DD143608A5 - PROCESS FOR PREPARING 4'-SUBSTITUTED 2,4-DICHLOR-ALPHA- (IMIDAZOLE-N-YLMETHYL) -DIBENZYLAETHERNES - Google Patents

Abstract

The invention relates to a process for the preparation of novel 4-substituted 2,4-dichloro-α- (imidazol-N-ylmethyl) -dibenzyl ethers, including their salts, which have superior pharmacological effects, especially against pils, yeasts and bacteria, especially because of their lower toxicity compared to that of the known products. The invention relates to a process for the preparation of substituted 2,4-dichloro-a- (imidazol-N-ylmethyl) dibenzyläthern of the general formula I, wherein R is a phenyl or phenylthio radical, and their salts with acids, which characterized is' that in known per se 1- (2 ', 4' -Dichlorphenyi) -2- (imidazole-Ы-у1) -ethanol with a Halogenbenzylderivat, eg 4-chloromethyl-diphenyl or 1-bromomethyl-4-phenylthiobenzene is condensed in a solvent, where appropriate, the resulting 4'-substituted 2,4-dichloro-a- (imidazol-Ы-!! Methyl) -dibenzyl ether base of the general Formula I is converted into a salt with an acid. - Formula I

Description

The invention relates to a process for the preparation of novel 4 ¹ -substituted 2,4-dichloro-C * - (imidazol- ¹ -ylmethyl) -

Dibenzyläthern including their salts with valuable pharmacological effects, especially against fungi, yeasts and bacteria.

ι Characteristic of the known technical solutions

The known antifungal agents, such as (imidazol-1-yl) -c (- (o-chlorophenyl) -o (, c (-diphenylmethane - [i- (o-chloro-o (, c <-diphenylbenzyl ) -imidazole 3 [clotrimazole] (The Merck Index, 2 370, page 309 and South African Patents 68/05392 and 69/00039) and 2,2 ', 4,4'-tetrachloro-c * - (imidazole-Ny: iiBe1hyl > dibenzyl ether [miconazole] (The Merck Index, 6,043, page 8O5 and German Patent 1,940,388) have the disadvantage that they are too toxic.

Object of the invention

The object of the invention is to provide novel 4'-substituted 2,4-dichloro-1- (imidazol-1-ylmethyl) -dibenzyl ethers which have superior pharmacological effects, especially against fungi, yeasts and bacteria, in particular due to their lower toxicity compared to that of the known products.

Explanation of the essence of the invention

The object of the invention is to provide a process for preparing the novel 4 ¹ -substituted 2,4-dichloro-c (- (imidazol- ¹ -ylmethyl) -dibenzyl ether having these superior pharmacological effects.

The above was surprisingly inventively by a process for the preparation of substituted 2,4-dichloro-ö: (ir-iidazol-i \ ^T -ylmethyl) -dibenzyläthern of

- X-

212866

general formula

in which R is a phenyl or phenylthio radical, that is to say 2,4-dichloro-4'-phenyl-o (- (imidazol-N-ylmethyl) -dibenzyl ether and 2,4-dichloro-4'-phenylthio-ov ( imidazol-N-ylmethyl) -dibenzyläther, and their salts with acids, which is characterized in that in a conventional manner 1- (2 ', 4 ^l -Dichlorph.enyl) -2- (imidazoi-N-yl) »Ethanol with a halobenzyl derivative of the general formula

in which R is as defined above and X is chlorine or bromine, is condensed in a solvent, where appropriate, the resulting 4. ^1- substituted 2,4-dichloro-o (- (imidazol-N-ylmethyl) -dibenzylätherbase the general formula I with one

- b- 2128 6 6

Acid is converted into a salt or optionally the resulting salt of 4'-substituted 2,4-dichloro-C *, -. - (imidazol-N-ylmethyl) -dibenzyläthers the general formula I in the corresponding free base of the general. Formula I or converted into another salt is achieved.

