AT291249B

1-(beta-aryl-ethyl)-imidazole ethers and amines

Abstract

This record has no abstract on file.

AT291249B, drawing sheet 1 — Sheet 1 of 15

Term

Term ended

Expired 18 August 1989, 37.1 years ago.

7 claims: 6 independent, 1 dependent

1
CLAIMS; 1. Process for the preparation of new imidazole derivatives of the general formula -N R * R * (X) R - C - C - O - (CH) - Ar * 1 ii 2 n Ar in which R, R x and R 2 independently of one another hydrogen atoms or lower alkyl radicals; 40 n zero, 1 or 2; Ar is phenyl, substituted phenyl, thienyl or halogenthienyl, wherein the Phenyl contains at least one substituent selected from the group consisting of halogen atoms, substituted lower alkyl radicals and lower alkoxy radicals; Nr.291249 Ar 'phenyl, substituted phenyl, wherein the substituted phenyl radical contains at least one substituent selected from the group consisting of halogen atoms, lower alkyl radicals, lower alkoxy radicals, cyano, nitro and amine; R * is hydrogen, methyl or ethyl; 5 R "is hydrogen or methyl; however a) in cases where Ar 'is a substituted phenyl radical containing at least one substituent selected from the group consisting of nitro and amino, n is zero, and b) in cases in which Ar * is a phenyl radical or substituted phenyl radical having at least one sub-substituent selected from the group consisting of halogen atoms, lower alkyl radicals, lower alkoxy radicals and cyano radicals, n is not zero, and their therapeutically active acid addition salts, characterized in that one compounds the general formula -N R "ll / e ' •NO I C-OM (VII) R Ar 2 15 in which M is an alkali metal, with compounds of the general formula Y - (CH) - Ar ' v 2 n (VI) in which Y is a halogen atom and Ar * has the abovementioned meaning, with the exception of aminophenyl, in the presence of a suitable solvent and subjecting the compounds (X) thus obtained to one or both of the following reactions, if desired:20 a) if in the product obtained Ar * is a nitrophenyl group;Reduction of this group to the corresponding aminophenyl group;b) Preparation of therapeutically active acid addition salts.
3
Third Process according to Claims 1 and 2 for the preparation of 1- [β- (p-chlorobenzyloxy) -phenyl] -imidazole or its therapeutically active acid addition salts, characterized in that the sodium salt of 1- (0-hydroxyphenylethyl) imidazole is replaced by p Reacting chloromethyl chloride and 35 optionally produces the therapeutically effective acid addition salts of the product.
4
4th Process according to Claims 1 and 2 for the preparation of 1- [2,4-dichloro-O- (p-chlorobenzyloxy) -phenyl] -imidazole or its therapeutically active acid addition salts, characterized in that the sodium salt of a - ( 2,4-dichlorophenyl) -imidazole-l-ethanol is reacted with p-chlorobenzyl chloride and optionally produces the therapeutically active acid addition salts of the product.
5
5th Process according to Claims 1 and 2 for the preparation of 1- [2,4-dichloro-β- (2,4-dichlorobenzyloxy) -phenyl] -imidazole or its therapeutically active acid addition salts, characterized in that the sodium salt of α- ( 2,4-dichlorophenyl) - imidazole-1-ethanol with 2,4-dichlorobenzyl chloride and, if appropriate, the therapeutically active acid addition salts 45 of the product. No. 291249
6
6th Process according to Claims 1 and 2 for the preparation of 1- [2,4-dichloro-β- (2,6-dichlorobenzyloxy) -phenyl] -imidazole or its therapeutically active acid addition salts, characterized in that the sodium salt of ot- ( 2,4-dichlorophenyl) -imidazole-l-ethanol with Converts 2,6-dichlorobenzyl chloride and optionally the therapeutically active acid addition salts 5 of the product.
7
7th Process according to Claims 1 and 2 for the preparation of 1-fp-chloro-β- (2,6-dichlorobenzyloxy) -phenyl] -imidazole or its therapeutically active acid addition salts, characterized in that the sodium salt of α- (p-chlorophenyl ) imidazole-1-ethanol with 2, 6-dichlorobenzyl chloride and optionally produces the therapeutically active acid addition salts of Pro 10 product. Pamphlets considered by the Patent Office to distinguish the subject-matter of the application from the prior art:GB-PS 1 099 787 OE - PS 260 235 Print: Ing.E. Voytjech, Vienna

Independent claims6

508 paragraphs in 19 sections, as filed

Beginning of the patent period: 15, November 1970.

The invention relates to a process for the preparation of novel imidazole derivatives of the general formula

RCC-0 - (CH) -Ar ', (X) 1 II 2 n

R2 Ar in which

R, Rx and R2 independently of one another hydrogen atoms or lower alkyl radicals; n zero, 1 or 2;

Ar is phenyl, substituted phenyl, thienyl or halogenthienyl, wherein the substituted

Phenyl contains at least one substituent selected from the group consisting of halogen atoms, lower alkyl radicals and lower alkoxy radicals;

Ar * phenyl, substituted phenyl, wherein the substituted phenyl radical contains at least one substituent selected from the group consisting of halogen atoms, lower alkyl radicals, lower alkoxy radicals, cyano, nitro and amine;

R 'is hydrogen, methyl or ethyl;

R "is hydrogen or methyl;

however

a) in cases where Ar 'is a substituted phenyl radical containing at least one substituent selected from the group consisting of nitro and amino, n is zero, and

b) in cases in which Ar * is a phenyl radical or substituted phenyl radical having at least one substituent from the group of halogen atoms, lower alkyl radicals, lower alkoxy radicals and cyano radicals, n is not zero.

No. 291249

The preparation of the therapeutically active acid addition salts of the above-mentioned compounds (X) is also within the scope of the invention.

The abovementioned lower alkyl radicals and lower alkoxy radicals may be straight or branched saturated hydrocarbon radicals having 1 to about 6 C atoms, for example methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl and the like. Alkyl radicals or the corresponding alkoxy radicals such as methoxy, ethoxy, propoxy, isopropoxy, etc. Preferred as the lower alkyl radical and lower alkoxy radical are the methyl radical or the methoxy radical. Suitable halogen atoms are those having an atomic number of less than 127, ie fluorine, iodine, bromine and chlorine, in question. As substituted phenyl radicals represented by Ar, mono-, di- and trihalogenophenyl radicals, lower alkylphenyl radicals and lower alkoxy-10-phenyl radicals are preferred, and as substituted phenyl radicals represented by Ar * are mono-, di- and trihalophenyl radicals, mono- and di - (Lower alkyl) phenyl, lower alkoxyphenyl, Cyanphenylreste, mono- and Dinitrophenylreste and Aminophenylreste preferred.

The ethers of the general formula (X) are obtained according to the invention by reacting compounds of the general formula

-N

(VII)

RCC-OM

I

R "Ar wherein M is an alkali metal, with compounds of the general formula

Y- (CH) - Ar'n

(VI) wherein Y is a halogen atom and Ar 'has the above-mentioned meaning except for aminophenyl, in the presence of a suitable solvent, and subjecting the compounds (X) thus obtained to one or both of the following reactions if desired;

a) if in the product obtained Ar 'is a nitrophenyl group reduction of this group to the corresponding aminophenyl group;

b) preparation of therapeutically active acid addition salts,

The starting materials of general formula (VII) can be obtained by treating the alcohol (V) with a suitable strong base, e.g. As an alkali or alkali metal hydride. Suitable solvents for the O-alkylation are, for example, aromatic hydrocarbons, for example benzene, toluene and xylene, the alkylformamides, for example dimethylformamide and diethylformamide, ethers, for example tetrahydrofuran and 1, 2-dimethoxyethane, and hexamethylphosphortriamide. To accelerate the reaction can be advantageously carried out at elevated temperatures. The resulting ethers (X) can be readily isolated in the form of the free base or as an acid addition salt. The one described above

O-alkylation can be illustrated by the following reaction scheme:

-N

Rx-CC - OH

R. Ar 2 (V)

R Ar 2 (VHa)

Nr.291249

Y - (CH) - Ar k 2'-

N

Ν '

R (VI) rrC-CO ~ (CH2)nAr '

R "Ar 2 (X)

The ethers of formula (X) wherein Ar * is aminophenyl are prepared by reduction of the corresponding nitrophenyl ethers by conventional methods for the reduction of a nitro function to an amino function, eg by catalytic hydrogenation, for example by treatment with hydrogen and a catalyst consisting of palladium on activated carbon in ethanol, or by treatment with nascent hydrogen, as by the action of a suitable metal and an acid, z, B, zinc and acetic acid, iron and aqueous ammonium chloride , Tin and hydrochloric acid u. Like., Is formed.

The alcohols (V) used to obtain the compounds of the general formula (VII) can be obtained by a number of synthetic methods, for example by the following methods, where the radicals R, RR2, Y, R ', R "and Ar have the meanings given above:

A. The Carbonyl Function of Ketones, R '

N (II)

Rt-CC = 0

R "Ar 2 is prepared by treatment with a suitable reducing agent, for example, sodium borohydride and lithium aluminum hydride, in a suitable solvent, e.g. As a lower alkanol, reduced to a carbinol function.

