IE43157B1

IE43157B1 - 1-(2-aryl-1,3-dioxolan-2-yal methyl)-1h-imidazoles methods for their preparation and compositions containing them

Info

Publication number: IE43157B1
Application number: IE13976A
Authority: IE
Original assignee: Janssen Pharmaceutica Nv
Priority date: 1975-01-27
Filing date: 1976-01-26
Publication date: 1980-12-31
Also published as: DK30276A; MX3143E; YU39956B; PT64741A; YU11276A; PH13605A; PL101460B1; ES444667A1; FI62081B; NZ179231A; CS202001B2; IL48902A0; DK157300C; SU850006A3; FI62081C; DK157300B; HU174593B; IL48902A; PT64741B; FI760175A

Abstract

The present invention relates to a process for preparing an imidazole derivative, which has the formula: (SEE FIGURE) wherein: Ar is phenyl, substituted phenyl, thienyl, halothienyl or naphthyl, and wherein the substituted phenyl has the meaning of a phenyl group having 1 to 3 substituents thereof consisting independently of halo, lower alkyl, lower alkyloxy, nitro or cyano, and R is alkyl having two to 10 carbon atoms, alkyloxymethyl in which the alkyl group has 1 to 10 carbon atoms, alkenyl, alkenyloxymethyl, wherein the alkenyl group has 2 to 10 carbon atoms, 2-propynyloxymethyl, hydroxymethyl, halomethyl, aryl, aryl-lower alkyl aryloxymethyl, arylthiomethyl or arylmethoxymethyl, wherein the aryl in a member selected from the group consisting of phenyl, phenyl substituted, naphthyl or mono- and di-halonaphthyl, wherein the substituted phenyl has a meaning of a phenyl group having 1 to 3 substituents therein consisting independently of halo, lower alkyl, lower alkyloxy, cyano, nitro, phenyl, phenylmethyl, benzoyl, halobenzoyl, lower alkylcarbonyl, lower alkyloxycarbonyl or trifluomethyl, with the proviso that when more than one substituent is present, only one of them can be selected from the group consisting of phenyl, phenylmethyl, benzoyl and halobenzoyl; characterized by reacting, preferably, at reflux temperatures, a compound of the formula (SEE FIGURE) or a metal salt of compound II, with a compound of the formula (SEE FIGURE) wherein W is a function of this reagent, in an organic solvent preferably in the presence of a metal iodide.

Description

The present invention relates to certain.1-(2-Ar4-R-l,3-dioxolan-2-ylmethyl)imidazoles which are useful as antifungal and antibacterial agents.

United States Patent Specifications Nos. 3,575,999 and 3,717,655 describe some 1-(2-aryl-l,3-dioxolan-2ylmethyl) imidazoles. The compounds of the present invention differ from these prior art compounds by the nature of the R-substituent, present in the 4-position of the dioxolane group.

The invention relates to novel imidazole derivatives having the formula: R and the therapeutically acceptable acid addition salts and stereochemical and optical isomeric forms thereof, i wherein: R is a phenyl, thienyl, halothienyl or naphthyl group, or a phenyl group substituted v/ith from 1 to 3 substituents which are independently halo, Ioweraikyl, loweralkyloxy, nitro or cyano; and an alkyl group having from 2 to 10 carbonatoms, aa alkyloxymethyl group wherein the alkyl- group has from 1 to 10 carbon atoms, an alkenyl or alkenyloxymethyl group, wherein said alkenyl group has from 2 to 10 carbon atoms, a hydroxymethyl, 2-propynyloxymethyl, halomefchyl, aryl, arylloweralkyl, aryloxymethyl, arylthiomethyl or arylmethoxymethyl group, wherein the aryl group is a phenyl, naphthyl, mono- or dihalonaphfchyl group or a phenyl group substituted with from 1 to 3 substituents which are independently halo, ioweraikyl, lower alkyloxy, cyano, nitro, phanyl, phenylmethyl, benzoyl, halobenzoyl, loweralkylcarbonyl, loweralkyloxycarbonyl or trifluoromethyl, provided that when more than one substituent is present only one substituent may be phenyl, phenylmethyl, benzoyl or halobenzoyl.

The term alkyl used in the definition of the group R includes straight and branched chain hydrocarbon radicals having from 2 to 10 carbon atoms, such as, for example, ethyl, propyl, 1-methylethyl, 1,l-dimethylethyl, butyl, pentyl, hexyl, heptyl, octyl or decyl? the term alkyl" as used in the definition of alkyloxymethyl includes straight and branched chain hydrocarbon radicals having from 1 to 10 carbon atoms, such as, for example, methyl and the alkyls mentioned herebefore; the term Ioweraikyl as used herein has the meaning of a straight or branched chain alkyl radical having from 1 to 6 carbon atoms, such as, for example, methyl, ethyl, propyl, 1-methylethyl, 1,l-dimethylethyl, butyl, pentyl or hexyl; the term alkenyl as used herein refers to - 4 straight and branched chain alkenyl radicals having from 2 to 10 carbon atoms, such as, for example, ethenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 2-hexenyl or 2-decenyl; and the term halo is generic to halogens of atomic weight equal to or less than 127, i.e., fluoro, chloro, bromo ahd iodo.

The compounds of formula (I) may be conveniently prepared by reacting imidazole (ll) with an appropriate reactive ester of formula (III) given below wherein Ar and R are as previously defined and wherein W is a reactive ester group, such as, for example, halo, 4methylbenzenesulfonyloxy or methylsulfonyloxy. Preferred reactive esters are halides and more particularly bromides and chlorides. j In one method of conducting the reaction between imidazole and the reactive ester (III), imidazole is first transformed into a metal salt thereof by treatment with an appropriate metallating agent such as, for example, a metal alkoxide, e.g., sodium- or potassium ) methanolate, or a metal hydride such as sodium hydride.

The metal salt so-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.

Alternatively, the reaction of imidazole with the reactive ester (III) may he carried out without previous ι salt formation, by bringing the reactants into contact with each other in an organic solvent such as, for example, dimethylformamide or dimethylacetamide. In these circumstances it is appropriate to use an excess of imidazole or to add to the reaction mixture a base, such as, for example, sodium or potassium carbonate or - 5 bicarbonate in order to bind the acid which is liberated during the course of the reaction. The use of an excess of imidazole is however preferred. Further it is advantageous to conduct the reaction in the presence of a metal iodide such as, for example, sodium or potassium iodide.

In each of the above procedures, somewhat elevated temperatures may be employed to enhance the rate of the reaction and most conveniently the reactions are carried out at the reflux temperature of the reaction mixture.

In these and the following preparations the reaction products may be isolated from the medium and, if necessary, further purified by methods generally known in the art, such as, for example, extraction, trituration, crystallization or chromatography.

The foregoing procedures are more fully illustrated by the following schematic representation: W-CH NaOCH, imidazole sodium salt Ar (II) (III) DMF (1) (II) Nal + (III) DMF An additional method of preparing the compounds of formula (I) is by the ketalization of an appropriate aroylmethylimidazole of formula (IV) (shown below) wherein Ar is as previously defined with an appropriate diol of formula (V) (shown below) wherein R is as previously defined.

This ketalization reaction may be carried out following methods such as those described in the literature, e.g., for the preparation of 2-bromomethyl-2,4.0 diphenyl-1,3-dioxolane /Synthesis, 1974 (I), 23/.

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

The foregoing reaction may be illustrated as follows: χ.

CH„ -C-Ar (IV) OH I R-CH-CH2-OH (V) 4-methylbenzenesulfonic acid _ (I) butanol benzene The compounds of formula (I) wherein R is an alkyloxymethyl, alkenyloxymethyl, 2-propynloxymethyl or arylmethoxymethyl group, (I-a) (formula shown below), may also be prepared by the reaction of an appropriate compound of formula (I) wherein R is hydroxymethyl (I-b) - 7 (formula shown below) with an appropriate reactive ester of formula (VI) wherein R1 is a C^-10 alkyl, C2~10 alkenyl, 2-propynyl or aryImethyl group, where aryl is as defined above, and W is a reactive ester group as previously defined, according to common O-alkylating procedures. Preferably the reaction is carried out in an organic solvent such as, dimethylformamide or dimethylacetamide in the presence of a strong metal base such as, sodium hydride, sodium carbonate or potassium carbonate.

(I-b) (I-a) The compounds of formula (I) wherein R is an alkyloxymethyl group, (I-c),(formula shown below),may also be prepared by the condensation of (I-b) with an appropriate C^-10 alkanol. This condensation reaction may be carried out by refluxing the reactants together under azeotropic water removal in an organic solvent such as, an aromatic hydrocarbon, e.g., benzene, methylbenzene or dimethylbenzene, a saturated hydrocarbon, e.g., cyclohexane, or in the alkanol itself, in the presence of a strong acid, such as, 4-methylbenzenesulfonic acid. - 8 (I-b) + alkyl-OH 4-methylbenzenesulfonic acid -,— -> dimethylbenz ene alkyl-0-CH2 (i-c) The compounds of formula (X) wherein R is alkyloxymethyl, alkenyloxymethyl, 2-propynyloxymethyl, arylmethoxymethyl or aryloxymethyl, (I-d) (formula shown below), may also be prepared by the reaction of an appropriate reactive ester of formula (VII) (formula shown below) wherein Ar and W are as defined hereinbefore with an appropriate hydroxy compound of the formula (VIII) (formula shown below) wherein R is a C^-^θ alkyl, C2~lO > alkenyl, 2-propynyl, arylmethyl or aryl group where aryl is as defined above according to common O-alkylating procedures as described herebefore.