According to the invention, the salts of the compounds of the general formula I can be prepared with pharmaceutically acceptable inorganic acids, advantageously hydrochloric, nitric, sulfuric or phosphoric acid, or organic acids, preferably methanesulfonic acid, p-toluenesulfonic acid, succinic acid, maleic acid, fumaric acid, citric acid or tartaric acid. Of these, the preparation of the salts with hydrochloric acid, sulfuric acid [especially in the case of 2,4-dichloro-4'-phenyl-c <- (imidazol-N-ylmethyl) -dibenzylätherj, nitric acid, phosphoric acid [especially in the case of 2,4-dichloro-4'-phenylthio-d- (imidazol-N-ylmethyl) -dibenzyl ether], maleic acid, methanesulfonic acid, especially in the case of 2,4-dichloro-4'-phenylthio-c (- - (imidazole -N-ylmethyl) -dibenzyl ether, p-toluenesulfonic acid and citric acid [especially in the case of 2,4-dichloro-4'-phenyl-c (- (imidazol-N-ylmethyl) -dibenzyl ether].) Most preferred is the preparation of salts with nitric acid

As the solvent, 1 or more aromatic hydrocarbons, dimethylformamide, tetrahydrofuran, hexamethylphosphoramide or dimethylsulfoxide or mixtures thereof can be advantageously used as a possibility. Dimethylsulfoxide is most preferably used because condensation is most complete, resulting in a higher yield and a purer product. In this case, it is not necessary to subject the 4'-substituted 2,4-dichloro-o <- (imidazol-N-ylmethyl) -dibenzyl ether base obtained in the condensation to purification by a chromatographic column while such purification

is required when using dimethylformamide or hexamethylphosphoramide as a solvent. A simple filtration of the solution of the 4'-substituted 2,4-dichloro Dir (imidazol-N-ylmethyl) -dibenzylätherbase by a silica gel column is able to retain the low impurity levels. In the case of the 4'-substituted 2,4-dichloro-Qi- (imidazol-N-ylmethyl) -dibenzyläthers of the general formula I in which R is a phenyl radical, that is the 2,4-dichloro-4'- phenyl-04- (imidazol-1-ylmethyl) dibenzyl ether, not even this filtration is required, and the crystallization of its nitrate results in a product sufficiently pure for pharmaceutical purposes.

The condensation is advantageous, in particular when using the above aprotic solvents, in the presence of an alkali metal hydride '. or -amides which is capable of converting the hydroxy group of 1- (2 ', 4'-dichlorophenyl) -2- (imidazol-N-yl) -äthanoles into a salt carried out. ..

As another possibility, 1 or more aliphatic alcohols having 3 to 6 carbon atoms may be used as the solvent in the condensation. In this case, preference is given to working in the presence of an alkali metal alcoholate instead of the alkali metal hydride or amide. Very particular preference is given as aliphatic alcohol tert-butanol, n-butanol or n-propanol and alkali metal all alcoholate as an alkali tert.butylat such as potassium tert.butylat, an alkali metal n-butoxide or an alkali metal n-propylate used.

Preferably, the condensation is carried out in the presence of potassium iodide as a catalyst. This may advantageously be added before the addition of the halobenzyl derivative of the general formula II in small amounts.

It is preferred to carry out the condensation at a temperature of 20 to 100 ^° C. for 6 to 56 hours. In this time, the duration of the optionally occurring salt formation of the 1- (2 ', 4'-dichlorophenyl) -2- (imidazol-N-yl) - may be included with ethanol.

The 1 "- (2 ', 4'-dichlorophenyl) -2- (imidazol-N-yl) -ethanol used as starting material in the process according to the invention can be prepared from i-chloroacetylbenz-dichlorobenzene (Beilstein, Handbuch der Org. Chem. J IV · Edition, Volume 7 »page 28) by reduction of the keto group using sodium borohydride and condensation with imidazole, which reduction and condensation may have been accomplished in any order The reduction can be carried out in methanol and the condensation in Dimethylformamide and methanol have been made in the presence of sodium.

The halobenzyl compounds of general formula II used as starting materials in the process according to the invention are known. The preparation of 4-chloromethyldiphenyl is described in Chem. Ber. 66B (1933), 1471 and the preparation of i-bromomethyl-4-phenylthiobenzene is described in U.S. Patent 3,242,193.

The preparation of salts of the 4'-substituted-2,4-dichloro-o <- (imidazol-N-ylmethyl) -dibenzyl ethers of all-Formula 1 may be carried out by conventional procedures, for example by adding the desired acid to the 4 '-substituted 2, 4-dichloro-C <- (imidazol-N-ylmetiiyl) dibenzyl ether base in an equimolar amount, followed by crystallization of the salt obtained from a solvent, carried out in vacuo.

As already mentioned, the compounds prepared according to the invention have valuable pharmacological effects, in particular against fungi, yeasts and Gram-positive aerobic and anaerobic bacteria. The effectiveness is paired with a low toxicity.