The ketones (II) can again be prepared by several synthetic methods. For example, the ketones (II) can be prepared by the following procedures, wherein R, R2, R ', R "and Ar have the meanings given above:

a) The known compound N-acetylimidazole (see Otting, Ber., 89 [1956], p. 1940) is reacted with a compound of the formula

Y - CH2- CO - Ar (Y = halogen atom) in a suitable organic solvent, e.g. As acetonitrile, preferably reacted under reflux for several hours. The solvent is then evaporated and the residue dissolved in water, optionally filtered. The aqueous solution is treated with a suitable base, eg sodium bicarbonate solution, to about pH 9 to precipitate the corresponding ketone, namely 1-aroylmethylimidazole. Optionally, the formed ketone may be dissolved in a suitable organic solvent and reprecipitated by conventional treatment with an acid acid addition salt.

b) 2-R'-4 (5) -R "-imidazole and a halide of the formula

Y-CR R - CO-Ar 1 2 are dissolved in a suitable solvent, eg dimethylformamide or a lower Al4

No. 291249 kanol, implemented. From the mixture, the desired ketone is precipitated by the addition of water. It is also possible to use a ketone of the formula

HCR, R - CO - Ar l. 2 to brominate first with liquid bromine by known methods, wherein the compound

Br-CR, R-CO-Ar

2 then formed with the 2-R * -4 (5) -R,,Imidazole is implemented,

c) The known compound ethyl-5-methylimidazole-4-carboxylate in the form of an alkali metal salt, preferably the sodium salt, is refluxed with a suitable 2-bromomethyl-2-ar-1,3-dioxolane of the formula

reacted in a suitable solvent, for example dimethylformamide, in the presence of potassium iodide. The product thus obtained, ethyl 1- (2-ar-1,3-dioxolan-2-ylmethyl) -5-methylimidazole-4-carboxylate:

CH OC, 2 5 ι

HC ' XN '

is then removed from the reaction mixture with a suitable solvent, e.g. As ether, extracted. By evaporation of the solvent, the ester is obtained. It is also possible to precipitate the ester by treating the extract with an acid, eg nitric acid. Conventional hydrolysis of the resulting ester or ester salt gives the corresponding 4-carboxylic acid derivative, which is then decarboxylated in the usual way, eg by heating (about 250 ° C) a mixture of the acid in paraffin oil until the formation of carbon dioxide ceases. The thus obtained 1- (2-ar-1,3-dioxolan-2-ylmethyl) -5-methylimidazole

No. 291249, which can be recovered by extraction and precipitation similar to the above-mentioned 4-carboxylate ester, is then preferably hydrolyzed under acidic conditions to convert the dioxolane function to a carbonyl function and to produce the desired 5-methylketone

Formula (II) is obtained:

HC

N'F

R is -C-C-Ar

B. 2-R ·- 4 (5) -R "-imidazole in the form of an alkali metal salt as obtained by treatment with sodium methoxide is treated with a compound of the formula

Y - CRjR2-CR (OH) - Ar in a suitable organic solvent, eg dimethylformamide. By subsequent addition of water to the reaction mixture, the desired alcohol is precipitated, which is then isolated by customary methods.

C. 2-R'-4 (5) -R ** - Imidazole is reacted with a compound of the formula <-> - Ar

O in a suitable organic solvent, for example a lower alkanol, and in the presence of a small amount of an organic base, for example pyridine, combined, wherein after addition of water as precipitation of the corresponding alcohol of the formula (V) in which R, R ^ and R2 are all hydrogen atoms is obtained.

Several of the halides used as reactants of the formula (VIII) have been mentioned in the literature (Cl Feugeas, Bull. Soc. Chim. Fr. [1963] (II), 2568 and AR Patei, J. Pharm. 52 (6), 588-593 [1963]). The hitherto unknown halides can be easily prepared by first a ketone of the formula

CH3-CO-Ar in which Ar has the abovementioned meaning, brominated by conventional bromination and the bromide thus obtained with ethylene glycol in a suitable organic solvent, for example an aromatic hydrocarbon such as benzene, toluene and xylene, to which a small amount of p-toluenesulfonic acid added can be implemented. The above reactions can be carried out byBr -CH-C -Ar HO -CH CH - OH

II -L _? ->

Benzene (VIII)

The available asymmetric carbon atoms present in compounds (I) indicate that they may be in the form of stereochemical isomers (enantiomorphic forms). If desired, the separation and isolation or formation of a particular shape is possible by applying the generally known principles. This production of enantiomorphic

Of course, forms are within the scope of the invention,

Depending on the conditions under which the reactions are carried out, the new compounds arise either in the form of the free bases or salts. The salts are converted in the usual way into the free bases, for. B. further illustrated by reaction with alkali such as sodium or potassium Scheme;

CH -C - Ar Br 3 II --- II dioxane

No.291249 hydroxyd. The compounds in base form may be prepared by reaction with suitable acids, e.g. As inorganic acids such as hydrohalic acids, ie Hydrochloric acid, hydrobromic acid, or hydroiodic acid, sulfuric acid, nitric acid or thiocyanic acid, a phosphoric acid, with organic acids such as acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, Oxal5 acid, Malonsäuie, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid , Mandelic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, p-aminosalicylic acid, 2-phenoxybenzoic acid or 2-acetoxybenzoic acid are converted into their therapeutically valuable acid addition salts.

The compounds of the formula (I) obtainable according to the invention and their acid addition salts are valuable for the control of small mushrooms and bacteria, as shown by the broad spectrum of their fungicidal and bactericidal activity. This effect is illustrated by the values in the following tables. The values reported in the tables were determined by the method described by Vanbreuseghem et al., Chemotherapia, 12, [1967], p. 107 has been described.

The experiments with mushrooms were carried out using liquid Sabouraud medium (1 g Neopepton 15 Difco and 2 g glucose Difco per 100 ml distilled water) in 16 x 160 mm test tubes each containing 4.5 ml of the liquid medium containing 15 min. autoclaved at 120 ° C. The preparation to be tested is first dissolved in 50% of ethanol to a concentration of 20 mg / ml. The solution is diluted to a concentration of 10 mg / ml with sterile distilled water. Successive dilutions to 1/10 of the previous concentration were made with distilled water. Into each test tube containing 4.5 ml of the liquid Sahouraud medium, 0.5 ml of a dilution of the preparation is added to obtain 1000, 500, 100, 10 and 1 y per ml of medium (y = microgram), a control jar was prepared by adding 0.5 ml of distilled water to 4.5 ml of medium. The ethanol concentration in the control test tubes was the same as in the test tubes containing 100 μl of compound per ml.

The filamentous fungi were incubated for 2 to 3 weeks at 25 ° C. A square block of 2 mm edge length was cut and seeded in the liquid medium. A three day culture on liquid Sabouraud medium was used for yeasts. The amount of inoculum was 0.05 ml / tube. All cultures were duplicated and incubated at 25 ° C for 14 days. The first test was made after 7 days and the last test after 14 days (the values in Tables I and Π are the final scores for each compound at the concentration of 100 y / ml of culture determined after 14 days). The score was set assuming a maximum growth for the control glass to which rating 4 was assigned. Complete lack of growth after 14 days was rated 0, while 1/4, 1/2 and 3/4 growth of the controls was rated 1, 2 and 3, respectively.

Bacterial tests were performed on phenol red dextron broth (Difco) and tryptone broth (Difco) by the same decimal dilution method as in the mushroom trials (100 y / ml and 10 y / ml). The amount of inoculum was 0.1 ml from a 24-hour culture diluted 10-fold with distilled water for Streptococcus pyogenes and 0.05 ml for other microorganisms. The results after 72 hours were + or 0 according to the presence or absence of Growth assessed. The results shown in Table ΙΠ illustrate the antibacterial activity.

With the performance of the compounds in the following tables, no limitation of the invention is intended. These compounds merely serve as examples to illustrate the valuable properties of all the compounds of formula (X), including their pharmaceutically acceptable acid addition salts.

No. 291249

Table la

<td rowspan="16">0 4 » fi > • rH Ö T3 0 fi L egg e ü \ _z ό oi- O- <s =\ 1 ZE = J °</td><td rowspan="11">fungistatic effect (final evaluation at 100 y / ml)</td><td>rH r-1</td><td>ooooooooooo</td>

<td>O rh</td><td>ooooooooooo</td>

<td>05</td><td>ooooooooooo</td>

<td>t</td><td>©© OOOr-iOOOr-tO</td>

<td>CO</td><td>tHOrHOOrHOT-it-lrHrH</td>

<td>LO</td><td>ooooooooooo</td>

<td>4</td><td>OOHOOMOOOOO</td>

<td>CQ</td><td>OOOOOOOOOOO</td>

<td>CQ</td><td>ooooooooooo</td>

<td>&</td><td>ooooooooooo</td>

<td colspan="2">f salt</td><td>oooooooooooo zzzzzzzzzzz eeeeeeeeeee</td>

<td colspan="2">fi</td><td>ι-ΗτΗγΗγΗγΗτΗτΗγΗγΗϊΗγΗ</td>

<td colspan="2">di</td><td>eeeeeeeeeee</td>

<td colspan="2">"- < <!</td><td>CQ CQ XX rta * ® * 'f * - 9 9 EEEE E * i? * »» X 9 9 9 9 O r, ® o ü υ '»'« ", Λ9ν-γ9ζΕΕΕ EOcL4ü4faOOOO« o 1 1 «1 · 1 1 1 1 1 U ^^ ^^ CQCQCQ CQCQ ^</td>

No. 291249

Table 1a (continued)

No. 291249

Table 1a (continued)

<td>Around</td><td>Ä</td><td>©</td><td>©</td><td>©</td><td>©</td><td>©</td><td>©</td><td>©</td><td>O</td><td>O</td><td>ο</td><td>ο</td><td>rh</td>

No. 291249

Table 1a (continued)

X

C- 00 Ο O rH

Second

B <U.

S ö

O

4- * o <

o 'S' ΰ fc. M r *

D. II II II II rH cq n xp ctf

Candida tropicalis

SIS = 5-chloro-2-thienyl.

