ketone (I) and crotyl Grignard is carried out in the presence of a catalytic amount of Lewis acid, the reaction is completed in a very short time with a high yield, and some erythro selectivity is observed. I understand. As a result of further intensive studies, we found that when a Lewis acid of more than the stoichiometric amount is mixed with the ketone (I) in a solvent, and then crotyl Grignard is added dropwise to the mixture, high erythro selectivity is observed. I found it. And in ketone (I), A is 1
, 2,4-triazol-1-yl group, the selectivity is further improved, and depending on the substituents on the phenyl group, the selectivity is 9:1.
We have found that extremely high erythro selectivity can be achieved. In addition, the ratio of erythro:threo is NM
Determined by integral value of R spectrum and high performance liquid chromatography.

That is, the method of the present invention is disclosed in Japanese Unexamined Patent Application Publication No. 1986-
Compared to the method described in Japanese Patent No. 36468, the reaction time is shortened, the reaction itself proceeds almost quantitatively, and the desired erythro form can be obtained with high selectivity. Using a Grignard reagent that is inexpensive and easily prepared without using expensive allyltins or allylsilanes, the reaction is performed on ketones rather than aldehydes, which tend to exhibit stereoselectivity as carbonyl compounds. Nevertheless, it is a surprising fact that such high erythroselectivity was observed.

The method of the present invention has the advantages of high yield, high selectivity, and short reaction time. In addition, it does not use expensive reactants and the reaction can be easily scaled up, making it economical as an industrial production method. It is also technically advantageous.

[0042] As the Lewis acid used in this reaction, any ordinary Lewis acid can be used, but it is preferable to use one that can be dried. Examples of such Lewis acids include lithium chloride, lithium bromide, magnesium chloride,
Magnesium bromide-diethyl ether complex, boron trifluoride-diethyl ether complex, boron trichloride, boron tribromide, aluminum chloride, diethylaluminum chloride,
Chlorotrimethylsilane, trimethylsilyltrifluoromethanesulfonate, t-butyldimethylsilyltrifluoromethanesulfonate, titanium tetrachloride, titanium trichloride, titanocene dichloride, zinc chloride, zinc bromide, zinc iodide, yttrium chloride, zirconocene dichloride, These include tin dichloride, tin tetrachloride, lanthanum chloride, and lanthanoid trichloride, and more preferably boron trifluoride-diethyl ether complex, titanium tetrachloride, zinc chloride, and zinc bromide.

The amount of Lewis acid used in the method of the present invention is not particularly limited, and may be a catalytic amount, a stoichiometric amount, or a greater than stoichiometric amount. However, even when a catalytic amount is used, a reaction promoting effect and some erythro selectivity are observed, but in order to increase the erythro selectivity, it is desirable to use a stoichiometric amount or more than a stoichiometric amount. The amount is 1 to 10 equivalents, more preferably 2 to 5 equivalents, relative to the compound (I).

The reaction of the present invention is not particularly limited as long as the solvent is inert to the reaction, but suitable solvents include hexane,
Hydrocarbons such as pentane, cyclohexane, benzene, and toluene; halogenated solvents such as dichloromethane, chloroform, dichloroethane, and tetrachloroethane; dioxane, diethyl ether, and tetrahydrofuran (THF).
), ethers such as ethylene glycol dimethyl ether, amides such as dimethylformamide, dimethylacetoacetamide, hexamethylphosphoric acid amide (HMPA), or mixtures thereof; more preferably, M is Mg
In the case of X, it is an ether, and when M is a trialkylsilyl or trialkylstannyl group, it is a halogenated solvent.

The amount of the organometallic compound represented by formula (II) used in the method of the present invention is not particularly limited as long as it is a stoichiometric amount or more with respect to the compound of formula (I), but preferably 1
to 10 equivalents, more preferably 1 to 2 equivalents.