Comparative experiments in which the pharmacological activity and toxicity of the compounds according to the invention were compared with those of 2 well-known antifungal agents, namely (imidazol-i-yl) -o (- (o-chlorophenyl) -u , c -diphenylmethane ciotrimazolj and 2,2 *, 4,4'-tetrachloro-oC-C imidazol-N-ylmethyl) dibenzyl ether [^ miconazole]]. ,

The results of these experiments are summarized in Tables I, II and III below.

Table I summarizes the acute toxicity values (LDrQ values) of the compounds according to the invention and the two comparison substances. The toxicity in mg / kg was determined by peroral administration to mice by conventional procedures.

Table II summarizes the minimum inhibitory concentrations of the tested hergesteisenverbindungen invention and two comparison substances in relation to fungi and yeasts. The values of the minimum inhibitory were determined according to the usual Brühendoppelserienverdünnumrsverfahrens \\ ^r ice.

The values of the minimum inhibitory concentrations of the tested compounds according to the invention and both reference substances with respect to gram-positive bacteria were also determined by the conventional double-batch digestion dilution method and they

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are summarized in Table III.

By minimum inhibitory concentrations are meant those minimum concentrations which are capable of inhibiting the growth of the investigated fungi, yeasts and bacteria.

The experimental conditions were as follows:

a) In mushrooms

Medium:

Sabouraud eluent with a pH of 5.7 (5 cnr per tube).

inoculum

A 10-day-old agar culture was washed with a physiological solution containing 10% of a polyoxyethylene sorbitan monooleate (Tveen 80), then filtered through cheesecloth and resuspended in the physiological solution to a dilution at which this suspension was in a spectrophotometer type Coleman Jr II at a wavelength of 650 nm a transparency (T)

of 50% showed. It became 0.1 cnr of

7th

Spore suspension used per 5 c ^ medium. Notwithstanding, Aspergillus niger, after filtration, prepared a 1:10 dilution of the physiological solution. Also from this dilution

2866

was used as inoculum 0.1 cur per 5 cm medium.

Otopeiralur and

-O

Hatchery: 25 G for 7 days.

b) in yeasts

Medium:

Sabouraud fluid with a pH of 5i7 (5 cm ^ per tube).

Inoculum: The yeasts were grown in the Sabouraud fluid, all except Cryptococcus neoformans for 24 hours and Cryptococcus neoformans for 2 days. The cells were collected by centrifugation at 6,500 revolutions per minute and resuspended in said physiological solution to a dilution at which this suspension in a spectrophotometer of the Coleman Jr II type with a length of 650 nm was transparent (T ) of 50%. 0.1 cnr of this suspension was used as

Inoculation material for each 5 turns.

cm medium

Teuiperatur and.

Bebrütungs-

Duration:

37 C for 48 hours.

- 10 -

c) Gram-positive bacteria

Medium:

Trypsin broth with a pH of 7i3 (5 cnr per tube)

inoculum:

The day before the experiment, the microorganisms to be examined are transferred to their respective media. After incubation for hours at $ 7 ° C .: 0.1 cm of a suspension of each

Strain in the broth in a dilution

z. of 1: 100 5 cm of each of the

Media containing the compounds to be tested in a concentration range of 0.009 to 160 ν / cnr vaccinated.

and temperature

Duration: 37 C during 18 hours.

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- .11 Table I

Akßt® toxicity

in mg / kg

böi peroral administration to mice

2,4-dichloro-4'-phenyl- "- (imidazol-N-ylmethyl) -dibenzyl ether

[Formula I

with R = · -C ₆ Hc ^

(Compound prepared according to the invention)

2,4-dichloro-4'-

-phenylthio-o ^ - (imida-

z ο 1-N-ylmethyl) -dibenzyl ether

[Formula I with R- .S- C ₆ H ₅ I

{Inventively Prepared Compound) ch 1 or-eo (imidazole-N-butylmethyl) dibenzyl ether