(VIII) (VII) (I-d) - 9 The imidazole derivatives of formula (I), obtained in base form in the foregoining preparations, may be converted to their therapeutically useful acid addition salts by reaction with an appropriate acid, for example, an inorganic acid such as a hydrohalic acid, i.e., hydrochloric, hydrobromic or hydroiodic acid; sulfuric, nitric or thiocyanic acid; a phosphoric acid; an organic acid such as acetic, propanoic, hydroxyacetie, a-hydroxypropanoic, 2-oxopropanoic, ethanedioic, propanedioie, 1,4-butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2- hydroxy-1,4-butanedioic, 2,3-dihydroxy-l,4-butanedioic, 2-hydroxy-l,2,3-propanetricarboxylic, benzoic, 3- phenylpropenoic, α-hydroxybenzeneacetic, methanesulfonic, ethanesulfonic, 2- hydroxyethanesulfonic, 4methylbenzenesulfonic, 2-hydroxybenzoic, 4-amino-2hydroxybenzoic, 2-phenoxybenzoic or 2 -acetyloxybenzoic acid. The salts are in turn converted to the corresponding free bases in the usual manner, e.g., by reaction with an alkali, such as sodium or potassium hydroxide.

The intermediates of formula (III) may be prepared by subjecting an appropriate ketone of formula (IX), (shown below) wherein Ar and W are as previously defined to a kefcalization reaction with an appropriate diol of formula (V) (shown below) wherein R is as previously described in the same manner as described hereinbefore for the preparation of the compounds (I) starting from (IV) and (V).

OH ii I IS I 4-methylbenzenesulfonic W-CH2-C-Ar + R-CH-CH2OH_acid_(III) butanol benzene (IX) (V) Π57 - 10 Alternatively the intermediates of formula (III) may be conveniently prepared by transketalization of a ketal derivative of a ketone formula (IX) such as, a Ioweraikyl ketal or a cyclic lower alkylene ketal, with a glycol of formula (V) under conditions similar to those described hereinbefore for the direct ketalization. The Ioweraikyl ketals and cyclic lower C-L_^o alkylene ketals used herein as starting materials are easily obtained by ketalization of a ketone of ι formula (IX) with a lower c^_10 alkanol or alkanediol according to methods known in the art. A number of such compounds and methods of preparing them are described in United States Patent Specifications Nos. 3,575,999 and 3,717,655.

A number of the precursor glycols of formula (V) are known and they may all be prepared according to known procedures as described in the literature.

In general they may be derived from the corresponding 2-R-oxiranes of formula (X) (show below) by ι hydrolytic cleavage of the oxirane nucleus with an appropriate strong acid such as, for example, ethanedioic acid, sulfuric acid or hydrochloric acid.

(COOH).

(V) ^0/1,4-dioxane (X) The oxiranes of formula (X) may in turn be obtained in a variety of ways. o Those of formula (X-a),(shown below) wherein R represents alkyl or arylloweralkyl group where aryl is as defined above may, for example, be prepared by oxidiz i.ng an appropriate alkene or arylalkene of - 11 formula (XI)(shown below) with an appropriate oxidizing agent such as, a benzeneperoxoic acid e.g., 3-chlorobenzeneperoxoic acid.

(XI) (X-a) Alternatively intermediates of formula (X-a) may also be obtained by i) converting an appropriate halide of formula (XII)(shown below) wherein R4 is an alkyl or aryl alkyl group where aryl is as defined above,having one carbon less than in the corresponding R , into a Grignard complex with magnesium; ii) reacting said Grignard complex with a 2-halomethyloxirane of formula (XIII)(shown below) to obtain a α-halomethyl alcohol compound of formula (XIV)(shown below); and iii) performing ring closure of (XIV) by treatment with alkali,e.g. with sodium hydroxide in an appropriate solvent such as 2,2'-oxybispropane.

The foregoing sequence of reactions is more fully illustrated in the following schematic representation: R4-halo + Mg solvent halo-CH2 (XII) OH f R -CH2-CH-CH2halo (XIV) (XIII) NaOH d -ρ R'"CH2 2,2'-oxybispropane (X-a) The intermediates of formula (X) wherein R is an alkyloxy methyl, alkenyloxymethyl, 2-propynyloxymethyl, arylmethoxymethyl or aryloxymethyl group, (X-b)(shown below),are conveniently obtained by the reaction of an appropriate hydroxycompound of formula (XV)(shown below) wherein R~> is a alkyl, C2_lo alkenyl, 2-propynyl, aryl or arylmethyl group where aryl is as defined above with a 2-halomethyloxirane of formula (XIII) following common O-alkylating procedures as generally known in the art.

Intermediates of formula (X) wherein R represents an arylthiomethyl group, (X-c),may be prepared in an analogous manner by the S-alkylation of an arylthiol of formula (XVI)(shown below) where aryl is as defined above with a 2-halomethyloxirane of formula (XIII).

The foregoing reactions are schematically illustrated hereafter - 13 RS-OH halo-CEL· K2co3 (XV) (XIII) Aryl-SH + (XIII) R -O-CH2-propanone K2CO3 2-propanone (X-b) _> Aryl-S-CH, (XVI) (X-o) Intermediates of formula (V) wherein R represents an alkenyl group may, for example, be prepared starting from an appropriate hydroxyalkylsubstituted ethanediol by ketalizing the ethanediol group with an appropriate ketone, e.g., 2-propanone, converting thereafter the remaining hydroxy group on the alkyl chain into a methane-sulfonate group by the reaction with methanesulfonyl chloride, splitting off methanesulfonic acid by treatment with an appropriate strong base such as, sodium hydride in a suitable solvent such as dimethylformamide, and finally liberating the free diol from the ketal by treatment with an appropriate strong mineral acid such as, hydrochloric or sulfuric acid. In a preferred manner of carrying out the aforementioned reactions, the ketone used in the ketalization step is an intermediate of formula (IX) whereby the alkenylsubstituted dioxolanes of formula (III) are directly obtained in the course of the foregoing reaction sequence.

The precursor arylketones of formula (IX) are generally known and may be prepared according to known - 14 procedures as described in the literature. Bromides are, for example, easily obtained by the bromination of the corresponding methyl aryl methanone with bromine. i The aroylmethylsubstituted imidazoles of formula (IV), a number of which are described in United States Patent Specifications Nos. 3,717,655 and 3,658,813, are conveniently prepared by the reaction of (IX) with imidazole in an analogous manner as previously described for .0 the preparation of the compounds (I) starting from imidazole and (III).

The reactive esters of formula (VII), used as intermediates in the preparation of the compounds (I-d) are easily obtained by converting the corresponding alcohol of formula (I-b) into a reactive ester thereof according to methods generally known in the art. For example, methanesulfonates and 4-methylbenzenesulfonates are conveniently prepared by the reaction of the alcohol with respectively methanesulfonyl chloride or 4-methyl0 benzenesulfonyl chloride and the halides may be prepared by the reaction of the alcohol with an appropriate halogenating agent such as, for example, sulfuryl chloride, phosphorus pentachloride, phosphorus pentabromide and phosphoryl chloride. When the reactive ester is an iodide, it is preferably prepared from the corresponding chloride or bromide by the replacement of that halogen with iodine.

From formula (I) it is evident that the compounds of this invention have two asymmetric carbon atoms in their structures,namely those located in the 2- and 4position of the dioxolane nucleus, and consequently they exist in different stereochemical and optical isomeric forms. The stereochemical and optical isomeric forms of (I) and the therapeutically active acid addition salts j thereof are included within the scope of this invention. - 15 The diastereomeric racemates of (I), denoted as cis and trans forms respectively, according- to the rules described in Naming and Indexing of Chemical Substances for Chemical Abstracts during the 9th Collective Feriod (1972-1976), published in C.A. 1972, 76, Index Guide Section 17, p 203, may be obtained separately by conventional methods. Appropriate methods which may advantageously be employed therefore include, for example, selective crystallization and column-chromatography. For a number of compounds the stereo-chemical configuration was experimentally determined. In the remaining cases it is conventionally agreed to designate the stereochemical form which is first isolated as A and the second as B, without further reference to the actual stereochemical configuration.

Since the asymmetric carbon atoms are already present in the intermediates (III) it is also possible to separate cis and trans forms, or generally A and B forms at this stage, whereupon the corresponding forms of (I) may be obtained after reaction of the foregoing with imidazole as previously described. The separation of cis and trans forms of (III) may be performed by conventional methods as described hereinbefore for the separation of the compounds (I) into their cis and trans forms. When R in the intermediates of formula (III) represent a hydroxymethyl group it may be advantageous to esterify first said hydroxymethyl group with an appropriate acylhalide, e.g., benzoyl chloride whereupon the esters so-obtained are separated into their cis and trans forms, from which the acyl group is subsequently split off hydrolytically in alkaline medium yielding the corresponding forms of the desired hydroxymethyl substituted intermediates of formula (III).

It is-evident that the cis and trans diastereomeric racemates may be further resolved into their optical isomers, cis (+), cis (-), trans (+) and trans ¢-) by the application of techniques known to those skilled in the 157 - 16 art.