The organometallic compound represented by formula (II) is usually added dropwise as a solution into a mixed solution or suspension of (I) and a Lewis acid. In this case, solvents used for the solution include hydrocarbons such as pentane, hexane, cyclohexane, benzene, and toluene, halogenated solvents such as dichloromethane, chloroform, and tetrachloroethane, dioxane, diethyl ether, tetrahydrofuran (THF), Ethers such as ethylene glycol dimethyl ether or a mixed solvent thereof, M
When M is MgX, it is preferably an ether, and when M is trialkylsilyl or trialkylstannyl, it is preferably a halogenated solvent. There is no particular limitation on the dropping time, but generally speaking, the longer the time, the better the results. Suitable drop times vary depending on the reaction scale, for example from 30 seconds to 5 minutes at a 0.2 mmol scale, and from 30 minutes to 5 hours at a 0.5 to 1 molar scale. Although the reaction time is not limited, the reaction itself is almost complete by the time the organometallic compound of formula (II) is added dropwise. Usually, in order to complete the reaction, stirring is continued for an additional 5 minutes to a day and night, preferably for 5 minutes to 4 hours, after the completion of the dropwise addition of (II).

The reaction temperature is not particularly limited, but it is preferably carried out at room temperature or lower, more preferably from -100°C to 10°C.
It is ℃.

Furthermore, general formula (I) used in the reaction of the present invention
Among the compounds represented by, those in which A is other than a chlorine atom are disclosed in Japanese Patent Publication No. 63-46075 and Japanese Patent Publication No. 63-53.
According to the method disclosed in Japanese Patent No. 90, A is synthesized in one step from a halogen atom.

After the reaction of the present invention, the compound of formula (III) can be obtained by conventional post-treatment. If further purification is required, a product with higher purity can be obtained by conventional purification methods such as chromatography and recrystallization. In addition, A is 1,2,4-triazole-1-
In the case of a basic 5- or 6-membered heterocyclic group such as an yl group, it can be easily separated from other organic impurities by forming it into a salt of various acids. In this case, the acid may be either an inorganic acid or an organic acid, such as hydrochloric acid,
Bromic acid, sulfuric acid, nitric acid, oxalic acid, etc. are used. The purified salt of the compound of formula (III) can be easily converted into purified (III) with a base. The base used is not particularly limited, but inorganic bases such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, etc. are usually used. Furthermore, A is 1, 2, 4
In the case of -triazol-1-yl group, the ratio of erythro form can be improved by recrystallizing with a suitable solvent. The recrystallization solvent is not particularly limited as long as it dissolves the compound of formula (III), but aromatic solvents such as toluene and benzene are preferred.

[0050]

EXAMPLES The method of the present invention will be explained in more detail by way of examples.

Example 1 2-(2,4-difluorophenyl)-3-methyl-1
-(1,2,4-triazol-1-yl)-4
- T of pentene-2-ol zinc chloride (203g)
A suspension of HF (750 ml) was stirred at room temperature for 2 hours, and then α-(1,2,4-triazol-1-yl)-
TH of 2,4-difluoroacetophenone (100g)
A solution of F (250 ml) was added dropwise over 30 minutes. This mixed solution was cooled to -18°C, and crotyl chloride (90%
ml), magnesium (23.5 g), and THF (
A THF solution of crotylmagnesium chloride prepared from 570 ml) was added dropwise over 2 hours, and the mixture was further stirred at the same temperature for 1 hour. Saturated ammonium chloride water (1
L) was added thereto, and 2N hydrochloric acid was added until the insoluble matter was dissolved (pH approximately 3), followed by extraction with ethyl acetate. High performance liquid chromatography (stationary phase:
Analysis using an ODS reverse phase silica gel column, mobile phase: water-methanol system, detection wavelength: 220 nm) revealed that the ratio of erythro form to threo form was 89:11. The extract was dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (eluted with hexane to (ethyl acetate-hexane)) to obtain the target compound (13
4g) was obtained.