[VergleJcihssubstanzj

(Imidazol-1-yl) -o (

- (o-chlorophenyl) -

-djphenylmethane

[ClotrimazolJ

{VeigleLchssubd; anzJ

WHERE

3,000

870

880

- 12 Table II

Efficacy against fungi and yeasts Minimum inhibitory concentration in Pathogenic Mi kroo rg anisiius -rt- (imidazol-N-ylmetiryl) - dibeazyLiZier · [Formula I where R = - C ₆ H ₅ ] {Invention accordingly prepared compound] 2,4-DL-chloro-4'-t-toenyl-tadjo-c <- oiiddazol-JN-yl-metfayl) -ditenzyläth er [formula I with R - - S - Q ₆ H ₅ ] {Invention invention prepared herge] op · IL h. l ^ rfhi-rn. CyC , * r, "T-t-ULO-chloro-o-mujciazolyl-ylmethyj) -diJ33a2yl ether rhi conazole] {Comparative Example) (I midazol-1-yl) -o <- - (o-cbl-4-phenyl) -c /, o (- -d-ishenylm etlian rciotrjmazolj {Vergjßichs- 0. albicans 1 040 10 80 20 40 C. albicais 1041 20 , 80 20 40 C. neoformana 0.512 0.156 0.078 0.625 T. mentagroih. 2 558 0.156 0.156 0.078 0.078 T. mientagrcfij. 10 148 0.625 0.625 0.625 1.25 T. rubrum 2 121 0.625 0.625 0.512 1.25 A. niger 20 10 40 10 P. chrysogenum 20 .5 20 40 E. floccosum 10 5 5 ".  5

- 13 Table III

Efficacy against bacteria Minimum inhibitory concentration in fl / cnr Pathogener. , Microorganism, 2, A-Dkhlo r-4 ¹ -jafaeoyl-coc (imide, az-ol-N-ylmethyl) -dibenzyl ether [Fam. with H. = - C ₆ H Λ {Inventions prepared according to the invention] 2, "icblor-4'-tibenyl-ttdo-ot- <3-imidazol-N-yl-metyl) -diban-2-ylitol. he [Fannel I with E - - S - P ₆ HcI {Inventive Herge set compound] 2,2 ', 4,4'-o-tetra-chloro -tyrimethyl]. -ylmethyl) -dibenzyl ether fMiconazoll {Vergleidisubstaaz} - (Imidazole-1-3i) -o <- - (o-cuccjiiHQyl) - v, oi- -d ijienylm eth to jClotrimazol] · [VarEledjchs-aibstanz \ S. aureus SG 511 0.039 "·; o, O39 0.312 0.312 3. aureus 10 B 0,039 0,018 0.312 1.25 St. Hemolyt 821 0.156 0.156 1.25 2.5 B. aubtilis 0.156 0.078. 0.625 2.5 Eq. novyi <1.25 5.0 <1.25 > 160 Str. Hein], - yt 203 0.312 0.078 0.625 5

-, 21 2866

Particularly revealing is the comparison between the activity and toxicity of the compounds according to the invention and those of 2,2 ', 4,4'-tetrachloro-o <- (imidazol-N-ylmethyl) -dibenzyläther [^ miconazole] · Jn 2,2 ', 4,4 * tetrachloro-cxr-i imidazol-N-ylmethyl) -dibenzyl ether. ^ Miconazole] are both benzyl groups in the 2- and 4-positions substituted by chlorine atoms, while in the compounds according to the invention the one benzyl group, v which is unsubstituted in the 2-position, is substituted in the 4-position by a phenyl or phenylthio radical. This difference leads to a considerable reduction in the toxicity, which in the compounds according to the invention 3 to 4 times lower than that of 2,2 ', 4,4'-tetrachloro-tf (iraidazol-Nylmethyl) -dibenzyläther [^ Miconazole]], wherein in the compounds according to the invention the activity against bacteria is also much better (sometimes even by 1 order of magnitude) than in the comparison substances and against fungi and yeasts the effectiveness of the compounds according to the invention is about the same as on average those of the comparison substances. Thus, the therapeutic indices of the compounds according to the invention are higher (in some cases even orders of magnitude and more) with respect to virtually all the bacteria tested and, for the most part, also with respect to the fungi and yeasts examined, than the two comparison substances and the remainder with respect to the investigated fungi and yeasts, higher than that of the reference substance (imidazol-1-yl) -o- (o-chlorophenyl) -c (o-diphenylmethane (clotrimazole) and almost equal to that of the reference substance 2,2 ', 4 , 4'-tetrachloro-o: (imidazol-N-ylmethyl) dibenzyl ether (miconazole).

The compounds according to the invention can

- Tt-

in Huinantherapie particularly useful for topical treatment of skin diseases or dermatoses, v / ie beard lichen .beigungweise trichophytia and candidiasis, and v / eiteren caused by the fungi staphylococci and streptococci infections are used.

