JPS5940387B2 - Method for stereospecifically producing cis-imidazolyl-oxime ether derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the chemical formula (where A means a 4-chlorophenyl group or a 2,4-dichlorophenyl group, and B means a 4-chlorobenzyl group or a 2,4-dichlorophenyl group).
・Means a 4-dichlorobenzyl group, and Im means an unsubstituted 1H-imidazol-1yl group). ether of the chemical formula It relates to a method for stereospecific production by reacting with a substance capable of producing it.

The concept "cis" is defined within the scope of the invention as described in the specification in the meaning of the chemical formula (c) above.

E/Z-method (C.A.Servicecell968, B
lackwOOd etc., IUPACTentativeR
ulesfOrtheNOmenclatureOfO
rganicChemistry), the formula [where A. B
and Im have the same meanings as in formula (Ic)] (wherein A and Im have the above meanings) The trans form corresponds to the E monoisomer and corresponds to the E monoisomer, ) or the "cis form" represented by the formula (in which A and Im have the meanings given above) corresponds to the Z monoisomer under this condition.

Imidazolyl-oxime derivatives of the chemical formula () and imidazolyl-oxime ether derivatives prepared therefrom are already known from JP-A-52102276.

The specification states that when 2,4-dichlorophenacylimidazole is oximeated with hydroxylammonium chloride in the presence of pyridine in ethanol, the rain point is 218.
1-(2,4-dichlorophenyl)-2- at ~220°C
It is stated that (1H-imidazol-1yl)monoethanoneoxyl is obtained. No assignment of compounds by stereochemistry was made. Analysis later carried out by the inventor revealed that this known oxime was 70:30
It was revealed that the compound was a mixture consisting of Z-oxime and E-oxime. However, other studies in this direction have shown that this reaction cannot be reproduced satisfactorily on an industrial scale and, contrary to all expectations, cannot be transferred to similar reactions.

Tests of analogous repurposing and stereospecific synthesis on a technical school scale or on a production scale have yielded mixtures of isomers but not pure isomers. Furthermore, 1-(2.
4-dichlorophenyl)-2-(1H-imidazole-
1-yl) ethanone oxime was etherified with 2,4-dichlorobenzyl chloride in the presence of sodium hydride in DMF at a reaction temperature gradually increased from room temperature to 80 °C as described therein. be done.

Furthermore, in this etherification, stereoisomers of 1-(2,4-dichlorophenyl) that are not stereochemically assigned the same
-2-(1H-imidazol-1-yl)-ethanone oxime-(2,4-dichlorobenzyl)-ether will be obtained. However, other studies in this direction have shown that such etherification of oximes does not occur stereospecifically when carried out on a large scale for production purposes. The NMR spectrum of this ether shows that even if, for example, small-scale purification yields sterically pure isomeric ethers, under such conditions a significant amount of the respective other isomer will always also be present in the desired product. It is obvious that it is contained within. However, it is highly desirable industrially to reliably produce valuable imidazolyl oxime ether derivatives, which are generally valued for their high antifungal activity, both in pure stereoisomeric form and in large quantities.

Although this is possible immediately on a laboratory scale, for example by chromatographic separation, such chromatographic separation is not economical for the industrial production of the active substance. This is not a good way to look at it. In view of this state of the art, it is possible to reliably and reproducibly lead to pure stereoisomers irrespective of the scale of production, yet with identical results for all specific compounds among the topical imidazolyl oxime ether derivatives. The object of the present invention is to provide a stereoselective method for the production of imidazolyl oxime ether derivatives of the formula (c) mentioned at the beginning, which can be applied to accommodate the following.

This problem was solved according to the present invention by suspending or dissolving the oxime derivative represented by the formula () in the form of the cis-stereoisomer in a polar organic solvent at room temperature, and then preparing a metal compound capable of forming a metal oximate at room temperature. and then, after addition of the halogen derivative of the formula () in the solution prepared in this way, carry out the etherification at a temperature not higher than 40°C.

Stereoisomeric imidazolyl oxime derivatives of formula (c), which as such are valuable substances as they exert antifungal and bactericidal action, are prepared as follows: Preparation of cis-oxime For this purpose, starting from the corresponding 2-halogenethanone of the general formula A-CO-CH2-Hal(), where A has the meaning given above and Hal is a halogen atom, then the formula () Ethanone represented by is first reacted with imidazole to form the corresponding 2-(imidazole-1-
formula (c) and then reacted hot in an alcohol solution with hydroxylamine or a hydroxylamine derivative that liberates hydroxylamine under the reaction conditions to obtain the formula (c).
) to form a cis-oxime.