[0052] NMR (270MHz) (erythro form)
δ(CDCl3) ppm: 0.84(d,3H,J
= 6.9Hz), 2.79 (dt, 1H, J = 8.8H
z, J = 6.9Hz), 4.48 (d, 1H, J = 14
．． 1Hz), 4.81 (d, 1H, J=14.1Hz)
, 5.19 (dd, 1H, J=1.6Hz, J=10.
1Hz), 5.21(dd, 1H, J=1.6Hz, J
=17.0Hz), 6.06(ddd, 1H, J=8.
8Hz, 10.1Hz, 17.0Hz), 6.73(m
, 2H), 7.37 (m, 1H), 7.77 (s, 1H
), 7.93 (s, 1H). From Example 2 onwards, "J=" in the coupling constant of nuclear magnetic resonance spectra is omitted.

Example 2 2-(4-chlorophenyl)-3-methyl-1-(
1,2,4-triazol-1-yl)-4-penten-2-ol Zinc chloride (203 g) in THF (7
50 ml) The suspension was stirred at room temperature for 2.5 hours, and then α
-(1,2,4-triazol-1-yl)-4-
Chloroacetophenone (106g) in THF (300g)
ml) solution was added dropwise over 45 minutes. This mixture -
Cool to 18°C, and add 3 ml of a THF solution of crotylmagnesium chloride prepared from crotyl chloride (95 ml), magnesium (24 g), and THF (570 ml).
The mixture was added dropwise over a period of time, and the mixture was further stirred at the same temperature for 2 hours. Saturated ammonium chloride water (1 L) was added to the reaction mixture, and 2N hydrochloric acid was added until insoluble matter was dissolved (pH approximately 3), followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain pale yellow crystals. The crystals were dissolved in ether (1.5 L), and concentrated nitric acid (100 m
A solution of 1) in ether (500 ml) was added over 20 minutes and stirred for 2 hours. The white powder that crystallized was collected by filtration and washed with ether. The obtained white powder was mixed with water (1.5 L
), sodium carbonate was added thereto, and the mixture was extracted with ethyl acetate. Finally, a two-layer solution was obtained, and sodium carbonate was added until the aqueous layer became alkaline (pH approximately 10) for extraction. When a very small portion of the extracted layer was analyzed by high performance liquid chromatography (analysis conditions were the same as in Example 1), the ratio of erythro form to threo form was 70:30. The extracted layer was dried over anhydrous sodium sulfate and concentrated to obtain the target compound as white crystals (103 g). This white crystal was recrystallized from toluene to obtain a white crystal (82 g) in which the ratio of erythro isomer to threo isomer was 89:11. When the reconsolidation mother liquor is concentrated, the ratio of erythro bodies and threo bodies is 43:5.
White crystals (18 g) of No. 7 were obtained.

[0054] NMR (270MHz) (erythro form)
δ(CDCl3) ppm: 0.85(d,3H
, J=6.9Hz), 2.58(dt, 1H, 8.9H
z, 6.9Hz), 4.42(d, 1H, 14.1Hz
), 4.54(d, 1H, 14.1Hz), 5.19(
dd, 1H, 1.6Hz, 9.8Hz), 5.20(d
d, 1H, 1.6Hz, 15.7Hz), 6.01(d
dd, 1H, 8.9Hz, 9.8Hz, 15.7Hz)
, 7.20 (d, 2H, 9.3Hz), 7.22 (d,
2H, 9.3Hz), 7.74 (s, 1H), 7.79
(s, 1H). (threo body) (270MHz), δ (CDCl3)
ppm: 1.04 (d, 3H, 6.9Hz), 2.
65 (dt, 1H, 8.5Hz, 6.9Hz), 4.5
2 (d, 1H, 14.1Hz), 4.65 (d, 1H,
14.1Hz), 5.06(d, 1H, 15.9Hz)
, 5.09 (d, 1H, 10.4Hz), 5.59 (d
dd, 1H, 8.5Hz, 10.4Hz, 15.9Hz
), 7.24 (s, 4H), 7.81 (s, 1H), 7
．． 86 (s, 1H). Example 3 1-chloro-2-(2,4-difluorophenyl)-3-
Methyl-4-penten-2-ol α-chloro-2,4-difluoroacetophenone (61
．． 7 mg) and zinc chloride (240.9 mg) in THF (
0.944 normal crotylmagnesium chloride in THF solution (0.52 ml) at -78°C.
was added dropwise over 30 seconds. The reaction mixture was treated with saturated ammonium water and extracted with ethyl acetate. After concentrating the organic layer, the target compound was obtained. When this was analyzed by high performance liquid chromatography (analysis conditions were the same as in Example 1), the ratio of erythro form to threo form was 77:22.