The compounds prepared according to the invention can be used to prepare medicament preparations, for example in the form of powders, ointments, creams, suspensions, dispersions, gels and solutions, with the aid of conventional pharmaceutical diluents, carriers and / or other excipients. The compound (s) prepared according to the invention in an amount of 0.5 to 5% by weight, in particular 1 to 3% by weight, is or will be advantageously used for this purpose.

f) Exemplary embodiments

, The invention will be explained in more detail with reference to the following examples.

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21 2B66-

Example 1 Preparation of

2,4-dichloro-V-phenylthio - * - (imidazole-N -ylmethyl) dibenzyl ether

["Formula I with E = Phenylthiorest 2 ^C a ^H 5" * ^S Procedure I

A solution of 2.57 g of 1- (2'-phenyl) -2- (imidazol-N-yl) -ethanol in 10 cc of hexamethylphosphoramide at 25 ° C in a suspension of 0.52 S sodium hydride (50%). -ige dispersion in oil) in 5 cnr hexamethylphosphoramide added dropwise. When hydrogen evolution ceased, salt formation was completed by heating to 50 ° C for 1 hour. After cooling to 25 ° C, 2.58 g of i-chloromethyl-4-phenylthiobenzene were added. The temperature was raised to 50 ° C and maintained at this value for 12 hours. At the end of the reaction, the mixture was poured into 200 cc of water, the product extracted with diethyl ether, the solvent evaporated, and the residue purified twice on a silica gel column using ethyl acetate as the eluent, the various fractions being examined by thin layer chromatography. The solvent of the middle fractions was evaporated to give 2.4 g of the desired 2,4-lichloro-4'-phenylthio-o, - - (imidazol-N-ylmethyl) -dibenzyl ether base as a yellowish oil which on thin-layer chromatography was a single Spot showed was obtained.

- 17 -

1286

Analysis:

calculated: C = 63.30%, H = 4.44%, N = 6.13%, Cl = S = 7.04%;

found: C = 63.86%, H = 4.24%, N = 6.41%, Cl = 15.25%, S = 6.97%.

Procedure II

0.66 g of sodium hydride (50% dispersion in oil) in a nitrogen atmosphere at 20 to 30 ° C was added to 3.86 g of 1- (2 ', 4'-dichlorophenyl) -2- (iiiQ.idazole-N -yl) - ethanol in 15 cm ^ dimethylsulfoxide (dried over calcium hydride) was added. The mixture was heated with stirring or shaking to 50 to 60 ⁰ C until the gas evolution was complete. After cooling to 20 to 25 ° C was added 0.5 6 potassium iodide and slowly added dropwise a solution of 3.51 S 1-chloromethyl-4-phenylthiobenzol in 4 cnr dimethyl sulfoxide. The mixture was stirred at 20 to 25 C until the addition of the i-chloromethyl-4-phenylthiobenzoles was completed. The mixture was then poured into 150 ml of water and extracted with diethyl ether. After drying over anhydrous sodium sulfate, an excess of a 4 N nitric acid solution in diethyl ether was added to the ethereal solution. The desired product precipitated as nitrate was an oil,

- 18 -

ΛΊτ- '£ Λ Z 8'

which became solid when standing. After standing for 20 hours, the ethereal liquid was decanted off and the residue was crystallized from ethanol. The nitrate thus obtained, which was not yet completely pure, was dissolved in water and an excess of sodium carbonate was added to liberate the base, which was then extracted with ethyl acetate. The resulting base was purified by filtration on a silica gel column using ethyl acetate as the eluent. The combined fractions containing the desired product were evaporated to dryness. The residue was dissolved in diethyl ether, transferred again into the nitrate and crystallized from ethanol,

Thus 3.1 g of 2, ^ were - dichloro ^ ¹ * -phenylthio- ~ r- - (imidazol-N-ylmethyl) -dibenzyläthernitrat as white crystalline powder having a melting point of 134 ^o C was obtained.

Analysis:

For C ₂₄ H ₂₀ N ₂ Cl ₂ OS. ENT ₅

calculated: C = 55.61%, H = 4.08%, N = 8.11%, Cl = 13.68%, S = 6.18%;

found: C = 55.32%, "H = 4.08%, N = 8.16%, Cl = 13.56% ^ S = 6.32%.