The stereoisomeric oximes of general formulas (t) and (c) show different chromatographic behavior, in particular clearly different RF values in thin layer chromatograms, and NMR spectroscopy. On the basis of analytical data, both stereoisomeric forms can be assigned to each other without any doubt.

Stereoisomeric imidazolyl-oxime ether derivatives of formulas (It) and (e) also show clearly different chromatographic behavior, as well as clearly different RF values, especially in thin layer chromatograms. shows.

The products can in each case be assigned unambiguously to the cis or trans form or to the (E) or (Z) form by means of the NMR spectra. In addition, this assignment can be made especially from the shift of the CH2-proton (δCis>δTrans). In a further development of the invention, in order to prepare the cis monoisomer of formula (Ic), stereospecific etherification is carried out, in particular K
In acetone with OH, in particular KOH is present in slightly less than equimolar amounts, in particular about 5 to 15 m01% less. The stereoisomeric imidazolyl-oxime ether derivatives thus prepared are liberated from the reaction mixture, in particular by precipitation as the nitrate with aqueous nitric acid. The stereoisomerically pure imidazolyl-ethanone oxime derivative of formula (e) required as an intermediate in this case is prepared as described above.

According to current knowledge, the greatest significance of the method of the invention is that
Group A of formula 1c is 4-chlorophenyl- or 2,4-dichlorophenyl group and group B is 4-chlorobenzyl-
or 2,4-dichlorobenzyl group, while in all these cases the group 1m is terminally substituted 1H-imidazole-1
It is possible to obtain compounds having one -yl group in stereochemically pure form even on a production scale. Hereinafter, the present invention will be explained in more detail by giving examples.

Example 1 (Z)-1-(2,4-dichlorophenyl)2-(
1H-imidazol-1-yl)-0(2,4-dichlorobenzyl)monoethanone oxime nitrate 216-218
(Z) of 2064f (7.64m01) showing the melting point in °C
-1-(2,4-dichlorophenyl)-2-(1H-imidazol-1yl)monoethanone oxime in a five-fold amount (1
Suspend in 0.3, e) acetone, stir vigorously, and (
90%) KOH45O7 is added in finely divided form.

At this time, the suspended ethanone oxime is gradually dissolved. After approximately 1 hour, 15547 (7.9m01) was added to the solution.
Add 2,4-dichlorobenzyl chloride little by little. The reaction that takes place is weakly exothermic, so that the reaction mixture warms to 35 to 40°C at most. Stirring is continued for a further 4 hours until the reaction is complete, taking care to ensure that the temperature of the reaction mixture does not rise above 40° C., with gentle cooling if necessary. After the reaction is finished, the reaction mixture is poured into 151 liters of water. The reaction product is then precipitated as a nitrate with 2nf) HNO3 water 61.

A few hours after the nitrate has precipitated, it is filtered off with suction and washed thoroughly with water. The crude nitrate thus separated is then recrystallized from 11.31 g of 94% ethanol. Next, a second recrystallization with three times the amount of ethanol yields 99
．． The desired product with a purity of 95% is obtained in the form of anhydrous crystals. The purity of the product thus obtained is monitored by thermal analysis. The melting point of the obtained crystals is 139.5-140.5℃
It is. Yield is 62.5%. Cl8Hl3Cl4
N3O-HNO3 (elemental analysis of molecular weight 492.17) δ of CH2-proton shift from NMR-spectrum
The values are 5.08 ppm and 5.35 for other isomers.
ppm, 5.34ppm and 5.64ppm
It turns out that m.

This result makes it possible to assign the obtained product to the (Z) form, since a larger proton shift can be expected in this obtained product. Example 2 (E)-1-(2,4-dichlorophenyl)2-(1H
-imidazol-1-yl)-0(2,4-dichlorobenzyl)monoethanoneoxynitrate 277 (0.1m01
) of (E)-1-(2,4 dichlorophenyl)-2-(
1H-imidazol 1-yl) monoethanone oxime
Dissolve in 00ml DMF.

Add 2,47 (0.1 m01) of NaH to this solution,
Stir for 1 hour at room temperature. Then, while stirring, add DMFlOO.
20 V (>0.1 m01) of 2,4-dichlorobenzyl chloride in ml is added dropwise. After 1 hour, the solvent is removed on a rotary evaporator.