II II 1Λ CO x

X

Nr.291249

Table lb

<td rowspan="3">R "-</td><td colspan="4">-N + - II</td><td colspan="7" rowspan="3">ether derivatives - (CH) - Ar ' 2 n</td>

<td>Connection +)</td><td colspan="11">fungistatic effect (final evaluation at 100 y / ml)</td>

+) Name of the compounds

<td>A</td><td>1- [p-chloro-β- (2,4-dichlorobenzyloxy) -phenyl] -5-methylimidazole nitrate</td>

<td>B</td><td>1- [p-chloro-β- (2,4-dichlorobenzyloxy) -phenyl] -2,4-dimethylimidazole nitrate</td>

<td>C</td><td>(+) - 1- [2,4-dichloro-β- (2,4-dichlorobenzyloxy) -phenyl] -imidazole nitrate</td>

<td>D</td><td>(-) - 1- [2,4-Dichloro-β- (2,4-dichlorobenzyloxy) -phenyl] -imidazole nitrate</td>

No, 291,249

<td>Ε</td><td>1- [2,4,6-trichloro-O- (2,4-dichlorobenzyloxy) -phenyl] -imidazole nitrate</td>

<td>F</td><td>1- [2,4,6-trichloro-β- (2,6-dichlorobenzyloxy) -phenyl] -imidazole nitrate</td>

<td>G</td><td>1- [2,4-dichloro-β- (3,4-dimethylbenzyloxy) -phenyl] -imidazole nitrate</td>

<td>H</td><td>1- [2,4-dichloro-β- (p-iodobenzyloxy) -phenyl] -imidazole nitrate</td>

<td>I</td><td>1- [2,4-dichloro-β- (2-methoxy-4-nitrobenzyloxy) -phenyl] -imidazole nitrate</td>

<td>J</td><td>α - [1- (2,4-dichlorophenyl) -2- (1-imidazolyl) ethoxy] -p-tolunitrile nitrate</td>

<td>K</td><td>1- [3,4-dichloro-β- (2,4-dichlorobenzyloxy) -phenyl] -imidazole nitrate</td>

<td>L</td><td>1- [3,4-dichloro-β- (2,6-dichlorobenzyloxy) -phenyl] -imidazole nitrate</td>

<td>M</td><td>1- [3,4-dichloro-β- (3,4-dichlorobenzyloxy) -phenyl] -imidazole nitrate</td>

<td>N</td><td>1- [2,4-dichloro-β- (3,4-dichlorobenzyloxy) -phenyl] -imidazole nitrate</td>

<td>0</td><td>1-Co-chloro-β- (3,4-dichlorobenzyloxy) -phenyl] -imidazole nitrate</td>

<td>P</td><td>1- [β- (3,4-dichlorobenzyloxy) -p-fluorophenyl] -imidazole nitrate</td>

<td>Q</td><td>1- [3,4-dichloro-β- (p-chlorobenzyloxy) -phenyl] -imidazole nitrate</td>

<td>R</td><td>1- [2,6-dichloro-β- (2,4-dichlorobenzyloxy) -phenyl] -imidazole nitrate</td>

<td>S</td><td>1- [2,6-dichloro-β- (2,6-dichlorobenzyloxy) -phenyl] -imidazole nitrate</td>

<td>T</td><td>1- [2,6-dichloro-β- (p-chlorobenzyloxy) -phenyl] -imidazole nitrate</td>

<td>u</td><td>1- [2,5-dichloro-β- (p-chlorobenzyloxy) -phenyl] -imidazole nitrate</td>

<td>V</td><td>1- [2,5-dichloro-β- (2,6-dichlorobenzyloxy) -phenyl] -imidazole nitrate</td>

<td>w</td><td>1- [2,5-dichloro-β- (2,4-dichlorobenzyloxy) -phenyl] -imidazole nitrate</td>

<td>X</td><td>1- [2,5-dichloro-β- (2,5-dichlorobenzyloxy) -phenyl] -imidazole nitrate</td>

<td>Y</td><td>1- [β- (p-tert-butylphenzyloxy) -2,4-dichlorophenyl] -imidazole nitrate</td>

<td>z</td><td>1- [2,4-dichloro-β- (p-cumenylmethoxy) -phenyl] -imidazole nitrate</td>

Nr.291249

<td>AA</td><td>1- [2,6-dichloro-β- (p-methoxybenzyloxy) -phenyl] -imidazole nitrate</td>

<td>BB</td><td>1- [p-chloro-β- (2,6-dichlorobenzyloxy) -α, α-dimethylphenethyl] -imidazole nitrate</td>

<td>CC</td><td>1- [p-chloro-β- (p-fluorobenzyloxy) -α, α-dimethylphenethyl] -imidazole nitrate</td>

<td>DD</td><td>1- [p-chloro-β- (2,4-dichlorobenzyloxy) -α, α-dimethylphenethyl] -imidazole nitrate</td>

No. 291249

Table Ila

<td rowspan="8">4) Cii 'S Ό <3 1 f-4 "5 lez ~ s ci 2 ü S-Λ 1 0 1 "ßä- <2 = | \ 1 ci 2-2 = J °</td><td rowspan="3">Bactericidal effect (final evaluation at 10y / ml)</td><td>CO</td><td>© © © © © © © © ©</td>

<td>CQ</td><td>OOOOOO + + OO o</td>

<td>W H</td><td>© οοοοοοοο o</td>

<td colspan="2">Base or salt</td><td>wwwww www _w w _w oooooooooo o ZZZZ2 22 2 22 2 2222222222 2</td>

<td colspan="2">| - Ar '</td><td>af afT x krt * bJ * mκ-ί * h-Γ * OOUO hh * hn '* X XXXXt.iiX X »O <© <©» 0 ^ NNN Ci 40 40υ υ............. υι ι I 1 0 ϋ Ο U 1 ' rt ι-1 ι-t ι-1 r-I ι ι ι | rM Fi OÜOOO'tf'tf '^' i'O o 1 1 1 1 ι - - - - 1 ι ψ'ψ'ψ'ψτίιΙΝΝΝΝ'ψ τ} <</td>

<td colspan="2">ß</td><td>rHrHrH rHpKrHrHrHiHrH τΗ</td>

<td colspan="2">Ar</td><td>" nXX τ 'v' f - η * Α xxxx κ ι% ι ο ο ο ο η®%> Ο -Ν % 1 1 1 »Λ VV Λ V? "2" 2 2 " 20 ^^ 9 ^^. 000 ο Ο | 1w I ι ι ι 1 O ^ TbCQCQCQ ^^ CQOQ</td>

No. 291249

Table Ila (continued)

<td rowspan="3">Bactericidal effect (final evaluation at 10y / ml)</td><td>w</td><td>ooooooooooot 1 1 1 IO</td>

<td>CQ</td><td>OOOOOOOOOOOOOOOOO</td>

<td>X ri</td><td>qoooooooooooooooo</td>

<td>Base or salt</td><td></td><td>ooo "oo" o "oo" ooooooooo " § gg § g 1 § § g § § 1 § o § §</td>

<td colspan="2">rt</td><td>rt KEEEEEEEEEEggggEE</td>

<td colspan="2">kl</td><td>Xf en X « E - - Ε E XE rt * * rt * * v UEE y, y® * *, «φ VV υβ υ E> «SV υ V? ? ? u 1-4 1 L ffi. Ä Q »-1 | ld | JT0 Γα Τα Γλ UUfc.äOüüOU '* (SE(Oet <)UUU · * ¢ 1, ^ 1 ^ 1- ^ 05 ^ 0303 ^ 03</td>

Nr.291249

Table Ha (continued)

<td rowspan="3">Bactericidal effect (final evaluation at 10y / ml)</td><td>co</td><td>oooooooooooo</td>

<td>03</td><td>© + OOOOOOOO + +</td>

<td>X</td><td>oooooooooooo</td>

<td colspan="2">Base or salt</td><td>cn cn cn cn cn cn cn θη. _cn _cn xXxXxXx0 S ffiffiSESaEaaaSm a</td>

<td colspan="2">• Ui</td><td>co ffi m "hf *" * ü " ffi ffi 'f ffi' f ffi 'i | ® υ ® υ "ο» ~ ® , 1 η10 1 ri "1 η ·» μ · οι ηωIIU 1 U 1 U * τ * 'τ1 AU not Μ 1 Ά- '' Υ yt ri ffi 'ο, rt «® 1" η n 2' o. V mUffiVO UffiYYTffi ff <ot 1 ffltllt ff 1 03000 03 03 ^^^ 03 ^ 03 ^</td>

<td colspan="2">α</td><td>t-frHrrir-ii-lOiHr-1 r-IrHO ©</td>

<td colspan="2">t-4 <</td><td>«Cn cj cn n co cq cm Hm im ir-1 hm HM H-4 hm wm 4m 4m 44 4m 44 4m 44 4m 40 <0 "tft 40 <0 40 ϊ vvvvv? v CM CM r - f Λ CM CM «. *0 CM CM CM CM i-4 t-4 t J \ 4 i-4 «-M Γ J i- (rH> -M fM u, υτ.υυτϋϋυο • - ir; rt 3 1 rt I 1 1 1 M'ffiM'UUM'M'UM'M'MiMi -, ®. 1 1. "1 NUoa M'M'OJINM'NOJOJCM</td>

Test not performed 2. Staphylococcus haemolyticus

Third Streptococcus pyogenes xx) 5-chloro-2-thienyl.

Nr.291249

Table Ilb

<td colspan="4">R II H / ether derivatives CRxR2-CRAr - 0 ~ (CHZ) - Ar *</td>

<td rowspan="2">connection x</td><td colspan="3">Bactericidal effect (final evaluation at 10y / ml)</td>

x The names of the compounds are given in Table I b.

In view of the aforementioned activity against fungi and bacteria, the invention provides valuable preparations containing the compounds (X) or acid addition salts obtainable according to the invention as active ingredients in a solvent or a solid, semisolid or liquid diluent or carrier. Furthermore, the invention provides an effective method for controlling fungi and bacteria by using an effective fungicidal or bactericidal amount of these compounds (X) or salts thereof available. The compounds obtainable according to the invention can be used in suitable solvents or diluents and extenders, in the form of emulsions, suspensions, dispersions or ointments, on suitable solid or semisolid carrier materials, in ordinary or synthetic soaps, detergents and dispersants together with other compounds with arachnicidal, insecticidal , ovicidal, fungicidal and / or bactericidal

Effects or with inactive additives.

No, 291249

As solid carriers are suitable for the preparation of preparations in powder form a variety of inert, porous and powdery distribution agents of inorganic or organic nature, for example tricalcium phosphate, calcium carbonate, in the form of chalk or limestone, kaolin, bolus, bentonite, talc, diatomaceous earth and boric acid. Cork powder, sawdust and other finely powdered materials of 5 origin are also suitable as carrier materials.

The active ingredient is mixed with these carriers, for example by grinding them with them. The inert carrier can also be impregnated with a solution of the active ingredient in a volatile solvent and the solvent subsequently removed by heating or suction filtration under reduced pressure. By adding wetting agents and / or dispersants these 10 powdered preparations can also be made slightly wettable with water, so that suspensions are obtained.