[0055] NMR (270MHz) (erythro body,
mixture of threoisomers) δ (CDCl3) ppm: 0.
84 (d, 5.8Hz), 1.09 (d, 6.9Hz)
,2.61(brs),2.67(brs),2.76
(brm), 3.91 (dd, 1.2Hz, 11.3H
z), 3.94 (dd, 1.2Hz, 11.3Hz),
4.27 (d, 11.3Hz), 4.30 (d, 11.
3Hz), 4.92 (brd, 11.7Hz), 4.9
4 (brd, 16.1Hz), 5.11 (m), 5.1
6 (m), 5.55-5.69 (m), 5.85-6.
01 (m), 6.73-6.95 (m), 7.48-7
．． 52 (m). Example 4 2-(4-methoxyphenyl)-3-methyl-1-
(1,2,4-triazol-1-yl-4-penten-2-olzinc chloride (4.56 g) and α-(
1,2,4-triazol-1-yl)-4-methoxyacetophenone (2.17 g) in THF (40
A THF solution (17.1 ml) of 0.89N crotylmagnesium chloride was added dropwise to the suspension at -15°C over 45 minutes, and the mixture was stirred at the same temperature for 45 minutes. Water was poured into the reaction mixture, the pH was adjusted to about 3 with 2N hydrochloric acid, and the mixture was extracted with ethyl acetate. When a portion of the extract was taken and NMR was measured, the ratio of erythro form and threo form was 86:24. The extracted layer was dried over anhydrous magnesium sulfate and then concentrated to obtain the target compound as a pale yellow viscous liquid (2.86 g). This was purified by silica gel column chromatography (eluted with ethyl acetate-hexane) to obtain the erythro form (2.0 g).
, threo form (88 mg) and mixture of both isomers (73
1 mg) were obtained as pale yellow viscous liquids. NMR (270MHz), (erythro form) δ (CD
Cl3) ppm: 0.87 (d, 3H, 6.9Hz
), 2.59 (dq, 1H, 9.3Hz, 6.9Hz)
, 3.75 (s, 3H), 4.39 (d, 1H, 13.
9Hz), 4.54 (d, 1H, 13.9Hz), 5.
17 (dd, 1H, 1.6Hz, 9.3Hz), 5.1
9 (dd, 1H, 1.6Hz, 16.5Hz), 6.0
3(ddd, 1H, 9.3Hz, 9.3Hz, 16.5
Hz), 6.78 (d, 2H, 8.9Hz), 7.15
(d, 2H, 8.9Hz), 7.62 (s, 1H), 7
．． 79 (s, 1H). (270MHz), (threo body) δ (CDCl3) ppm: 1.05 (d, 3H,
6.9Hz), 2.65 (brq, 1H, 6.9Hz)
, 3.76 (s, 3H), 4.50 (d, 1H, 14.
1Hz), 4.63 (d, 1H, 14.1Hz), 5.
06 (d, 1H, 18.5Hz), 5.08 (d, 1H
, 10.1Hz), 5.62(ddd, 1H, 8.1H
z, 10.1Hz, 18.5Hz), 6.79(d, 2
H, 8.7Hz), 7.20 (d, 2H, 8.7Hz)
, 7.80 (s, 2H). According to the method of Examples 3 and 4, an example of the reaction represented by the following formula is shown in Table 1 below.

In Table 1, Triz represents a 1,2,4-triazolyl group, Imid represents an imidazolyl group, THF
represents tetrahydrofuran, Et2O represents diethyl ether, and HMPA represents hexamethylphosphoric triamide.