The 1- (2 ', 4'-dichlorophenyl) -2- (imidazol-N-yl) ethanol used as starting material was prepared as follows:

49.5 S sodium borohydride was slowly added in small portions to a stirred or shaken suspension of 233 S <X, 2,4-trichloroacetophenone in 1 liter of methanol at room temperature. The resulting solution was stirred or shaken for a further 2 hours at room temperature and then poured into 1 l of an ice-cooled 5 * i hydrochloric acid. After extracting with ethyl acetate or chloroform, the extract was washed with water, a η sodium hydroxide solution, then again with water until the neutral reaction was reached and finally with a saturated sodium chloride solution. The extract was dried and the solvent was evaporated. There were obtained 220 g of an oil. This oil solidified upon standing, and this solid, which was 1- (2 *, 4'-dichlorophenyl) -2-chloroethanol, had a melting point of 48 to 51 ° C.

Analysis:

For C ₀ H _n Cl _x O ο / 3

calculated: C = 42.61%, H = 3.13%, Cl = 47.17%; found: C = 42.75%, H = 3.19%, Cl = 47.43%.

- 20 -

- -β- 21

50 g of sodium was added to a solution of 88.5 S imidazole in 600 cc of methanol. Then the solvent was evaporated. The residue

was dissolved in 300 cm of dimethylformamide and heated to 115 to 120 C. The solution thus obtained was added dropwise with stirring or shaking a solution of 225 S obtained as described above 1- (2 ', 4'-dichlorophenyl) -2-chloroethanol in 400 cur dimethylformamide. The mixture was heated to 115 to 120 ° C and held for 20 minutes at this temperature and then after cooling to 40 C 2 500 cur ice water were added with vigorous stirring or shaking. The product precipitated upon stirring for about 2 hours, after which the supernatant liquid was decanted off, an additional 2500 cc of water was added, and after standing, the whole was filtered. The resulting precipitate was dried and the toluene crystallized. There were thus obtained I70 g of 1- (2 ', 4'-dichlorophenyl) -2- (imidazol-N-yl) -ethanol having a melting point of 134 to 135 ° C.

Analysis:

For C ₁₁ H ₁₀ Cl ₂ N ₂ O '

calculated: C = 51.38%, H = 3.92%, N = 10.89%, Cl = 27.58%;

found: C - 51.62%, H = 3.80%, N = 10.73%,

ei = 27.76%.

- 21 -

Example 2 Preparation of

2,4-dichloro-4'-phenyl -: ω- (imidazole-N-butylmethyl) -dibenzyl ether

Π? Οπηβ1 I with R = phenyl radical

Procedure Ia

A mixture of 2.02 g of potassium tert-butylate in 30 cc of tert-butanol in a nitrogen atmosphere at 20 to 25 ° C was prepared. Then, 3.86 g of 1- (2 ', 4'-dichlorophenyl) -2- (imidazol-N-yl) ethanol prepared as described in Example 1 was added. The solution was refluxed for 1 hour and then cooled to 20-25 ° C. 3 g of 4-chloromethyldiphenyl were added and the solution was heated to boiling again under reflux for 5 hours, after cooling to 20 to 25 ° C., the whole was poured into water and the 2,4-dichloro-4'-dichlorobenzidine was added. phenyl-a- (imidazol-N-ylmethyl) -dibenzyl ether base extracted with ethyl acetate. The extract was washed with Biauyi and the solvent was evaporated. The residue was dissolved in 80 cm diethyl ether and left over liactt. The insoluble substances were filtered off and the filtrate was treated with nitric acid dissolved in diethyl ether. An oil which solidified on standing was obtained. The 2,4-dichloro-4 ¹ -phenyl- c?, (Imidazol- ¹ -ylmethyl) -dibenzyläthernitrat

- 22 -

21 2866

»Existing residue was crystallized from ethanol or> ethyl acetate.

Thus, the product 4.3 g of 2,4-dichloro-4'-phenyl-c - (iniidazol-1-ylmethyl) -dibenzyläthernitrat, which proved to be pure in the thin-layer chromatography and a melting point of 140 to 141 ° C. had received.

Analysis: For

Calculated: C = 59.25%, H = 4.35%, N = 8.64%, Cl = ^ found: C = 59.17%, H = 4.14%, U = 8.61%, Cl = 14.46%.