The compounds of formula (I) and the acid addition salts thereof are useful agents in combatting fungi and bacteria. As such they are valuable in the treatment i of human beings, animals and plants suffering from pathogenic microorganisms and in the destruction of microorganisms on materials. The broad spectrum of antifungal and antibacterial activity of the compounds of formula (I) is clearly illustrated by the experimental data presented hereafter. The compounds in the tables are not listed for the purpose of limiting the invention thereto, but only in order to exemplify the useful properties of·· all the compounds within the scope of formula (I).

The test for antifungal activity was performed using Sabouraud's liquid medium in test tubes each Containing 4.5 ml of liquid medium, autoclaved at 120°C for 15 minutes. The substances were dissolved in 50% ethanol at a concentration of 20mg/ml and subsequently diluted with sterile distilled water to a concentration of lOmg/ml. Successive decimal dilutions were then made with distilled water to give a series of stock solutions. To each tube containing 4.5 ml of Sabouraud1s liquid medium was added 0.5 ml of one of the stock i solutions to give a concentration of the drug under investigation of 100 pg, 10 pg, 1 pg or 0.1 pg per ml of medium. Filamentous fungi were incubated at 25°C for 2-3 weeks. A square block of size 2 mm. was excised and inoculated into the liquid medium. A threei day old culture on Sabouraud's liquid medium was used used for yeasts, and the inoculum was 0.05 ml per tube. All the cultures Were incubated at 25°C for 14 days.

The final readings were taken after two weeks and are summarized in the Tables A as follows: - 17 ++++ = complete inhibition of growth at 0.1 ug/ml +++ = complete inhibition of growth at 1 ug/ml ++ = complete inhibition of growth at 10 ug/ml + = complete inhibition of growth at 100 ug/ml = no effect i.e. growth was observed at the highest concentration tested (100 ug/ml).

In a first screening the drugs under investigation were tested against the following 11 fungi: 1. Microsporum canis (M.c. in the tables) 2. Ctenomyces mentagrophytes (Ct. m. in the tables) 3· Trichophyton rubrum (Tr. r. in the tables) 4. Phialophora verrucosa (Ph. v. in the tables) . Cryptococcus neoformans (Cr. n. in the tables) 6. Candida troplcalis (C. tr. in the tables) 7. Candida albicans (C. alb. in the tables) 8. Mucor species (Muc. in the tables) 9. Aspergillus Fumigatus (A. f. in the tables) . Sporotrichum schenckii (Sp. s. in the tables) 11. Saprolegnia species (Sap. in the tables) A number of the substances showing activity against the Phycomycetes Mucor at the 10 ug/ml concentration were also tested against four other species of phycomycetes, namely: 1. Absidia ramosa (Abs. r. in the tables) 2. Basidlobolus meristosporus (Bas. m. in the tables) 3. Mortierella species (Mort. in the tables) 4. Rhizopus (Rhi. in the tables).

The method used in this second screen was exactly the same as described above, and the results are given in Tables B. 3157 - 18 Bactericidal tests were performed on cultures on phenol red dextrose broth Difco (Registered Trade Mark) medium. The same decimal dilution techniques as described herebefore were used. The inoculum consisted of a platinum loop (5 mm. diameter) from a 24 hour broth culture. 48 Hours after incubation, subcultures were made from each culture and for the assessment of the bactericidal activity of the drugs under investigation the presence or absence of growth after 7 days incubation was scored as described above.

The substances were tested against the following grampositive bacilli and cocci: 1. Erysipelothrix insidiosa (E. ins. in the table) 2. Staphylococcus hemolyticus (Staph, in the j table), and 3. Streptococcus pyogenes (Strept. in the table).

The results are summarized in Tables C. Bacteriostatic activity means that no growth was observed in the test tube 48 hours after inoculation. For bacteriocidal ) activity it is further required that the subcultures taken after 48 hours are negative after 7 days of incubation.

