DK157300B - ANALOGY PROCEDURE FOR THE PREPARATION OF IMIDAZOLD DERIVATIVES - Google Patents

Description

1 DK 157300 B

The present invention relates to an analogous process for the preparation of novel racemic or optically active 1- (2-Ar-4-R-1,3-dioxolan-2-yl-methyl) imidazole derivatives which are valuable valuable drug-active antifungal and antibacterial agents.

The novel imidazole derivatives are prepared according to the present invention

DK 157300 B

(CH)

"I I

or are acid addition salts thereof, wherein:

Ar represents phenyl, thienyl, halogen thienyl, naphthyl or a phenyl group having 1-3 substituents, each of which is halogen, alkyl of 1-6 carbon atoms, alkyloxy of 1-6 carbon atoms, nitro and cyano, and R represents alkyl of 2 to 10 carbon atoms, alkyloxymethyl, wherein the alkyl group has from 1-10 carbon atoms, alkenyl, alkenyloxymethyl, wherein the alkenyl group has 2-10 carbon atoms, 2-propynyloxymethyl, hydroxymethyl, halomethyl, aryl, arylalkyl, wherein the alkyl moiety has 1-6 carbon atoms, aryloxymethyl, arylthiomethyl or arylmethoxymethyl wherein the aryl group is phenyl, naphthyl, mono- or di-halo naphthyl, or a phenyl group having 1-3 substituents each being halogen, alkyl of 1-6 carbon atoms, alkyloxy of 1-6 carbon atoms, cyano, nitro, phenyl, phenylmethyl, benzoyl, halo-benzoyl, alkylcarbonyl with 1-6 carbon atoms in the alkyl moiety, alkyloxycarbonyl with 1-6 carbon atoms in the alkyl moiety or trifluoromethyl, provided that only one of the substituents when other substituents present may be phenyl, phenylmethyl, benzoyl and halogenobenzoyl.

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3 In the definition of R, the term "alkyl of 2-10 carbon atoms" should include straight and branched hydrocarbon groups having from 2-10 carbon atoms such as e.g. ethyl, propyl, 1-methylethyl, 1,1-dimethylethyl, butyl, pentyl, hexyl, heptyl, octyl and decyl. In the definition of alkyloxymethyl, "alkyl" should include straight and branched hydrocarbon groups having from 1 to 10 carbon atoms such as e.g. methyl and the above alkyl groups. "Alkyl of 1-6 carbon atoms" means a straight or branched alkyl group having from 1-6 carbon atoms such as e.g. methyl, ethyl, propyl, 1-methylethyl, 1,1-dimethylethyl, butyl, pentyl and hexyl. "Alkenyl" refers to straight-chain and branched alkenyl groups having from 2 to 10 carbon atoms, e.g. ethenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 2-hexenyl and 2-decenyl. The term "halogen" is generic for halogens having an atomic weight of less than 127, i.e. fluorine, chlorine, bromine and iodine.

The compounds of formula (I) are prepared by the method according to the invention, which is characterized by the characterizing part of the claim.

According to a first process variant, an imidazole (II) having a correspondingly reactive ester of formula (III) is reacted wherein Ar and R have the meanings set forth above and wherein W denotes a reactive ester function such as e.g. halogen, 4-methylbenzenesulfonate, methylsulfonate and the like. Preferred reactive esters are halides and more particularly bromides and chlorides.

In one embodiment of the reaction between the imidazole (II) and (III), the imidazole (II) is first converted to a metal salt thereof by treatment with a metallizing agent such as e.g. a metal alkoxide, e.g. sodium or potassium methanolate or a metal hydride such as sodium hydride. The metal salt thus obtained is then reacted with (III) in an organic solvent such as, for example. dimethylformamide or dimethylacetamide. A small amount of a metal iodide such as sodium or potassium iodide may advantageously be added to promote the reaction, especially when the reactive ester is a chloride or bromide.

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4

Alternatively, the reaction of the imidazole (II) with the reactive ester (III) can also be carried out without prior salt formation by contacting the reactants with each other in an organic solvent such as, for example. dimethylformamide or dimethylacetamide. Under these circumstances, it is appropriate to use an excess of the imidazole (II) or to add a base such as, for example, to the reaction mixture. sodium or potassium carbonate or bicarbonate to bind the acid which is released during the course of the reaction. However, use of an excess of the imidazole is preferred. Furthermore, it is appropriate to carry out the reaction in the presence of a metal iodide such as sodium or potassium iodide.

In each of the above processes, somewhat elevated temperatures can be used to increase the reaction rate and most conveniently, the reactions are carried out. the reflux temperature of the reaction mixture.

In these and the following processes, the reaction products can be isolated from the medium and, if necessary, further purified according to commonly known methods, e.g. extraction, trituration, crystallization, chromatography, etc.

The foregoing methods are further elucidated by the following reaction schemes: N r W-GH

L, J --3-51 «ait of + 9 Q

N Limidazoles R -J-I

H

(II) (III)

DMF

V

(I) (Π) + - (ni) NaI y (I)

DMF

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5

A further process for the preparation of compounds of formula (I) consists in the ketalization of an aroylmethyl imidazole of formula (IV) wherein Ar has the same meaning as above, with a diol of formula (V) wherein R has the meaning above.

This ketalization reaction can be carried out according to analogous methods described in the literature e.g. for the preparation of 2-bromomethyl-2,4-diphenyl-1,3-dioxolane ^ Synthesis, 1974 (I), 23 /.

In a preferred embodiment of the reaction, both reactants are refluxed together for several hours with azeotropic water removal in an organic solvent, preferably in the presence of a simple alcohol such as, for example. ethanol, propanol, butanol, pentanol and the like, and in the presence of a strong acid such as 4-methylbenzenesulfonic acid. Suitable organic solvents are e.g. aromatic hydrocarbons, such as benzene, methylbenzene, dimethylbenzene and the like and saturated hydrocarbons such as cyclohexane.

The aforementioned revenue can be illustrated as follows:

ISLAND

O OH 4-methylbenzene-CH 2 -C-Ar + R-CH-CH 2 -OH sulfonic acid (i) butanol (IV) (V) benzene

Furthermore, the compounds of formula (I) wherein R represents an alkyl-oxymethyl, alkenyloxymethyl, 2-propynyloxymethyl or arylmethoxymethyl group (Ia) can be prepared by reacting a compound of formula (I) wherein R represents hydroxymethyl (Ib) reactive ester of formula (VI) wherein R 1 represents alkyl of 1-10 carbon atoms, alkenyl of 2-10 carbon atoms, 2-propynyl or aryl methyl, wherein aryl

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The portion 6 has the meaning given above under R, and W represents a reactive ester group as defined above, in accordance with conventional O-alkylation methods. Preferably, the reaction is carried out in a suitable organic solvent such as, for example. dimethylformamide or dimethylacetamide in the near-room of a suitably strong metal base such as e.g. sodium hydride, sodium carbonate, potassium carbonate and the like.

Ç IJ

CH ___ S-A * + Ri _w NaH „CH? ^ / Ar

0X0 -> X

HOCtI2J-1 - (vi) DMF, Ri-O-CH, J '3 c * d-b) (i-a)

The compounds of formula (I) wherein R is alkyloxymethyl having 1-10 carbon atoms in the alkyl moiety (I-c): can further be prepared by condensation of (I-b) with an alkanol having 1-10 carbon atoms in the alkyl moiety. This condensation reaction can be carried out by refluxing the reactants with each other during azeotropic water removal in a suitable organic solvent such as e.g. an aromatic hydrocarbon, e.g. benzene, methylbenzene, dimethylbenzene and the like, a saturated hydrocarbon, e.g. cyclohexane, or in the alkanol itself, in the presence of a strong acid such as e.g. 4-methylbenzenesulfonic acid.

n 4-methylbenzene - N / (I-b) + alkyl-OH eulfonic acid dimethylbenzene

alkyl-O-CH-1-J

Ct (I-c)

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7

Further, the compounds of formula (I) wherein R represents alkyloxymethyl, alkenyloxymethyl, 2-propynyloxymethyl, arylmethoxymethyl or aryloxymethyl (Id) can be prepared by reacting a reactive ester of formula (VII) wherein Ar and W have the means having a hydroxy compound of formula (VIII) wherein R represents alkyl of 1-10 carbon atoms, alkenyl of 2-10 carbon atoms, 2-propynyl, arylmethyl or aryl, wherein aryl has the meaning given above under R according to conventional O-alkylation methods as described above.

_m .-- N

ο V

Χττ Λ t CHn Ar

K CO

+ * "0H ———> O ^ O

ψ-CH-L - 1 / DMF R -O-CH-J-1 W 2 n 2 (VIII) 1 (VII) (I-d)

The imidazole derivatives of formula (I) obtained in base form by the aforementioned methods can be converted into therapeutically valuable acid addition salts by reaction with an acid such as e.g. an inorganic acid such as hydrogen halide acid, i.e. hydrogen chloride, hydrogen bromide or hydrogen iodide acid, sulfuric, nitric or thiocyanic acid, a phosphoric acid, an organic acid such as acetic, propionic, hydroxyacetic, α-hydroxy-propionic, 2-oxopropionic, oxalic, malonic , amber, maleic, fumaric, apple, wine, 2-hydroxy-1,2,3-propane tricarboxy, benzo-, 3-phenylpropionic, α-hydroxybenzeneacetic acid, methanesulfone, ethanesulfone -, 2-hydroxyethanesulfone, 4-methylbenzenesulfone, 2-hydroxybenzo, 4-amino-2-hydroxybenzo, 2-phenoxybenzo or 2-acetyloxybenzoic acid. The salts can again be converted to the corresponding free bases in the usual manner, e.g. by reaction with base, such as sodium or potassium hydroxide.

The intermediates of formula (III) can be prepared by:

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8 is subjected to a ketone of formula (IX) wherein Ar and W have the meanings set forth above, a ketelization reaction with a diol of formula (V) in the same manner as described above to prepare the compounds (I) from (IV) and (V).

O OH

| î | 4-methylbenzenesulfonic acid W-CH 2 -C-Ar + R-CH-CH 2 OH -} (III) butanol (IX) (V) benzene

Alternatively, the intermediates of formula (III) are conveniently prepared by transketalizing a ketone derivative of a ketone of formula (IX), such as e.g. a lower alkyl ketal or a cyclic lower alkylene ketal with a glycol of formula (V) under similar conditions as described above for the direct ketalization. The lower alkyl ketals and cyclic lower alkylene ketals used herein as starting materials are readily obtained by the ketalization of a ketone of formula (IX) with a lower alkanol or alkanediol according to methods known per se. A number of such compounds and processes for their preparation are described in U.S. Patent Nos. 3,575,999 and 3,717,655.

The intermediates of formula (III) wherein -Ar, - R and W have the above meanings with the proviso that R is different from phenyl when Ar represents phenyl is assumed. to be so far unknown.

A number of the precursor glycols of formula (V) are known and can all be prepared according to known methods described in the literature. Generally, they can be derived from the corresponding 2-R oxiranes of formula (X) by hydrolytic cleavage of the oxirane nucleus with a strong acid, such as e.g.

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9 oxalic acid, sulfuric acid, hydrochloric acid and the like.

R-Δ (COOH) + (v) Η9θ / 1,4-dioxane 4r (X)

The oxiranes of formula (X) can again be obtained in a variety of ways.

Such a formula (X-a) wherein R represents alkyl of 2-10 carbon atoms or arylalkyl wherein the alkyl moiety has 1-6 carbon atoms and aryl has the meaning given above under R may, for example. is prepared by oxidation of a corresponding alkene or aryl alkene of formula (XI) with an oxidizing agent such as e.g. a benzene peroxoic acid e.g. 3-chlorbenzenperoxosyre.

R3-CH = CH2 + 30030 · ^^ \ CH CL Cl L ù (XI) (X-a)

Alternatively, the intermediates of formula (Xa) may also be obtained by: i) the conversion of a corresponding halide of formula 4 (XII) wherein R represents alkyl or arylalkyl having 3 a carbon atom less than in the corresponding R to a Grignard complex having magnesium, il) reacting the Grignard complex with an appropriate 2-halo-methyloxirane of formula (XIII) to obtain an α-halo-methyl alcohol of formula (XIV) and iii) cyclizing (XIV) by treatment with base, e.g.

with sodium hydroxide in a suitable solvent, e.g. 2,2'-oxybispropane.

The above reaction course is further illustrated in the reaction scheme below:

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10

Γ -, O

R4-halo + - + halo - CH · - solutions · 2 / µm part _ (XII) (XIII)

OH O

R4-CH2-CH-CH halo _NaQH> R4_çh - -ZA

diisopropyl ether (XIV) (X-a)

The intermediates of formula (X) wherein R represents alkyl-oxymethyl, alkenyloxymethyl, 2-propynyloxymethyl, arylmethoxymethyl or aryloxymethyl (Xb) are conveniently obtained by reacting a hydroxy compound of formula (XV) wherein R represents alkyl of 1 -10 carbon atoms, alkenyl of 2-10 carbon atoms, 2-propynyl, aryl or arylmethyl, in which aryl has the meaning given above under R, with a 2-halo-methyloxirane of formula (XIII) according to conventional O-alkylation methods which are aiment known.

Intermediates of formula (X), wherein R represents arylthiomethyl (Xc), can be prepared by analogy by S-alkylation of an arylthiol of formula (XVI) wherein aryl has the meaning given above under R with a 2-halo-methyloxirane of formula (XIII).