Procedure Ib

It would lead to a solution of 0.37 S sodium

7. metal in 20 cnr of n-propanol 4.1 g of 1- (2 ·, 4 ^l -dichlorophenyl) -2- (imidazol-lT-yl) -ethanol prepared as described following Example 1 was added and the mixture became With stirring or shaking for 2 hours and heated to reflux under reflux. After cooling to room temperature, 0.5 g of potassium iodide and 3.25 g of 4-chloromethyl diphenyl were added with stirring or shaking, and the mixture was again heated to boiling under reflux. At the end of the reaction, the mixture was filtered and washed with ethanol. The filtrate was evaporated to dryness and the residue was dissolved in diethyl ether,

- 23 -

- ΛΑ,

The insoluble residue was filtered off and the resulting clear ethereal solution was treated with a mixture of nitric acid and diethyl ether. The thus obtained 2,4-dichloro-4'-phenyl-o (- (imidazol-N-ylmethyl) -dibenzyläthernitrat was crystallized from ethanol. As a product, 2.1 g of 2,4-dichloro-4'-phenyl c (- (iiaidazole-L ^T - -ylmethyl) dibenzyl ether nitrate having the same properties as that of that prepared by the above procedure Ia which showed a single spot on thin layer chromatography.

Procedure II

It was 0.66 g of sodium hydride (50% dispersion in oil) in a nitrogen atmosphere at 20 to 25 ⁰ C to a solution of 3.86 g of 1- (2 ', 4'-dichlorophenyl) -2- (imidazol- K-yl) -ethanol in 15 cnr dimethylsulfoxide (dried over calcium hydride) was added. The mixture was heated to 50 to 60 C until gas evolution ceased. Then, the mixture was cooled to 20 to 25 ° C. There were added 0.5 S potassium iodide and a solution of 3.03 g of 4-chloromethyldiphenyl in 7 cnr dimethyl sulfoxide (dried over calcium hydride) was added dropwise. The whole was stirred or shaken at 20 to 25 ° C for about 20 hours and then poured into water. The product was extracted with ethyl acetate and then treated in the manner described in Procedure I.

Thus, 4.6 g of 2,4-DiChIOr- ^ ¹ -phenyl-f'- (imidazol-N-ylmethyl) -dibenzyläthernitrat have been obtained with the same properties as those prepared by the procedure I above.

Example 5

Production of

Salts of 2,4-dichloro-4'-phenylthio-CN- (imidazol-N-ylmethyl) -dibenzyl ether and 2, ^ -dichloro-1'-phenyl-c <.- (imidazol-1-tylmethyl) -dibenzyl ether

Salts of 2,4-dichloro-4'-phenylthio-c <- (imidazol-N-ylmethyl) dibenzyl ether were prepared by reacting the free 2,4-dichloro-4 · phenylthio-c <- (imidazole) ylinethyl) dibenzyl ether base prepared in solution in ethanol with an alcoholic solution of the desired acid and then crystallizing the resulting salt from a solvent. The free 2,4-dichloro-4'-phenylthio-x-imidazole-N-methylmethyl-dibenzyl ether base was carried out according to Example 1, Procedure I or by liberating from its nitrate prepared according to Example 1, Procedure II Treat with sodium carbonate _t Extract with diethyl ether and evaporate.

Similarly, salts of 2,4-dichloro-4'-phenyl-c < ^: - (imidazol-N-ylmethyl) -dibenzyl ether were prepared.

- 25 -

In the following Table IV, the crystallization solvents, the elemental analysis and the melting points of salts of 2,4-di chloro <4 -'-phenylthio-t <- (imidazol-N - ylmethyl) - dibenzyläther compiled.

In the following Table V, the same data of salts of 2,4-dichloro-4 ^f -phenyl-i << - (iiiiidazol-- -N-ylmethyl) -dibenzyläther are compiled.