ANTIFUNGAL ACTIVITY 4S15? 157 - 20 (uuminuea,) ANTIFUNGAL ACTIVITY 157 - 22 (continued) ANTIFUNGAL ACTIVITY Sap. (11) + + + + + + + + O + + + + + + + + + + + + + w o • rH to + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + Ή σ> ίί + +++ ++ + + + + + + + + + + ++ + + + + + O + + + + + + + + + + + + + □ 0 oo S'-* + + + + + + + + O + + + + + + + O + + + + + + C. alb. (7) + + + OO + OO + OOO + +O + + O CM ffi CN CN CN CN CN CN Η Η ί-Η Η Η H ο ο υ u ο o rH 1 «—1 | rHlHrHrHIrHrHI WI □ STUN4 CJN’OUUn’UU^ Cd I κ | κ 1 K 1 1 I κ 1 1 A. |K ^‘ffiCN’tfCNffi’tfCN’tf^CNCNCN’tffNffiM'CN i—l CN CN CN rH rH rH CJ cn o a ffi cn HrHHWWIO 1 rH rH W Η 1 W ffi CJ CJ U ffi ffi O *a< U U ffi U ffl O 1 1 1 I 1 κ 1 - I I ί 1 i 1 *4* *H*’«3’CN ’5j«ffiCN ffi’N’CN'sl‘CNCNN1ffi'N’ ANTIFUNGAL ACTIVITY 3187 ANTIFUNGAL ACTIVITY CJ 1 ooooooooooo c • in o + + 4* + + + + 4* + + + + + + + + + + + + + + + > Xi"-' pi 0 + 0 + 0 + + + 0 + 0 • m + ++ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + • CM 4jx-> CJ □ • 1—J S'- + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + O + + + + + + + O + + Isomer to to m S <5 ω m •Η M W -rl -rl 0 +J +1 o ri! ffl OrtJrtJrtm CM Pi <-4 «—I U U CM I 1 ςρ ·ςΡ r4 K K U cn cn cn cn m m m « 33 w r4 H a H « 1 UUCJUOOFmUCJO^ 1 I J 1 1 1 1 I 1 1 *· CM’«4’CM’4’’5S,'3''^CMCMCMfM pT γ4γ4γ4Ηγ4γ4γ4γ4γ4γ·ΙΗ CJCJOUCJOOCJOOCJ ! 1 ! I 1 ! i 1 I I K - 25 4S1S7 W w Hi s ¢1 β •rl P β ϋ CM 315 TABLES A ANTIFUNGAL ACTIVITY (continued - 3) ' (connnuea Μ + + -Ρ d- Φ ο + + O o O β ' υ ri + + + d- + • ιη + + + + + Μ —· + + + + o + Η Ο Η > Η Η U • > Ο S D • θ' χ: ·«-* Ρ< ο + + o o + Cm Η • κ + + + 3 d- + + + + + co + + + + + + Η — • + + + + + + 8 d- + + d- + d- + • Cd + + d- + + + -Ρ — Q + d- + + + d- ο + + d- d· + •h + • rd + + + + + d- S — d- + + + + + Μ <ϋ £ ο ffl < + ω Η (O • o Cd as P 1 □ ri Cd o* co 1 Λ Χ-» ® r* id rd υ ffi •P U Cd co ·. P ro 1 O rd a) 1 a: in Ή u -P in o *. 1 1 1 »». 1 co 'tf* Cd O' CO ro Cd cd cd Cd Cd Cd χ~». rd rd rd rd rd rd u u o u o o rd I 1 1 ! I 1 α o o* O' O’ O' O’ *» ·» •w ·» k •k Cd Cd Cd Cd Cd Cd 431S7 TABLES A ANTIFUNGAL ACTIVITY (continued - 5) 157 - 30 CL I—ί nJ ·—j CO — + + +4-+ + + + + + + + + + + + + + + + + + + + O • o Ch»-4 CA — + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + O □ co 51 — + + + + + + + + + + Ο + + + + + + + + ΟΟΟ Λ I—J (β r* 0000000000000+0000 0) s in H fit* rij rfl ril T-! CO rij υ ffi « o u I I u I 1 -+ r4 CM CM CM CM o CM J m H «-4 r4 -+ r4 ra O u U H o o K m ·** ··—' ·*-- cn XX u r*4 K 1 (-4 M i I i-4 ra r4 1 1 o o o Ο ra -+ υ O o υ co ΙΛ I 1 1 I 1 K «k. 1 t 1 1 k. ». «=3* -+ CM CM ·+ -+ cm ra cn cn CM CM CM CM cn CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM ^k. r4 r4 H r4 r4 i-t p*4 «-4 r4 c4 r4 r4 p4 r-1 «-4 «-4 τ—i u u U u o υ O U u U U υ υ o □ u O u — — I — — — — — — — — — — — — — — — I -+ 1 -+ 1 -+ 1 -+ -+ -+ 1 -+ -+ I -+ t -+ 1 -+ 1 -+ I -+ ( -+ I -+ -+ + 1 -+ •k •k k. kk k »k kk k k k •k •k kk «k CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM «—i ANTIFUNGAL ACTIVITY rI EH CM ANTIFUNGAL ACTIVITY Sap. (Il) 4 4 4 4 4 + + + + + + OO + + OO + + OO + ro —« C • rd Ch'co + + + + + + + + + + + + + + ++ ++ + + + + + + + OO + + + O + + + O + Ud — + + + + + + + + + + + + + + + + + + + + + OO + + + + + + + + + 0 X- 2 co S + + + + + OO + O + OOO + + + O + + O + + C. alb. (7) O + + O + OOOOOOOO + OOO Isomer m m mm a: + mii;rtra + ffli CM « • r-i oj cm cm m +i u .-, Λ m P OJ 1 m mm U ΰ — m a m a ο- ι · η a m in o O U a Ό -p u οι Β a " — — m - H m U Η Η Η Η H a ID 1 HI 1 CJ r-i GJ 1 a ommfQmmtJucDmcain-riUJJino lllillii ' 1 '1111 '1 CM Η a ϋ a □ fc Η § β • ιη C 4- + + + + + + + +++ + + + +++ + + + + ++ + Pjrd OJ rd ω + + O + + + 01 r-s o • rd CU-» 03 + + + + + ++ + + + + + + + + + > • «φ Λ—* fc + Ο O + + 4- Md G\ • —> < + + + + + + + + + + + + + + + + + + fc * CO 5-1 ~ Ε·< + + + + + + + + + + + + + + + + + + + + + + + + ϋ 3 CO S'-1 + ++ + + + + + o + + e - CN +> U + + + + + + + + +++ + + + + + + + + + + + + + JQ rd Γ• —> U + O Q Ο O + + ο — rd a + ++ + + ++ + + + + + + + + + + + + + 5d dJ kO • *-> a + + ++ + + + o + + + Η 0) § ω Η m m + + rf) «! Pi 0) § 02 H ffl ffl + + «! < CN fc CN CN rd rd Ο O cn rd 1 I U rd O <4« k£> Ο O I -- 1 1 CN CN CN sr *4« ® CN fc CN CN rd rd U O 1 Ν’ K ι—1 fc CN CN CN CN CN C rd rd rd rd rd rd υ υ α ο υ u 1 1 I 1 1 I •Φ Ν’ n* n* sr Ν’ CN CN CN CN CN CN rd fc CN CN CN CN CN CN rd rd rd rd rd rd a u a ο a u t I f 1 1 I Ν’ Ν* Ν’ Ν’ Ν’ Ν’ CN CN CN CM CN CN TABLES A ,__ ANTIFUNGAL· ACTIVITY continued ANTIFUNGAL ACTIVITY -M d + + 4*4- + + Ο O + + + + OOO + Cr. n. (5) i + +++ + + + +++ + + + + .+ + + + + + + + + + + + > • *3· Λ — tf + ++ + + + + + + + + + + + + + u • co M — H + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + 04 d o + + + + + + + + + + +++++++ +++++ + + + + + + + + + + + + ό rH s'' + + ++++ + + + + + + + + + + + + + + + + + + + + + + + + + tf Η n in i' D Γ- d r—I Η Η Η iC tnininininEEffi ffi K K CJ iBKEKK n v in ο > ω ι CMCNlMOJOJCJCJtJ CJ CJ CJ rl UCJUUCJddd driCCJ m tf 04 CO tf tf O rH CO CO CO CO CO CO CO VO 1 O >itftftf tftftftf O CO 1 tflOlDWlOOiDlO I tf co 0)000 OOOO ι—1 U . ι—1 ·Η 1 I I till Ο Ο H >i +J CM Ol CM Ol fM CM 01 ι ι o +: +> ^J4 Tt4 *"' -Ρ 1 rH rH r-H rH rH rH rH * 1 +3 04 Ο Ο O OOOO σι *- in CL l ® rH - (tf rH I I 1 lilt OO^CO^·^·^ M4 -4* *3' -44 II ^|| ·. - *. * cMCMmoiincMoicM oi oi cm cm TABLES A ANTIFUNGAL ACTIVITY 3? ) ) TABLES Α Π ,P ANTIFUNGAL ACTIVITY o I o I I—I >1 Λί rH \D Eh H > W a 0 B a fe H Eh +i ♦ \O □ "·* + + + + + O + + + + OO ΰ • «Λ Μ υ + + + + + + + + + + + + + + + + + + + + Χί ~ λ + + + + + + + + + + in • η ίπ — EH + + + + + + + + + + + + + + + + + + + + + + + β • 04 υ + + + + + + + + + + + + + + + + + + + + + + + + 0 • rH s — + + + + + + + + + + + + + + Q) § M •rl ω cq Ci ωβω+υιωωω •rl Μ ·Η ·γΙ ·Η ·Η Ή O&HOrijOOOU rH >1 Λί rH Hfomr* LH 0* ι—ί pH rH rH mSCISKKKWK rd rqm’+inor-'OJ UCOOOUUU β β β β β β 3157 - 40 ft r-i Ιΰ r—t to • o Ch r—! to o Ci co s OOO + + + + + 000 + 0000 w ω S o Ul H ω β ui nJ to •H w -H ϋ +> ϋ Ul Ή α Ul Ul Ul •Η ·Η Ή Ο Ο 0 >1 Γ*· ΟΥ γ-1 ι—1 ι-Η ι—I (Λ ffi ffi ffi ffi ffi ffi m ffi m in co r* co ffi cmOOOUOU OUflCCCCC - 41 TABLES A ANTIFUNGAL ACTIVITY >H EH H > W § ·< a Θ fe H +) r-. ID O 0 0 + 00 fi • ID Ci O + + + + + + o + + o > • M* Xi — fe 0 0 + 00 • cn Cl — + + + + + + 4- ψ _j_ + 4- g CM J u + + + + + + + + + + + + + + + □ • H S'- + + + + o o + + + isomer ω w fi fi ω rt ω ω rt •H Ci Ή Ή Cl ϋ -μ ϋ o +> Aryl cn ma a a a id ID ID ID O o O ο 1 1 ! a 1 157 - 42 i i ANTIFUNGAL ACTIVITY CU rd rd ω *- + 00 + +.0 V) • o CU rd ω + + + o o + + + Ud Xcn + + 00 + + 0 O x3 co £ + + o o + + + Λ rd χ~~ ttf > ύ 0 0 + 00 1 isomer to to c c to nJ to ω ni •rd id -rl td Jd 0+)00 + Aryl m m sp si* K W K ffi vo x>. LT) Lfl CJ rd rd 33 « 1 CJ o (0 <0 id — — CJ CJ 1 1 — — sp sp 111-·· sp sp -cP CM OI - 43 TABLES A ANTIFUNGAL· ACTIVITY 3187 - 44 λ,Τ,ΤΛΤ.Τ.