The above reactions are schematically illustrated below: R5-OH + halo-CH2-ZA K2C ° 3; R5-Q-CH2 - 2-propanone (XV) (XIII) (X-b)

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11

ISLAND

Aryl-SH + (XIII) K 2 C 3 Aryl-S-CH 2 -2-propanone (XVI) (X-c)

Intermediates of formula (V) wherein R represents alkenyl of 2 to 10 carbon atoms may e.g. is prepared from a corresponding hydroxyalkyl-substituted ethanediol by ketizing a ethanediol group with a ketone, e.g. 2-propanone, subsequent conversion of the residual hydroxy group on the alkyl chain to a methanesulfonate group by reaction with methanesulfonyl chloride, decomposition of methanesulfonic acid by treatment with a strong base, e.g. sodium hydride in a solvent such as dimethylformamide, and finally the release of the free diol from the ketal by treatment with a strong mineral acid such as e.g. hydrochloric or sulfuric acid.

In a preferred embodiment of the aforementioned reaction, the ketone used in the ketization step is an intermediate of formula (IX) whereby the alkenyl-substituted dioxolanes of formula (III) are obtained directly in the 10bet of the aforementioned reaction.

The precursor aryl ketones of formula (IX) are generally known and can be prepared according to known methods described in the literature. For example, bromides are readily obtained by bromination of the corresponding methylarylmethanone with bromine.

The aroylmethyl-substituted imidazoles of formula (IV), a number of which are disclosed in United States Patent Nos. 3,717,655 and 3,658,813, are conveniently prepared by reacting (Γ with imidazole analogous to the above-described process for preparing the compounds). (I) from imidazole and (III).

The reactive esters of formula (VII) used as intermediates for the preparation of the compounds (I-d)

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12 is readily obtained by converting the corresponding alcohol of formula (I-b) into a reactive ester thereof by methods well known in the art. Eg. for example, methanesulfonates and 4-methylbenzenesulfonates are conveniently prepared by reacting the alcohol with methanesulfonyl chloride or 4-methylbenzenesulfonyl chloride, respectively, and halides can be prepared by reacting the alcohol with a halogenating agent, such as sulfuryl chloride, phosphorus pentachloride, phosphorus pentabloride, phosphorus and the like. When the reactive ester is an iodide, it is conveniently prepared from the corresponding chloride or bromide by replacing this halogen with iodine.

From the formula (I), it is obvious that the compounds prepared according to the invention have two asymmetric carbon atoms in their structures, namely those located at the 2- and 4-position of the dioxolane nucleus, and therefore exist in different stereochemical optical isomeric forms. The preparation of the stereochemically optically isomeric forms of (I) and the therapeutically active acid addition salts thereof proceed within the scope of the invention.

The diastereomeric racemates of (I) / called cis and transforms according to the rules described in "Naming and Indexing of Chemical Substances for Chemical Abstracts during the 9th Collective Period (1972-1976)" published in CA 1972, 76, Index Guide Section IV, p. 85, can be obtained separately using conventional methods. Methods which may advantageously be employed include, e.g. selective crystallization and column chromatography. For a number of compounds, the stereochemical configuration was determined experimentally. In the other cases, there is conventional agreement to designate the stereochemical form which is first isolated as "A" and the second as "B" without further reference to the current stereochemical configuration.

Since the asymmetric carbon atoms are already present in the intermediates (III), it is also possible to separate the cis and transforms or the ordinary "A" and "B" forms of

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13, the corresponding forms of (I) can be obtained after reaction of the above with imidazole soin described above. The separation of the cis and transformers of (III) can be carried out by conventional methods as described above to split the compounds (I) into their cis and transforms.

Where R in the intermediates of formula (III) represents a hydroxymethyl group, it may be convenient to first esterify the hydroxymethyl group with an acyl halide, e.g. benzoyl chloride, after which the esters thus obtained are cleaved into their cis and transforms, from which the acyl group is subsequently hydrolytically cleaved in basic medium to form the corresponding forms of the desired hydroxymethyl substituted formula (III).

It is to be understood that the cis and trans diastereomeric racemates can be further cleaved into their optical isomeric cis (+), cis (-), trans (+) and trans (-) using methods known in the art.

The compounds of formula (I) and the acid addition salts thereof have valuable drug activity to control fungi and bacteria. As such, they are valuable for treating humans and animals suffering from pathogenic microorganisms.

From U.S. Pat. No. 3,575,999, it is known that compounds which differ in particular from the compounds of the present invention by containing a methyl group at the 4-position of the dioxolane ring possess antifungal and antibacterial activity. It has been unexpectedly found that the compounds prepared by the process of the present invention exhibit a higher degree of systemic activity than the aforementioned known 4-methyl-substituted imidazole derivatives, as illustrated in the following comparative reports.

14

DK 157300 B

Comparative Report 1 Vaginal candidosis test in rats 1. Test method

Female rats weighing 100 g were ovariectomized and hysterectomized. Three weeks later and every week thereafter throughout the trial, 100 µg of ostradiol undecylate in sesame oil was injected subcutaneously into each rat. The induced pseudo-oestrus was checked by microscopic examination of vaginal scraping. Only animals in pseudo-oestrus were used for the experiment.

The animals were infected intravaginally with a suspension containing 8 x 10 C.F.U. (colony forming units) of Candida albicans in 0.2 ml saline. The animals were then treated orally once daily for 14 consecutive days starting on the day of infection, either with solvent (PEG 200) or with a solution of one of the test compounds in PEG 200. Vaginal scrapings were performed from all animals 24 hours after the last treatment. treatment, was grown on Sabouraud agar medium containing penicillin (20 IU / ml) and streptomycin (40 µg / ml) and the number of Candida colinis was then counted. The results are expressed as ED₂-Q values (in mg / kg body weight), ie. the daily dose of the test compound at which 50% of the animals are found to be completely free of Candida albicans infection.

2. Tested compounds

Compounds prepared according to the invention: j

Clh. ,Year

2X

0 O

1 _i

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15

Compound Ar_R

1 2-CH3-C6H4 C2H5 2 2-Cl-CgH ^ C2H5 3 2,4-Cl2-CgH3 C2H5 4 2,4-Cl2 “C6H3 nC3H7 5 2,4-Cl2-C6H3 nC4H9 6 2,4-Cl CcH ^ nCpH-, 263 5 11 7 2,4-Cl2-C6H3- nC7H15 8 2,4-Cl2-C6H3 nC8H17 9 2-Clf4-F-C6H3 C2H5 10 2-C1,4-Br-C ^ Hr . C0Hj- 6 5 2 5

Known compounds:

r_N

1 il. CH ^ Ar

ISLAND ISLAND

CI13

Compound _Ar_A 4-Cl-C6H4) B 3-Cl-CcH. ) 6 4 C 2 -C 1 -C 6 H 4) According to United States Patent No. 3,575,999 D 2,4-Cl 2 -C 6 H 3) E 3,4-Cl 2 -C 6 H 3) 16

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3. Test results

Compound Vaginal candidosis test in rats ED, -0 in mg / kg (oral) 1 10 2 10 3 10 4 10 5 10 6 5 ..... 7 -------------- '----------------- 10 ......

8 10 9 10 10 5

Compound Vaginal candidosis test in rats EDç-q in mg / kg (oral A -) B -) C -) completely inactive at 10 mg / kg D -) E ........; - --------- -) -Research Report 2

Vaginal candidosis test in rats 1. The test method was similar to that reported in test report 1.1.

2. Tested compounds

_N

[i IJ C1 L2 ^ fvcl 17

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Compound R_ 1 c2h5 2 nC3H7 Compounds prepared according to 3 nC ^ Hg invention 4 nC5H11 A CHy Known compound according to US Patent No. 3,575,999 3. Test results

Compound Vaginal candidosis test in rats Number of ED tested, -q in mg / kg (oral) rats 1 10 10 2 10 6 3 10 6 4 5 6 A 40 10

Jen broad-spectrum antifungal and antibacterial; :: ivi of the compounds of formula (I) are clearly illustrated by the test results presented below. The interconnectors in the tables are listed for the purpose of exemplifying the valuable properties of all interconnectors that fall within the scope of formula (I).

The antifungal activity test was performed using Sabouraud's liquid medium in test tubes, each containing 4.5 ml of the liquid medium and autoclaved at 120 ° C for 15 minutes. The substances were dissolved in 50% ethanol at a concentration of 20 mg / ml and then diluted with sterile distilled water to a concentration of 10 mg / ml. Subsequent decimal dilutions were then made with distilled water to obtain a variety of stock solutions. Into each tube containing 4.5 ml of Sabouraud's liquid medium was added 0.5 ml of one of the stock solutions to obtain concentrations

of past nrïfsl son. snm çVnl 1 p nndprcMrrpa T ΠΠ No. 1 (1 No. T

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18

Threaded fungi were incubated at 25 ° C for 2 - 3 weeks. A square block of 2 mm since was cut and seeded in the liquid medium. A 3-day-old culture on Sabouraud's liquid medium was used for the mushrooms and the inoculum was 0 · 05 ml per ml. test tube. All cultures were incubated at 25 ° C for 14 days. The final readings were made after 2 weeks and are summarized in Table A on the following: ++++ = complete growth inhibition at 0 µg / ml +++ = complete growth inhibition at 1 µg / ml ++ = complete growth inhibition at 10 µg / ml + = complete growth inhibition at 100 µg / ml 0 = no effect, ie growth was observed at the highest concentration tested (100 µg / ml).

In a first screening, the compounds tested for the following 11 fungi were tested: 1. Microsporum canis (Mc in the table) 2. Ctenomyces mentagrophytes (Ct. In the table) 3. Trichophyton rubrum (Tr. In the table) 4. Phialophora verrucosa (Ph. V. In the table) 5. Cryptococcus neoformans (Cr. N. In the table) 6. Candida tropicalis (C.tr. In the table) 7. Candida albicans (C. alb. In the table) 8. Mucor- strains (Mue. in the table) 9. Aspergillus fumigatus (A. f. in the table) 10. Sporotrichum schenckii (Sp «s. in the table) 11. Saprolegnia strains (Sap. in the table).

A number of the compounds that exhibited activity against Phycomycetes Mucor at the concentration of 10 µg / ml were also tested against four other strains of Phycomycetes, namely: 1. Absidia ramosa (Abs. R. In the table) 2. Basidiobolus meristosporus (Bas. M. I table) 3. Mortierella strains (Mort, in the table) 4. Rhizopus (Rhi. in the table).

The method used in this second screening was exactly the same zone described above and the results are listed in Table B.

19

DK1573Ü0E

Bactericidal tests were performed on cultures of phenolic red dextrose "Difco" substrate medium. The same decimal dilution technique was used as described above. The inoculum consisted of a platinum (5 mm diameter) portion from a 24 hour old substrate culture.

Forty-eight hours after incubation, subcultures were prepared from each culture and to assess the bactericidal activity of the compounds to be tested, the same scale as described above was used for presence or absence after 7 days of incubation.

The compounds were tested for the following gram-negative bacilli: 1. Salmonella pullorum gallinarum (SPG in the table) 2. Escherichia coli (E. coli in the table) and 3. Pseudomonas aeruginosa (Ps. Aer. In the table), and for the following grams -positive bacilli and cocci: 1. Erysipelothrix insidiosa (E. ins. in the table) 2. Staphyloccus hemolyticus (Staph. in the table) and 3. Streptococcus pyogenes (Strept. in the table).

The results are summarized in Table C.

20 ----- *,

DK 157300 B

. + + + + ·! Ο.ΓΓ + + + + O + + + + + + + + + +,

rj · ή I

10 µl

- .. ..... ........ iw ++ i +++ ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ + + + +, CO wl ......... ----... ___ — _ '

* «- + + + + + + + I

• σ '+ + H- + + + + + + + + ·

<î ^ + + + +0 + + + + + + + + + + I

-! ΰ 'ST' + + + 1

3C0 + + + 0 +. + + + + + + O- + + + I

z!

----- ----------, ............ .............. I

.O I

Τ '+ + +00 + 00 -I-0 0 0+ +, O «

. t- I

E- <U i W 1 - H 1> · · 1 • r-4 · H, -. 1 fi Pi E- o ++ W. tü,.: '-' · +00 +0000 + +000 + 0 D i --- i · *; \ _ s c ++ ++ ++, ri! D.'T * +++ + + + + + + + Y (X. ^ Ü + + + + 0 + 0 + ++ + + + + + β λ H υ! 0 / '0— g ·

1 * = \ X1 *. J

a _ ί

rfî I

'..........' .................... 1st-11th (

ú + »I

-— * »++. -ί- +. + + + + + + + -I- -K + | ^ rn +++ +++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ + + + + + + + + + + +! (SJ + + + + + + + + + + + + + + + ♦ ♦ J <-> + + + + + + + + + + + + · + + »υ t! ——--» - = - \ i ü + · +++++++++++++++++++++++++++++++++++++++++++++++++++ + i * '"" "p - j IC'J cn3 oJ {si ro i

C-Γ ^ 7 * r — t J

csj u, îj (j cj! ^ υ ^ υ υ ^ -οου ^ υο ^! i.!. Ι.ίΙΙ.ΙΙ. '»SN + <\ î K c \!' ψ -4 'c \! < M ro · <} <cm} <H l u) la ^^^! E- <H ι-l tO —I r- '| ---------------- υ a U O ·

Γ "ίν» I—- r — J I — i Il | Ü | r — j, - <^ 1 | J

05 UU Ο P3 PO + Ο OUWU ^ \ '' ii «, 1„ - w »» i »>, I 4,4''l, '' i, '), (' J4, WNÆri <NTiiNN (,. 21

DK 157300 B

s Q, ^ (+ + + + 4- + H- + + + + + + + + + + + + in'- 'W0 4- + + + + + + + + + + + + P / -' + + + + + + + +0 + + + + + + + w *** ^ + + + + + + · -4- 4- ++; 2l + · + + + + + + + + + + < <+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ ar ~ * -J .f.