- 26 -

- 26 Table IV

salt Kiristal LimaMettel Melting point C Calculated N Cl S C Found N Cl S - (imtfazole-N-y! methyl) - isopropanol 181 to 183 ° C 58.61% H 5.69% 21.62% 6.51% 58.42% H 5.67% 21.40% 6.79% 2,4-3Dichloro-4'-nityltomethyl dibenzyl etherate ethanol 117 to 118 ^° C 58.85% 4.30% 4.90% 12.41% 5.61% $ 58.61 4.31% 4.77% 12.24% 5.91% - (imidazole-K-ylmethyi) - -dibaiylate harbors clay oilate ethanol 153-155 ⁰ C 54.45% 4.23% 5.08% 12.86% 11.63% 54.21% 4 ", 50% 4.78% 12.97 * 11.94% 2,4-D-idilor-4-pBS-butylthio-coca- (imidazol-N-ylmethyl) -di- ' btiiQ / lütte r-p-toluo isulibnate ethanol 127 to 128 ⁰ C 59.33% 4.39% 4.46% 11.30% 10.22% 59.43% 4.32% 4.43% 11.63% 10.44% - (imidazol-N-ylmethy I) - ethanol 143 to 145 ⁰ C 52.09% 4.50% 5.06% 12.81% 5.79% 51.86% 4.49% 5.12% 12.90% 5.91% 4.19% 4.18%

Table V

salt KristcilLisabjssnslaangj medium Melting point Calculated C H N Cl S Found C H N Cl S 2 ^ -Dicblor ^ '- phenyl-cX- (iaidazol-N-ylmethyl) -di- - y-yl-yl-yl-hydrochloride id / iüylacetat 171 bia 172 ⁰ O 62.69% 4.60% 6.09% 23.13% 62.40% 4.80% 5.86% 23.18% 2, 4-Bkhlcir-4 ^l -iteQyl-<< - - (iiridaol-1-yl-yl-yl) -dibenzyl ether sulfate ethanol 72 to 8O ⁰ C. 55.28% 4.25% 5.37% 13.60% 6 "15% 54v99% 3.90% 5.25% 13.48% 6.23% 2,4-dichloro-4-phenyl- (X.- (imMasDl-ii-yl-mettyl) -di- benzyl-ateiimalinate ethanol 128 to 129 ⁰ C 62.35% 4.48% 5.19% 13.14% 62.05% 4.19% 4.91% 13.51% 2, ^ -Dicilor- ^ '- p-butyl ex - - (imidazol-N-ylmethyl) -dibenzyläth-r-p-toboluenesulfonate ethanol 182 bi3i84 ° C 64.25% 4.8%? 4.83% 12.23% 5.53% 63.81% 4.82% 4.54% 12.52% 5.63% 2, 4-diol ^ 4-alkylbenz.- (ϊιοΐάΰζοΙ-ίΙ- ^ ΙτΕίί ^ Ι) - ^! - benzylethyl citrate ethanol 150 ⁰ C 58.55% 4.58% 4.55% 11.52% 58.97% 4.47% 4.61% 11.60%

invention claim

Claims (8)

invention claim 1.) Process for the preparation of substituted 2, A-Di chi or-Cv- (imidazole-N-y! Methyl) -dibenzyläthern the general formula in which R stands for a phenyl or phenylthio radical, and their salts with acids, characterized in that 1- (2 ', 4'-dichlorophenyl) -2- (imidazol-N-yl) is used in a manner known per se. ethanol with a halobenzyl derivative of the general formula wherein R is as defined above and X is chlorine or bromine, condensed in a solvent, followed by the optionally obtained 4''-substituted 2,4-dichloro-tf- (imidazol-N-ylmethyl) -dibenzylätherbase the _q general formula I with an acid in a salt or optionally the resulting salt of the 4 ¹ -substituted 2,4-bichlor-c <- (imidazole-N-methylmethyl) -dibenzyläthers the general formula I in the corresponding free base of the general Formula I or converted into another salt. 2.) Method according to item 1, characterized by in that the solvent used is 1 or more aromatic hydrocarbons, dimethylformamide, tetrahydrofuran, hexamethylphosphoramide or dimethylsulfoxide or mixtures thereof. 3.) Process according to item 1 or 2, characterized in that one carries out the condensation in the presence of an alkali metal hydride or amide. ·. · 4.), method according to item 1, characterized in that the solvent used is 1 or more aliphatic alcohols having 3 to 6 carbon atoms. 5) Process according to item 1 or 4, characterized in that the condensation is carried out in the presence of an alkali metal alcoholate. 6.) Procedure according to item 1, 4 or 5? characterized in that one uses as the alcohol tert-butanol, n-butanol or n-propanol and alkali metal as an alkali metal tert.butylat, alkali metal n-butylate or alkali metal n-propylate. 7.) Process according to item 1 to 6, characterized in that one carries out the condensation in the presence of potassium iodide as a catalyst. 8.) Procedure according to point 1 to. 7, characterized in that the condensation is carried out for 6 to 36 hours at a temperature of 20 to 100 ⁰ C.