Ων HVnNTn.ffT.T.kTW· 431S7 - 45 TABLE Β ACTIVITY AGAINST PHYCOMYCETES *1R2 Abs. r. Bas. m. Mort. Rhi. 2,4-(Cl)2 4-C1 ++ ++ + ++ 4-Br 2-Cl + + + ++ 4-Br 4-Br +++ ++ ++ ++ 4-CH3 4-Cl ++ + + 2,4-(Cl)2 4-Br +++ ++ ++ ++ 4-C1 4-Br +++ ++ ++ ++ 2-Cl 4-Br ++ ++ + ++ 4-Br 4-CH3 ++ ++ + ++ 4-Cl 4-F ++ ++ + + 4-Br 4-F ++ ++ + ++ 3187 - 46 TABLE Β - CONTINUED R R2 Isomer Abs. r. Bas.m. Mort. Rhi. •Cl 4-Cl B +++ + + •Cl 4-F cis ++ + + + Cl 2-CH3 A ++ ++ + Cl 2,4-(Cl)2 B +++ ++ ++ + 4-(Cl) 2 2~CH3 A + + + + 4-(Cl)2 4-C1 trans ++ + ++ + 4-(Cl)2 2-CH3,4-Cl A + B ++ ++ + + Cl 2,6-(Cl)2 A ++ + + + 4-(Cl)2 2-CH3 A ++ ++ + + 4-(Cl) 2 4-CH3 A + ++ + + 4-(Cl)2 4-OCH3 A ++ ++ + + 4-(Cl)2 4-Cl cis ++ ++ + + 4-(Cl)2 4-Br A +++ ++ ++ ++ 4-(Cl)2 H A ++ ++ + + 4-(Cl) 2 3,4-(Cl)2 A +++ +++ ++ 4-(Cl)2 3-C1 A ++ +++ ++ ++ 4-(Cl) 2 2-C1 A +++ ++ + 4-(Cl)2 2-Br cis ++ ++ + + BACTERIOSTATIC AHD BACTERIOCIDAL ACTIVITY The table summarized the activity against the gram-positive R1R2 Bacteriostatic activity E. ins. Staph. Strept. 4-Cl 4-Cl ++ ++ ++ 4-Cl H ++ ++ +++ 4-Cl 2,4-(Cl)2 +++ ++ +++ 4-Br 4-Cl +++ +++ +++ 4-Br 2,4-(Cl)2 +++ + +++ 2,4—(Cl)2 H ++ 0 ++ 4-OCH3 4-Cl ++ + ++ H 2,4-(Cl)2 ++ ++ +++ 2,4-(Cl)2 4-Cl +++ ++ +++ H 4-Cl +++ + +++ 4-Cl 2-Cl +++ ++ +++ 2-Cl 2,4-(Cl)2 +++ ++ +++ 4-Br 2-Cl +++ + ++ 2-Cl 4-Cl +++ + +++ 2,4-(Cl)2 2,4-(Cl)2 +++ ++ +++ 4-Br H ++ + +++ H 4-Br +++ 0 +++ 4-CH3 2,4-(Cl)2 +++ +++ +++ 4-Br 4-Br +++ ++ +++ 2,4-(Cl)2 2-Cl +++ +++ +++ 4-CH3 4-Cl +++ ++ +++ 2,4-(Cl)2 4-Br +++ ++ +++ 4-Cl 4-Br +++ ++ +++ 4-CH3 4-Br +++ ++ +++ 1 5137 - 48 3LE_C - continued LR2 bacteriostatic activity E. ins. Staph. Strept -Cl 2,4-(Cl)2 ++ + +++ -Cl 4-Br ++ ++ ++ CH, 2-C1 +++ + +++ •Cl 4-CH3 +++ + +++ -Br 4-CH3 +++ ++ ++ Cl 4-F + 0 ++ Br 4-F ++ + +++ R2 bacteriocidal activity E. ins. Staph. Strept. Cl 4-Cl ++ ++ ++ Cl Η ++ + +++ Cl 2,4-(Cl)2 ++ ++ +++ Br 4-C1 +++ + +++ Br 2,4-(Cl)2 +++ + +++ 4-(Cl)2 H ++ 0 ++ OCH3 4-Cl + + ++ 2,4-(Cl)2 + + ++ 4-(Cl)2 4-C1 ++ + ++ 4-C1 + + ++ Cl 2-C1 ++ + ++ Cl 2,4-(Cl)2 ++ + +++ 3r 2-Cl +++ + ++ Cl 4-C1 +++ + +++ 1-(C1)2 2,4-(Cl)2 +++ + +++ 3r H ++ + +++ 4-Br +++ 0 +++ ch3 2,4-(Cl)2 +++ ++ +++ 3r ' 4-Br +++ + +++ 1-(C1)2 2-C1 +++ ++ +++ :h3 4-C1 +++ + +++ 431 S7 - 49 TABLE C - continued R1R2 bacteriocidal activity E. ins. Staph. Strept. 2,4-(Cl)2 4-Br + ++ 4-Cl 4-Br +++ ++ ++-; 4-CH3 4-Br +++ + +++ 3-C1 2,4-(Cl)2 ++ + +++ 2-Cl 4-Br ++ + ++ 4-CH3 2-C1 ++ + +++ 4-Cl 4-CH3 ++ + +++ 4-Br 4-CH3 ++ + ++ 4-Cl 4-F + 0 ++ 4-Br 4-F ++ + _ +++ S7 BLE C - 50 BACTERIOSTATIC AND BACTERIOCIDAL ACTIVITY 1R2 Isomer bacteriostatic activity E. ins. Staph. Strept. 1 2-CH3,4-Cl cis ++++ 0 ++++ 1 4-CH3 trans +++ ++ +++ I 2-CH3,4-Cl trans ++++ ++ ++++ 1 4-CH3 cis +++ ++ +++ I 4-Cl A ++++ + +++ 1 4-C1 B ++++ ++ +++ L 2,4-(Cl)2 A 0 0 ++ L 4-F cis +++ 0 +++ L 2-CH3 A ++++ ++ ++++ L 2-Cl A +++ 0 +++ L 2-CH3 B ++++ ++ +++ L 2,4-(Cl) 2 B ++++ ++ ++++ L 4-OCH3 A +++ 0 +++ L 4-F trans ++ + ++ I 4-OCH3 B ++ + ++ I 2,6-(Cl)2 A +++ 0 ++++ L 2-Cl B +++ + ++ L 2,6-(Cl) 2 B +++ ++ +++ •(CD 2 4-CH3 B ++ ++ ++ (Cl) 2 4-F A ++ ++ ++ -(Cl)2 2-CH3 A +++ + +++ •(Cl)2 4-CH3 A +++ ++ +++ ! (Cl)2 4-OCH3 A ++ + ++ ) s •(ci)2 4-Cl cis ++ + ++ 1 (Cl)2 2-CH3 B +++ + +++ J TABLE C continued - 51 - R1R2 Isomer bacteriostatic activity E.ins. Staph. Strept. 2, 4-(Cl)2 2,4-(Cl) 2 A +++ 0 +++ 2,4-(Cl)2 4-Cl trans +++ ++ +++ 2, 4-(Cl) 2 4-Br ! A 1 +++ + +++ 2, 4-CC1)2 2,4-(Cl)2 B } +++ ++ +++ 2, 4-(01)2 H A j +++ + +++ 2, 4-(Cl)2 3,4-(Cl)2 A +++ ++ +++ 2,4-(Cl)2 3-C1 A +++ ++ +++ 2,4-(Cl)2 2-C1 A +++ ++ +++ 2,4-(Cl).2 2-CH3,4-Cl A + B +++ ++ +++ 2,4-(Cl)2 2-C1 B +++ + +++ 2, 4-(Cl)2 2,6-(Cl)2 A +++ ++ +++ 2, 4—(Cl)2 3,5-{CH,),,- 4-Cl A +++ 0 +++ 2, 4-(Cl)2 2,4-(Br) 2 A +++ 0 +++ 2, 4-(Cl) 2 4-CN A +++ + ++ 2, 4—(Cl)2 2-Br cis +++ ++ +++ 2, 4-(Cl)2 2-OCH, A +++ + +++ 2, 4-(Cl)2 2-Br trans +++ ++ ++ 2, 4-{Cl)2 2,4,6-{Cl)3 A +++ 0 +++ 2, 4-(Cl)2 2,5-(CH,), A +++ ++ +++ 2, 4-(Cl)2 i 2,5-(CH3), B +++ ++ +++ 2, 4-(Cl)2 t 2-Cl,4-tertT but. A +++ ++ +++ 2, 4-(Cl>2 ί 2,4,5-(Cl)3 A ++++ 0 ++ 2, 4-(Cl)2 2-Cl,4-tert.· but. B ++++ ++ ++++ 2, 4-(Cl)2 2,4,5-(Cl)3 B +++ + +++ 2, 4-(Cl) 2 2,5-(Br)2,4- ! A +++ + +++ 2, 4-(Cl)2: 2-F A +++ + ++++ 4- CH3 ' 4-Br A +++ ++ ++++ 4- Cl ;4-Br A ++++ ++ ++++ 4-f Br i 4-Br A ++++ + ++++ 2, 4-(Cl)2 !2-OC,Hc ' 2 5 A ++++ 0 ++++ 13157 - 52 °.BLE C continued R1R2 Isomer 1 bacteriostatic activity Ξ. ins. Staph. Strept. 4-Br A + B ++++ ++ ++++ 4-Br B +++ ++ ++++ 4-Br A +++ ++ ++++ 4-Br A ++++ +++ ++++ 4-Br B ++++ ++ ++++ (Cl) 24~C6H5 A + B ++++ 0 ++ (Cl) 2 4-C6H5 B 0 0 ++++ (Cl) 2 2,6-(CII3)2 A ++++ ++ ++++ (Cl) 2 4-Br B +++ +++ +++ (Cl) 2 2,6-(CH3)2 A + B +++ ++ +++ (ci)2 3,5-(CH3)2 A +++ ++ +++ (ci)2 4-iC3H7 A + B ++ ++ +++ (Cl) 2 2-Cl,6-CH3 A ++ ++ ++ (Cl) 2 4-tert.but. A 4-++ ++ ++ (Cl) 2 3,5-(Cl)2 A ++ +++ ++++ :cd2 3-CH3, 4-Cl A +++ ++ ++ I R2 Isomer bacteriocidal activity E.ins. Staph. Strept. 2-CH3,4-Cl cis ++++ 0 ++++ 4-CH3 trans +++ + +++ 2-CH3,4-Cl trans ++++ + +++ 4-CH3 cis +++ + +++ 4-Cl A ++++ +++ 4-Cl B ++++ 4* +++ 2,4-(Cl)2 A 0 0 ++ 4-F cis +++0 +++ 2-CH3 A ++++ + ++++ 2-Cl A +++ 0 +++ 2-CH3 B +++ 4- 4-4*4- - 53 TABLE C continued R1R2 Isomer bacteriocidal activity E.ins. Staph. Strept. 2-C1 2,4-(Cl)2 B ++++ ++ ++++ 2-C1 4-OCH3 A ++ 0 ++-*- 2-C1 4-F trans + + ++ 2-C1 4-OCHj B + + ++ 2-Cl 2,6-(Cl)2 A ++ 0 ++++ 2-C1 2-C1 B ¢++ + ++ 2-C1 2,6-(Cl)2 B +++ + +++ 2,4-(Cl)2 4-CH3 B ++ + ++ 2,4-(Cl)2 4-F A ++ 0 ++ I 2,4-(Cl)2 2-CH3 A +++ + +++ 2,4—(Cl)2 4-CH3 A +++ + +++ 2,4-(Cl)2 4-OCH3 A ++ + ++ 2,4-(Cl)2 4-Cl cis ++ + ++ 2,4-(Cl) 2 2-CH3 B +++ + +++ 2,4-(Cl)2 2,4-(Cl)2 A +++ 0 +++ 2,4-(Cl)2 4-Cl trans +++ ++ +++ 2,4-(Cl)2 4-Br A +++ + +++ 2,4-(Cl)2 2,4-(Cl)2 B ++ + +++ 2,4-(Cl)2 H A +++ + +++ 2,4-(cl)2 3,4-(Cl)2 A +++ + +++ 2,4-(Cl)2 3-C1 A +++ ++ +++ 2,4-(Cl)2 2-Cl A +++ + +++ 2,4-(Cl) 2 2-CH3,4-Cl A + B ++ - + +++ 2,4—(Cl)2 2-Cl B ++ + +++ 2,4-(C1j2 2,6-(Cl)2 A ++ + ++ 2 j 4" (Cl i 2 3,5-(CH3)2,4-Cl A +++ 0 +++ 2,4-(Cl J 2 2,4-(Br)2 A +++ 0 +++ 2,4-(Cl)2 4-CN A 0 0 ++ 2,4-(Cl)2 2-Br cis +++ + +++ 2,4-(Cl)2 2-OCH3 A +++ + +++ 2,4-(Cl)2 2-Br trans ++ + ++ 2,4-(Cl)2 2,4,6-(Cl)3 A ++ 0 ++ 03157 U.E C '.ontinued 1R2 Isomer bacteriocidal activity E.ins. Staph. Strept (Cl)2 2,5-(CH3)2 A +++ + +++ (Cl) 2 2,5-(CH3)2 B +++ + +++ (Cl) 2 2-Cl,4-tert.but. A ++ 0 ++ (Cl) 2 2,4,5-(Cl)3 A +++ 0 ++ (Cl) 2 2-Cl,4-tert.but. B +++ + +++ (Cl) 2 2,4,5-(Cl)3 B ++ + ++ (Cl; 2 2,5-(Br)2,4-CH3 A ++ + ++ ί (Cl) 2 2-F A ++ + +++ 5 4-Br A ++ + +++ 4-Br A +++ + +++ 4-Br A +++ + +++ :ci)2 2-OC2Il5 A +++ 0 +++ 4-Br A + B +++ + +++ 4-Br B ++ + +++ 4-Br A + 0 +++ 4-Br A +++ ++ +++ 4-Br B +++ + ++++ Cl) 2 4-C6H5 A + B +++ 0 ++ Cl) 24~C6H5 B 0 0 +++ Cl) 2 2,6-(CH3)2 A +++ ++ +++ Cl) 2 4-Br B ++ + ++ Cl) 2 2,6-(CH3)2 A + B ++ + ++ Cl) 2 3,5-(CH3)2 A +++ + +++ Cl) 2 4-iC3H? A + B ++ + ++ Cl) 2 2-Cl, 6-CH3 A ++ + ++ Cl) 2 4-tert.but. A ++ + ++ Cl) 2 3,5-(Cl)2 A ++ ++ +++ Tl)2 3-CH3, 4-Cl A ++ ++ + Bacteriostatic and Bacteriocidal Activity R1R2 Isomer Bacteriostatic activity E. ins. Staph. Strept. 2,4-(Cl)2 4-Br A + B +++ ++ ++++ 2,4-(Cl)2 H A + B ++++ ++ ++++ R1R2 Isomer Bacteriocidal activity Ξ. ins. Staph. Strept 2,4-(Cl)2 4-Br A + B ++ + +++ 2,4-(Cl) 2 ..........-.-----* H A + B +++ + +++ 31S7 - 56 iBLE C BACTERIOSTATIC AND BACTERIOCIDAL ACTIVITY ch2-ch2 1R2 Isomer bacteriostatic activity E. ins. Staph. Strept. -(Cl) 2 2-Cl ++++ +++ ++++ -(ci)2 2,4-(Cl)2 ++++ +++ ++++ -(ci)2 2,6-(01)2 A + B ++++ +++ ++++ -(ci)2 4-0CH3 A + B ++++ + +++ -(Cl) 2 4-Cl ++++ ++ -(Cl) , H +++-; ++ +++ LR2 Isomer bacteriocidal activity Ξ. ins. Staph. Strept. -(cl)2 2-Cl +++ ++ +++ -(Cl)2 2,4-(Cl)2 +++ ++ +++ -(Ci)2 2,6-(Cl)2 A + B +++ ++ ++++ -(CL)2 4-OCH3 A + B +++ + ++ -(Cl)2 4-Cl +++ + +++ -(Cl)2 H +++ 0 ++ TABLE C BACTERIOSTATIC AND BACTERIOCIDAL ACTIVITY ¢7 / N Ar CH.