[0057]

[Table 1]

[0058]

[Chemical formula 12]

──────────────────────────
────────────Example number A Ar
Lewis acid Reaction temperature Solvent Erythro:Threo ──────────
──────────────────────────
─ 5 Triz 2,4-F2-Ph
ZnBr2 -78℃
THF 76:24 6
Triz 2,4-F2-Ph T
iCl4 -78℃ THF
67:33 7 Triz 2,4-
F2-Ph BF3・OEt2 -7
8℃ THF 71:29
8 Triz 2,4-F2-Ph
ZnCl2 -78 ~ 0℃ Et2
O 83:17 9 Triz
2,4-F2-Ph ZnCl2
-78℃ THF-HMPA 76:24
10 Imid 2,4-F2-Ph
ZnCl2 -78℃
THF 71:29 11 Tri
z Ph ZnCl
2 -78℃ THF 85
:15 12 Triz 4-F-Ph
ZnCl2 -78℃
THF 89:11 13
Triz 2-Cl-Ph Z
nCl2 -78℃ THF
68:32 14 Triz 4-Br-
Ph ZnCl2-78
°C THF 75:25 15
Triz 4-CH3-Ph
ZnCl2 -78℃ THF
79:21 16 Triz 4-
iPr-Ph ZnCl2
-78℃ THF 81:19
17 Triz 4-CF3-Ph
ZnCl2 -78℃T
HF 78:22 18 Triz
4-OCF3-Ph ZnCl2
-78℃ THF 80:2
0 19 Triz 2-Cl,4-F-P
h ZnCl2 -78℃
THF 62:38 20Tr
iz 4-Cl,2-F-Ph ZnC
l2 -78℃ THF 8
4:16 21 Triz 2-Cl,6-
F-Ph ZnCl2 -78℃
THF 72:28 22
Triz 3-Cl,4-Cl-Ph
ZnCl2 -78℃ THF
76:24 23 Triz 3,5-
Cl2,4-CH3-Ph ZnCl2 -7
8℃ THF 79:21 24
Triz 2,4-Cl2,3-CH3-P
h ZnCl2 -78℃ THF
67:33 Reference example 1 Cl 2,4
-F2-Ph-
0℃ THF 51:49────
──────────────────────────
─────── In Table 1, Reference Example 1 is
This was carried out by a method similar to the method described in Japanese Patent Publication No.-36468.

Table 2 shows NMR spectrum data for each compound in Table 1.

[0061]

[Table 2]

[0062]

[Reference example]

Regarding the determination of steric coordination, the steric coordination was determined by converting the compound of Example 1 into an oxetane derivative.
IX and X, NOE by X-ray crystallography and NMR
This was confirmed by measuring. Regarding the other Examples, the steric properties could be easily confirmed by comparing the NMR spectra with Example 1.

a) (2R*,3S*)-2-(2,
4-dichlorophenyl)-4,5-epoxy-3-methyl-1-(1,2,4-triazol-1-yl)
-2-Pentanol obtained in Example 1 (2R*,3
S*)-2-(2,4-difluorophenyl)-3-methyl-1-(1,2,4-triazol-1-yl)
80% metachloroperbenzoic acid (1,360 mg) was added to a solution of -4-penten-2-ol (960 mg) in dichloromethane (30 ml) at 0°C for 5 minutes, and the mixture was further stirred at room temperature for 12 hours. The reaction solution was diluted with ethyl acetate and washed successively with an aqueous sodium sulfite solution, an aqueous sodium bicarbonate solution, and a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The resulting residue was subjected to silica gel column chromatography (eluted with hexane to ethyl acetate).
This was purified to obtain a low polar isomer (320 mg) and a high polar isomer (206 mg) of the target compound.

