JPS5843957A - Stereoselective manufacture of imidazolyl oxime derivative and derivative thereby - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the chemical formula [wherein M means a carbocyclic monocyclic or bicyclic aromatic group; or variously, and the halogen atoms, alkyl carbon atoms, can be substituted with up to 4 alkyl- or alkoxy groups, S-1 or amino groups; and I! -imidazol-1-yl group (this group is a monomer, an amine, or an alkyl or alkoxy group having 1 to 4 alkyl carbon atoms)
or doubly substituted)].

Concerning a method for the stereoselective production of a corresponding substituted nine ketone represented by the chemical formula (%) with a corresponding imidazole derivative and a do-imidazole amine. Within the scope of the present invention as stated in the specification, the concept of "cis" refers to the above-mentioned chemical formulas (It) and (10
) Defined to mean 0. φ one type (0, mu, 8・
rma IC・, 196B, Bl Tsuru Okvood 4$
,xT:IP OTentative Ru1es
for th@Nom@nclatureof
Organlo Chemistry) uses the formula (It)
The "trans form" defined by K corresponds to a negative isomer when the radical is a substituted 9 or unsubstituted phenyl group, and the "cis form" of formula (C) is a 2-isomer under this condition. −
Corresponds to an isomer.

Imidazolyl-oxime derivatives represented by the chemical formula (1) and imidazolyl-oxime ether derivatives produced therefrom are already known from JP-A-52-102276. The specification states that when 2,4-dichloro7'enacylimidazole is oximeated with hydroxyl ammonium chloride in the presence of pyridine in ethanol, it produces 1-(2,4-dichloro-7'enacylimidazole) with a melting point of 218-220°C. phenyl)-2-(1g-imidazol-1-yl)-
It is stated that ethanone oxime is obtained. No assignment of compounds by stereochemistry was made. "Later, the inventor's analysis revealed that this known oxime was a mixture of 7010 z-oxime and 1-oxime.

However, other studies in this direction have shown that etherification of such oximes, when carried out on a large scale for production purposes,
It has become clear that this is not done stereospecifically. The MMR spectrum of this ether shows that even if purification on a small scale yields sterically pure isomeric ethers, under such conditions a significant amount of each other isomer will always also be present in the desired product. It is clear that it is included in the text.

However, even when producing 1 gram of highly valuable imidazolyl oxime derivatives and imidazolyl oxime ether derivatives, which are generally ranked 9th in terms of their high antifungal activity, in the form of pure stereoisomers or in large quantities, it is possible to obtain 11 KI! It is industrially desirable to produce This means that on the scale of experiment ii,
For example, 4. separation by chromatography; Although it is possible to separate using Ri-a mudgraphy in this way,
From an economic point of view, this is not desirable for industrial production of the effective substance.

Considering that this technology water 11kK leads reliably and reoperably to pure stereoisomers irrespective of the scale of production, for all specific compounds among the imidazolyl oxime derivatives that have been discussed, The object of the present invention is to provide a stereoselective process for the preparation of the imidazolyl oxime derivatives of the formulas (It) and (IQ) mentioned at the outset, which can be applied with good results.

This problem is solved by the present invention; imidazolyl-oxime derivatives of stereoisomers represented by formulas (It) and (RinC) (Mukuro derivatives are valuable substances as they themselves have antisodium and bactericidal effects. In the present invention, cis-oxime and trans-oxime are produced as follows: cis-oxime and trans-oxime are produced by the general formula % (%) (wherein M has the above meaning and Hat represents a halogen To prepare the cis-oxime of formula (10), the ethanone of formula (f) is first converted to imidazole or the corresponding It is reacted with an imidazole derivative to give the corresponding 2-(imidazol-1-yl)-derivative, which is then reacted hot in an alcohol solution with hydroxylamine or a hydroxylamine derivative that liberates hydroxylamine under one reaction condition to form the formula ( 10) In order to convert the cis-oxime shown by formula (It) into a trans-oxime shown by formula (It), the ethanone shown by formula (W) is first treated with hydroxylamine or human gastric cyamine. The resulting hydroxylamine derivative is reacted with the 2-halo-cis-oxime KL of the formula in an alcoholic solution for no more than a negligible second at room temperature, and then with imidazole or a corresponding imidazole derivative and cooled in a neutral solvent. The mixture is then reacted to form trans-O+'/5 represented by the formula (t) by cis-trans rearrangement. This imidazolization of the O2-halo-cis-oxime of the formula (vc), which takes place under a cis-trans transition, is carried out in particular in a non-polar neutral solvent, such as chloroform, at a temperature in the range from 0 to 5 DEG C.