+ ^ - 00 + 0 + + 00 + 0 + + + + £ 4 u w

Eh -------

H

Ehh

W H

p EH "O + + + H Î4 OOO + + + + + 00 + 00 © + +> <S! 3 ------ ^ 2 ti 4- + + + + + +, g ++ + + + + + + + + + + + + dg + + + + 4- + + + 0 + + + + + 4- + § h υ 3 gd 5 ---

Pu <h> _ 3, c'CÎ. + -I- + + + 4-4- + OO + + + + + + <Ph + 4- + + + + + + 4-4- 4- +. + 4- + + D-Cl + + 4- + 4- + 4- ++++++ +++ ^ -I- 4- +++++++++ +++++

Fj +++ ++ +++++++++++++++++++++++++++++++++++++++++++++++++++ + + + + + + •• w <»4- + + + + + + + + + + + + + + ^ + + + + + + + + + + + + + + + + - f \] r- * Γ4 U + 1 ro

pd 'I ^ 1 H h 1 h X S

• «4MilUUfl« ffl4'flUUUhh ïï µ '· ι ,,,,, »ΙΙΙΙΙΙ ^« ++ f \ J + PJ ++ <++ (\] -ψ (\) .ψ - ^ (-ψ, 31

ISLAND

rH M4 ----—-—- (U -

-Q

M <M (M

en- ςτ. cr

H «*> U ro {O.

pi υο + υ + υυυυυυαυ «

I * 1 ►_ * 1. 1 * 1 · 1 I I I I I I I I l I

Λ rj * r | * <\ i Μ «++ f *)» n | & ^ j —DK 157300 B, 22 2 -.

.— · t + 4-4- + + + I

C / 5 C- O + + + + 4- + + o 4- + 4- + 4- + 4- O »w!

.04 »J

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ACTIVITY OVER PHYCOMYCETER

Table B.

-. j R2 Abs. r. Bas.m. Mort. Rhi.

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32 DK 157300 B

Table C. BACTERIOSTATIC AND BACTERIOCID ACTIVITY

The table summarizes the activity against the gram-positive bacteria.

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R

] 2 bacteriostatic activity bacterlocid activity E. ins. Staph. Strept. E. ins. .Staph. Strept.

4-C1 4 -Cl · ++ 4+ 4+ ++ 4+ 4+: 4-Cl H 4+ 4+ + 4 ++ · · 4 4 + 4: 4-Cl 2, 4- (Cl) "+4+ 4+ 4 + 4 ++ 4+ +4+! 4-Br 4-Cl '2 + 4+ +++ +4+ +++ + +++ | 4-Br 2,4- (Cl) +++ + 44+ 4 + 4 + -I - ++ in E, 4- (Cl) H 2 + 4 0 4+ 4+ 0 4+! 4-AND 4 -Cl ++ + +4 4 4 4+! H Z, 4- (Cl) _ ++ +4 +4+ 4 4 4+.

| 2,4- (CL) _ 4-Cl 2 +++ ++ +++ ++ + 44 H 2 4-Ci. +++ + +++ 4 4 +4 4-C1 · 2-C.1 +++ +4 +4+ 4+ 4. 4+ 2-Cl 2,4- (Cl) 4 + 4 + 4 + 4+ 44 4 + 4+ '4-Br:. 2-C1 4 + 4 4 +4 444 4 4+ 2- Cl 4-Cl +++ H · 44+ 444 4 +44 j 2.4- (Cl) 2.4- (Cl) +++ ++ 4+ + +++ 4 +++! 4-Br 2 H 2 4+ 4 + 4+ + 4 + 4 + 4 H 4-Br + 4+ 0 444 + 4+ 0 + 4+ 4-CH '2,4- (ClL +++ +++ 4 + 4 +44 4+ +44 4-Br3 4-Br 2 4 + 4 ++ +++ +++ + +44 2.4- (Cl) 2-Cl 4 + 4 + 4+ 4 ++ +++ 4+ +44 4-Cl-I3 2 4-Cl +4+ 4+ +++ +4+ + +44 2.4- (Cl)? 4-Br +++ +4 +++ +++ ++ 4 -Cl 4 -Br + 4+ 4+ +4+ +44 4+ 4-14 4-CH 4-Br 4 + 4 + 4 +++ +44 4 4 + 4 3- Cl 3 2.4- (ClL ++ 4 ++ 4 4+ + +++ 2-Cl 4-Br 2 +4 4+ 4+ 44 4 4+ 4- CH 2-Cl 4 + 4 + 4 ++ ++ + 4 + 4 4- Cl 4-CH ++ - l · f 444 44 -1- +4+ | 4-Br 4_CH? +++ ++ ++ ++ + 44 1 4-C1 4-F 3 4 0 44 4 0 4+ 4-Br 4-F 4+ 4 4 + 4 -1+ 4 + 4 +

Tabei C 33 DK 157300B

2 BACTERIOSTATIC AND BACTERIOCID ACTIVITY

, _N

O R1

^ .O-ch2-1_J

"J Bacteriostatic",,, ... ... ...

-: -bacteriocia act Ί -n? τ —akhiviteb .—— ----— r J- R- Isomcr in E. ins, Staph. Strept. E. ins. Slaph. Strept.

4_C1 2-CH, 4-Cl cis ++++ 0 ++++ ++++ 0 ++++ 4-C1 4-CH, trans +++ ++ +++ +++ + ^ ++ 4_C1 2-CH ,, 4-C1 trans ++++ ++ ++++ ++++ + +++ 4.Cl 4-CH, cis, +++ ++ +++ +++ ++ ++ 4-C1 4-C1 3 Λ +++++ +++ +++++ +++: 4_ci 4-C1 B ++++ ++ +++ ++++ + +++ 4 -C1 2,4- (Cl), Λ 0 0 ++ 0 0 ++ 4_C1 4-F 3 cis +++ 0 +++ +++ 0 ++ '· 4-C1 Z-CH, Λ ++ ++ ++ ++++ ++++ + ++++ 4-C1 2-C1 3 Λ! +1 + 0 +++ +++ 0 + - * + 4-Cl 2-CH B; ++++ ++ ++ Ί +++ +++ 4-C1 2,4- (Cl) _ B; 4-4 4-4- ++, ++++ ++++ ++ ++ ++ 4-C1 4-OCIT, 3 A i +++ 0 +++ ++ 0 +++ 4-C1 4-F trans 1 + 4 ++ ++ ++ ++. 4-C1 4-AND, B! ++ ++ ++ ++ ++, 4-Cl 2,6- (Cl), Λ · +1+ 0 ++++ ++ 0 ++++ j 4-Cl 2-Cl B +++ + ++ +++ + ++ '4-Cl 2,6- (Cl) .B +++ ++ +++ +++ + +++ 2.4- (Cl), 4-CH B' ++ + + ++ ++ ++ ++ 2.4- (Cl), 4-F 3 Λ I ++ ++ ++ ++ 0 ++ 2.4- (Cl), 2-CH, A! +1 + + +++ +++ + + * + 2.4- (Cl) 3 4-CH, A! H ++ ++ +++ Ί ++ ++ · '+ 2.4- (Cl), 4-OCIi A! ++ ++ ++ ++ ++ 2.4- (Cl), 4-Cl cis I ++ ++ ++ ++ ++ ++- (Cl), 2-CH, B +++ + +++ + ++ ++ ++; 2.4- (Cl), 2.4- (ci) _ a; +++ 0 +++ +++ 0 +++ '2,4- (Cl), 4-Cl trans' +++ ++ +++ +++ 4+ ++ + 2,4- (Cl ), 4-Br · A +++ + +++ +++ +++, 2,4- (Cl 2,4- (Cl) - B +++ ++ +++ ++ ++) ++ 2.4- (Cl) 'JHA +++ + +++ +++ + +++ 2,4- (Cl), 3, .4- (Cl), A +++ ++ ++++ ++ ++ ++ 2.4- (Cl), 3-C1 A +++ ++ +++ +++ ++ +++ 2.4- (Cl), 2-Cl A +++ + 1 · ++ + +++ + +++ 2.4- (Cl) Î; 2-CH-, 4-Cl A 4 · B +1+ ++ +++ ++ ++ +++ 2.4- (C1), 2-C1 B +++ + +++ 4+ + +++ 2.4- (Cl), 2.6- (0) A +++ ++ +++ ++ + '· + 2.4- (Cl), 3, 5- (01), 4-GA +++ 0 +++ +++ 0 +++ 2.4- (0) 7 2.4- (Br) ', A +++ 0 +++ ++ + ù || + 2.4- (Cl), 4-CN ^ A +++ + ++ 0 0 ++ 2.4- (Cl), 2-liter cis 4 1+ +++ '+ +++ + ^ 2.4 - (Cl), 2-OCI1 A 44+ + +++ +++ + +++ 2.4- (Cl), 2-Br 3 'trans 4 4-4- 4-4- ++ ++ 4 ++ • 2.4- (Cl) * 4.4.6 - (Cl) Λ +4 4 · 0 ++ 4- 4+ 0 ++ 2.4- (Cl)? 2.5- (01,), A 4 4 4 + 4- + 4 + +++ + -> ++ 2.4- (0) 3 2.5- (01¾ B + '+ ++ +++ +++ ++ 34

DK 157300 B

Table C 2 (continued)

BACTERIOSTATIC AND BACTERIOCID ACTIVITY

Bacteriostatic Bacteriocid, -, 9 Active Tactivity _ R -1- R Isomer "E. inc. Staph. Strept. E. ins. Staph. Strept.

2.4- (θ), 2-0, 4-times. but. A ++ ++ +++ ++ 0 ++ '2,4- (0) 2 2,4,5- (0) 3 A ++++ 0 ++ ++ ·: · 0 ++ ; 2,4- (0) -, 2-0,4-tert. but. B ++++ ++ ++++ +++ + +++ 2.4- (0) 2 2,4,5- (0) 3 B +++ + +++ ++ + ++ î 2, 4- (0) 2, 5- (Br) 2.4-CH3 A +++ + +++ ++ ++; 2,4- (0) 2 2-FA +++ + ++++ +++ +++ 4-01, 4-Br A +++ ++ ++++ +++ +++ 4- 0 4-Br A ++++ ++ ++++ +++ + +++ 4-Br 4-Br A - * - +++ + ++++ +++ + +++ 2.4- ( 0) 2 2-OC2H5 A +++ + 0 ++++ +++ 0 +++ 2-0 4-Br A + B ++++ ++ ++++ +++ + +++ 2 -0 4-Br B +++ ++ ++++ +++ +++ pj 4-Br A +++ ++ ++++ + 0 +++ 2-Br 4-Br Λ + -H - + +++ + -H + +++ ++ +++ 2-Br 4-Br B + -H- + ++ 4 +++ +++ + ++++ 2.4- (0) -. 4-C / IIr A + B ++++ 0 ++ +++ 0 ++ 2.4- (0) 2 4-C51IÏ; B 0 0 +++ 4 0 0 444 2.4- (0) 2 2, 6- (01,) 2 A 4444 44 4444 444 44 444 2.4- (0), 4-Br B 444 444 444 44 4 44 2, 4 (0) 92.6- (013), A4 B 444 44 444 44 4 44 2.4- (0), 3.5- (0î3) 2 A 444 44 444 444 4 444 2.4- (0)? 4-iC3II7 A 4 B 44 44 444 44 4 44 2.4- (0) 2 2-0.6-043 A 44 44 44 44 4 44. 2.4- (0), 4-tert. but. A 4 + 4 44 44 44 4 44 2.4- (0) 2 3.5- (0) 2 A 44 444 4444 44 44 4 + 4 2.4- (0) 2 3-OI3, 4-0 AI +++ + ++ ++ ++ ++

DK 157300 B

Table C

3 BACTERIOSTATIC AND BACTERIOCID ACTIVITY

fine

O R1 s << r ^ f> 5-CH2-1-1 bacteriostatic bacteriocide -, o _ activity__activity _ R + Isomer-- E. ins. Staph. Strept. E. ins. Staph. Strept.

2.4- (Cl) p 4-Br A + B +++ ++ ++++ +++ +++ 2.4- (Cl) 2 II A + B ++++ ++ ++++ +++ + +++

Table C

4

, -N

U1 y- X \ ch2-ch2-1-1 bacteriostatic bacteriocide R1 R2 Icomer i.VÎ .te.t ____ activity _ E. ins, Staph. Strept. E. ins. Staph. Strept, 2, 4- (Cl) 2 2-C1 4444 444 4444 44 t * 44 444 2, 4 ~ (Cl) y 2,4- (Cl);> 44 ^ 4 444 4444 444 44 444 2P 4- ( 01) 2 2.6- (Cl) 2 Λ 4 B 4 + 4 + 444 4444 444 44 444 2, 4 "(Cl) 2 4-OCH3 A 4 J3 444 * i * 4 444 444 4 44 2.4- (01 ) 2 4-01 4444 44 4444 444 4 444 2.4- (0 ^ 2 H 4441 44 444 444 0 44. 36

DK 157300 B

T ^ IdôI. C

~ BACTERIOSTATIC AND BACTERIOCID ACTIVITY

5 ~~ -a Ο ^ Ό R J-1. ^^ Bacteriostatic Activity Bacteriocidal Activity {? ,, jjiB. filnpli. ClrepU E). IUK. 'Slaph. Slrr.pl 4- (r, l) ^ - C6H3 CzHc. A + B 3 3 + + 3- +++ ++ ° Ή + .a.C; H1 C? A + B 3 3- + o ++ + ° H, C_Hr A +] 3 3 + o ++ ° ° °

3 (> 4 Z J

rH -CHCHAHB -H · + ++ ++ ° ++ 3 (> 1 1 ·>, 3.4- (01), - (:, 11, C..H A + B · 1 · Μ · + -I · Η + H ++ + "" "j> b ZZ b -Β, -. Ο, Η, C_H AI B -H- + ++ ++ ° η ·) Z 5 3- (C))" - C6H c:? have AIB -H · + ++ '++ °:

Cl, Λ -F- CA H CZHf, A + B ++ 0 ++ ++ ° ++. p, r - C, H C..H A + B 3 3 o + ++ ° + 6 Ί Z 5 -Cl »C, H CCH A + B 1+ o 3-3- ++ o ++ 6 4 eg -Cl, 4-Br-C, H, C_H. A + B +++ + ++ +++ + · + '6 3 z b

4- lSr ^ -C ^ H C2H5 A ·! B-I ++ + ++ + 'H

• AND ~ C, H. C Ht. A -IB + o + +0 + 3 6 4 Z b -t bien y] C? H A + B -I ο + ο o J.