NMR spectrum of low polar isomer (90M
Hz), (CDCl3)δppm: 0.82(d
, 3H, 7.3Hz), 1.74(quint, 1H,
7.3Hz), 2.54(dd, 1H, 4.4Hz),
3.3-3.4 (m, 1H), 6.6-6.8 (m, 2
H), 7.3-7.5 (m, 1H), 7.79 (s, 1
H), 7.80 (s, 1H). NMR spectrum of highly polar isomer (90MHz), (
CDCl3) δppm: 0.94 (d, 3H, 6.
9Hz), 1.86 (quint, 1H, 6.9Hz)
, 2.74 (dd, 1H, 4.8Hz, 2.8Hz),
2.95 (t, 1H, 4.8Hz), 4.80 (d, 2
H, 13.7Hz), 4.92(s, 1H), 7.6-
7.8 (m, 2H). .

b) (2R*, 3S*, 4S*)-
2-(2,4-difluorophenyl)-3-methyl-1
-(1,2,4-triazol-1-yl)-2,4
-low polar isomer obtained with pentanediol a) (320 m
Lithium aluminum hydride (84 mg) was added to a solution of g) in ether (20 ml) under ice cooling, and the mixture was refluxed for 1 hour. After cooling on ice again, water (2 ml) was slowly added and stirred for 10 minutes. After filtration through Celite, the mixture was extracted with ethyl acetate. It was dried over anhydrous magnesium sulfate and then concentrated. The obtained residue was purified by silica gel column chromatography (eluted with ethyl acetate-chloroform-hexane) to obtain the target compound (240 mg).

NMR (90MHz), δ(CDCl3
) ppm: 0.80 (dd, 3H, 6.9Hz, 3
．． 0Hz), 2.00(dq, 1H, 6.9Hz, 1.
6Hz), 3.86(dd, 1H, 6.9Hz, 1.6
Hz), 4.62 (d, 1H, 14.0Hz), 4.9
3 (s, 2H), 6.7-6.9 (m, 2H), 7.5
0(dt, 1H, 8.9Hz, 6.5Hz) 7.82(
s, 1H), 8.13 (s, 1H). .

c) (2R*, 3S*, 4S*)-2
-(2,4-difluorophenyl)-4-(methanesulfonyloxy)-3-methyl-1-(1,2,4-triazol-1-yl)-2-pentanol b) obtained with *,3S*,4S*)-2-(2,4-difluorophenyl)-3-methyl-1-(1,2,4-triazol-1-yl)-2,4-pentanediol (213 mg) Methanesulfonyl chloride (140 mg) was added to a pyridine (4 ml) solution at 0°C, and the mixture was stirred for 2.5 hours. After the reaction was completed, pyridine was distilled off under reduced pressure, a dilute aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extracted layer was dried over anhydrous magnesium sulfate and then concentrated to obtain the target compound (270 mg).

NMR (90MHz), δ(CDCl3
) ppm: 0.79 (dd, 3H, 6.5Hz, 0
．． 8Hz), 1.49 (d, 3H, 6.5Hz), 2.
6-2.8 (m, 1H), 3.08 (s, 3H), 4.
85 (d, 2H, 13.9Hz), 5.3-5.4 (m
, 1H), 6.6-6.8 (m, 2H), 7.2-7.
4 (m, 1H), 7.76 (s, 1H), 7.81 (s
, 1H). .

d) (2R*, 3S*, 4R*)-
2-(2,4-difluorophenyl)-3,4-dimethyl-2-[(1,2,4-triazol-1-yl)
methyl] Oxetane (IX)c) obtained with (2R*
,2S*,4S*)-2-(2,4-difluorophenyl)-4-(methanesulfonyloxy)-3-methyl-1-(1,2,4-triazol-1-yl)-
2-pentanol (389 mg) in methanol (10 m
l) A 15% aqueous solution of sodium methyl mercaptan (309 mg) was added to the solution, and the mixture was stirred at room temperature for 12 hours. The reaction solution was poured into ice-cold water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The obtained residue was subjected to silica gel column chromatography (hexane to
(Elution with ethyl acetate-hexane)) to obtain the target compound (143 mg).