Ar R isomer Bacteriostatic activity E. ins. Staph. Strept. 2,4-(Cl),-CfiH,C2H5 A + B +++ ++ +++ 2-Cl-CgH4c2H5 A + B ++ + 0 2-CH3-C6H4C2H5 A + B ++ 0 ++ 4-CH3-CgH4 ^2¾ A + B ++ + ++ 2,3 ,4-(Cl)3-CgH2C2H5 A + B +++ ++ +++ 2-Br-CgH4 c2h5 A + B ++ + ++ 2,3-(Cl)2-C6H3C2H5 A + B ++ + ++ 1 2-Cl,4-F-C6H3C2H5 A + B ++ 0 ++ 4-Br-CgH4C2H5 A + B ++ 0 + 3-Cl-CgH4C2H5 A + B ++ 0 ++ 2-Cl,4-Br-CgH3C2H5 A + B +++ + ++ 2,4-(Br)2-CgH3C2H5 A + B +++ + ++ . 4-OCH3-CgH4C2K5 A + B + 0 + 2-thienylC2H5 A + B+ 0 + 2-CH3,4-Cl-CgH3C2H5 A + B +++ + + 2-Cl, 4-OCH3 A + B ++ + ++ 2-naphthylC2H5 A + B +++ + ++ 5-Cl-2-thienylC2H5 A + B ++ + ++ 2-OCH3,4-Cl-CgH3C2H5 A + B j + ' 0+ ΐ 2,4-(Cl)2-CgH3 A + B +++ ί ++ +++ [ 2,4-(Cl),-C6H, nC4Hg A + B +++ +++ +++ ί 2,4-(Cl)2~CgH3 nC5Hu A + B +++ ++ +++ 2,4-(Cl)2-CgH3 nCgH13 A + B +++ ί +++ +++ 2,4-(Cl)2-CgH3nC7H15 A + B +++ +++ +++ 2,4-(Cl)2-CgH3nC8H17 A + B +++ ++ j +++ 2,4-(Cl)2-CgH3 ch2ci A + B + ί 0 ί ί 2,4-(Cl)2-CgH3 ch2oh trans + ι0 ί + BLE C continued Bacteriostatic activity r R isomer E. ins. Staph. Strept. (ci)2-c6h3 CH2OH A + B ++ 0 + (Cl)2-CgH3 ch2oh cis + 0 0 5-(Cl)3-C6H2C2H5 A + B +++ ++ +++ r y- jR isomer Bacteriocidal activity E. ins. Staph. Strept. (C1)2-C6H3C2H5 A + B ++ 0 +++ :C6H4C2H5 A + B ++ +0 1 5~C6H4C2H5 A + B 0 00 i iC6H4C2H5 A + B ++ 0 ++ ί ,4-(C1)3-c6h2 c2h5 A + B +++ + +++ :C6n4C2H5 A + B ++ 0 ++ :ci)2-c6h3C2H5 A + B ++ + ++ 4-F-CgHC2H5 A + B ++ 0 ++ C& A + B ++ 0 + } <6"4CA A + B ++ 0 ++ { 4-»r-CgII3 % A + B +++ + ++ Br)2-C6H3C2H5 A + B +++ + ++ 3~i'6H4C2H5 A + B + 0 + enylC2H5 A + B 0 0 + ,4-Cl-CgH3C2S5 A + B +++ + + 4-OCH3C2H5 A + B + 0 + hthyl c2h5 A + B + 0 + 2-thienylC2H5 A + B 0 0 03, 4-Cl-CfiH3C2H5 A + B j + 0 + C1)2-C6H3nC3H7 A + B +++ + +++C1^2-C6H3n^4a9 A + B +++ +++ +++ cd2-c6h3nC5Hll A + B +++ ++ +++ ci)2-c6h3nC6H13 A + B +++ +++ 2-C6H3nC7H15 A + B +++ ++ +++C1,2-C6H3nC8H17 A + B +++ ++ +++ ch2ci A + B + 0 + 43137 TABLE C - 59 5 continued Ar R isomer Bacteriocidal activity E. ins. Staph. Strept. 4-(Cl)2-CgH3 4-(C1)2-c6h3 4-(Cl)2-C6H3 4,5-(Cl)3-CgH2 ch2oh ch2oh ch2oh C2H5 . trans A + B cis A + B 0 ++ + ++ ...... + o o o + + 0 1 ++ j TABLE C Bacteriostatic· and Bacteriocidal Activity N Alkyl-O-CH2 Bacteriostatic activity Alkyl isomer Ξ. ins. Staph. Strept. ch3 cis + 0 0C2H5 trans ++ + ++ nC3H7 cis ++ + + nC^Hg A + B +++ ++ +++ nC5Hu cis +++ +++ +++ nCgHi3 cis +++ ++ ++ nC?H15 cis +++ +++ +++nC8H17 j - —- - ----1 cis +++ ++ +++ 3157 - 60 ILE C continued Alkyl isomer Bacteriocidal activity E. ins. Staph. Strept H9 A + B + 0 + *11 cis +++ 0 ++ *13 cis ++ + ++ *15 cis +++ + ++ cis ++ + +++ LE C Aryl-CH2-O-CH2- yi isomer Bacteriostatic activity E. ins. Staph. Strept. W-C6*4 cis +++ +++ +++ CfiHR)-CfiH4 trans +++ ++ +++r-C6*4 cis +++ ++ +++ -(cD2-c6*3 cis +++ +++ +++ -(C1)2-C6H3 trans +++ ++ _ +++ Bacteriocidal activity ryl isomer E.ins Staph. Strept. 6*5>-<7η4 cis +++ + +++3*r))-C6H4 trans +++ ++ +++C6*4 cis +++ + +++ (Cl)9-CfiH? cis ++ + ++ ; (Cl)2-C6*3 trans +++ + ++ 5 ί 315 - 61 TABLE C Bacteriostatic and Bacteriocidal Activity Aryl Bacteriostatic activity E. ins. Staph. J- | Strept.C6H5 +++ ++ ++ 4-Cl-C6H4 +++ ++ ++ 4-F-CgH4 +++ ++ ++ 4-CH3-C6H4 +++ ++ +++ 4-Br-C6H4 +++ ++ +++ 4-OCH3-c6H4 +++ + +++ 4-(C6H5)-c6H4 +++ ++ +++ Aryl Bacteriocidal activity E. ins. Staph, Strept.C6H5 +++ + ++ 4-Cl-C,H4 +++ ++ ++ 4-F-C6K4 ++ + ++ 4-CH3-C6H4 +++ ++ +++ 4-Br-CbH4 +++ ++ +++ 4-OCH3-C6H4 +++ + +++ 4-(C6H5)-C6H4 ++ + ++ ,3157 - 62 In view of the aforementioned antifungal and antibacterial activities this invention provides valuable compositions comprising the subject l,3-dioxolan-2ylmethyl imidazoles (I) or the acid addition salts thereof as the active ingredient in a solvent or a solid, semisolid or liquid diluent or carrier, and, in addition, it provides an effective method of combatting fungus or bacterial growth by use of an effective anti-fungal or anti-bacterial amount of such ketals (I) or salts thereof. The compounds of the invention can be used in suitable solvents or diluents, in the form of emulsions, suspensions, dispersions or ointments, on suitable solid or semisolid carrier substances, in ordinary or synthetic soaps, detergents or dispersion media, if desired, together with other compounds having arachnicidal, insecticidal, ovicidal, fungicidal and/or bactericidal effects, or together with inactive additives.