-CH0, 4 - CJ -C / Hn C, H A + B +++ + + +++. + 3 b j cj .i

Cl, 4 - OC H- °? A5 A lB '' '++ + °' -ftnnbUiyl C ^ II, - A + B) + -! 3 3 ++ + 0 -01 -1 Ivjenyl C ^ AIR ++ -I Ή ο o -OCH. ,, 4 -Cl-C, BU CHA -1 B -I o +++ ° +:> b J Δ br 4- (Cl) - C, BR «COH_ A + B -1 + 3 3+ 3 3+ +++ + + 3-, Z o:> (r 4- (01 L ~ not-L nC A + B 3 + 3- + 3-I 3 + 3- +++ +3+ + 1! Z 6 3 ί 9 r4- (Cl), - C, H_) iC..H A + B 3 1 · + 3 + +3 3 3 +3 ++! 3: Z 6 3 b 1 1 r4- (C.))? .- C6H3 »C6h] 3 A + B 3 3 3 3 3 + 3 3 1 +3 3 + + 013 f 4- (C1), - C, H »C, Their AIR 33+ il! 3 + 3 3-H 3 3 3 3 3 Z 6 3 <\ j 4— (C. 1)., - C 14 iiC33, r A 3 B 3 1+ +3 3 13 3 +3 3 1 3 3 r Z 6 3 h J i, 4- (C1) 0-C6ho CH? D A 3 BI o 3 + o 3, 4- (01) + -CB H .. CH, OH {mouse + ο + ο o +

1 e. 0 -> Z

4 - (0]) ,, -C HCH..OH A! B ++ ο I + 1- ο 3

B Z

/ 1- ί é ', 1 \ -C H f'H OH (-1 r; +. O O + .O O

37

Table C BACTERIA OS TATIS K AND BACTERIOCID ACTIVITIES 1 5 7 3 0 0 B

6 _N

You? CH2

Alkyl-O-CH 2 -J- * —— 1 | '' '' J i "" .....

bacteriostatic activity bacteriocidal activity Alkyl isomer £. ^ ns <staph. Strept. E, ins, Staph. Strept.

CH ^ cis + ο ο + ο o C „H trans ++ ++ ++ o + Z 5 nC ^ H ^ cis ++ ++ ++ ο o nC, H„ AiB +++ ++ +++ + 0-1- 4 9 nCJI cis +++ +++ +++ +++ o ++ 5 11 nC.H _ .cis +++ ++ ++. ++ ++ ++ b 10 nC "H" cis +++ +++ +++ +++ + ++ 7 15 nC0H cis +++ ++ +++ ++ ++ ++ o 17 '

Table C

7 r-N

ISLAND

Island Island

Aryl-CH2-0-CH2-1-1 bacteriostatic activity bacteriocidal activity

Aryl isomea .-----------; ---- E. ins. Staph. Strept. E. ins. Staph. Strept.

4 ~ (C / 1 + -) - 0, H + cis +++ +++ '+++ +++ + î ++ 6 5 5 4 4- (0.1 + -) = 0.14. trans +++ ++ +++ +++ ++ ++ + '6 5 6 4 4-Br-G / H. cis +++ ++ +++ +++ + +++ 6 4 2.4- (01) -0 / H cis +++ +++ +++ +++ ++ '2 6 3 2.4- (01) 2-0 ^ Ι + 2 trans +++ ++ +++ +++ + ++

: 33 DK 157300 B

RACTERIOSTATIC AND BACTERIOCID ACTIVITY

Table C

8

, -N

O vC1 0x0 \ == /

Aryl-Cl 2 J-1 ----- bacteriostatic activity bacteriocidal activity

Aryl --—----- E. ins. Staph. Strepfc. E. ins. Staph. Strept.

CkHL +++ 44 44 +++ 4 44 6 5 4-C1-C, H. 444 44 i + 444 44 44 6 4 4_F-C / H. 444 44 ++ I ++ + · 44 6 4 4-CH0-C, H. +++ 4+ 444 4 + 4 44 444 3 6 4 4-Br-C / H. 444 44 444 4r4 44 444 6 4 4-OGH --- C / H. 444 4 444 444 4 444 3 6 4 4— (C, H _) - C, H. 444 44 444 44 4 44 v 6 5 6 4 39

DK 157300 B

Table D

-N

y o ÔH, -Ar 0 ^ 0

Vaginal candidosis i

Ar rots: ED ^ Q values in pig / kg body weight • (orally) 2 j 4-C1 -C, H CH OH 10 C 0 j ù 2.4- Cl, -C, H, CH., OC., H 10

L O J L L D

2.4- Cl, - C, H, CH On. CH 10 2 6 3 2 4 9 2.4- CL, ^ C, H CHOOCHOC = CH 8

ù O 5 LL

2.4- C1 -C, H. CH OCHO -C, H - 10 2 6 3 2 2 6 4 (4-Br) 2.4- Cl2-C6H3 CH2OC6H5 5 2.4- Cl2-C6H3 CH2OC6H3 (2-Cl, 5 4-t.C4H9) 2.4- Cl2-C6H3 CH2OC6H4 (4-CeH5; 2.4-Cl2-C6H3 CH2O- (2-naphthyl) 2.4-Cl2-C6H3 CH2S-C6H4 (4-Br) 2..5 2-Cl-C, H. CHOCH-C, H_ L 10 6 4 2 2 6 5 4-CH-C .HC, H. (4-CH_) 10 364 64 '3' 4-Br-C, HC, H (4-F) · 2.5 6 4 6 4 4 -Cl-C6H4 C6H4 (2-C1) 2.4-Cl2-C6H3 C6H3 (2.4-C12) 2.10 4-Cl-C6H5 C6H4 (4-Br) 10 2.4- Cl2-C6H3 C6H4 (4-OCH3) 10 2.4-CH-CH, C, H (4-C1) 10 2.4-Cl2-C6H3 C6I-I (4-CN) 10

DK 157300 B

When the compounds of this invention are used in combination with suitable carriers, e.g. in solution, suspension, powder, powder, ointment, emulsion and similar forms, a high activity is observed over a very large dilution interval. For example, it has been found that concentrations of the active ingredient ranging from 0.1 to 10% by weight based on the weight of the composition used are effective in controlling fungi or bacteria. Of course, higher concentrations can also be used depending on the particular situation.

The process of the invention is illustrated in more detail in the following Examples, wherein all parts are by weight.

Example 1.

A mixture of 1.1 parts of imidazole, 1 part of 2- (bromomethyl) - 2,4-bis (4-chlorophenyl) -1,3-dioxolane, 0.4 parts of potassium iodide and 20 parts of dimethylformamide is stirred and refluxed for 12 hours. Water is added and the product is extracted with diethyl ether. The extract is washed twice with water, dried, filtered and evaporated. The residue of 1- [2,4-bis (4-chlorophenyl) -1,3-dioxolane-2-methylmethyl] imidazole is converted to the nitrate salt. It just sits fr .; -filtered and crystallized from a mixture of 2-propanol and diisopropyl ether to give 1- [2,4-bis (4-chlorophenyl) - 1,3-dioxolan-2-ylmethyl] imidazole nitrate, mp 192.3 ° C.

Example 2.

A mixture of 7 parts of imidazole, 7.5 parts of 2- (bromomethyl) -2- (4-chlorophenyl) -4-phenyl-1,3-dioxolane, 2 parts of sodium iodide and 100 parts of Ν, Ν-dimethylformamide is stirred and refluxed 48 hours. The reaction mixture is allowed to stand at room temperature and poured into water. The product is extracted twice with benzene. The extract is washed twice with water and the solvent removed in vacuo. The residue of 1- [2- (4-chlorophenyl) -4-phenyl-1,3-dioxolan-2-ylmethyl] imidazole is converted to the nitrate salt in 4-methyl-2-pentanone and diisopropyl ether. It was about 41

DK 157300 B

is filtered off and crystallized from 4-methyl-2-pentanone to give 1- [2- (4-chlorophenyl) -4-phenyl-1,3-dioxolan-2-ylmethyl] imidazole nitrate, mp 153.2 ° C.

Example 3

Using the procedure of Example 2 and equivalent amounts of the corresponding starting materials, the following imidazoleic acid addition salts are prepared:

, -N

U

^ xO ~ r6 r6 7 Salts ______ R Acid salt melting point

4 ° Cl 2.4- (Cl) 2 HNOs 196.6 ° C

4-Br 4-C1 HNO3 152.6 ° C

4-Br 2.4- (Cl) 2 HNO 3 205.3 ° C

2.4 - (Cl) 2 - 2 (COOH) z 107.7 ° C

4-OCH3 4-C1 HNOs 196.3 ° C

2.4- (Cl) 2 hNOs 163.8 ° C

2.4- (Cl) z 4-Cl1 1/2 (COOH) + 119.9 ° C

4-Cl HNO, 134.70 C

â '

4 ° C1-C1 HNO3 183.8 ° C

2-Cl 2.4 ”(C1) 2 HNO3 164.2 ° C

2.4- (Cl) 2 2-Cl HNO3 151 ° C

4-Br 2-Cl HNO 3 194.7 ° C

2.4- (Cl) 2 2.4- (Cl) 2 HNOs lll {29C

4 Br - HNOs 156 (5 ° C

4-Br HNO3 131.1 ° C

4-CH3 2.4- (Cl) 2 hNOs 193.6 ° C

4-Br 4-Br HNC> 3 144.3 ° C

4-ch3 4-C1 HNO3 200.8 ° C

4-C1 4-Br HNO3 145.2 ° C

42 DK 157300 B

"6 t, 7 c" rMal. The melting point of the salts

4-CH3 4-Br HNOs 210.5 ° C

3- C1 2.4- (Cl) 2 HNO3 165.4 ° C

2-C1 4-Br HN ° 3 184, IeC

4- CH3 2-C1 HNO3 207.5 ° C

4-C1 4 “CH3 HNO3 144.3 ° C

4-Br 4 “CH 3 HNO 3 140.2 ° C

4-C1 4-F HNO3 163.2 ° C

4-Br 4-F HNO3 179.3 ° C

Example 4.

A mixture of 13.6 parts of imidazole, 18.5 parts of 2- (bromomethyl) -2 "(o-chlorophenyl) -4- (p-chlorophenyl) -1,3-dioxolane, 4 parts of sodium iodide and 150 parts of dimethylformamide Stir and reflux for 72 hours. Water is added and the product is extracted twice with diisopropyl ether. The combined extracts are washed twice with water, dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using trichloromethane as eluant. The pure fractions are collected and the eluent is evaporated. The residue of 1- [2- (o-chlorophenyl) -4- (p-chlorophenyl) -1,3-dioxolan-2-ylmethyl] imidazole is converted to the nitrate salt in 2-propanol and diisopropyl ether. . The salt is filtered off and crystallized from a mixture of ethanol and diisopropyl ether to give 1- [2- (o-chlorophenyl) -4- (β-chlorophenyl) -1,3-dioxolan-2-ylmethyl] imidazole nitrate, m.p. 183.1 ° C.

Example 5

Using the procedure of Example 4 and substituting the 2- (bromomethyl) -2- (2-chlorophenyl) -4- (4-chlorophenyl) -1,3-dioxolane used therein, equivalent to 2- (bromomethyl) ) -4- (4-bromophenyl) -2- (2,4-dichlorophenyl) -1,3-dioxolane is prepared: 1- C4- (4-bromophenyl) -2- (2,4-dichlorophenyl) -1,3 -dioxolan-2-ylmethyl] imidazole nitrate, mp 141.9 ° C

43 DK 157300 B

Example 6

To a stirred solution of 2r3 parts of sodium in 80 parts of methanol is added 6 »8 parts of imidazole, followed by the addition of 100 parts of dimethylformamide, and the methanol is removed by heating at atmospheric pressure to an internal temperature of 130 ° C is obtained. Then 7 parts of A-2- (bromomethyl) -2- (p-chloro-phenyl) -4- (4-chloro-o-tolyloxymethyl) -1,3-dioxolane are added and the mixture is stirred and refluxed for 3 hours. The reaction mixture is poured into water and the product is extracted with benzene. The extract is dried and evaporated in vacuo. The residue of A-1- [2- (p-chlorophenyl) - 4- (4-chloro-o-tolyloxymethyl) -1,3-dioxolan-2-ylmethyl] -1-imidazole is converted to the nitrate salt in 2-propanol. Upon the addition of diisopropyl ether, the salt precipitates. It is filtered off and crystallized from a mixture of methanol and diisopropyl ether to give cis-1- [2- (p-chlorophenyl) -4- (4-chloro-o-tholyloxymethyl) -17 3-dioxolan-2-ylmethylimidazole nitrate, melt -164.3 ° C.