The inert solvents used for the preparation of liquid preparations should preferably not be readily flammable, nor should they be as odorless and as nontoxic as possible for warm-blooded animals or plants in the environments in question. Suitable solvents for this purpose are high-boiling oils of, for example, vegetable origin and lower-boiling solvents having a flash point of at least 30 ° C., eg Isopropanol, dimethyl sulfoxide, hydrogenated naphthalenes and alkylated naphthalenes. Of course, solvent mixtures can also be used. The solutions can be prepared in the usual way, if appropriate using solubilizers. Other candidate liquid forms consist of emulsions or suspensions of the active ingredient in water or suitable inert solvents or also concentrates for the preparation of these emulsions, which can be adjusted directly to the required concentration. For this purpose, the active ingredient is mixed, for example, with a dispersing agent or emulsifier. The active ingredient may also be dissolved or dispersed in a suitable inert solvent and mixed simultaneously or subsequently with a dispersant or emulsifier.

It is also possible to use semi-solid excipients, such as creams, ointments, pastes or waxes, into which the active ingredients can optionally be incorporated using solubilizers and / or emulsifiers.

Vaseline and other ointment bases are examples of semi-solid carriers.

It is also possible to use the active ingredient in the form of aerosols. For this purpose, the active ingredient is optionally with the aid of suitable inert solvents as carrier liquids, for. B. difluorodichloromethane boiling at atmospheric pressure at temperatures below room temperature, or dissolved or dispersed in other volatile solvents. In this way solutions are obtained under pressure, which form on spraying aerosols, which are used for the destruction or control of

Fungi and bacteria, for example, in closed rooms and storage rooms and for application to the vegetation for the destruction of fungi or bacteria or to prevent the infestation with fungi or bacteria are particularly suitable.

The compounds obtainable according to the invention and the preparations containing them can be applied by the usual method. For example, fungi or bacteria or materials to be treated or protected from attack by fungi or bacteria may be suitably obtained with the compounds of this invention and with the preparations by dusting, sprinkling, spraying, brushing, dipping, lubricating, impregnating or otherwise be treated.

When the compounds obtainable according to the invention in combination with suitable Trägerstof45 fen, for example in solution, suspension, as dusts, powder, ointment, emulsion u.ähnl. Forms used is very high activity over a very wide range of dilutions. For example, concentrations of the active ingredient of 0.1 to 10% by weight, based on the weight of the preparation used, have been shown to be effective in controlling fungi or bacteria. Of course, higher concentrations can be used which are justified in the respective situation.

In the following examples, all parts are parts by weight unless otherwise stated.

Example 1; A mixture of 11 parts of N-acetylimidazole and 19 parts of phenacyl bromide in

Parts of acetonitrile are refluxed for 2 hours with stirring. The solvent is evaporated under reduced pressure. The residue is taken up in hot water and the solution is cooled and filtered. To the aqueous filtrate is added a solution of sodium carbonate in water until pjj 9. The product is precipitated immediately. It is filtered off and recrystallized twice,

No. 291249 namely first from hot water and then from a mixture of diisopropyl ether and 2-propanol. Hiebei l- (benzoylmethyl) -imidazole of melting point 114 to 117 ° C is obtained.

By repeating the experiment described in Example 1 using an equivalent amount of the corresponding ketone in place of phenacyl bromide, the following compounds are obtained:

1 - [(4-methylbenzoyl) methyl] -imidazole, m.p. 133-134 ° C. 1- (4-methylbenzoylmethyl) imidazole hydrochloride, mp 210.5-216 ° C,

1- (4-chlorobenzoylmethyl) imidazole hydrochloride, m.p. 228-229 ° C.

Example 2; To a solution of 20.4 parts of imidazole in 40 parts of methanol are added 10 23.3 parts of o-chlorophenacyl bromide. The mixture is stirred for 2 h at 0 ° C. The solvent is evaporated under reduced pressure and the residue poured into water. The product, 2 * -chloro-2- (imidazolyl) -acetophenone, is extracted with chloroform. From the free base remaining as the residue, the hydrochloride is prepared in the usual manner, after which, on recrystallization, first from a mixture of 2-propanol and diisopropyl ether and then from a mixture of methanol and diisopropyl ether 2 * -chloro-2- (1-imidazolyl) Acetophenone hydrochloride of melting point 186, 5 to 1 89 ° C is obtained.

Example 3; To a solution of 276 parts of p-fluoroacetophenone in 400 parts of dioxane and 640 parts of dry ether is added dropwise 320 parts of bromine while cooling on ice and stirring. The mixture is then brought to room temperature and the solvent removed under reduced pressure until an internal temperature of 110 ° C has been established. The residue is cooled on an ice-salt bath, whereupon 640 parts of acetone are added. At a temperature of 0 ° C, a solution of 528 parts of imidazole in 640 parts of methanol is added with stirring. The mixture is stirred for a further 3 days with cooling. The solvent is removed at normal pressure up to an internal temperature of 125 ° C. After cooling, 750 parts of chloroform and 500 parts of water are added to the residue after cooling. The chloroform layer is separated, stirred for 30 min, washed with water, dried, filtered and evaporated. From the residue containing l- (p-fluorophenacyl) imidazole, the hydrochloride is prepared in the usual manner. The crude salt is recrystallized twice from a mixture of 2-propanol, methanol and diisopropyl ether. The free base is re-released by treatment with an equivalent amount of sodium hydroxide. After Umkristal30 lisäfion from a mixture of 2-propanol and diisopropyl ether about 178 parts of l- (p-fluorophenacyl) -imidazole of melting point 149 to 155 ° C are obtained.

By repeating the experiment described in Example 3 using an equivalent amount of a corresponding methyl aryl ketone or 2-methylpropiophenone in place of p-fluoroacetophenone, the following compounds are obtained.

3'-Chloro-2- (1-imidazolyl) acetophenone nitrate, m.p. 179.7 ° C.

4'-Bromo-2- (1-imidazolyl) acetophenone, m.p. 164 ° C.

2 ', 4'-dichloro-2- (1-imidazolyl) acetophenone nitrate, m.p. 164.5 ° C.

2- (1-imidazolyl) -2 * methyl acetophenone nitrate, m.p. 165.5-167 ° C.

2- (1-imidazolyl) -2'-methoxyacetophenone hydrochloride, m.p. 208 ° C.

(l-imidazolylmethyl) -2-thienyl ketone nitrate, melting point 136 ° C.,

2- (1-imidazolyl) -2-methylpropiophenone nitrate, m.p. 167.5 ° C.

Example 4; To a cooled (5 to 15 ° C) slurry of 120 parts of imidazole in 125 parts of dimethylformamide is added portionwise 82 parts of 2- (5-chloro-2-thienyl) -acetyl bromide of the formula

CH - CO 2 \

Cl in 125 parts of dimethylformamide. After complete addition, the mixture is stirred for 2 h on ice. The reaction mixture is poured into water to give the product (5-chloro-2-thienyl) - (1-imide)

No. 291249 azolylmethyl) ketone is precipitated. The product is filtered off and taken up in 750 parts of chloroform and washed with water. The chloroform is evaporated. The residue is triturated in ether and filtered again to give the free base of melting point 190 to 106 ° C. From this fraction, 4.4 parts are converted into the nitrate. Hiebei are obtained after recrystallization of the crude solid salt from ethanol 3.7 parts of (5-chloro-2-thienyl) - (l-imidazolylmethyl) -ketonnitrat the melting point of 161.5 ° C.

By repeating the experiment described in Example 4, substituting, if necessary, the imidazole with an equivalent amount of the corresponding imidazole and the 2- (5-chloro-2-thienyl) acetyl bromide with an equivalent amount of a corresponding acetophenone or propiophenone, the following compounds are obtained:

4 * -chloro-2- (1-imidazolyl) -isobutyrophenone nitrate, m.p. 178.2 ° C.

4 * -chloro-2- (2-methyl-1-imidazolyl) -acetophenone, mp 209.5 ° C.

4 * -chloro-2- (2-ethyl-1-imidazolyl) acetophenone, m.p. 160 ° C.

4.Chloro-2- (2,4-dimethyl-1-imidazolyl) acetophenone, m.p. 185.8 ° C.

Example 5: To a stirred and hot (60 to 80 ° C) solution of 155 parts of p-chloroacetophenone in 250 parts of propylene glycol is added dropwise 160 parts of bromine. The mixture is further stirred overnight. The reaction mixture is poured into a dilute sodium hydroxide solution and the product is extracted with benzene. The extract is dried and evaporated under reduced pressure. The oily residue is distilled to give 220 parts of oily 2- (bromomethyl) -220- (p-chlorophenyl) -4-methyl-1,3-dioxolane of boiling point 131 to 133 ° C / 1.25 mm Hg. When the distillate is triturated in 400 parts of 2-propanol with cooling, the oil solidifies. It is filtered off and recrystallized from 2-propanol to give 2- (bromomethyl) -2- (p-chlorophenyl) -4-methyl-1, 3-dioxolane of melting point 71 ° C is obtained.

In the manner described in Example 5, using an equivalent amount of a corresponding ketone and a corresponding glycol in place of the acetophenone and the glycol, the following compounds are obtained:

2- (Bromomethyl) -2-o-tolyl-1,3-dioxolane, b.p. 113-115 ° C / 0.8 mm Hg. 2- (Bromomethyl) -2-p-tolyl-1,3-dioxolane, b.p. 135-137 ° C / 2.5 mm Hg. 2- (Bromomethyl) -2- (2,5-dichlorophenyl) -1,3-dioxolane, mp 61.5 ° C.

2- (bromomethyl) -2-m-tolyl-1,3-dioxolane, m.p. 59 ° C.

2- (bromomethyl) -2- (o-methoxyphenyl) -1,3-dioxolane, m.p. 99-100 ° C. 2- (bromomethyl) -2- (p-fluorophenyl) -1,3-dioxolane, m.p. 50 ° C.

Example 6: 37.8 parts of methyl 2-thienyl ketone are brominated with 48 parts of bromine in 48 parts of dioxane and 96% dry ether while being cooled and stirred. The solvent is removed under reduced pressure. To the residue are added 60 parts of ethylene glycol in 160 parts of toluene and a few crystals of p-toluenesulfonic acid. The mixture is refluxed for 15 hours with stirring in a water-trap device. The reaction mixture is cooled and the toluene layer separated, washed once with potassium carbonate solution and once with water, dried, filtered and evaporated under reduced pressure. The oily residue is distilled under reduced pressure from potassium carbonate to give 2- (bromomethyl) -2- (2-thienyl) -1,3-dioxolane of

Boiling point 95 ° C / 0.6 mm Hg is obtained.