The residue is mixed with water by stirring and crystallized with 2N HNO3 water. The crude nitrate thus obtained is filtered off with suction, dried and then recrystallized from alcohol. This gives the pure target product 10.5f in the form of colorless crystals with a melting point of 164 DEG-165 DEG C. Cl8Hl4Cl
In the elemental analysis NMR spectrum of 4N3C-HNO3 (molecular weight 492.17), the δ value of CH2-proton is 5.08.
ppm and 5.35 ppm.

Since these values are smaller than the shift values found for other isomers, these values allow us to assign the isomer prepared in this example 2 to form (E). Example 3 (E)-1-(4-Chlorphenyl)-2-(1H-imidazol-1-yl)-0-(4chlorobenzyl)monoethanone oxime nitrate The method described in Example 2 was repeated in 2.4
- Repeat, changing to use an equivalent amount of p-chlorobenzyl chloride instead of dichlorobenzyl chloride.

When recrystallized from ethanol, the colorless, crystalline reaction product exhibits a melting point of 172°C. Example 4 (Z)-1-(4-Chlorphenyl)-2-(1H-imidazol-1-yl)-0-(4chlorobenzyl)monoethanone oxime nitrate The process described in Example 1 was repeated to prepare 2.4- Repeat, changing to use an equivalent amount of p-chlorobenzyl chloride instead of dichlorobenzyl chloride.

Precipitation with aqueous nitric acid and recrystallization with ethanol gives the pure desired product in the form of colorless crystals with a melting point of 161°C.
Example 5 E-1-(4-chlorophenyl)-2-(1H imidazol-1-yl)-ethanone oxime 23.47 (0.
1 m01) of p-chlorphenacyl bromide for 300 m
Dissolved in 1 methanol, 20.97 (0.3m01)
of hydroxylammonium chloride.

It is then briefly stirred and left at room temperature for approximately 14-16 hours.
Then, upon dilution with water, the reaction product precipitates. The precipitate is collected by absorption filtration, washed with water and dried. 207 already very pure crude products are obtained.

Next, this is recrystallized from benzine. The obtained Z-1-(
4-chlorophenyl)2-promuethanone oxime is
It forms colorless crystals with a melting point of 106°C. 57 (0.0
2 m01) of the obtained halogen-Z oxime was dissolved in 40 m1 of imidazole 47 (0.06 m01) of chloroform.
Add to the solution supplied by.

The reaction temperature is maintained in the range between 0°C and 5°C using an ice bath.
The halogen-oxime is added to the imidazole solution with constant stirring. After the addition is complete, stir for an additional 3 hours.
The precipitate is then filtered off with suction and washed with water. 37 crude products are obtained.

This is recrystallized with alcohol. Stereochemically pure E-1-(4-chlorophenyl) thus prepared
-2-(1H-imidazol-1-yl)ethanone oxime forms colorless crystals with a melting point of 185-186°C. Elemental analysis of CllHlOClN3O (235.7) C
(%) H (%) N (%) CI (%) Calculated value 56,
064.2817.8315.04 Actual value 56.21
4.3017.2215.18 Example 6 Z-1-(4-Chlorphenyl)-2-(1H imidazol-1-yl)monoethanone oxime 89.27 of 4-chlorphenacyl bromide was dissolved in 170 ml of chloroform (or Add dropwise to a solution of imidazole 1567 in chloroform (or methylene chloride) in 600 WLI at 0-5°C.

Stirring is then continued at this temperature for 4 hours, the solvent is distilled off on a rotary evaporator and the residue is treated with water. After suction filtration and drying, 65yf) p-chlorophenacylimidazole or 1-(4-chlorophenyl)-2(1H-imidazol-1-yl)-1-ethanone was dissolved in toluene at 158-160°C. Obtained as colorless crystals with a melting point. 117 (0.05 m01) of the p-chlorfenacyl thus obtained was reduced to 5.27 (0.075 m01).
) with hydroxylammonium chloride 110
Dissolve in ml of ethanol.

107 (0.25 m01) of solid sodium hydroxide was added to this solution while stirring. Then heat to boiling temperature under reflux for 1 hour. After cooling, the reaction mixture is poured into 175 ml of 1nf) HCl water to precipitate the oxime. The crude product obtained in this way in almost quantitative yield is recrystallized from alcohol. Thereby Z-1-(4-chlorophenyl)-2-(1H imidazol-1-yl)
Monoethanone oxime is obtained in the form of colorless crystals with a melting point of 194-195°C. CllHlOClN3O(2
Elemental analysis of 35.7) C (%) H (%) N (%)
Cl (%) calculated value 56.064.2817.8315
．． 04 actual measurement value 56.224.3117.4515.1
The following compound is further prepared as described in Example 2: E-1-(2,4-dichlorophenyl)-2-(1
H-imidazol-1-yl) monoethanone oxime (melting point 205-206°C).