Example 7

Using the procedure of Example 6 and equivalent amounts of the corresponding starting materials to form, the following imidazoles and imidazole acid addition salts are added: o

.-N 0 P

44 DK 157300 B

c 7 Acid salt

Isomer Rb R. or Melting point of the salt, - base - trans 4-Cl 4-01, 2-01 ^ HNO3 190 “190 r 7 cis 4-Cl. 4-CH3 HNO3 140 2 ° trans 4-Cl 4-CH. HNO3 l60 ° trans 4-01 4-01 HNO3, 17118 - 176.9 cis 4-ci 4-ci HNO3 165.8 - 169.6 ° B 4-Cl 2.4-01 HNO3 l60 - 165/3 ° cis 4-01 4-F HNO3 172.3 - 174.5 ° trans 4-01 4-F HNO3 175.9 ° A 4-01 2-CH3 HNO3 134.6 - 145.4 ° B 4-01 2- CH3 HNO3 156.6 - 161.6 ° B 4-01 2-01 HNO3 170 5 ° B 4-01 4-OCH3 HNO3 133 2 °

A 4-Cl 2,4- (Cl) 2 base 175.4-179, 5eC

A 4-Cl 2-C1 base 140.8-143.6 ° C

A 4-Cl 4-OCH 3 base 111.1 C

Example 8.

To a stirred solution of 4.6 parts of sodium in 160 parts of methanol is added successively 13.6 parts of imidazole, 300 parts of dimethylformamide and 4 parts of sodium iodide. The methanol is distilled off at atmospheric pressure until an internal temperature of 130 ° C is reached. Then 25.9 parts of A + B-2- (bromomethyl) -2- (p-chlorophenyl) -4- (2,6-dichlorophenoxymethyl) -1,3-dioxolane are added and the whole is stirred at reflux for 2 hours. The reaction mixture is allowed to cool to room temperature and poured onto 45

DK 157300 B

on water. The product is extracted twice with benzene. The combined extracts are washed twice with water, dried and evaporated in vacuo. The residue containing "A" and "B" isomers is chromatographed over silica gel with chloroform as eluant. The "A" isomer is collected as an oily free base and converted to the nitrate salt in 2-propanol. The crude crystallized from 2-propanol to give 3.8 parts of Al- [2- (p-chlorophenyl) -4- (2,6-dichlorophenoxymethyl) -1,3-dioxolan-2-ylmethyl] imidazole nitrate, m.p. 145 The "B" isomer is also collected as an oily free base and converted to the nitrate salt in 2-propanol and diisopropyl ether. The crude crystallized from 2-propanol to give 2.2 parts of B1- [2- (β-chlorophenyl) -4- (2,6-dichlorophenoxy, ethyl) -1,3-dioxolan-2-ylmethyl] imidazole nitrate, m.p. 197-200.5 ° C.

Example 9

Using the procedure of Example 8 and equivalent amounts of the appropriate starting materials, the following imidazoles and imidazole acid addition salts are prepared: Al- [2- (2,4-dichlorophenyl) -4- (o-tolyloxymethyl) -1,3- dioxolan-2-ylmethyl] imidazole nitrate, mp 156.2 ° C, B1- [2- (2,4-dichlorophenyl) -4- (o-tolyloxymethyl) -1,3-dioxolan-2-ylmethyl] imidazole sesquioxalate, mp 138 , 5 ° C, Al- [2- (2,4-dichlorophenyl) -4- (2,2-dimethylphenoxymethyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole nitrate, m.p. 155.6 ° C and A + B1- [2- (2,4-dichlorophenyl) -4- (2,6-dimethylphenoxy-methyl) -1,3-dioxolan-2-ylmethyl] -1H-imidaxol nitrate, mp 134.5 ° C

Example 10

A mixture of 6.8 parts of imidazole, 7.8 parts of A-2 ~ (bromethyl) -2- (2,4-dichlorophenyl) -4- (phenoxymethyl) -1,3-dioxolane, 4 parts of sodium iodide and 150 parts of dimethylformamide stirred and returned 46

DK 157300 B

The reaction mixture is allowed to cool to room temperature, poured on water and the product is extracted twice with diisopropyl ether. The combined extracts containing Al- [2- (2,4-dichlorophenyl) -4- (phenoxymethyl) -1,3-dioxolan-2-ylmethyl] imidazole are washed twice with water and acidified with an excess of concentrated nitric acid solution. The salt is filtered off and crystallized from a mixture of ethanol and diisopropyl ether to give 5.6 parts of Al- [2- (2,4-dichlorophenyl) -4- (phenoxymethyl) -1,3-dioxolan-2-ylmethyl] imidazole nitrate, mp 180.5 ° C

Example 11.

Using the procedure of Example 10 and equivalent amounts of the corresponding starting materials, the following imidazoles and imidazole acid addition salts are prepared:

--N

ISLAND

^ * 6 VFY

Acidic salt, c Melting or

Ieomer R ° R5 point base 7Γ 2.4- (Cl) z 3, 4- (C1) z-C6H3 152.1 ° C HNO3 A 2.4 = (Cl) 2 3-Cl-C6H4 120.9eC HN03 A + B 2.4- (Cl) 2 2-CH3,4-Cl-C6H3 121.9 ° C HNO3 A 2.4 »(C1) 2 2.4- (Br) 2-C6H3 164.9eC HN03 cis 2 , 4- (Cl) 2 2-F-C6H4 135.9 ° C HNC> 3 A - 4-Br-C6H4 167.6 ° C HNOs B 2,4- (Cl) 2 4-Br-C6H4 131.1 ° C HNO3 cie 2.4- (Cl) 2 4-F-C6H4 151 -152 ° C HNO3 A 2.4- (Cl) 2 4-CH3-C6H4 141.8 ° C HN03 B 2.4- (Cl 145.1 ° C (COOH) 2 cis 2,4- (Cl ') 2 4-OCH3-C6H4 184.7 ° C (COOH) 2 cis 2,4- (Cl) 2 4-Cl -C6H4 152.7 ° C HNO3

47 DK 157300 B

Acid salt 6 c Melting or

Isomer RR point base AZ, 4- (C1) 2 2.4- (Cl) 2-C6H3 146.5 ° C HNO3 A 2.4- (Cl) 2 4-Br-C6H4 158.9 ° C HNC> 3 AZ, 4- (C1) 2 3.5- (CH3) 2,4-C1-C6H2 185.7 ° C HNO3 A 2.4- (C;) 2 4-CN-C6H4 208 ° C HNO3 A 2, 4- (C1) 2 2 -OCH3-C6H4 110.6 ° C 2 (COOH) 2 AZ, 4- (C1) 2 6-Br-2-naphthalenyl 195.5 ° C HNC> 3 cis 2,4- ( Cl) 2 2-naphthalenyl 156.3 ° C HNC> 3 A + B 2,4- (Cl) 2 4-Cl-2-naphthalenyl 136.7 ° C HNO 3 cis 2,4- (Cl) 2,4 BrB-C 6 H 4 121.8 ° C base

Example 12 »

A mixture of 13.6 parts of imidazole, 22.2 parts of A + B-2- (bromomethyl) -4- (o-chlorophenoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolane, 4 parts potassium iodide and 150 parts of dimethylformamide are stirred and refluxed for 3 days. The reaction mixture is allowed to cool to room temperature, poured into water and the product is extracted twice with diisopropyl ether. The combined extracts are washed twice with water, dried over filtration and evaporated. The residue is purified by column chromatography over silica gel using of chloroform as eluant to form two fractions.

The first fraction is evaporated and the residue of A- [4- (o-chlorophenoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl] imidazole is dissolved in a mixture of 4-methyl-2- pentanone and diisopropyl ether. The solution is acidified with an excess of concentrated nitric acid solution. The nitrate salt is filtered off and crystallized from a mixture of 4-methyl-2-pentanone and diisopropyl ether to give A-1- [4- (o-chlorophenoxymethyl) -2,4-dichlorophenyl) ~ 1,3-dioxolan-2-ylmethyl] imidazole nitrate, 48

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mp 136.2 ° C.

The second fraction is evaporated and the residue of B1- [4- (o-chlorophenoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl] imidazole is dissolved in a mixture of 4-methyl-2 -pentanone and diisopropyl ether. The solution is acidified with an excess of oxalic acid. The oxalate salt is filtered off and crystallized from 4-methyl-2-pentanone to give 4 parts B1- [4- (o-chlorophenoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl] imidazole dioxalate, mp 103.5 ° C.

Example 13 «

Using the procedure of Example 12 and equivalent amounts of the corresponding starting materials, the following imidazoles and imidazole acid addition salts are prepared. Where only one isomer is indicated, no other fraction is obtained by chromatography.

ISLAND

E7 ^ 49

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salt

Isomer R5 R / Acid salt Melting point A 2.4- (Cl) 2 2.6- (Cl) 2 HNO ^ 159 ° cis 2.4- (Cl) 2 2-Br HNO3 142.2 ° trans 2.4- ( Cl) 2 2-Br 2 (C 30 H) 2 151.3 ° A 2.4- (ci) 2 2.5- (ch 3) 2 hno 3 180.9 ° B 2.4- (01) 2 2.5- (CH3) 2 1.5 (C00H) 2 142.7 ° A 2.4- (Cl) 2 2.4.6- (Cl) 3 HNO3 181.6 ° B 2.4- (ci) 2 2, 4.6- (ci) 3 2 (cooh) 2 143.9 ° A 2.4- (Cl) 2 2-Cl, 4-C (CH 3) 3 HNO 3 141 (2 ° B 2.4- (Cl) 2 2-C1,4-C (CH 3) 3 HNO 3 144, 1 ° A 2,4- (01) 2 2,4,5- (Cl) 3 HNO 3 196,1 ° B 2,4- (ci) 2 2,4,5 ”(C1) 3 (5) (COOH) 2 173.6 ° C in 2.4- (01) 2 2.5- (Br) 2,4-CH 3 HNO 3 175 A ° A 2, 4- (Cl) 2 20C2H5 hn ° 3 117.7 ° A + B 2-01 4-Br HK03 145.3 ° B 2-C1 4-Br KNO3 152.7e A 2-Br 4-Br HNQ3 149.9 ° B 2-Br 4-Br HNO3 169.3 ° A 2.4- (01) 2 2-C1, 6-GH3 HNO3 154.2 ° 50

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Example ü.4.

A mixture of 9/7 parts of 1H-imidazole / 12/5 parts of A + B-2- (bromomethyl) -4- (4-bromophenoxymethyl) -2- (4-methylphenyl) -1,3-dioxolane / 3 parts potassium iodide and 135 parts N / N-dimethylformamide are stirred and refluxed for 72 hours. The reaction mixture is poured into water and the product is extracted twice with diethyl ether. The extract containing Al- [4- (4-bromophenoxymethyl) -2- (4-methylphenyl) -1,3-dioxolan-2-ylmethyl] -ΙΗ-imidazole is washed twice with water7 and an excess of concentrated nitric acid solution and 2 2'-oxybispropane is added. The damied site is filtered off and crystallized from a mixture of ethanol and diisopropyl ether to give 5.6 parts of Al- [4- (4'hromophenoxymethyl) -2- (4-methylphenyl) -1,3-dioxolan-2-ylmethyl] - 1H-imidazole nitrate / mp 175.5 ° C

Example 15

Using the procedure of Example 14, but substituting the A + B-2- (bromomethyl) -4- (4-bromophenoxy-methyl) -2- (4-methylphenyl) -173-dioxolane used in equivalent amounts of A + B-2- (bromomethyl) -4- (4-bromophenoxymethyl) -2- (4-chlorophenyl) -1,3-dioxolane and A + B-2- (bromomethyl) -4- (4-bromophenoxy) -methyl) -2- (4-bromophenyl) -1,3-dioxolane is prepared Al- [4- (4-bromophenoxymethyl) -2- (4-chlorophenyl) -1,3-dioxolan-2-ylmethyl] -1H- imidazole and its nitral salt, m.p. 158 ° C and A- [4- (4-bromophenoxymethyl) -2- (4-bromophenyl) -1,3-dioxolan-2-ylmethyl] -ΙΗ-imidazole and its nitrate salt, mp 170, 8 ° C =

Example 16.

A mixture of 7.9 parts of 1H-imidazole / 11/5 parts of A + B-2- (bromomethyl) -2- (2,4-dichlorophenyl) -4- (4-phenylphenoxymethyl) -1,3-dioxolane / 4 parts potassium iodide and 135 parts of N, N-dimethylformamide are stirred and refluxed for 3 days. Reaction mixture 51

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gene is poured into water and the product is extracted twice with diethyl ether. The combined extracts are washed with water, dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using trichloromethane as eluant.

The first fraction is collected and the eluent is evaporated. The residue is converted to the nitrate salt in 4-methyl-2-pentanone and diisopropyl ether. The salt is filtered off and crystallized from a mixture of ethanol and diisopropyl ether to give A + B1- [2- (2,4-dichlorophenyl) -4- (4-phenylphenoxymethyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole nitrate, mp 187.9 ° C.

The second fraction is collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone to give trans-1- [2- (2,4-dichlorophenyl) -4- (4-phenylphenoxymethyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole, m.p. 155.7 ° C.

Example 17

A mixture of 6.8 parts of imidazole, 8.5 parts of B-2- (bromomethyl) -4- (g-chlorophenoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolane, 2 parts of sodium iodide. and 100 parts of dimethylformamide are stirred and refluxed for 36 hours. The reaction mixture is allowed to cool to room temperature and poured into water. The product is extracted twice with benzene. The combined organic layers are washed twice with water, dried and the solvent removed in vacuo. The residue is purified by column chromatography over silica gel using chloroform as eluant. The pure fractions are collected and the eluent is evaporated. The residue of B-1- [4- (p-chlorophenoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl] -imidazole is converted to the oxate salt in 4-methyl-2-pentanone. After the addition of diisopropyl ether, the salt was precipitated. It is filtered off and crystallized from 4-methyl-2-pentanone to give 3.1 parts of trans-1- [4-p-chlorophenoxy]

52 DK 157300 B

methyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl] -imidazole sesguioxalate, m.p. 101 ° C.

Example 18.