By repeating the experiment described in Example 6 using an equivalent amount of a corresponding ketone and a corresponding glycol in place of the acetophenone and glycol used therein, the following dioxolanes are prepared:

2-bromomethyl-2- (o-chlorophenyl) -1,3-dioxolane, b.p. 130 ° C / 0.8 mm Hg,

2- (bromomethyl) -2- (m-methoxyphenyl) -1,3-dioxolane, m.p. 61 ° C,

2- (bromomethyl) -2- (2,3,4-trichlorophenyl) -1,3-dioxolane, m.p. 59, 5 ° C,

2-bromomethyl-2- (m-chlorophenyl) -1,3-dioxolane, boiling point 149 ° C / 0, 2 mm Hg.

Example 7: 154 parts of a solution of 23 parts of sodium in 600 parts of ethanol

Ethyl 5-methylimidazole-4-carboxylate. Then 440 parts of ethanol are evaporated. To the warm residue, 1600 parts of 2-diisopropyl ether are added. After cooling, this separates

Sodium salt of ethyl-5-methylimidazole-4-carboxylate, which is filtered off.

A mixture of 17.7 parts of the sodium salt of ethyl 5-methylimidazole-4-carboxylate,

Nr.291249

2-Bromomethyl-2- (p-chlorophenyl) -1,3-dioxolane (described by A. R. Patelin J. Pharm., Sci., 52 (6) [1963], pp.588 to 592), 22.5 Parts of potassium iodide, 30 parts of dimethylformamide and 4 parts of toluene is refluxed for 12 hours with stirring. The reaction mixture is cooled and treated with 400 parts of ether. The organic phase is washed three times with water, dried and treated with concentrated nitric acid in excess. The precipitated nitrate salt is filtered off and recrystallized from a mixture of 40 parts of absolute ethanol and 400 parts of diisopropyl ether to give ethyl 1- [2- (p-chlorophenyl) -1,3-dioxolan-2-ylmethyl] -5-methylimidazole-4 Carboxylate nitrate of melting point 130.3 ° C is obtained.

A mixture of 2 parts of this compound and 7.5 parts of a 10 N sodium hydroxide solution is refluxed for 15 minutes with stirring. Then 20 parts of water and then 4.5 parts of acetic acid are added, whereby the product is precipitated. It is filtered off and recrystallized from 80 parts of ethanol to give 1- [2- (p-chlorophenyl) -1,3-dioxolan-2-ylmethyl] -5-methylimidazole-4-carboxylic acid of melting point 258.3 ° C.

To 40 parts of paraffin oil are added portionwise 25 parts of 1- [2- (p-chlorophenyl) -1,3-dioxolan-2-yl15-methyl] -5-methylimidazole-4-carboxylic acid at 250 ° C. The mixture is heated to 270 ° C until no more carbon dioxide is formed. The reaction mixture is cooled and treated with 240 parts of ether. The solution is filtered and the filtrate is treated with concentrated nitric acid solution in excess. The precipitated nitrate is filtered off and recrystallized from a mixture of 120 parts of ethanol and 340 parts of diisopropyl ether, to give 1- [2- (p-chlorophenyl) -1,3-dioxolan20-2-ylmethyl] -5-methylimidazole nitrate, melting point 153. 6 ° C is obtained.

A mixture of 13 parts of 1- [2- (p-chlorophenyl) -1,3-dioxolan-2-ylmethyl] -5-methylimidazole,

100 Parts of acetic acid and 50 parts of dilute hydrochloric acid is heated under reflux with stirring for 18 h. The solvents are evaporated off and to the residue are added successively 100 parts of water and excess of sodium hydroxide to precipitate the product, 4'-chloro-2- (5-methyl-1-imidazolyl) -25-acetophenone. The product is filtered off and recrystallized from 10% of dimethylformamide (50 parts) to give 6.5 parts of 4-chloro-2- (5-methyl-1-imidazolyl) -acetophenone of melting point 123 ° C.

Example 8; To a stirred and cooled (5 ° C) suspension of 6 parts 2-bromo-2., 4'-6'-Trichloroacetophenone in 24 parts of methanol are added 0.3 parts of sodium borohydride. After the addition has taken place, the mixture is stirred on an ice-bath and then for 2 hours at room temperature. The mixture is cooled again to 5 ° C, whereupon a further 0.3 parts of sodium borohydride are added in portions. After the addition is first stirred for 1 h in an ice bath and then for a further hour at room temperature. Finally, a third portion of 0.3 part of sodium borohydride is added in portions at 5 ° C and the mixture is stirred for 30 min in an ice bath and 30 min 35 at room temperature. Then hydrochloric acid is added to pn 3 and the mixture is evaporated. The residue is taken up in 200 parts of boiling water. After cooling, the solution is extracted with carbon tetrachloride. The organic phase is washed with water, dried over magnesium sulfate and evaporated to give α- (bromomethyl) -2,4,6-trichlorobenzyl alcohol.

Example 9 4 parts of sodium borohydride are added in portions to a suspension of 40 parts of 1- (p-chlorobenzoylmethyl) -imidazole in 40,120 parts of methanol while cooling on ice and stirring. After 30 min, the reaction mixture is heated under reflux for 1 h with stirring and treated with 100 parts of water. The methanol is removed at atmospheric pressure. After addition of 16 parts of concentrated hydrochloric acid solution, the mixture is heated for 5 min with stirring at reflux. After cooling on an ice bath, ammonium hydroxide solution is added in excess to precipitate the desired alcohol product. The product is filtered off, washed with water and recrystallised from a mixture of dimethylformamide and water to give a- (p-chlorophenyl) -imidazole-1-ethanol

No. 291249

ch2- CHOH

Cl of melting point 180 ° C is obtained.

The experiment described in Example 9 is repeated with the difference that an equivalent amount of corresponding ketones is used to give as products the following alcohols, some of which have been converted by treatment in a conventional manner with the corresponding acid in said acid addition salt ;

a- (o-chlorophenyl) -imidazole-1-ethanol nitrate, melting point 143 ° C. α- (p-fluorophenyl) -imidazole-1-ethanol, melting point 146.5 ° C. a - (2,4-dichlorophenyl) imidazole 1-ethanol, melting point 136.5 ° C. a-o-tolylimidazole-1-ethanol nitrate, melting point 131 ° C. α-p-tolylimidazole-1-ethanol, melting point 155 ° C. α- (phenyl) -imidazole-1-ethanol α - (m-chlorophenyl) -imidazole-l-ethanol, melting point 109.8 ° C α- (p-bromophenyl) -imidazole-l-ethanol, melting point 188.5 ° C α- (o-methoxyphenyl) -imidazole-l -äthanolhydrochlorid, Melting point 171.5 ° C a - (5-chloro-2-thienyl) -imidazole-l-ethanol, melting point 131.5 ° C a - (2-thienyl) -imidazole-1-ethanol ß, ß -Dimethyl- a -phenylimidazole-1-ethanol, melting point 139 ° C a - (p-chlorophenyl) - ß, ß-dimethylimidazol-l-ethanol, melting point 187.5 ° C α- (p-chlorophenyl) -2-methyl-l-imidazoläthanoI , Melting point 165.5θΟ & - (p-chlorophenyl) -5-methylimidazole-1-ethanol, mp 194 ° C α- (p-chlorophenyl) -2,4-dimethylimidazole-1-ethanol, mp 128, 8 ° C a - (p-chlorophenyl) -2-ethyl-l-imidazolethanol, m.p. 151.5 ° C

Example 10; To a sodium 25 methoxydlösung prepared from 9.2 parts of sodium in 140 parts of methanol are successively added 27.2 parts of imidazole and 100 parts of dimethylformamide. The solvent is removed with stirring at normal pressure. At an internal temperature of l30 ° C (all the ethanol has been removed) 47 parts of α-chloromethyl-a-methylbenzylalkohol be added. The mixture is stirred for 1 h at 130.degree. After addition of 500 parts of water, the alcohol product is crystallized. The product is filtered off and crystallized from toluene to give a-methyl 30 -ot-phenylimidazol-1-ethanol of formula

Ν '

CH

I 2

CH2- c - oh

of melting point 119.5 ° C is obtained.

No. 291249

By repeating the experiment described in Example 10 using an equivalent amount of α-chloromethyl-α-methyl (p-chlorobenzyl) alcohol in place of α-chloromethyl-α-methylbenzyl alcohol, α- (p-chlorophenyl) -a-methylimidazole -l-ethanol obtained from the melting point 140 ° C.

Example 11 To a suspension of 4.5 parts of a 30% sodium methoxide solution in 15 parts of dimethylformamide and 16 parts of benzene are added 2 parts of imidazole. The solvent is distilled off until an internal temperature of 130 ° C is reached. Then, a solution of 5.4 parts of a- (bromomethyl) -3,4-dichlorobenzylalcohol in 5.5 parts of benzene (temperature 130 to 115 ° C) was added and the solvent was distilled off. The temperature is brought back to 130 ° C, whereupon 10 is slowly cooled to 40 ° C. After addition of 32 parts of diisopropyl ether, followed by addition of 50 parts of water and cooling, the product is crystallized. It is filtered off, washed with ether and boiled for a few minutes in 25 parts of dimethylformamide and 5 parts of water. The product is recrystallized at room temperature and separated to give oc- (3,4-dichlorophenyl) -imidazole-1-ethanol of melting point 148.7 ° C.

In the manner described in Example 11, but using an equivalent amount of a corresponding starting alcohol in place of α- (bromomethyl) -3,4-dichlorobenzyl alcohol, the following compounds are prepared:

a - (2,5-dichlorophenyl) -imidazole-1-ethanol, m.p. 145.3 ° C a - (2,6-dichlorophenyl) -imidazole-1-ethanol, m.p. 131.6 ° C a - (2.4 , 6-trichlorophenyl) -imidazole-1-ethanol, mp 151.8 ° C.