The oximation to cis-oxime is carried out in particular in an alkaline alcoholic solution, especially in the presence of an excess of alkali relative to the 2-(imidazol-1-yl)-monoderivative. The invention is reliably reproducible and can be carried out on an industrial scale for virtually any compound within these classes of oximes. A method for stereoselective preparation of these p-stereoisomers is provided. In that case, in order to produce the cis-oxime represented by the general formula (C), the corresponding 2-/logene ethanone represented by the formula (W) is first imidazolized, and then the next oxyhatching is carried out. On the other hand, in order to produce a shim represented by the general formula (It), 2-hap
Genethanone is first converted into an oxime. Moreover, the formula <Va>
It is converted into oxime to 2-halo cis-shim shown by. This then changes to the trans form by subsequent imidazolization (J.

Amer, Ch@ms, soC, 94, 9274-
77).

The stereoisomeric oximes of the general formulas (t) and (10) show different climadogtastic behavior, clearly different Rr values in the lIK thin-layer chromatogram, and liMR-min. Based on the optical data, both stereoisomeric forms can be assigned 5POK without any doubt.

The method of the present invention is distinguished by its reliability and applicability to all nine classes of compounds defined by chemical formulas. However, in that case, within the class of nine compounds defined by the chemical formula, there are currently 41 heavy l! The compound has a phenyl group in which the group of Formula 1 to V is unsubstituted or mono- or doubly substituted as described above, a halogen atom at 41,
It is a compound in which the functional group is a 9-phenyl group substituted with a chlorine atom, and 1 represents an unsubstituted 1H-imidazol-1-yl group. According to current knowledge, the greatest significance of the method of the present invention is that while the radical of the formula is 4-arylphenyl or 2,4-dichlorophenyl, in all these cases the radical is not present. The point is that such compounds, which are substituted 1H-imidazol-1-yl groups, can be obtained in stereochemically pure form even on a production scale.

Substances of the formula ■ are fungicides and bactericides, which are used in human medicine, veterinary medicine, and in the field of plant protection.
) is also used as an active ingredient in appropriately formulated preparations. However, the scissor substances are used above all as intermediates for the preparation of the corresponding oxime ethers in the respective pure isomeric 2- or 2- or 2- or 2-forms.

Hereinafter, the present invention will be explained in more detail with reference to Examples.

Example 1 Dissolve 500 g of p=/μ rufenacylbaid of 1-(4-coolphenyl)-2-(14 color axis HO' 25.4.9 (0,1 Wool) in 40 methanol.

20,? JF (0,5 ot) Add 0 hydroxylammonium chloride and stir for a short time.
The reaction product is allowed to stand at room temperature for about 14-16 hours and then diluted with water to precipitate the reaction product. Aspirate the precipitate, wash with water,
dry. 20jO already a very pure tk@ product is obtained. Next, this is recrystallized from benzine. Obtained Z
-1-(4-Riprufeel) -2'-Fum ethanone o-meishim forms colorless crystals with a melting point of 104°C.

5JF(o, o2mot) o obtained tL7'j8E1ge -z-oxime, isadazole 4.9 (0,06m
ot) into the supplied solution of chloroform 40111K. At this time, the reaction temperature was maintained in the range between 0°C and 5°C using a water bath. The hapgen-oxime is added to the imidazole solution with constant stirring. After the addition is complete, stir for an additional 5 hours. The precipitate is then suctioned off and washed with water. A crude product of sg is obtained. This is recrystallized with alcohol. Nine stereochemically pure z-1-(4
-chlorophenyl)-2-(IH-imida-1- to-1-
4)-ethanone oximuha forms colorless O crystals with a melting point of 185-186°C.

0,,II,O,Q,O(255,7) 0 Elemental analysis calculated value 54.06 4.28 17. Ji3 15.0
4. Measured value 54,21 4.50 17.22 15.
18 cases 2 Shim 89.2JF 4-cool phenacyl pro 2 do 170
Dissolve @l in chloroform (or methylene chloride) and add dropwise to a solution of Indazole 154j in chloroform (or methylene chloride) 4001111 at 0-5°C.Then continue to stir at this temperature for 4 hours to remove the solvent. Distill it using an evaporator, and partially layer the remaining liquid with water. After drying and drying, 451OP-chlor7enacyl-imidazole or 1-(4-chlorophenyl)-
2-(IH-imidazol-1-yl)'-1-ethanone may be a colorless crystal with a melting point of 158-160<0>C.