Using the procedure of Example 17, prepare: B1- [4- (2,4-dichlorophenoxymethyl) -2- (2,4-dichloro-phenyl) -1,3-dioxolan-2-ylmethyl] imidazole sugioxalate, m.p. 121 , 2 ° C, by reacting B-2- (bromomethyl) -4- (2,4-dichloro-phenoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolane with imidazole «

Example 19.

A mixture of 8.6 parts of 1H-imidazole., 11.3 parts of A-2- (bromomethyl) -2- (2,4-dichlorophenyl) -4- (3,5-dimethylphenoxy-methyl) -1,3- dioxolane, 4 parts potassium iodide and 135 parts N, N-dimethylacetamide are stirred and refluxed for 3 days. The reaction mixture is poured into water and the product is extracted twice with diisopropyl ether. The combined extracts are washed twice with water and an excess of concentrated nitric acid solution is added. The nitrate salt formed is filtered off and crystallized from a mixture of 2-propanol and diisopropyl ether. The product is again filtered off and recrystallized from 4-methyl-2-pentanone to give Al- [2- (2,4-dichlorophenyl) -4- (3,5-dimethylphenoxymethyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole nitrate hydrate, m.p. 122.6 ° C.

Example 20

Using the procedure of Example 19 and equivalent amounts of the corresponding starting materials, the following imidazoles and imidazole acid addition salts are prepared: 53

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ISLAND

"V0 *"

κ'-Ο ^ ο-0Η2 ^ -J

Isomer R ^ 1 Acid salt The salt _______ melt> uniquely

A 2-CH -4-C1 4-Br HNO, 159.3 ° C

5 5

A = cis 2-CH3-4-Br 4-Br HNC> 3 164.3 ° C

A = cis 3-Br 4-Br HN ° 3 158.7 ° C

A = cis 3-Br-4-CH 3 4-Br HNC> 3 201.1 ° C

, 7 Salt's

Isomer Rb R 'Acid salt melting point

A = cis 4-CN 4-Br HNCXJ 190.1 ° C

A 2.4- (Cl) 2 4- (C6H5-CH2) HNC> 3.H2O 110.3eC

A = cis 3.5- (Cl) 2 4-Br HNO 3 167.1 ° C

A = cis 3-NO2 4-Br HNOs 148.8 ° C

A = cis 2,4- (Cl) 2 2-NO2 2 (COOH) 2 95.2 ° C

B = trans 2.4 ~ (C1) 2 2 -NO2 (COOH) 2 157.2 ° C

B = trans 2.4- (Cl) + 4- (C, He-CH2) (GOGH), 137 ° C

ICi I O D fa I ό \ ί

2.4- (Cl) 2 2- (C6H5) HNO3 109.3 ° C

A + B 2.4- (Cl) 2 4- / CH3-CH (CH3 ^ HNO2 115.2eC

A 2.4- (Cl) 2 4- / CH3-C (CH3 ^ HNO3 169.5 ° G

A 2,4- (Cl) 2 3,5- (Cl) 2 ΗΝ03.Η2θ | 136.7 ° C

A 2s4- (C1) 2 3-CH3,4-Cl HNO3 j 142.8CC

A 2,3,4- (Cl) 3 4-Br HNC> 3 174.4eG

A 2,4- (Cl) 2 2-Br, 4-CH 3 HNC> 3 137, leC

54

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Example 21.

A mixture of 42 parts of 1H-imidazole, 63 parts of A + B-4 - ([1,1 * -biphenyl] -4-yloxymethyl) -2- (bromomethyl) -2- (2,4-dichlorophenyl) - 1,3-dioxolane, 20 parts potassium iodide and 675 parts Ν, Ν-dimethylformamide are stirred and refluxed for 3 days. The reaction mixture is poured into water and the product is extracted with diisopropyl ether. The extract is dried, filtered and evaporated. The residue is converted to the nitrate salt in 4-methyl-2-pentanone and diisopropyl ether. The product is excreted as an oil. The supernatant is decanted and the residual oil solidifies by trituration in 4-methyl-2-pentanone. The nitrate salt is filtered off and crystallized from ethanol to give 5 parts of cis-1- [4 - {[1,1'-biphenyl] -4-yloxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole nitrate, mp 186.5 ° C

Example 22

Using the procedure of Example 21 and equivalent amounts of the corresponding starting materials, the following compounds are prepared: cis ° 1- [2- (2,4-dichlorophenyl) -4- (2-methoxyphenoxymethyl) -1,3-dioxolane-2 ylmethyl] -1H-imidazole oxalate, hemihydrate, melting point 123/6 ° C and cis-1- [2- (2,4-dichlorophenyl) -4- (4-fluorophenoxymethyl) -1,3-dioxolan-2-ylmethyl] - ΙΗ-imidazole, m.p. 106.7 ° C.

Example 23

A mixture of 6.4 parts of 1H-imidazole, 10 parts of A + B-2- (bromomethyl) -4- (3-chloro- [1,1'-biphenyl] -4-yloxymethyl) -2- (2.4 -dichlorophenyl) -1,3-dioxolane and 135 parts of Ν, Ν-dimethylacetamide are stirred and refluxed for 5 days. The reaction mixture is allowed to cool to room temperature and poured into water. The product is extracted twice with diethyl ether. The combined extracts are washed with water, filtered and evaporated. The residue is 55

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is crystallized from 4-methyl-2-pentanone to give 2.2 parts (22%) of trans-1- [4- (3-chloro- [1,11-biphenyl] -4-yloxymethyl) -2- (2, 4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole, m.p. 140.8 ° C.

Example 24.

A mixture of 10, 2 parts of 1H-imidazole and 26, 8 parts of sodium methoxide solution 30% is stirred and refluxed for 15 minutes. Next, 90 parts of Ν, Ν-dimethylformamide are added. The methanol is distilled off to an internal temperature of approx. 130 ° C. After adding an additional 90 parts of Ν, Ν-dimethylformamide, 50 parts of A + B-4 - '(L1 / 1,' - biphenyl] -4-yloxymethyl) -2- (bromomethyl) - 2- (2,4-dichlorophenyl) -1,3-dioxolane portionwise at ca. After addition, stirring is continued for 5 hours at reflux temperature. The reaction mixture is poured onto a mixture of water and methylbenzene. The organic phase is separated and stirred with activated charcoal. The latter is filtered off and the filtrate is evaporated. The residue is purified twice by column chromatography over silica gel using trichloromethane and 1% methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2-propanol to give 9 parts of cis-1- [4- ([1,1 * -biphenyl] -4-yloxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolane -2-ylmethyl] -1H-imidazole, m.p. 150.7 ° C.

Example 25

A mixture of 17 parts of 1H-imidazole, 27.4 parts of A + B-4 - ([1,1'-biphenyl] -4-yloxymethyl) -2- (bromomethyl) -2- (3,4,5-tri (Chlorophenyl) -1,3-dioxolane and 135 parts of N, N-dimethylacetamide are stirred and refluxed for 5 days. The reaction mixture is cooled and poured into water. The product is extracted twice with diethyl ether. The combined extracts are washed with water, dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using trichloromethane as eluent. The first fraction is collected and the eluent is evaporated. The residue is converted to the nitrate salt in 4-methyl-2-pentanone and diisopropyl ether. The salt is filtered off and crystal 56

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is licensed from a mixture of acetonitrile and diisopropyl ether to give 1.9 parts of trans-1- [4 - ([1,1'-biphenyl] -4-yloxy-methyl) -2- (3,4,5-trichlorophenyl) ) -1,3-dioxolan-2-ylmethyl] -1H-imidazole nitrate, mp 158 ° C.

Example 26

When used in the procedure of Example 25 and equivalent amounts of the appropriate starting materials, the following imidazoles and imidazole acid addition salts are obtained: cis-1- [4- ([1,1'-biphenyl] -4-yloxymethyl) -2 - (4-bromo-2-chlorophenyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole, m.p. 161.8 ° C, trans-1- [4- ([1,15-biphenyl] -4 -yloxymethyl) -2- (4-bromo-2-chlorophenyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole, mp 154.6 ° C, cis-i- [4- ([1,1 -biphenyl] -4-yloxymethyl) -2- (2-naphthalenyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole, mp 152.6 ° C, trans-1- [4 - ([1 , 1'-biphenyl] -4-yloxymethyl) -2- (2-naphthalenyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole nitrate, mp 230/6 ° C, cis-1- [4- ( [1,1'-biphenyl] -4-yloxymethyl) -2- (2,4,5-trichlorophenyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole nitrate, m.p. 199.2 ° C and trans. 1- [4 - ([1,1'-biphenyl] -4-yloxymethyl) -2- (2,4,5-trichlorophenyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole, m.p. 139, 2 ° C.

Example 27

A mixture of 11.5 parts of 1H-imidazole, 17.5 parts of A + B-2- (bromomethyl) -2- (2,4-dichlorophenyl) -4- (3,4,5-trichlorophenoxy-methyl) -1 , 3-dioxolane, 3 parts potassium iodide and 180 parts N, N-dimethylacetamide are stirred and refluxed over the week-end. The reaction mixture is poured into water and the product is extracted 4 times with diethyl ether. The combined extracts are washed some 57

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once with water, dry / filtered and evaporated. The oily residue is purified by column chromatography over silica gel using trichloromethane soin eluent. The first fraction (A-isomer) is collected and the eluent is evaporated. The oily residue is converted to the nitrate salt in 4-methyl-2-pentanone. The salt is filtered off and crystallized from a mixture of 4-methyl-2-pentanone and diisopropyl ether to give, after drying, 7.5 parts (40%) of cis-1- [2- (2,4-dichlorophenyl) -4- (3,4,5-trichlorophenoxymethyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole nitrate, hydrate, m.p. 149.9 ° C.

The second fraction (B isomer) is collected and the eluent is evaporated. The oily residue is converted to the nitrate salt in 4-methyl-2-pentanone. The salt is filtered off and crystallized from a mixture of 4-methyl-2-pentanone and diisopropyl ether to give, after drying, 6.2 parts (27%) of trans-1- [2- (2,4-dichlorophenyl) -4- (3,4,5-trichlorophenoxymethyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole nitrate, m.p. 169.3 ° C.

Example 2g.

Using the procedure of Example 27 and equivalent amounts of the appropriate starting materials, the following imidazoles and imidazole acid addition salts are prepared. When only one isomer is added, no other fraction is obtained from the chromatography.

cis-1- [4- (2-chloro-5-methylphenoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole, mp 131.7 ° C, trans -1- [4- (2-chloro-5-methylphenoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole sesquioxalate, m.p. 148.7 ° C, Al [4 - [(1,6-dibromo-2-naphthalenyloxy) methyl] -2- (2,4 'dichlorophenyl) -1,3-dioxolan-2-ylmethyl] -1-imidazole nitrate, m.p. 179.4 ° C, 58

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Al- [4- (2,3-dichlorophenoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole dioxalate, mp 151.6 ° C and B1- [4- (2,3-dichlorophenoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole sesguioxalate, mp 156.3 ° C.

Example 29.

Using the procedure of Example 28 and equivalent amounts of the corresponding starting materials, the following compounds are prepared: A + B1- [4- (4-bromophenylthiomethyl) -2- (2,4-dichloro-phenyl) -1,3-dioxolane- 2-ylmethyl] -1H-imidazole nitrate, m.p. 170 ° C and A + B1- [2- (2,4-dichlorophenyl) -4- (phenylthiomethyl) -1,3-dioxoian-2-ylmethyl] -1H-imidazole nitrate, mp 122 ^ 3 ° C.

Example 30.

A mixture of 4.5 parts of 1H-imidazole, 6.5 parts of A-2- (bromomethyl) -4- (4-bromophenoxymethyl) -2- (2,3-dichlorophenyl) -1,3-dioxolane and 125 parts Ν, Ν-dimethylacetamide are stirred and refluxed for 2 days. The reaction mixture is allowed to cool to room temperature, poured into water and the product is extracted twice with diethyl ether. The combined extracts are washed twice with water and an excess of concentrated nitric acid solution is added. The nitrate salt formed is filtered off and crystallized from 4-methyl-2-pentanone to give 5 parts (68%) of cis-1- [4- (4-bromophenoxymethyl) -2- (2,3-dichlorophenyl) -1,3 -dioxolan-2-ylmethyl] -1H-imidazole nitrate, mp 138.9 ° C.

Example 31.

Using the procedure of Example 30 and equivalent amounts of the corresponding starting materials, the following imidazole acid addition salts are prepared: 59

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cis-1- [4- (3-chloro [1,11-biphenyl] -4-yloxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl] -Ih-imidazolnitrat, m.p. 171.1 ° C, cis-1- [4 - ([1,1'-biphenyl] -4-yloxymethyl) -2- (2-chloro-4-methoxyphenyl) -1,3-dioxolan-2-ylmethyl ] -1H-imidazole nitrate, m.p. 172.9 ° C, A + B1- [2- (2,4-dichlorophenyl) -4- (phenylmethyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole dioxalate , m.p. 117.1 ° C, A + B1 - 2- (2,4-dichlorophenyl) -4 - [(4-fluorophenyl) thiomethyl] -1,3-dioxolan-2-ylmethyl] -1H-imidazole dioxalate, m.p. 129.8 ° C, A + B1- [4- (4-chlorophenylmethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole sesguioxalate, mp 141.6 ° C, A + B1- [2- (2,4-dichlorophenyl-4- (4-methoxyphenylmethyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole dioxalate, m.p. 94.2 ° C, cis-2- [2 - (2,4-Dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] benzonitrile nitrate, m.p. 162.1 ° C and cis-butyl 4- [2- (2.4 dichlorophenyl) -2- (IH-imidazol-l-yl-methyl) -1,3-dioxolan-4-ylmethoxy] benzoatnitra t, m.p. 90.5 ° C.