Further compounds are prepared as described in Example 6: Z-1-(2,4-dichlorophenyl)-2-(1H
-imidazol-1-yl) monoethanone oxime (melting point 218-220°C).

Claims (1)

[Claims] 1 Chemical formula ▲ Numerical formula, chemical formula, table, etc. ▼ (Ic) Cis form (in the formula, A means 4-chlorophenyl group or 2,4-dichlorophenyl group, B means 4 -chlorobenzyl group or 2
・4-dichlorobenzyl group, and Im means unsubstituted 1H-imidazol-1-yl group) A cis-imidazolyl-oxime ether derivative represented by the chemical formula ▲ mathematical formula, chemical formula, table, etc. There is ▼(II)(
In the form of its metal oximate, the corresponding substituted oxime derivatives of the formula This is a stereospecific production method by reacting with a substance capable of producing an ether represented by the formula (I).
The oxime derivative represented by I) is suspended or dissolved in a polar organic solvent at room temperature in the cis-stereoisomer ▲ mathematical formula, chemical formula, table, etc. ▼ (IIc) form of the cis form, and then the metal After adding a metal compound capable of producing oximate and then adding a halogen derivative represented by formula (III) to the solution thus prepared, 4
A process characterized in that the etherification is carried out at a temperature not higher than 0°C. 2 Starting from the corresponding 2-haloethanone of the general formula A-CO-CH_2-Hal(IV), where A has the above meaning and Hal is a halogen atom, the haloethanone is first reacted with imidazole. The corresponding 2-(imidazol-1-yl)-derivative is then reacted hot in an alcohol solution with hydroxylamine or a hydroxylamine derivative that liberates hydroxylamine under the reaction conditions to obtain the compound represented by formula (IIc). The cis-oxime thus produced is then suspended or dissolved in a polar organic solvent at room temperature, then a metal compound capable of forming a metal oximate is added at room temperature, and then the cis-oxime thus prepared is 2. The process as claimed in claim 1, wherein after addition of the halogen derivative of formula (III) in solution, the etherification is carried out at a temperature not higher than 40[deg.]C. 3. The method according to claim 1 or 2, wherein KOH is used as the metal compound capable of producing metal oximate. 4 Adding a metal compound capable of producing a metal oximate in an amount that is somewhat less than the equimolar amount, and especially about 5 to 15 mol% less than the equimolar amount, calculated from the oxime derivative represented by formula (IIc). A method according to any one of claims 1 to 3. 5. The method according to any one of claims 1 to 4, wherein the etherification is carried out in acetone as a solvent. 6 The oxime ether derivatives of the formula (Ic) can be prepared with inorganic or organic acids, especially aqueous nitric acid, in the form of acid addition salts which are not dangerous for the intended use of the product in each case. 6. A method according to claim 1, wherein the method is isolated from the reaction mixture by precipitation. 7 (Z)-1-(2,4-dichlorophenyl) shown by the formula ▲Mathematical formulas, chemical formulas, tables, etc.▼
-2-(1H-imidazol-1-yl)-O-(2.
In order to produce (Z)-1-(2,4-dichlorobenzyl)-ethanone oxime (cis-isomer) and its nitrate with the formula ▲mathematical formulas, chemical formulas, tables, etc.▼, Chlorphenyl)-2-(1
H-imidazol-1-yl)-ethanone oxime,
K is suspended in approximately 5 times the amount of acetone calculated from the weight of the oxime, and finely ground as a solid while stirring vigorously.
OH (at most equimolar amounts, especially relatively small amounts up to approximately 15 mol %) is added, stirring until the oxime is completely dissolved; after approximately 1 hour, approximately equimolar amounts of 2 OH are added to the solution in portions. add 4-dichlorobenzyl chloride and then stir for approximately another 4 hours, taking care that the temperature of the reaction mixture does not rise above 40° C., with additional cooling if necessary; The reaction mixture is then poured into water and worked up to give the oxime ether in the usual manner; or the nitrates are precipitated and liberated by adding 2N aqueous HNO_3 to the aqueous reaction mixture and the precipitated nitrates are filtered. 5. A method according to any one of claims 1 to 4, comprising separating and optionally recrystallizing with ethanol.