DE2954650C2 - 2-Aryl-2-hydroxyethyl-imidazole and -triazole derivs. prepn. - Google Patents

Abstract

Prepn. of imidazole or triazole derivs. of formula (I) is carried out by reacting an oxirane of formula (II) with an azole of formula Az-H (III) in the presence of an alkali metal alcoholate and a diluent: (where Az is an imidazolyl or triazolyl gp.; R is opt.substd. phenyl, naphthyl or tetrahydronaphthyl; R1 is H, halogen, alkyl, alkoxy, haloalkyl, opt. substd. phenyl or cycloalkyl and R2 is H, or R1 and R2 in adjacent positions form an opt. substd.polymethylene bridge or complete a naphthyl or opt. substd. fluorenyl gp.; R3 is halogen, alkyl, alkoxy or haloalkyl; n = 0-3). Oxiranes of formula (II), except when R1 is H, halogen, alkyl, alkoxy or haloalkyl, are new.(I) have antimycotic activity (see DT 2623129, 2851143 and 2851116).The process gives higher yields (e.g. >=80%) than the process of DT 2623129

Description

The present invention relates to new oxiranes, which as Intermediates for the production of hydroxyethyl azoles serve with antifungal properties.

Oxiranes are already known from DE-OS 24 08 658.

Now there were new oxiranes of the formula

in which
R represents phenyl, which is optionally mono- or disubstituted by chlorine, fluorine or methyl, represents naphthyl and tetrahydronaphthyl;
R¹ is fluorine, methyl, ethyl, ethoxy, furthermore phenyl, cyclopentyl or cyclohexyl, which can optionally be mono- or disubstituted by chlorine, bromine, fluorine, nitro, methyl or methoxy;
R² represents hydrogen or
R¹ and R² together are in the ortho position to each other for a tri, tetra or pentamethylene bridge, which are optionally substituted by chlorine or methyl, or together with the phenyl ring to which they are attached, for naphthyl or optionally substituted by chlorine or methyl Stand fluorenyl;
R³ represents fluorine or methyl and
n stands for 0 and 1,
found.

The oxiranes of formula (I) are obtained by corresponding ketones of the formula

in which
R, R¹, R², R³ and n have the meaning given above,

• α) with dimethyloxosulfonium methylide of the formula in a manner known per se in the presence of a diluent, such as, for example, dimethyl sulfoxide, at temperatures between 20 and 80 ° C (see also the information in JACS 87, 1353-1364 [1965]) or
• β) with trimethylsulfonium methyl sulfate of the formula in a manner known per se in the presence of a two-phase system and, if appropriate, in the presence of a phase transfer catalyst at temperatures between 0 and 100 ° C (see also the information in Heterocycles 8, 397 [1977]).

The ketones of the formula (II) are generally known Organic Chemistry Compounds.  

The dimethyloxosulfonium methylide of formula (III) is also known and used in situ by Trimethyloxosulfonium iodide with sodium hydride (see also the above-mentioned literature reference).

The trimethyl sulfonium methyl sulfate is also known and is used in situ by using dimethyl sulfide Dimethyl sulfate converts (see also the above-mentioned literature reference).

Examples of the oxiranes of the formula (I) are:

The oxiranes are suitable as intermediates for the production of partially known hydroxyethyl azoles general formula

in which
R¹, R², R³ and n have the meaning given above
and
Az represents imidazolyl-1-yl- or 1,2,4-triazol-1-yl.

This gives hydroxyethyl azoles of the formula (V), if to get oxiranes of the formula

in which
R, R¹, R², R³ and
n have the meaning given above,
with azoles of the formula

H-Az (VI)

in which
Az has the meaning given above,
in the presence of an alkali alcoholate and in the presence of a diluent.

If, for example, 2- (4-biphenylyl) -2- (2-chlorophenyl) oxirane is used, Imidazole and sodium methylate as Starting materials, the course of the reaction can be the following formula scheme is shown:

The reaction to the production of hydroxyethyl azoles of the formula (V) is in the presence of an alkali alcoholate carried out. These preferably include the methylates and ethylates of sodium and potassium.

For the implementation for the production of hydroxyethylazoles of the formula (V) come as a diluent preferably inert organic solvents. These preferably include nitriles, such as in particular Acetonitrile; aromatic hydrocarbons, such as benzene, Toluene and dichlorobenzene; Formamides, such as in particular Dimethylformamide; halogenated hydrocarbons, such as Methylene chloride or carbon tetrachloride; such as Hexamethylphosphoric triamide.  

The reaction temperatures can be carried out of the process for the preparation of hydroxyethyl azoles of the formula (V) varied over a wide range will. Generally one works between about 30 to 150 ° C, preferably between 30 ° C and 100 ° C.

When carrying out the process for producing Hydroxyethyl azoles of the formula (V) are set at 1 mol Oxirane of formula (I) preferably 1 to 3 mol of azole Formula (VI) and 1 to 2 mol of alkali alcoholate. The The end products are generally isolated Wise.