Example 32.

A mixture of 14.4 parts of 1H-imidazole, 18.5 parts of A + E-2- (bromomethyl) -2- (2,4-dichlorophenyl) -4- [2- (4-methoxyphenyl) ethyl] -1,3- dioxolane, 5 parts potassium iodide and 135 parts N, N-dimethylacetamide are stirred and refluxed for 2 days. The reaction mixture is allowed to cool to room temperature and poured into water. The product is extracted twice with diisopropyl ether. The combined extracts are washed with water, dried, filtered and evaporated. The residue is converted to the oxalate salt in 4-methyl-2-pentanone and

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The salt is filtered off and crystallized from a mixture of diisopropyl ether and ethanol to give A + B1 - 2- (2,4-dichlorophenyl) -4- [2- (4-methoxyphenyl) ethyl] -1,3-dioxolane 2-ylmethyl-1H-imidazole sesguioxalate, m.p. 130.7 ° C.

Example 33

Using the procedure of Example 32 and equivalent amounts of the corresponding starting materials, the following imidazoles and imidazole acid addition salts are prepared: 1- (4- [2- (4-chlorophenyl) ethyl] -2- (2,4-dichlorophenyl) - 1,3-dioxoian-2-ylmethyl] -1H-imidazole dioxalate, mp 131.9 ° C, 1- [2- (2,4-dichlorophenyl) -4- (2-phenylethyl) -1,3-dioxolan-2-ylmethyl ] -1H-imidazole sesguioxalate, m.p. 117.8 ° C and A B-1- [2- (2,4-dichlorophenyl) -4- [2- (4-methylphenyl) ethyl] -1,3-dioxolane-2 ylmethylj-1H-imidazole sesguioxalate, hydrate, mp 123.8 ° C

1- [4- [2- (2-chlorophenyl) ethyl] -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole nitrate, m.p. 98.8 ° C, 1-2 - (2,4-dichlorophenyl) -4- [2- (2,4-dichlorophenyl) ethyl] -1,3-dioxolan-2-ylmethyl] -1H-imidazole nitrate, mp 158.1 ° C and A + B1 - 2- (2,4-dichlorophenyl) -4- [2- (2,6-dichlorophenyl) ethyl] -1,1-dioxolane ^ -ylmethyl] -1H-imidazole nitrate, m.p. 140, 1 ° C.

Example 34.

To a stirred sodium methoxide solution / prepared from 3.8 parts of sodium in 40 parts of methanol, add 11 parts of 1H-imidazole and 225 parts of Ν, Ν-dimethylformamide. The methanol is distilled off to an internal temperature of 150 ° C. Then 19 parts of A + B-2- (bromomethyl) -2- (2,4-dichlorophenyl) -4-ethyl-61 are added.

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1,3-dioxolane and the whole is stirred and refluxed for 1 hour. The reaction mixture is allowed to cool to room temperature and poured into water. The product is extracted three times with diethyl ether. The combined extracts are washed with water / dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using trichloromethane and 1% methanol as eluent. The first fraction is collected and the eluent is evaporated. The residue is converted to the nitrate salt in diisopropyl ether. The salt is filtered off and crystallized from a mixture of 2-propanol and diisopropyl ether to give 12 parts (56%) of A + B1- [2- (2/4-dichlorophenyl) -4-ethyl-1,3-dioxolane-2 -ylmethyl] -IH-imidazole nitrate, mp 149.1 ° C.

Example 35.

To a stirred sodium methoxide solution / prepared from 2.8 parts of sodium in 40 parts of methanol, add 8 parts of 1H-imidazole and 225 parts of Ν, Ν-dimethylformamide. The methanol is distilled off to an internal temperature of 150 ° C. Next, 30 parts of A + B-2- (4-bromo-2-chlorophenyl) -2- (bromomethyl) -4-ethyl-1,3-dioxolane are added. and stirring is continued for one hour at reflux temperature. The reaction mixture is cooled and poured into water. The product is extracted twice with diisopropyl ether.

The combined extracts are washed with water, dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using trichloromethane and 2% methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted to the nitrate salt in diisopropyl ether. the salt is filtered off and crystallized from 4-methyl-2-pentanone and diisopropyl ether to give 8.5 parts (26%) of A + B1- [2- (4-bromo-2-chlorophenyl) -4-ethyl-1,3 -dioxolan-2-ylmethyl] -1H-imidazole nitrate, mp 162.2 ° C.

Example 36.

Using the procedure of Example 35 and equiv.

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lime amounts of the corresponding starting materials, the following imidazole acid addition salts are prepared: 9 * CH, Ar crO a + b R -J-1 j Ar R Acid salt Melting point

· 2 - Cl - C 2 H 5 HNO 3 147.6 C

2-CH3-C6H4 G2H5 HNO3 117.5eC

4-CH, ~ G, H, C + H HNO, 172.7 ° C

3 6 4 2 5 3 1

2, 3S 4- (Cl) + C, H C, H HNO, 176.4 ° C

5 Ο 2 CO 3

2-Br-C.H, C, Hc HNO, 135.3 ° C

o 4 2 5 3

2.3- (Cl) 2-C6H3 C2H5 HNO3 140.3 ° C

I3-C1-C6H4 C2H5 HNO3 151.6 ° C

4-OCH, -C, H, G, H HNO, 157.1 ° C

3 o 4 f cb 3

2-CH, -4-Cl-C, H CH HNO 126.8 ° C

3 6 3 2 5 3 1

2-Cl-4 = OCK, -C, H, C, Hc HNO 117f7eC

3 6 3 j 2 5 3

. 3,4,5- (Cl) -C6H2 C2H5 HNOs 195.8 ° C

2-naphthyl HNOs 195.1 ° C

2-OCH, -4-Cl-C, H, C, H HNO, 131.8 ° C

2,4,5- (Cl) 3-C6H2 C2H5 HNO3 180.1 ° C

2.4- (01), -0, H nC, H_ HNO, 119.2 ° C

'' 2 6 3 3 7 3 1

2.4- (Cl), - G, H nC. H HNO, 113.1 ° C

'2 6 3 4 9 3

2.4- (Cl) -C6H3 nC5H11 HN ° 3 128.3 ° C

2,4- (Cl) 2-C6H3 η06Η13 HNOs 99.4 ° C

2,4- (Cl) 2-C6H3 nC7H15 2 (COOH) 2 131 ° C

2,4- (Cl) 2-C6H3 nC8H17 2 (COOH) 2 132.8 ° C

63

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Example 37.

A mixture of 32 parts 1- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl) ethanone, 55 parts 1,2,3-propanetriol, 35 parts 4-methylbenzenesulfonic acid, 96 parts butanol and 360 parts dimethylbenzene is stirred and refluxed for 5 days with water separator. The reaction mixture is cooled, washed with potassium carbonate solution and with water, dried / filtered and evaporated. The residue is dissolved in a dilute oxalic acid solution. The resulting solution is washed twice with diethyl ether. The aqueous phase is separated and neutralized with potassium carbonate. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and 2% methanol as eluent. The first fraction is collected and the eluent is evaporated. The residue is converted to the nitrate salt in diisopropyl ether. The salt is filtered off and crystallized from a mixture of 4-methyl-2-pentanone and diisopropyl ether to give 5.5 parts (9.8%) of A + B1- [4- (butoxymethyl) -2- (2,4- dichlorophenyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole nitrate, m.p. 101, 8 ° C.

The second fraction is collected and the eluent is evaporated. The residue is triturated in diethyl ether. The product is filtered off and crystallized from a mixture of 4-methyl-2-pentanone and petroleum ether to give 9.75 parts of A + B-2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) - 1,3-dioxolane-4-methanol, m.p. 128, 1 ° C.

Example 38

A mixture of 7.7 parts of 1H-imidazole, 8 parts of cis-2- (bromomethyl) -2- (2,4-dichlorophenyl) -1,3-dioxoan-4-methanol, 1 part potassium iodide and 180 parts Ν , Β-Dimethylacetamide is stirred and refluxed for 3 days. The reaction mixture is cooled and evaporated. Next, 50 parts of water and 300 parts of trichloromethane are added to the residue. It is all washed three times with water, dried, filtered 64

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triturate and evaporate. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and 2% methanol soin eluent. The pure fractions are collected and the eluent is evaporated to give 9, 2 parts of cis-2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolane-4-methanol, m.p. ° C

Example 39

Using the procedure of Example 38 and an equivalent amount of trans-2- (bromomethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolane-4-methanol as the starting material, obtaining: trans-2- (2 , 4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolane-4-methanol + mp 129 ° C.

Example 40.

To a stirred mixture of 4 parts of cis-2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolane-4-methanol, 2/2 parts of iodomethane and 90 parts Ν Ν-Dimethylformamide is added to 0/5 part sodium hydride dispersion (78%) and stirring is continued for 2 hours at room temperature. The reaction mixture is poured into water and the product is extracted three times with diethyl ether. The combined extracts are washed with water and acidified with nitric acid solution in diethyl ether. The nitrate salt formed is filtered off and crystallized from 4-methyl-2-pentanone to give 2.2 parts (45%) of cis-1- [2- (2,4-dichlorophenyl) -4- (methoxymethyl) -1, 3-dioxolan-2-ylmethyl] -1H-imidazole nitrate, m.p. 140 ° C.

Example 41.

To a stirred mixture of 4 parts of cis-2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolane-4-methanol, 1.7 parts of bromethane and 90 parts of Ν Ν-Dimethylformamide is added 0.5 part sodium hydride dispersion (78%). It is all stirred for 1 hour at room temperature. The reaction mixture is poured into water three times with diisopropyl ether. The combined extracts are washed with water and acidified with nitric acid solution in diisopropyl ether. It 65

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formed nitrate salt is filtered off and crystallized from a mixture of 4-methyl-2-pentanone and diisopropyl ether to give 4.7 parts (93%) of cis-1- [2- (2/4-dichlorophenyl) -4- (ethoxy) -methyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole nitrate, mp 134.7 ° C.

Example 42

Using the procedure of Example 41 and an equivalent amount of a suitable bromoalkane or bromoalkane in place of the bromethane used in the example, the following imidazole acid addition salts are obtained: cis-1- [2- (2,4-dichlorophenyl) -4- ( propoxymethyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole nitrate, mp 131.7 ° C, cis-1- [2- (2,4-dichlorophenyl) -4- (pentyloxymethyl) -1,3-dioxolane 2-ylmethyl] -1H-imidazole nitrate, m.p. 78.6 ° C, cis-1- [2- (2,4-dichlorophenyl) -4- (hexoxyloxymethyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole nitrate, m.p. 87.1 ° C, cis-1- [2- (2,4-dichlorophenyl) -4- (heptyloxymethyl-1,3-dioxolan-2-ylmethyl] -1H-imidazole nitrate, mp 80.7 ° C, cis -1- [2. (2,4-Dichlorophenyl) -4- (octyloxymethyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole nitrate, m.p. 73.4 ° C and cis-1- [2- ( 2,4-dichlorophenyl) -4- (2-propenyloxymethyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole nitrate, m.p. 116.3 ° C.

Example 43>

To a mixture of 4 parts of trans-2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolane-4-methanol, 1.7 parts of bromethane and 90 parts of Ν, Ν-Dimethylformamide is added 0.5 part sodium hydride dispersion (78%) and it is all stirred for two hours at room temperature. The reaction mixture is poured into water and the product is extracted twice with diisopropyl ether. The combined extracts are washed with water and taken up in diisopropyl ether. The solution is acidified with nitric acid. The nitrate salt formed is filtered off 66

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and crystallized from 4-methyl-2-pentanone to give 3.5 parts (69%) of trans-1- [2- (2,4-dichlorophenyl) -4- (ethoxymethyl) -1,3-dioxolane-2 ylmethyl] -1H-imidazole nitrate, mp 151.4 ° C

Example 44

To a stirred mixture of 2.5 parts of 1-chloro-4- (chloro-methyl) benzene, 4 parts of cis-2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1, 3-dioxolane-4-methanol and 90 parts of N, N-dimethylformamide are added 0.5 parts of sodium hydride dispersion (78%). Stirring is continued for 5 hours at room temperature. The reaction mixture is poured into water and the product is extracted twice with diisopropyl ether. The combined extracts are washed with water, dried, filtered and acidified with nitric acid. The nitrate salt formed is filtered off and crystallized from a mixture of 4-methyl-2-pentanone and diisopropyl ether. The product is filtered off and recrystallized from a mixture of 4-methyl-2-pentanone and diupropyl ether to give 3.5 parts (56%) of cis-1- [4- (4-chlorophenylmethoxymethyl) -2- (2 4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole nitrate, mp 131.7 ° C.

Example .45.

Repeating the procedure of Example 44 and replacing the compound 1-chloro-4- (chloromethyl) benzene used with an equivalent amount of a suitable (chloromethyl) benzene, obtained: cis-1-4 - [(4-bromophenyl) methoxymethyl] -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole nitrate, m.p. 101.4 ° C and cis-1- [2- (2,4-dichlorophenyl) -4 - [(4-fluorophenyl) methoxy-methyl] -1,3-dioxolan-2-ylmethyl | -1H-imidazole nitrate, m.p. 107 ° C.

Example 46 ·

To a stirred mixture of 3.3 parts of 2,4-dichloro-1- (chloromethyl) benzene, 5 parts of A + B-2- (2,4-dichlorophenyl) -2- (1H- 67

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imidazol-1-ylmethyl) -1,3-dioxolane-4-methanol and 90 parts of N, N-dimethylformamide are added part of sodium hydride dispersion (78%) and stirring is continued for 3 hours at room temperature. The reaction mixture is poured into water and the product is extracted three times with diisopropyl ether. The combined extracts are washed with water, dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using trichloromethane soin eluent. The first fraction (A-isomer) is collected and the eluent is evaporated. The residue is converted to the nitrate salt in 4-methyl-2-pentanone and diisopropyl ether. The salt is filtered off and recrystallized from a mixture of 4-methyl-2-pentanone and diisopropyl ether at 0 ° C to give 2.9 parts (35%) of cis-1- [2- (2,4-dichlorophenyl) -4- [(2,4-dichlorophenyl) -methoxymethyl] -1,3-dioxolan-2-ylmethyl] -1H-imidazole nitrate, m.p. 96r9 ° C.