Game 12; This example illustrates the separation of a typical alcohol of formula (V) into its optical isomers.

154.8 parts of ct- (2,4-dichlorophenyl) -imidazole-1-ethanol (prepared according to Example 11) are suspended in 960 parts of acetone at 50.degree. By adding 107.4 parts of dibenzoyl-D-tartaric acid in 25 120 parts of acetone, a single-phase system is obtained. This solution is filtered at 50 ° C. The temperature is allowed to drop to 20 ° C (2 h) and the product is filtered off (filtrate A). It is washed with 400 parts of acetone. The product consists of the diastereoisomeric salt of (+) - a- (2,4-dichlorophenyl) -imidazole-1-ethanol with dibenzoyl-D-tartaric acid. The compound is a 1: 1 addition product because the analytical values are as follows:

(+)

OH

CH - CH- {^ -Cl (-) 01 = - /

COOH O

O HC - O - C / Γ7 / _CO - CH

COOH

The yield of dibenzoyl-D-tartaric acid compound with (+) - ct- (2,4-dichlorophenyl) -imidazole-1-ethanol (1: 1) is 101 parts (54.3%); a ° -20 ° (c = 1, methanol). By liberating the corresponding free base by conventional treatment of the salt with strong alkali 33.5 parts of (+) - a- (2,4-dichlorophenyl) -imidazol-l-ethanol from the melting point of 112 to 115, 2 ° C obtained. This is the dextrorotatory enantiomer with a specific rotation «q0 + 100 ° (c = 1, methanol).

The original mother liquor (filtrate A) thus contains 34.8 parts of (+) - α- (2,4-dichlorophenyl) -imidazole-1-ethanol, 77.4 parts of (-) - α- (2,4-dichlorophenyl) -imidazol-1-ethanol and 49 parts of dibenzoyl-D-tartaric acid. By acidification with 2-propanol / HCl, the hydrochlorides of (+) - «- (2,4-dichlorophenyl) -imidazole-1-ethanol and (-) - a- (2,4-dichlorophenyl) -imidazole-1 Ethanol abge40 separated. The yield is 84 parts, and the material has a specific rotation a -18 ° (c = 1, methanol), the (-) form is thus in excess of the (+) - form.

However, part of the (+) - <x- (2,4-dichlorophenyl) -imidazole-1-ethanol remains in solution, since it is possible after filtration of the hydrochloride, from the filtrate a further 14 parts (+) - a- (2,4-dichlorophenyl) -imidazole-l-ethanol to isolate. This compound is filtered off. The filtrate is evaporated and the residue dissolved in water. This aqueous solution is made alkaline and extracted with chloroform. The solvent is evaporated and the residue is crystallized from acetone to give 14 parts of (+) - a- (2,4-dichlorophenyl) -imidazole-1-ethanol. This compound has a specific rotation ctp of -80 ° (c = 1, methanol). This means that these 14 parts of 10% (+) - ot- (2,4-dichlorophenyl) -imidazol-l-ethanol and 90% (-) - a- (2,4-dichlorophenyl) -imidazole-l-ethanol (assuming that the pure enantiomer has a specific rotation of -100 °).

The optical purification of this (-) - enriched fraction is carried out as follows: A crystalline salt is precipitated by adding 3 parts of dibenzoyl-D-tartaric acid to a solution of 11 parts (taken from the above 14 parts) in 80 parts of acetone consisting of the dibenzoyl-D-tartaric acid salt of (-) - a- (2,4-dichlorophenyl) -imidazole-1-ethanol (1: 2). The specific rotation οίρ ° is -100 ° (c = 1, methanol). This salt has the following structure according to the analysis values:

-N

COOH 'NOH

O HC (-) ch2-ch- ^ ci (-) // \ _ /

OC - / ^

-CO-CH ci

COOH

A sample of 7 parts of this diastereoisomeric salt gives after release of the free base

3 Parts of (-) - α- (2,4-dichlorophenyl) -imidazole-1-ethanol of melting point 111.4 to 113.4 ° C with a specific rotation a® of -99 ° (c = 1, methanol).

Example 13; A solution of 140 parts of imidazole, 240 parts of 2-phenylethylene oxide, 400 parts of denatured absolute ethanol and 8 parts of pyridine is heated to reflux temperature (here an exothermic reaction takes place, which requires cooling with an ice-bath). When the formation of heat ceases (about 15 to 30 minutes), the mixture is allowed to cool to 50 ° C. After addition of 240 parts of diisopropyl ether, the mixture is poured into 1000 parts of water. The crude product is filtered off after cooling, triturated in ice-cold acetone, filtered again, washed with ice-cold acetone and then with water to give 1- (β-hydroxyphenylethyl) -imidazole from

Melting point 149 to 150 ° C is obtained.

80 Parts of 1- (β-hydroxyphenylethyl) imidazole are dissolved in 250 parts of dry hexamethyl phosphoric triamide at about 40 ° C, with a foam contraceptive added. This solution is added over 1 h to 22 parts of a sodium hydride dispersion in 100 parts of dry hexamethylphosphorotride while cooling to 5 to 15 ° C. After completion of the addition leaves the mixture of the heating to room temperature (about 30 min). The mixture is stirred at 45 to 50 ° C for 1 h and then cooled to 5 ° C whereupon 80 parts of p-chlorobenzyl chloride are added while maintaining the temperature below 25 ° C. The mixture is stirred for 30 min at room temperature, then warmed to 45 ° C and allowed to cool to room temperature (about 1 h). After addition of 1500 parts of water, the ether product, 1- [ß- (p-chlorobenzyloxy) -phenyl] -imidazole of the formula

CH - CH - O - CH - S - Cl 2 I 2 \ = /

No. 291249 extracted three times with ether. The combined extracts are washed with water, after which excess nitric acid is added. After cooling, the precipitated nitrate is filtered off, triturated twice in 40% acetone / ether and dried under reduced pressure to give 1- [β- (p-chlorobenzyloxy) -phenyl] -imidazole nitrate of melting point 132 ° to 134 ° C.,

In the manner described in Example 13, but using in each case an equivalent amount of a corresponding imidazole alcohol and an equivalent amount of the corresponding benzyl halide in place of 1- (β-hydroxyphenylethyl) imidazole and p-chlorobenzyl chloride, the following compounds are prepared.

1-tp-chloro-β- (2,4-dichlorobenzyloxy) -phenyl] -2-methylimidazole nitrate, m.p. 117 ° C 10 l- [p-chloro-β- (2,6-dichlorobenzyloxy) -phenyl] -2- methyl imidazole nitrate, m.p. 162.5 ° C 1- [p-chloro-β- (2,6-dichlorobenzyloxy) -phenyl] -2-ethylimidazole nitrate, m.p. 146 ° C 1- [p-chloro-β- (2,4-) dichlorobenzyloxy) phenethyl] -2-ethylimidazole nitrate, m.p. 134, 5 ° C.

Example 14; To a heated under stirring reflux of 40 parts of benzene and 35 parts of dimethylformamide (both solvents previously azeotropically dried) are successively 15 1.6 parts of sodium hydride and 7.7 parts of a- (2,4-dichlorophenyl) -imidazol-l- given ethanol (cooling on ice is necessary). After the addition is heated for a further 30 min with stirring at reflux. Then 7.8 parts of 2,6-dichlorobenzyl chloride are added, whereupon the mixture is heated for a further 3 h with stirring at reflux. The reaction mixture is poured into water and the product, 1- [2,4-dichloro-β- (2,6-dichlorobenzyloxy) -phenyl] -imidazole, is extracted with benzene. The extract 20 is washed twice with water, dried, filtered and evaporated under reduced pressure. The residue remaining as a base is dissolved in a mixture of acetone and diisopropyl ether. To this solution is added a concentrated nitric acid solution in excess. The precipitated nitrate salt is filtered off and recrystallized from a mixture of methanol and diisopropyl ether to give 1- [2,4-dichloro-β- (2,6-dichlorobenzyloxy) -phenylethyl] -imidazole nitrate of melting point 179 ° C.

In the manner described in Example 14, but using an equivalent amount of the corresponding imidazole alcohol in place of a- (2,4-dichlorophenyl) -imidazole-1-ethanol and using an equivalent amount of a corresponding benzyl halide instead of

2,6-dichlorobenzyl alcohol, the following compounds are prepared;

l- (β-benzyloxyphenethyl) -imidazole nitrate, melting point 93 ° C 1- [2,4-dichloro-β- (m-methoxybenzyloxy) -phenyl] -imidazole nitrate, m.p. 115, 5 ° C 1- [2,4-dichloro - ß - (o-fluorobenzyloxy) -phenyl] -imidazole, melting point 146, 5 ° C l- [2,4-dichloro-ß - (p-fluorobenzyloxy) -phenyl] -imidazolnitrate, melting point l4l ° C l- [2 , 4-Dichloro-β- (p-methoxybenzyloxy) -phenyl] -imidazole nitrate, m.p. 148 ° C.

Example 15; A suspension of 5 parts of a- (p-chlorophenyl) -imidazole-1-ethanol and 1 part of sodium hydride in 27 parts of dry tetrahydrofuran is refluxed for 2 hours with stirring, whereupon evolution of hydrogen ceases. After addition of 30 parts of dimethylformamide and 4, 8 parts of p-chlorobenzyl chloride, the mixture is heated for 2 h with stirring at reflux. The tetrahydrofuran is evaporated at atmospheric pressure and the dimethylformamide solution poured into water.

The product is extracted with benzene. The extract is washed with water, dried, filtered and evaporated under reduced pressure. The residue is washed with petroleum ether. The petroleum ether is decanted, and from the remaining as a residue oily free base, 1- [p-chloro-ß- (p-chlorobenzyloxy) -phenyläthyl] imidazole, the sodium salt in the usual manner from nitric acid in

2-propanol produced. The crude solid salt is filtered off and from a mixture of 2-propanol and

Recrystallized diisopropyl ether to give l- [p-chloro-ß- (p-chlorobenzyloxy) phenylethyl] -imidazolnitrat of melting point 155 ° C.