Solid carrier substances which are suitable for the preparation of compositions in powder form include various inert, porous and pulverous distributing agents of inorganic or organic nature, such as, for example, tricalcium phosphate, calcium carbonate, in the form of prepared chalk or ground limestone, kaolin, bole, bentonite, talcum, kieselguhr and boric acid; powdered cork, sawdust, and other fine pulverous materials of vegetable origin.

The active ingredient is mixed with these carrier substances, for example, by being ground therewith; llternatively, the inert carrier substance is impregnated with a solution of the active component in a readily volatile solvent and the solvent is thereafter eliminated by heating or by filtering with suction at reduced pressure. By adding wetting and/or dispersing agents, such pulverous preparations can also be made readily wettable with water, so that suspensions are obtained.

Inert solvents used for the production of liquid - 63 preparations should preferably not be readily inflammable and should be as far as possible odorless and as far as possible non-toxic to warm-blooded animals or plants in the relevant surroundings. Solvents suitable for this purpose are high-boiling oils, for example, of vegetable origin, and lower-boiling solvents with a flash point of at least 30°c., such as, polyethylene glycols, isoprcpanol, dimethylsulfoxide, hydrogenated naphthalenes and alkylated naphthalenes. It is, of course, also possible to use mixtures of solvents. Solutions can be prepared in the usual way, if necessary, with assistance of solution promotors. Other liquid forms which can be used consist of emulsions or suspensions of the active compound in water or suitable inert solvents, or also concentrates for preparing such emulsions, which can be directly adjusted to the required concentration. For this purpose, the active ingredient is, for example, mixed with a dispersing or emulsifying agent. The active component can also be dissolved or dispersed in a suitable inert solvent and mixed simultaneously or subsequently with a dispersing or emulsifying agent.

It is also possible to use semi-solid carrier substances of a cream ointment, paste or waxlike nature, into which the active component can be incorporated, if necessary, with the aid of solution promotors and/or emulsifiers. Vaseline (Registered Trade Mark) and other cream bases are examples of semi-solid carrier substances.

Furthermore, it is possible for the active component to be used in the form of aerosols. For this purpose, the active component is dissolved or dispersed, if necessary, with the aid of suitable inert solvents as carrier liquids, such as difluorodichloromethane, which at atmospheric pressure boils at a temperature lower than room temperature, or in other volatile solvents. In this way, solutions under pressure are obtained which, when sprayed, yield aerosols which are particularly suitable for controlling or combatting fungi and bacteria, e.g., 157 - 64 in closed chambers and storage rooms, and for application to vegetation for eradicating or for preventing infections by fungi or bacteria.

The compounds of the present invention and compositions thereof can be applied by conventional methods. For example, a fungus or bacterial growth or a material to be treated or to be protected against attack by fungus or bacterium can be treated with the compounds of the invention and the compositions thereof by dusting, sprinkling, spraying, brushing, dipping, smearing, impregnating or other suitable means.

When the compounds of the invention are employed in combination with suitable carriers, e.g., in solution, suspension, dust, powder, ointment, or emulsion, a high activity over a very high range of dilution is observed. For example, concentrations of the active ingredient ranging from 0.1 to 10 percent by weight, based on the weight of composition employed, have been found effective in combatting fungi or bacteria. Of course, higher concentrations may also be employed as warranted by the particular situation.

The following examples are intended to illustrate, but not to limit, the scope of the present invention. Unless otherwise stated, all parts are by weight.

Example I A mixture of 11.7 parts of 2-bromo-4'-chloroacetophenone, 9 parts of l-(£-chlorophenyl)-l,2-ethanediol, 0.5 parts of g-toluenesulfonic acid and 80 parts of benzene is stirred and refluxed for 2 days with a waterseparator. The reaction mixture is cooled and washed successively twice with a sodium hydrogen carbonate solution and once with water. The organic phase is dried and evaporated. The residue is triturated in petroleum ether and cooled on ice. The precipitated product is filtered off, crystallized from methanol, stirred in acetonitrile while cooling on ice, filtered off again and washed once more with acetonitrile, yielding 2(bromomethyl) -2,4-bis (p-chlorophanyl) -1,3-dioxolane.

Example II A mixture of 11.6 parts of 2-bromo-4'-chloroacetophenone, 8.4 parts of 1-phenyl-l,2-ethanediol 0.1 parts of p-toluene sulfonic acid, 210 parts of benzene and 40 parts of ethanol is stirred and refluxed for 24 hours.

The reaction mixture is evaporated and the residue is triturated in methanol. The product is filtered off and crystallized from methanol, yielding 2-(bromomethyl)-2(p-chlorophenyl)-4-phenyl-l,3-dioxolane; mp. 60°C.

Example III A mixture of 11.6 parts of 2-bromo-4'-chloroacetophenone, 12.4 parts of l-(2,4-dichlorophenyl)-l,2ethanediol, 0.1 parts of p-toluenesulfonic acid, 80 parts of n-butanol and 160 parts of benzene is stirred and refluxed for 24 hours with water-separator. The solvent is removed in vacuo and the residue is triturated in methanol. The product is filtered off and crystallized from petroleum ether, yielding 2-(bromomethyl)-2-(pchloropheny1)-4-(2,4-dichlorophenyl)-1,3-dioxolane; m.p. 82.7°C.

EXAMPLE IV Following the procedure of Example III and using equivalent amounts of the appropriate starting materials the following dioxolanes are obtained eventually after optional further purification by one of the following procedures: a) by column-chromatography over silica gel using trichloromethane as eluent; or 157 - 66 b) by stirring the product with silica gel in trichloromethane, filtering off the silica gel and evaporating the solvent.

R6 R7 Melting Point Purification procedure 4-Br 4-Cl 101.3°C - 4-Br 2,4-(Cl) 2 99.9°C - 4-OCH3 4-Cl 115.6°C - - 4-Cl 63.9°C - 4-CH3 2,4-(01) 2 89.9°C - 4-Br 4-Br 96.8°C - 4-CR3 4-Cl 122°C - 4-CH3 4-Br 118.6°C - 4-CH3 2-C1 - - 2,4-(01) 2 - - a - 2,4-(Cl) 2 - a 2,4-(Cl) 2 4-Cl - a 4-Cl 2-C1 - b 2-Cl 2,4-(Cl) 2 - b 4-Br 2-C1 - b 2-C1 4-Cl - b 2,4-(Cl) 2 2,4-(Cl) 2 - b 4-Br - 70°C b - 4-Br 71.3°C b 2,4-(Cl) 2 2-C1 - b 4S157 R6 R7 Melting Point Purirication procedure _ 2,4-(Cl)2 4-Br - b 4-C1 4-Br 80.5°C b 3-Cl 2,4-(Cl)2 - b 2-Cl 4-Br - b 4-Cl 4-CH3 - b 4-Br 4-CH3 - b 4-Cl 4-F - b 4-Br 4-F - b Example V To a stirred and refluxing Grignard-complex, previously prepared starting from 98 parts of 1-(chloro5 methyl)-2,4-dichlorobenzene and 14 parts of magnesium in parts of 1,1-oxybisethane, is added dropwise a solution of 46.5 parts of 2-(chloromethyl)oxirane in 350 parts of 1,1-oxybisethane. Upon completion, stirring at reflux temperature is continued overnight. The reaction mixture is cooled in an ice-bath and decomposed by dropwise addition of 120 parts of a concentrated hydrochloric acid solution. The whole is poured onto water and the layers are separated. The organic phase is washed three times with water. The aqueous phase is extracted with 1,1'15 oxybisethane. The combined organic phases are dried, filtered and evaporated. The residue is distilled, yielding 2,4-dichloro-a-(chloromethyl)benzenepropanolj bp. 130°C. at 0.04 mm, pressure.