The second fraction (B isomer) is collected and the eluent is evaporated. The residue is converted to the nitrate salt in 4-methyl-2-pentanone and diethyl ether. The salt is filtered off and recrystallized from a mixture of 4-methyl-2-pentanone and diisopropyl ether to give 1.6 parts (19%) of trans-1- [2- (2,4-dichlorophenyl) -4 - [(2, 4-dichlorophenyl) methoxymethyl] -1,3-dioxolan-2-ylmethyl] -1H-imidazole nitrate, mp 131.9 ° C.

Example 47.

Repeating the procedure of Example 46 and substituting the compound 2,4-dichloro-1-chloromethyl-benzene used with an equivalent amount of 4- (chloromethyl) -1,1'-bi-phenyl, obtained: cis -1- [4 - ([1,1'-biphenyl] -4-ylmethoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole dioxalate, m.p. 107.6 ° C and trans-1- [4 - ([1,1'-biphenyl] -4-ylmethoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole nitrate, mp 168 ° C

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68 Example 48,

A mixture of 2.2 parts (4-hydroxyphenyl) phenylmethanone, 4.2 parts cis-2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl-methyl) -1,3-dioxolane-4 Yl-methylmethanesulfonate, 2 'of potassium carbonate and 68 parts of Ν, Ν-dimethylformamide are stirred overnight at 100 ° C. The reaction mixture is cooled and poured into water. The product is extracted twice with diethyl ether. The dried extracts are washed with water, dried, filtered and evaporated. The residue is converted to the nitrate salt in 4-methyl-2-pentanone and diisopropyl ether to give 4.5 parts (78%) of cis-4- [2- (2,4-dichloro-phenyl) - = 2 = (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] -

) Q

phenyB phenylmethanone nitrate, m.p. 179 C.

J

Example 49.

Using the procedure of Example 48 and replacing (4-hydroxyphenyl) phenylmethanone with an equivalent amount of a corresponding phenol, the following imidazoles and imidazole acid addition salts are obtained: cis-5-chloro-2- [2- (2,4- dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] -4-methylphenyl-phenylmethanone, oxalate, m.p. 170.8 ° C, cis-methyl-4- [ 2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] benzoate, nitrate, m.p. 167, 8 ° C, cis-j2- [2- (2,4-Dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] -5-methylphenyl] phenylmethanone, nitrate, mp 145.4 ° C, cis ° (4- 2- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] -4-methoxy-phenyl] -methanone, m.p. 168.3 ° C, cis-j 2- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] -4-methoxyphenyl] phenylmethanone, m.p. 149.2 ° C,

69. DK 157300 B

cis-1- [2- (2,4-dichlorophenyl) -4- [3- (trifluoromethyl) phenoxymethyl] -1,3-dioxolan-2-ylmethyl] -1H-imidazole nitrate, mp 152.6 ° C 1- ^ 4- [2- (2,4-dichlorophenyl) -2- (lH-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] -phenyl | ethanone nitrate, mp 182.6 ° C, cis-methyl-2- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] benzoate nitrate, mp 140.5 ° C and cis-1- [4- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] phenyl) -1-propanone nitrate, m.p. 176.2 ° C.

Example 50

A mixture of 12.5 parts of 1,2-butanediol, 19 parts of 1- (2-chloro-4-fluorophenyl) -2- (1H-imidazol-1-yl) ethanone hydrochloride, 16 parts of 4-methylbenzenesulfonic acid, 40 parts 1-Butanol and 225 parts of dimethylbenzene are stirred and refluxed for 6 days with water separator. After cooling, the reaction mixture is filtered and the filtrate is washed with a dilute sodium hydroxide solution and with water. After the addition of diisopropyl ether, the whole is acidified with a nitric acid solution. The nitrate salt formed is filtered off and crystallized from a mixture of 4-methyl-2-pentanone and diisopropyl ether to give 5.7 parts (22%) of A + B1- [2- (2-chloro-4-fluorophenyl) -4-ethyl - 1,3-dioxolan-2-ylmethyl] -1H-imidazole nitrate, mp 132f4 ° C.

Example 51.

Using the procedure of Example 50 and equivalent amounts of the corresponding starting materials, the following imidazoles and imidazole acid addition salts are obtained; A + B-1- [2- (4-bromophenyl) -4-ethyl "1,3-dioxolan-2-ylmethyl] -imidazole nitrate, m.p. 194.7 ° C, 70

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A + B1- [2- (2,4-dibromophenyl) -4-ethyl-1,3-dioxolan-2-ylmethyl] -1H-imidazole nitrate, m.p. 149.7 ° C, A + B1- [4-ethyl- 2- (2-thienyl) -1,3-dioxolan-2-yl-methyl] -1H-imidazole nitrate, mp 135.4 ° C, A + B1- [2- (5-chloro-2-thienyl) -4 -ethyl-1,3-dioxolan-2-ylmethyl] -1H-imidazole nitrate, mp 164.3 ° C, A + B1- [4- (chlorophenyl) -2- (2,4-dichlorophenyl) -1,3- dioxolan-2-ylmethyl] -1H-imidazole nitrate, m.p. 166.1 ° C, A + B1- [4- ([1,1,1-biphenyl] -4-ylmethyl) -2- (2,4-dichloro-phenyl) ) -1,3-dioxolan-2-ylmethyl] -1H-imidazole dioxalate, m.p. 116/3 ° C, A * B1-12- (2,4-dichlorophenyl) -4- (4-fluorophenylmethyl) -1,3-dio ' 1- [2-ylmethyl] -1H-imidazole sesquioxalate, mp 153.1 ° C, A + B1- (2-, 2,4-dichlorophenyl) -4 - [(4-methylphenyl) methyl] -1,3- dioxolan-2-ylmethyl | -IH-imidazole sesquioxalate, m.p. 123.1 ° C, A + 3-1- [4- (4-bromophenylmethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl-3H-imidazole dioxalate, m.p. 128, -8 ° C, A + B1- {4- [2 - ([1,1'-biphenyl] -4-yl) ethyl] -2- (2,4-dichlorophenyl) -1,3-dioxolane 2-ylmethyl] -1H-imidazole sequioxalate, hemihydrate, mp 143.9 ° C and A + B-1- ^ 2- (2,4-dichlorophenyl) -4- [2- (phenylmethyl) phenoxymethyl] -1,3- dioxolan-2-ylmethyl | -1H-imidazole sesquioxalate, hemihydrate, mp 113 ° C

Example 52.

A mixture of 13.8 parts of 1- (2-chloro-4-fluorophenyl) -2- (1H-imidazol-1-yl) ethanone hydrochloride, 14.6 parts of 3- ([1,1'-biphenyl] -4- yloxy) -1,2-propanediol, 16 parts 4-methylbenzenesulfonic acid, 40 parts butanol and 225 parts dimethylbenzene are stirred

71 DK 157300 B

reflux for a week with water separator. After cooling, diethyl ether is added and the whole washed successively with a dilute sodium hydroxide solution and with water, dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using trichloromethane as eluant. The first fraction (A-isomer) is collected and the eluent is evaporated. The residue is converted to the nitrate salt in 4-methyl-2-pentanone and diisopropyl ether. The product is filtered off and crystallized from a mixture of acetonitrile and diisopropyl ether to give 5 parts of cis-1- [4 - ([1,1'-biphenyl] -4 -yloxymethyl) -2- (2-chloro-4-fluorophenyl) -1,3-dioxolan-2-ylmethyl] -ΙΗ-imidazole nitrate, m.p. 185.7 ° C.

The second fraction (B isomer) is collected and the eluent is evaporated. The residue is converted to the nitrate salt in 4-methyl-2-pentanone and diisopropyl ether. The salt is filtered off and crystallized from a mixture of acetonitrile and diisopropyl ether to give 5.9 parts of trans-1- [4- ([1,11-biphenyl] - 4-yloxymethyl) -2- (2-chloro-4-fluorophenyl) -1,3-dioxolan-2-yl-methyl] -1H-imidazole nitrate, mp 156.9 ° C.

Example 53.

Using the procedure of Example 52 and equivalent amounts of the corresponding starting materials, the following imidazoles and imidazole acid addition salts are obtained. When only one isomer is indicated, no other fraction is obtained by chromatography.

cis-1- [4- ([1,1'-biphenyl] -4-yloxymethyl) -2- (2-thienyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole, m.p. 149.5U C , trans-1- [4- ([1,11-biphenyl] -4-yloxymethyl) -2- (2-thienyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole, m.p.> 300 ° C Cis-1- [4- ([1,1'-biphenyl] -4-yloxymethyl) -2- (2,4-dibromo-phenyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole nitrate, mp 174.4 ° C.

trans -1- [4 - ([1,11-biphenyl] -4-yloxymethyl) -2- (2,4-dibromo-

72 DK 157300 B

phenyl) -1,3-dioxolan-2-ylmethyl] -ΙΗ-imidazole nitrate, m.p. 141J 8 ° C and cis-1- [4 - ([1,11-biphenyl] -4-yloxymethyl) -2- ( 5-chloro-2-thienyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole nitrate, m.p. 170 ° C.

Example 54.

To a stirred mixture of 1.1 parts of 3-chloro-1-propynyl 4 parts of cis-2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolane-4 methanol and 90 parts of Ν, Ν-dimethylformamide are added 0.5 part sodium hydride dispersion (78%). Stirring is continued for 3 hours at room temperature. The reaction mixture is poured into water and the product is extracted twice with diethyl ether. The combined extracts are washed with water, dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using trichloromethane and methanol (98: 2) as eluent. The pure fractions of amies and the eluent are evaporated. The residue is converted to the oxalate salt in 4-methyl-2-pentanone and dxisopropyl ether.

The salt is filtered off and crystallized from 4-methyl-2-pentanone to give 3.6 parts (55%) of cis-1- [2- (2,4-dichloro-phenyl) -4- (2-propynyloxymethyl) -1 , 3-dioxolan-2-y-line to 1] -1H-imidazole dioxalate, m.p.

Example 55

A mixture of 17 parts of 1H-imidazole, 16 parts of A + B-2- (bromomethyl) -2- (2,4-dichlorophenyl) -4-ethenyl-1,3-dioxolane and 225 parts of Ν, Ν-dimethylformamide is stirred and stirred. reflux for 3 days. The reaction mixture is cooled, poured into water and the product is extracted twice with diethyl ether. The combined extracts are washed with water, dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using trichloromethane as eluant. The pure fractions are collected and the eluent is evaporated. The residue is converted to the nitrate salt in 4-methyl-2-pentanone and diisopropyl ether. The salt is filtered off and crystallized from 4-73

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methyl 2-pentanone to give 2.4 parts (131) of A + B1- [2- (2,4-dichlorophenyl) -4-ethenyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole nitrate, mp 150.9 ° C.

Example 56

Single blend of 33 parts (A + B) -2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolane-4-methanol, 20 parts 4-methylbenzenesulfonic acid, 40 parts 1-Butanol and 180 parts of dimethylbenzene were stirred and refluxed for 14 days using a water separator. The reaction mixture was cooled and washed successively with a sodium carbonate solution and with water. The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98: 2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted to the nitrate salt in diisopropyleth. , 3-dioxolan-2-ylmethyl] -1H-imidazole nitrate, m.p. 102 C.

Claims (2)

76 Ar 151500 B wherein Ar has the above meaning, with a compound of the formula OH 1 V r-ch-ch 2 -oh wherein R has the above meaning, the reaction being preferably carried out by refluxing compounds IV and V under azeotrope water removal in an organic solvent in the presence of a simple alcohol and a strong acid; or c) reacting a compound of formula -NI j NI Ib CH2 Ar hoch2 J-1 wherein Ar is as defined above, with a compound of formula R '- W VI wherein W has the meaning given above and R' represents alkyl of 1-10 carbon atoms, alkenyl of 2-10 carbon atoms, 2-propynyl or arylmethyl, wherein the aryl portion has the meaning given above under R, according to known O -alkylation methods, preferably in the presence of an organic solvent and a strong base to prepare a compound of the formula ON Ta 1. a CH Or d) condensing a compound of formula Ib with an alkanol of the formula alkyl-OH, wherein the alkyl moiety has 1-10 carbon atoms, preferably by refluxing the reactants together in an organic solvent in the presence of a strong acid to prepare a compound of the formula n N Ic CH 2 Ar alkyl-O-CH 2 - wherein Ar has the meaning given above and the alkyl group has 1-10 carbon atoms, or e) that one translates a compound of the formula ON j VII CH- Ar 2> <T y P w-ch2 ~ î ----! wherein Ar and W are as defined above, with a compound of formula R 2 - OH VIII 2 wherein R represents alkyl of 1-10 carbon atoms, alkenyl of 2-10 carbon atoms, 2-propynyl, arylmethyl or aryl, wherein aryl has the above under the meaning of R, according to known O-alkylation methods, preferably in the presence of an organic solvent and a strong base for the preparation of a compound having a 78 DEG 157300 BONI T-fl CH Ar 1 a οχ; 2 · R -O-CH -1 2 wherein Ar and R have the meaning set forth above and, if desired, produce acid addition salts of the compounds thus obtained by reaction with an acid and furthermore, if desired, the compounds thus obtained split into stereochemically optical isomeric forms using standard methods.