The O-alkylation process described in Example 15 is repeated except that an equivalent amount of a corresponding alcohol and an equivalent amount of a corresponding halide are used as starting materials, respectively. The following imidazole ethers are obtained;

Nr.291249

<td>salt</td><td>oooooooooooooooooo EEEEEEESEEEEgggEEE eeeeeeeeeeeeeeeeee</td>

<td>Melting point (° C) Boiling point / mm / Hg</td><td>ß ß ß lss ß ß ß ß ßßß co w c © cT © σΓ o * ι-f co © * w σΓ ci o * ß crcooJc-cocicooawcqrHcococ-cococaci t-irHrHrHrH rHrHrHrH-rH rHrHrHrHrHt-lrH rH</td>

<td>• km</td><td>χί rfi jd xj xsjsxi c? xs CL, O, CU CU CU CU Oh 0 « t i ι i iii _L i I- (r-4 «-H r -I r-4 ^ -4 r-4 Γ2 rH Oh CU CU "rH" Η Η Η C C C C C C C Oh Oh Oh r H H Oh ι ι ι ι 73 73 73 Ό 1 1 Ό Ό Ό ι γ ι Ό ό) ( υ υ ο ό, β. ο, & υ υ ο, ο, ο. υ λ υ a. S u cu cu cu ό * oo oo cu Oh oo * o cu o cu d o o</td>

<td>fi</td><td>rHrHrHrHrHrHrHrHrH-l-rHrHrHrHrHrHrHrHi</td>

<td>Ar</td><td>rfi X3 a- S ffi jrt Oh «r * 4 1» OI | , CU CU Q CU Oh, oh Oh 7727 ^ 70041^^41 22721 · RH t Ι «__ · lh ^^ H rM. .. 1 ΓΗ uuftü • · 1 . 1 1 1 1 1 1 1 1 Xi X3 l I - ί »O 0 O CU CU 0 O CU O CU O Oh cu cu CU 0 CU</td>

<td>04 CD</td><td>ΗΗ ΗΜΗ-ΙΚΗΙ-ΓΗΗΗΙτΗΗΜΧτΗΙη-ΙΡτΗΤ ^ Τ ^ Τ ^ Τ ^ Τ ^ Τ ^ Τ ^</td>

<td>w CD</td><td>7 'h hm rM hm ht rrn to him "p4 hm h h h TM 7" * 77 TM 7 ** 77 hr1 7 "· "IHL UM HHHH ll UH-lhUhUl-HTJ LLJ Lt. MbUH-thUtLtHU</td>

<td>CD</td><td>eeeeeeeeeeeeSSSSee</td>

No. 291249

Continuation:

<td>Melting point (° C) Boiling point / mm / Hg</td><td><-s th O* io lo lo lo io lo oo oo © LO 05 Often O r ~ T rH Th LO O CO 5 S S2 S 2 oooooooLocoiccacaxii ^ oo 3ΏΞ »w 1 f {| | Hl i tH tH r-( O 05 ri</td>

<td><</td><td>n 'xs fC 43 ö Qm CU © fe .2 7.7 , 1 t-4 rM i <i-1 £ MP OOO £ 3 pounds Λ., ΏίΐΟ ''0· '' !! > · iSSSSo a. £ o on o. , , ι ι ι ι ι i - • 'Llh' ^ HGÖ CU CU CU OOOO CU LO CU CU CU GGG</td>

<td>w d</td><td>O EEEEEEEEEEKKSEEE</td>

<td>d</td><td>EEEEEEEEEEEEEEEE</td>

Nr.291249

Continuation:

<td>salt</td><td>co cq eo co cq cq co co cq co co cq cq OOOOOOO oOOOO a) OO EEEEEEEJSggBS iS gg EEEEEEEmEEEEmEE</td>

<td>Melting point (° C) Boiling point / mm / Hg</td><td>«3 rHc-C-CDrtmcONC-OOCOC- t * - * © co οό οό oo τΒ o co co co co co lo co fTf <OCO ^ CtC-V> C "OCt-OOCOCQ ι-l tH rH rH rH rH rH rH 04 rH rH rH rH</td>

<td>c</td><td>rHrHrHrHrHrHrHrHtHrHrHt-HrHrHrH</td>

<td>Ar</td><td>43 fixiÄÄÄxjxiiJxixifJx: Qh ß-O Oh O-Qt Om Gm Om Qh P- »Oh CU 1 1 1 1 lt 1 ttttt rH for H ι-1 rH r * H t * H ι-1 »-H rH i <r-1 υ - γυυυυυουυυυ 1 7? .rH 1 ι I ι 1 ι 1 1 ι ι ι • rH Oh pG »0 · ι-1» rH «rH rH« rH · ι-Η · ι-Η «ι-H« rH »rH * rH -3 1 0.7-0-3-3-3-3-3-0-0-3-3-3 ιrt · o. ' 1 1 '' '' 1 '' ' ο υ tu, co CD CO Oißißißiß ooo ο O GGC4C4O4 O 04 04 04 04 Ο Ο O</td>

<td>Oil CD</td><td>ΕΕΕΕΕΕΕΕΕΕΕΕΕΕ®</td>

<td>w CD</td><td>EEEKKEEKEEXEKKK</td>

<td>CD</td><td>eeeeeeekeeeekee</td>

No. 291249

Continuation:

<td>salt</td><td>oooooooooooooo xeeexxexsexeee</td>

<td>Melting point (° C) Boiling point / mm / Hg</td><td>oococaocaor HLOrHOioocaooca Mi'cacOOiOi ^ OrHOOCao'oOt-CO M <C-CarHO5rH © C000 <OCOcql>!> ΓΗγΗγΗγΗγΗγΗγΗγΗγΗγΗγΗγΗγηιΗ</td>

<td>Ar *</td><td>£ XJ Ä X! xj xj xi ft · XJ XJ Cu CU CM 0-1 «- ('GhPmLÄ Λ ΛΛΛ O Ο Λ Λ 1 a. oooooo-S-aooT # '1 _ <1 1 £! *> .0 ι 1.-1 - ft. Ο x Xl -. -. -1 ft. 1 t xj xj Ό i · 5) T3 ft. Ό Ό T3 I OtcoTSO i ft. ± w 1 1 «ll 3} ~ 'CU ·, ΓΛ StO & uC ^ CUOUSHiG - '^0 - Ψ i «.i μ« «» γ * ιι 0.01 0.0 O 03 (XO 03 O 03 tj ft. Ft.</td>

<td>Ar</td><td>r3 r3 xj x! xi ft · ft. x: xj xj p, CU Cb *. * Qi P-ι O4 T 1 1 Ε Π · '1 , -1 r-) (JU »-1 r-t O _, xi x; ^ UO'ä'dOUU • pH X Ph PL. | 1 ft * X! X * 1 1 Xj Xj Xj XJ 1 1 1, - «Γ-ίΐ'Ό'βςοςαΌ'Ο ^ Ϊ "R-lr-Hr-tr-SRAI l | t _ · 1 · ® Ο Ο Ο T, O ft. <X -ψ «<ft. Ft.« Ft 03 CU Cu o. BE o, d 0 «ci d 0 0 '</td>

<td>od</td><td>KffiXXEEEEEEEEEE</td>

No. 291249

At the age of 16; 7.9 parts of a- (p-chlorophenyl) -5-methylimidazol-1-ethanol are added in portions to a warm mixture of 1.66 parts of ethyl sodium hydride in 45 parts of tetrahydrofuran at 50 ° C. with stirring. After the addition is stirred after 3 h at the reflux temperature. Then, 7.3 parts of 2,4-dichlorobenzyl chloride are added, whereupon the mixture is heated under reflux for a further 5 h. The reaction mixture is cooled and treated with 240 parts of ether. The ether phase is washed four times with water and dried. After addition of concentrated nitric acid in excess, the salt is precipitated. The salt is filtered off, triturated with ether acetate and recrystallized from a mixture of 2-propanol and diisopropyl ether (1: 9 by volume), giving 1- [p-chloro-β- (2,4-dichlorobenzyloxy) -phenyl] -5-methylimidazole nitrate from the melting point

150.7 ° C is obtained.

By repeating the procedure described in Example 16, but using an equivalent amount of a- (p-chlorophenyl) -2,4-dimethylimidazole-1-ethanol or 2-ethyl-4 (5) -methylimidazol-1-ethanol (Windaus and coworkers, Ber. 5513, 3706 [1922]) instead of a- (p-chlorophenyl) -5-methylimidazole-1-ethanol, the following compound is prepared:

1- [p-chloro-β- (2,4-dichlorobenzyloxy) phenethyl] -2,4-dimethylimidazole nitrate, m.p. 145.1 ° C.

Example 17: A mixture of 8.7 parts of a- (2,4-dichlorophenyl) -imidazole-1-ethanol hydrochloride and 3.4 parts of sodium hydride in 40 parts of benzene and 35 parts of dimethylformamide is stirred while cooling on ice (the solvents have previously been dried azeotropically). Next, 3 parts of manganese dioxide and then 8 parts of p-nitrofluorobenzene are added. The mixture is stirred for 3 h at room temperature. The reaction mixture is filtered through kieselguhr and water is added. The product is extracted with benzene and the extract dried, filtered and evaporated under reduced pressure. From the residual free base, the nitrate is prepared in the usual way in acetone. The precipitated solid salt is filtered off and recrystallized from a mixture of methanol and diisopropyl ether to give 1- [2,4-dichloro-β- (p-nitrophenoxy) -phenyl] -imidazole nitrate of melting point 167 ° C.

In the manner described in Example 17, but using an equivalent amount of 2,4-dinitrochlorobenzene in place of p-nitrofluorobenzene, becomes 1- [2,4-dichloro-β- (2,4-dinitrophenoxy) phenylethyl] -imidazole nitrate obtained from the melting point 167.5 ° C.

EXAMPLE 18 To a mixture of 13.5 parts of iron, 10 parts of ammonium chloride and 150 parts of water, heated to reflux while stirring, are added in portions 20 parts of 1- [2,4-dichloro-β- (p-nitrophenoxy) -phenyl] -imidazole nitrate given. The mixture is refluxed for an additional 6 hours with stirring. The reaction mixture is cooled on an ice bath and treated with methylene chloride. The mixture is filtered through kieselguhr. From the filtrate, the methylene chloride layer is separated from 35, dried, filtered and evaporated under reduced pressure. The residue is recrystallized from diisopropyl ether to give l- [β- (p-aminophenoxy) -2,4-dichlorophenethyl] imidazole of melting point 94 ° C.