111 (0,05mot) and (D!
ol) together with hydroxylammonium chloride in 110-ethanol. Add 10Ii (0,25'mot) of solid hydroxide to this solution with stirring.9
cum was added. Then heated to boiling temperature under reflux for 1 hour. After cooling, the reaction mixture was poured into 175111 [nQHOt water and the oxime precipitated. The crude product thus obtained in almost quantitative yield is recrystallized from alcohol.

in addition! 1l-1-(4-coolphenyl)-2-(1
11-imidazol-1-yl)-ethanone oxime is obtained in the form of colorless crystals with a melting point of 194-195°C.

0,. Elemental analysis calculation value of 11,0D1sO (2s 5.y) 56,06 4.28 1755 15.04
Actual column value 54,22 4. ! %1 17.45 15.
Further compounds are prepared as in Example 12: 1-(2,4-dichlorophenyl)-2-(11
1t//-1-yl)-ethanone oxime (melting point 2
05-206°C) The following compound is further prepared as described in Example 2: Z -1-(2,4-dichlorophenyl)-2-(II
I-imidazol-1-yl)-ethanone oxime (melting point 218-220°C).

Embodiments of the method according to the invention are described below: In the form of a metal oximate, the chemical formula (can have one of the unsubstituted aromatic groups as a substituent directly or via an oxygen atom)
or an alicyclic or monocyclic to tricyclic aromatic O group (substituted by one or more herogen atoms, nitro group or lower alkyl group or alkoxy group) X is a rogen atom]. Ninth, to stereospecifically produce the idendazolyl oxime ether derivative represented by .

Claims (1)

[Scope of Claims] t Chemical formula [In the formula, m means a carbocyclic monocyclic or bicyclic aromatic group, and each aromatic group ta is singly or doubly monocyclic or bicyclic. < can be substituted in a variety of ways, and the carbon atoms of the atom, alkyl, and alkyl can be substituted with up to 4 furkyl- or alkoxy groups, =) a- or hydroxy groups; and Tsuji 1-H-i2dacyl-1-yl group (this group is
halogen, amine or alkyl carbon atom can be substituted singly or doubly with 1 to 4 alkyl or alkoxy groups] Stereoselective imidazolyl oxime derivatives represented by In order to produce cis-oxime and human cis-oxime, the corresponding 2- Starting from asphl-ethanone, the ethanone represented by the Ka formula is first reacted with imidazole or a corresponding imidazole derivative to produce the corresponding 2-(imidazole-1- yl)-derivative, then K
k-dop-xylamine or hydroxyl 7ξ under reaction conditions
The cis-oxime of formula (IC) is produced by hot reaction with a hydroxylamine derivative liberating the hydroxylamine derivative in an alcoholic solution, and the trans-oxime of formula (It) is produced by the following procedure: The ethanone represented by M) is first reacted with hydroxylamine or a hydroxylamine derivative yielding hydroxylamine in an alcoholic solution at no more than an insignificant temperature above room temperature to form the 2-halogen-cis-oxime represented by the formula. First, it is reacted with imidazole or a corresponding imidazole derivative in a neutral solvent in a cold state to cause a cis-trans rearrangement and a reaction with the formula (I
t) A method characterized by forming a trans-oxime of 2. The method according to claim 1, which uses a combination of chloride and dotetraxyl ammonium as the chemical that liberates hydroxylamine by oximation. The oximation of 2-imidazol-1-yl-derivatives of formula (C) in alkanols containing 41 or 2 carbon atoms in methanol, especially in the presence of an alkali metal hydroxide, at RR temperature A process according to claim 1 or 2 for converting the cis-oxime into a cis-oxime represented by O*Vm. 4. A process according to claim 1 or claim 2, in which oximation of 2-halethanone of formula OF) to 2-halosis-oxime of formula (VO) using methanol as a solvent at room temperature. (5) Formulas that occur under cis-trans rearrangement (VC)
The imidazolization of the O2-halocis-oxime is carried out in a non-polar neutral solvent, in particular in chloroform, at a temperature of from 0°C to 5°C.
The method described in section. & 2-iζdashi-1-yl-ethanone derivative is oximedized in the presence of excess alkali to give cis-1x-5 of formula (C), according to any one of claims 1 to 5. Method described. 7, (Z) -1-(2,4-dichlorophenyl)
-2-(lH-imidazol-1-yl)-ethanone oxime. & (Z) -1-(4-chlorophenyl)-2-(
IH-imidacyl-1-yl)-ethanone oxime.