MASS (m/z): 279 (M+),
246, 231, 224, 213, 197, 182, 1
67,149,141,127,113,101,83
．． NMR (90MHz), δ(CDCl3)ppm
:0.83 (brd, 3H, 7.2Hz), 1.18
(d, 3H, 7.0Hz), 3.18 (quint, 1
H, 7Hz), 4.50 (d, 1H, 14.5Hz),
4.58 (quint, 1H, 7.0Hz), 4.94
(d, 1H, 14.5Hz), 6.8-6.9 (m, 2
H), 7.4-7.5 (m, 1H), 7.87 (s, 1
H), 8.24 (s, 1H). e) (2R*, 3S*, 4S*)-2-(2,4
-difluorophenyl)-3,4-dimethyl-2-[(1
,2,4-triazol-1-yl) methyl]
(2R*,3S*)-2-(2,4-dichlorophenyl)-4,5-epoxy-3-methyl-1 obtained with oxetane (X) a)
The highly polar isomer of -(1,2,4-triazol-1-yl)-2-pentanol was reacted in the same manner as in b) to d) to obtain the target compound.

MASS (m/z): 279 (M+),
270, 256, 234, 224, 197, 179, 1
65, 151, 142, 127, 113, 101, 82
．． NMR (90MHz), δ(CDCl3)ppm
:0.86 (dd, 1H, 7.0Hz, 2.5Hz)
, 1.11 (d, 3H, 7Hz), 2.73 (quin
t, 1H, 7Hz), 4.23(quint, 1H, 7
．． 0Hz), 4.42(d, 1H, 14.5Hz), 4
．． 81 (d, 1H, 14.5Hz), 6.8-7.0 (
m, 2H), 7.5-7.7 (m, 1H), 7.93 (
s, 1H), 8.28 (s, 1H). .

The steric configurations of (IX) and (X) were determined by measuring NOE (nuclear Overhauser effect).

[0073]

[Chemical formula 13]

[0074] Regarding (X), X-ray crystal analysis was also carried out and this stericity was confirmed.

[0075]

[Chemical formula 14]

[0076]

[Effects] As is clear from the above examples, according to the present invention, it is possible to provide a process for producing the erythro form of compound (III) which is advantageous for industrial implementation.

Claims (1)

[Claims] Claims 1: General formula (I) [In the formula, A is a halogen atom or an aryl group (the aryl group may be substituted with 1 to 3 halogen atoms or a lower alkyl group); ) or a 5- to 6-membered heterocyclic group (the heterocyclic group contains 1 to 3 nitrogen atoms or 0 or 1 sulfur or oxygen atom, and is substituted with 1 to 3 lower alkyl groups or halogen atoms) ), and R1, R2, and R3 are the same or different from each other and each represents a hydrogen atom, a halogen atom, a lower alkyl group, or a lower alkoxy group (the lower alkyl group or lower alkoxy group may contain 1 to 3 (may be substituted with a halogen atom)
, an aryl group or an aryloxy group (the aryl group or aryloxy group may be substituted with 1 to 3 halogen atoms or a lower alkyl group). ] and the general formula (II) [Chemical formula 2] R4 CH=CHCHR5 M (
II) [In the formula, R4 represents a lower alkyl group, R5 represents a hydrogen atom or a lower alkyl group, and M represents a MgX group (X
indicates a halogen atom. ), represents a tri-lower alkylsilyl group or a tri-lower alkylstannyl group. ] in the presence of a Lewis acid to form a compound of the general formula (III) [wherein A is a halogen atom, an aryl group (the aryl group has 1 to 3 halogen atoms or ) or a 5- to 6-membered heterocyclic group (the heterocyclic group contains 1 to 3 nitrogen atoms or 0 or 1 sulfur atom or oxygen atom; (optionally substituted with 3 lower alkyl groups or halogen atoms), and R1, R2, and R3 are the same or different from each other and each represents a hydrogen atom, a halogen atom, a lower alkyl group, or a lower alkoxy group (the lower alkyl group or lower alkoxy group may be substituted with 1 to 3 halogen atoms)
, represents an aryl group or an aryloxy group (the aryl group or aryloxy group may be substituted with 1 to 3 halogen atoms or a lower alkyl group), and R4
represents a lower alkyl group, and R5 represents a hydrogen atom or a lower alkyl group. ] The 2nd and 3rd positions of the compound represented by
A method for preferentially producing an erythro form [(2R*, 3S*) form] of two diastereomers at an asymmetric carbon position.