By using an equivalent amount of 1- [p-chloro-β- (p-nitrophenoxy) -phenyl] -2-ethylimidazole in the reduction of the nitro compound to the amine compound described in Example 20, the product is 1- [p-chloro-β- ( p-aminophenoxy) -phenyl] -2-ethylimidazole,

Example 19 To a mixture of 10.32 parts of (+) - a- (2,4-dichlorophenyl) -imidazole-1-ethanol in 75 parts of tetrahydrofuran is added portionwise with stirring 2.1 parts of 50% sodium hydride. The mixture is refluxed for 1 h with stirring. Then 44 parts of dimethylformamide and then 8.7 parts of 2,4-dichlorobenzyl chloride in 22 parts of dimethylformamide zu45 set. After the addition is stirred after 2 h at the reflux temperature. The tetrahydrofuran is distilled off under reduced pressure and the residue is poured into 200 parts of water. The product is extracted several times with xylene (successively with 160, 80 and 40 parts). The combined extracts are dried over magnesium sulfate, filtered and evaporated. The residue is dissolved in 36 parts of tetrahydrofuran and the solution is acidified with a concentrated nitric acid solution. The nitrate salt crystallizes at room temperature. It is filtered off and dried to give (+) - 1- [2,4-dichloro-β- (2,4-dichlorobenzyloxy) -phenyl] -imidazole nitrate. Melting point 135.3 ° C; p + 59 ° (c = 1, methanol).

Example 20 To a mixture of 10.32 parts of (-) - a- (2,4-dichlorophenyl) -imidazole-1-ethanol in 75 parts of tetrahydrofuran is added portionwise with stirring 2.1 parts of 50% sodium hydride. The mixture is refluxed for 1 h with stirring. Then 44 parts Dime31

No. 291249 thylformamide and then added 8.7 parts of 2,4-dichlorobenzyl chloride in 22 parts of dimethylformamide. After the addition is stirred for a further 2 h at the reflux temperature. The tetrahydrofuran is distilled off under reduced pressure and the residue is poured into 200 parts of water. The product is extracted several times with xylene (successively with 160, 80 and 40 parts). The United

Extracts are dried over magnesium sulfate and evaporated. The residue is dissolved in 36 parts of tetrahydrofuran and the solution is acidified with a concentrated nitric acid solution. The nitrate crystallizes at room temperature after addition of 32 parts of diisopropyl ether, the salt is filtered off and dried to give (-) - l- [2,4-dichloro-ß- (2,4-dichlorobenzyloxy) ~ phenethyl] - imidazole nitrate. Melting point 135 ° C; -58 ° (c = 1, methanol).

Example 21;

A. A solution of 188 parts of dl-α-phenyl-1-imidazolethanol in 600 parts of 2-propanol is prepared. To this solution is added a solution of 118 parts of (+) camphor-10-sulfonic acid monohydrate in 200 parts of 2-propanol. The resulting precipitate is filtered off to give the crude (-) - a-phenyl-1-imidazole ethanol (+) - camphorsulfonate; α p - 15 ° (c = 1, methanol). (The filtrate ent 15 keeps the (+) - a-phenyl-l-imidazolethanol (+) - kampfersulfonat.) 163 parts of the crude (-) - a-phenyl-l-imidazoläthanol - (+) - kampfersulfonats are from 1000 Recrystallizing water to give the pure compound; -15 ° (c = 1, methanol). This pure fighter sulfonate is dissolved in water. The solution is made alkaline with ammonium hydroxide and the resulting precipitated free base is filtered off to give (-) - a-phenyl-1-imidazolethanol of melting point 147.8 to 152.2 ° C; - 42 ° (c = 1, methanol).

B, A mixture of 5.5 parts of sodium hydride and 25 parts of hexamethylphosphoramide (previously dried over sodium hydride) is cooled to 10 ° C. While maintaining the temperature below 15 ° C, a solution of 20 parts of (-) - α-phenyl-1-imidazole ethanol in 65 parts of hexamethylphosphoramide is added. After the addition has taken place, the mixture is first stirred at room temperature for 30 minutes and then at a temperature between 45 and 50 ° C. for 1 hour. The mixture is cooled again to 5 ° C, whereupon 20 parts of p-chlorobenzyl chloride are added. The mixture is stirred at room temperature for 30 minutes, warmed to 50 ° C and left to cool to room temperature while stirring. After adding 500 parts of water, the product is extracted three times with toluene (successively with 240, 160 and 80 parts). The combined extracts are washed with 250 parts of water, over

Dried magnesium sulfate and evaporated. The residue is taken up in 40 parts of toluene, followed by the addition of concentrated nitric acid. The precipitated nitrate salt is filtered off with suction and washed with diisopropyl ether to give (-) - l- [β- (p-chlorobenzyloxy) -phenyl] -imidazole nitrate. A sample of 10 parts is recrystallized from benzene and stirred in diisopropyl ether to give 9 parts of (-) - 1- [β- (p-chlorobenzyloxy) -phenyl] -imidazole nitrate from

Melting point 78 ° C, α® - 85 ° C.

Contents19

77 members in 28 offices

This recordMember, by publication datePriority claim18 more offices are in the list below

Priority claims2

Priority claims
Document	Office	Kind	Date
75372968	United States of America	A	1968-08-19
84876769	United States of America	A	1969-07-23

Members77

Family members, oldest first
Document	Office	Kind
LU59301A1	Luxembourg	A1	1970-01-06
BE737575A	Belgium	A	1970-02-18
IE33297L	Ireland	L	1970-02-19
NL6912331A	Netherlands (Kingdom of the)	A	1970-02-23
DE1940388A1	Germany	A1	1970-02-26
FR2015913A1	France	A1	1970-04-30
ZA695965B	South Africa	B	1971-03-31
ZM13669A1	Zambia	A1	1971-05-21
ES370593A1	Spain	A1	1971-07-01
AT291249BThis record	Austria	B	1971-07-12
BE761412R	Belgium	R	1971-07-12
NL7100072A	Netherlands (Kingdom of the)	A	1971-07-15
DE2063857A1	Germany	A1	1971-07-22
CH511238A	Switzerland	A	1971-08-15
GB1244530A	United Kingdom	A	1971-09-02
FR2081427A2	France	A2	1971-12-03
AT296289B	Austria	B	1972-02-10
US3658813A	United States of America	A	1972-04-25
AT299194B	Austria	B	1972-06-12
US3674667A	United States of America	A	1972-07-04
CH526553A	Switzerland	A	1972-08-15
ZA71174B	South Africa	B	1972-08-30
IL32840A	Israel	A	1972-09-28
NO126180B	Norway	B	1973-01-02
CH532585A	Switzerland	A	1973-01-15
US3717655A	United States of America	A	1973-02-20
BR6911658D0	Brazil	D0	1973-04-19
GB1318590A	United Kingdom	A	1973-05-31
US3740256A	United States of America	A	1973-06-19
US3740325A	United States of America	A	1973-06-19
SU408476A3	Soviet Union (until 1991)	A3	1973-12-10
SE363330B	Sweden	B	1974-01-14
ES390807A1	Spain	A1	1974-03-16
US3808115A	United States of America	A	1974-04-30
IE33297B1	Ireland	B1	1974-05-15
IT974527B	Italy	B	1974-07-10
FR2081427B2	France	B2	1974-08-23
US3839574A	United States of America	A	1974-10-01
RO56625A	Romania	A	1974-11-11
FI751886A	Finland	A	1975-06-25
FI751886A7	Finland	A7	1975-06-25
OA03898A	African Intellectual Property Organization (OAPI)	A	1975-08-14
JPS5039664B1	Japan	B1	1975-12-18
JPS5039665B1	Japan	B1	1975-12-18
DK579675A	Denmark	A	1975-12-19
JPS51115B1	Japan	B1	1976-01-05
IN139930B	India	B	1976-08-21
SU557755A3	Soviet Union (until 1991)	A3	1977-05-05
DK135769B	Denmark	B	1977-06-20
SE394432B	Sweden	B	1977-06-27
SE395690B	Sweden	B	1977-08-22
FI52858B	Finland	B	1977-08-31
DE1940388B2	Germany	B2	1977-09-15
DK135769C	Denmark	C	1977-11-21
FI52858C	Finland	C	1977-12-12
ES393167A2	Spain	A2	1977-12-16
DE1940388C3	Germany	C3	1978-05-11
DK137947B	Denmark	B	1978-06-12
SU617011A3	Soviet Union (until 1991)	A3	1978-07-25
CS184753B2	Czechoslovakia (until 1993)	B2	1978-09-15
CS184771B2	Czechoslovakia (until 1993)	B2	1978-09-15
CS184772B2	Czechoslovakia (until 1993)	B2	1978-09-15
YU212669A	Yugoslavia, later Serbia and Montenegro (until 2006)	A	1978-09-18
DK137947C	Denmark	C	1978-11-06
DK139255B	Denmark	B	1979-01-22
DE2063857B2	Germany	B2	1979-02-22
YU34194B	Yugoslavia, later Serbia and Montenegro (until 2006)	B	1979-02-28
NL159662B	Netherlands (Kingdom of the)	B	1979-03-15
FI55434B	Finland	B	1979-04-30
DK139255C	Denmark	C	1979-06-18
DK140213B	Denmark	B	1979-07-09
FI55434C	Finland	C	1979-08-10
CS194656B2	Czechoslovakia (until 1993)	B2	1979-12-31
DK140213C	Denmark	C	1980-01-14
MX3611E	Mexico	E	1981-03-31
NL169071B	Netherlands (Kingdom of the)	B	1982-01-04
NL169071C	Netherlands (Kingdom of the)	C	1982-06-01

1-(beta-aryl-ethyl)-imidazole ethers and amines

Abstract

Term

-N

(VII)

RCC-OM

I

-N

N

N (II)

HC

N'F

X

O

X

CH

OH

COOH O

COOH

-N

COOH 'NOH

COOH

Priority claims2

Members77

Events

Numbers

Titles2

Classification