In a preferred embodiment, the according Process (α) and (β) obtained oxiranes of formula (I) directly implemented without isolation (compare the Manufacturing examples).

The active ingredients of the formula (V) are notable for good antifungal activity (compare DE-OS 26 23 129, DE-OS 28 51 143 and DE-OS 28 51 116).  

Manufacturing examples Example 1

2.7 g (0.09 mol) of 80% sodium hydride and 19.8 g (0.09 mol) trimethyloxosulfonium iodide are within 90 ml of dimethyl sulfoxide were added for 20 minutes. To ceased hydrogen evolution becomes a solution of 22 g (0.075 mol) of 2-chloro-4'-phenyl-benzophenone in 60 ml Dimethyl sulfoxide was added dropwise and the mixture was stirred at 50 ° C. for 1 hour. The cooled reaction mixture is with 200 ml Water is added and the mixture is shaken out with ether. The ether solution is washed with water, dried over sodium sulfate and by distilling off the solvent in Vacuum concentrated. The residue is made from diisopropyl ether recrystallized. 15 g (65% of theory) are obtained. 2- (4-biphenylyl) -2- (2-chlorophenyl) oxirane from Melting point 70 ° C.

According to Example 1, the following table listed new intermediates of formula (I) will be obtained:

Table 1

The process for the preparation of the Hydroxyethylazole der Formula (V) is illustrated by the following examples:  

Example 9

3.6 g (0.12 mol) of 80% sodium hydride and 26.4 g (0.12 mol) trimethyloxosulfonium iodide are within 120 ml of dimethyl sulfoxide were added for 20 minutes. To ceased hydrogen evolution becomes a solution of 25.8 g (0.1 mol) of 4-biphenylyl-phenyl-ketone in 150 ml Dimethyl sulfoxide added dropwise and 2 hours at 60 ° C. stirred. The reaction mixture obtained is added dropwise with 300 ml of water. The resulting Oil is separated from the aqueous phase, dissolved in chloroform, the solution washed with water, dried over sodium sulfate and by distillation of the solvent concentrated in vacuo. The so obtained crude 2- (4-biphenylyl) -2-phenyl-oxirane is dissolved in 150 ml Dimethylformamide dissolved. This solution is added dropwise a mixture of 7 g (0.13 mol) of sodium methylate, 40 ml Methanol and 15 g (0.22 mol) imidazole. The reaction mixture is heated to 80 ° C for 4 hours. After that it will The reaction mixture was concentrated in vacuo and poured onto water, the resulting crystals are filtered off and washed with acetonitrile. 26.7 g (83.5% of theory) 1- (4-biphenylyl) -2- (imidazol-1-yl) -1-phenylethanol melting point 224 ° C.  

Example 10

3.5 g (0.065 mol) of sodium methylate in 20 ml of methanol dissolved and mixed with 7.5 g (0.11 mol) of imidazole. A solution of 15 g (0.05 mol) of 2- (4-Bi phenylyl) -2- (2-chlorophenyl) oxirane in 75 ml of dimethylformamide added dropwise and the reaction mixture for 1.5 hours heated to 80 ° C. Then the reaction mixture is on Poured water, the resulting crystals filtered off and dried. 14.7 g (79% of the Theory) 1- (4-biphenylyl) -1- (2-chlorophenyl) -2-imidazol-1-yl-ethanol melting point 222 ° C.

Correspondingly, the following in Table 2 Compounds of formula (V) listed will:

Table 2

Those that can be produced from the oxiranes according to the invention Compounds are otherwise more good antifungal in vitro effect on Trichophyton mentagrophytes and Microsporum canis DE-OS 26 23 129 known compounds clearly think.

Active ingredients and minimal inhibitory concentrations go from the following table.  

Table 1

Claims (3)

1. Oxiranes of the formula in which
R represents phenyl, which is optionally mono- or disubstituted by chlorine, fluorine or methyl, represents naphthyl and tetrahydronaphthyl;
R¹ is fluorine, methyl, ethyl, ethoxy, furthermore phenyl, cyclopentyl or cyclohexyl, which can optionally be mono- or disubstituted by chlorine, bromine, fluorine, nitro, methyl or methoxy;
R² represents hydrogen or
R¹ and R² together are in the ortho position to each other for a tri, tetra or pentamethylene bridge, which are optionally substituted by chlorine or methyl, or together with the phenyl ring to which they are attached, for naphthyl or optionally substituted by chlorine or methyl Stand fluorenyl;
R³ represents fluorine or methyl and
n stands for 0 and 1. 2. A process for the preparation of oxiranes of the formula (I) according to claim 1, characterized in that ketones of the formula (II) in which
R, R¹, R², R³ and n have the meaning given above,

• α) with dimethyloxosulfonium methylide of the formula in the presence of a diluent at temperatures between 20 and 80 ° C in a conventional manner;
  or
• β) with trimethylsulfonium methyl sulfate of the formula

in the presence of a two-phase system and, if appropriate in the presence of a phase transfer catalyst at temperatures between 0 and 100 ° C implemented in a conventional manner.