Example VI Following the procedure of Example V and using equivalent amounts of the appropriate starting materials, the following compounds are prepared: - 68 3LS7 OH R, R, ch2-ch2-ch-ch2ci '8 '8 boiling point 118°C 136°C 14O°C 2-Cl 2,6-(Cl)2 4-OCH, 4-Cl 118 C. at 0.01 mm. pressure 136°C. at 0.2 mm. pressure 140°C. at 0.2 mm. pressure 13O-135°C at 0.3 mm. pressure Example VII A solution of 87 parts of 2,4-dichloro-a-(chloromethyl) benzenepropanol in 144 parts of concentrated sodium hydroxide solution and 350 parts of 2,2'-oxybispropane is stirred overnight at room temperature. The product is extracted with 2,2'-oxybispropane. The extract is washed with water, dried, filtered and evaporated, The oily residue is distilled, yielding /2-(2,4-dichlorophenyl)ethyl7oxirane; bp· 9O-98°C. at 0.01 mm. pressure.

Example VIII Following the procedure of Example VII and using equivalent amounts of the appropriate starting materials, the following oxirane derivatives are prepared: R, ,0 - 69 Rg boiling point 2-Cl 66-7O°C. at 0.01 mm. pressure 2,6-(Cl)2 85-89°C. at 0.01 mm. pressure 4-0CH3 80-90°C. at 0.05 mm. pressure 4-Cl 106-115°C. at 0.03 mm. pressure Example IX To a stirred and refluxing Grignard-complex, previously prepared starting from 89 parts of 4-(chloromethyl) -1, l'-biphenyl and 12.5 parts of magnesium in 350 parts of l,l'-oxybisethane, is added dropwise a solution of 60 parts of 3-bromo-l-propene in 180 parts of tetrahydrofuran. Upon completion, stirring is continued for 2.50 hours at reflux temperature. The reaction mixture is cooled and poured onto water. The layers are separated and the aqueous phase is extracted with l,l'-oxybisethane. The combined organic phases are washed with water, dried, filtered and evaporated. The residue is filtered and the filtrate is evaporated, yielding 60 parts of 4-(3-butenyl)1,1’-biphenyl as a residue.

To a stirred mixture of 88 parts of 3-chiorobenzeneperoxoic acid and 650 parts of dichloromethane are added dropwise 60 parts of 4-(3-butenyl)-1,1'-biphenyl. Upon completion, stirring is continued over week-end at room temperature. Then there are added dropwise 50 parts of a potassium carbonate solution. The organic phase is separated, washed with a sodium bisulfite solution and with water, dried, filtered and evaporated, yielding 63.5 parts (70.87%) of /2-(/1,l'-biphenyl/-4-yl)ethyl/oxirane as an oily residue.

Example X To a stirred mixture of 86 parts of 3-chlorobenzeneperoxoic acid and 650 parts of dichloromethane are added 131S7 dropwise (slowly) 53 parts of l-fluoro-4~(2-propenyl)benzene. Upon completion, stirring is continued overnight at room temperature. Then there are added dropwise 92 parts of a potassium carbonate solution and the layers are separated. The organic phase is washed with a sodium bisulfite solution, dried, filtered and evaporated, yielding 58.4 parts (98%) of 2-(4-fluorophenylmethyl)oxirane as an oily residue.

Example XI To a stirred mixture of 44.5 parts of 4-chloro-lnaphthol and 115 parts of 2-(chloromethyl)oxirane are added portionwise 17.1 parts of potassium hydroxide (exothermic reaction). When the exothermic reaction is ceased, the whole is heated to reflux and stirred at reflux temperature for 2 hours. Water is added and the whole is extracted twice with trichloromethane. The combined extracts are washed three times with water, dried and evaporated. The residue is distilled, yielding 45.3 parts of 2-/’(4-chloro-l-naphthoxy)methyl7oxitane(· bp. 15O-151°C at 0.2 mm. pressure.

Example XII To a stirred solution of 139 parts of 2-nitrophenol and 138 parts of potassium carbonate in 640 parts of 2propanone are added dropwise 215 parts of 2-(chloromethyl) -oxirane. Upon completion, stirring is continued for 2 days at reflux. The formed precipitate is filtered off and the filter-cake is washed with 2-propanone. The filtrate is evaporated. The residue is crystallized from a mixture of 2,2'-oxybispropane and petroleum ether (1:1 by volume). The product is filtered off and dried, yielding 38 parts (20%) of 2-(2-nitrophenoxymethyl)oxirane; mp. 56°C. - 71 Example ΧΙιΙ Following the procedure of Example XII and using an equivalent amount of an appropriately substituted phenol or naphthalenol in place of the 2-niirophenol used therein, the following 2-aryloxymethyloxiranes are obtained: 2-/~(2-chloro-5-methylphenoxy)methyl/oxitane; bp. 115°C at 0.05 mm. pressure; 2-(3,4,5-trichlorophenoxymethyl)oxirane as an oily residue; 2-(3-chloro-/I,l'-biphenyl/-4-yloxymethyl)oxirane as a residue; and 2-/'(l,6-dibromo-2-naphthyloxy)methy1/oxirane as a solid residue.

Example XIV To a stirred solution of 38 parts of 2-(2-nitrophenoxymethyl)oxirane in 10 parts of ethanedioic acid and 300 parts of 1,4-dioxane are added 100 parts of water. The whole is stirred and refluxed for 2 days. The reaction mixture is evaporated and the residue is crystallized from a mixture of 2,2'-oxybispropane and petroleum ether. The product is filtered off and recrystallized from 2,2'-oxybispropane, yielding 29.5 parts (13%) of 3-(2~nitrophenoxy)-l,2-propanediol; mp. 96°C.

Example XV Following the procedure of Example XIV and using an equivalent amount of an appropriately substituted oxirane in place of the 2-/~(2-nitrophenoxy)methy1/oxirane used therein, the following diols are obtained: 3-(4-chloro-l-naphthyloxy)-1.2-propanediol; mp. 120°C; ί57 - 72 3-(2-chloro~5-methylphenoxy)-1,2-propanediol; mp. 59°C; 3-/4-(phenyi.methyl)phenoxy7-l,2-propanediol; mp. 70°C; 3-(3,4,5-trichlorophenoxy)-l,2-propanediol; mp. 64°C; 3-(3-chloro-/l,1'-biphenyl/-4-yloxy)-1,2-propanediol; mp. 60°C; 3-(l,6-dibromo-2-naphthyloxy) -1,2-propanediol; mp. 139°C; 3-(4-bromophenyl)-1,2-propanediol; mp. 6O.6°C; 3- (4-fluorophenyl)-1,2-propanediol; bp. 125°C at 0.05 mm. pressure; and 4- (/l,l'-biphenyl/-4-yl)-1,2-butanediol; mp. 125.9°C. 1-/2-(2,4-dichlorophenyl/7-1,2-butanediol; mp. 83.2°C; 1-/2-(2-chlorophenyl)_/-l, 2-butanediol mp. 64.1°C; 4-(2,6-dichlorophenyl)-1,2-butanediol; mp. 111.7°C; and 4-/2-(4-chlorophenyl)_7-l,2-butanediol bp. 150°C at 0.02 mm. pressure .

Example XVI To a stirred solution of 12 parts of 2-/2-(4methoxyphenyl)-ethyl7oxirane in 1.8 parts of sulfuric acid and 160 parts of 2-propanone are added 100 parts of water. The whole is stirred for 2 days at room temperature The reaction mixture is stirred with a sodium bicarbonate solution and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated, yielding 4-/2-(4-methoxyphenyl1/-1,2-butanediol as a residue.

Example XVII A mixture of 11.7 parts of 2-bromo-4'-chloroacetophenone, 11.9 parts of 1-(4-chloro-o-tolyloxy)-2,3propanediol, 2.5 parts of £-toluenesulfonic acid and 240 parts of benzene is stirred and refluxed for 24 hours in a four-necked round-bottomed flask equipped with a watertrap. The benzene solution is washed successively with a dilute sodium hydroxide solution and with water. The solvent is removed in vacuo. The residue is crystallized from methanol and the less pure fraction is recrystallized from 2,2-oxybispropane, yielding A-2-(bromomethyl)2-(g-chlorophenyl)-4-(4-chloro-o-tolyloxymethyl)-1,3dioxolane; mp. 102.5°C. The methanol filtrate is evaporated in vacuo, yielding B-2-(bromomethyl)-2-ip10 chlorophenyl)-4-(4-chloro-2-tolylcxymethyl)-1,3-dioxolane as a residue.

Example XVIII Following the procedure of Example xvn and using equivalent amounts of the appropriate starting materials the following dioxolanes are obtained eventually after optional purification of the products by: a) column-chromatography over silica gel using trichloromethane as eluent; or b) stirring the product with silica gel in trichloromethane, filtering off the silica gel and evaporating the solvent. 31S7 R R Melting Point Purification procedure 4-Cl 4-CH3 4-Cl 4-CH3 - - 4-Cl 2,4-(Cl)2 87-89°C - 4-Cl 2,4-(Cl) - - 4-Cl 4-F 102°C - 4-Cl 4-F - - 4-Cl 2-CH3 82.2-85°C - 4-Cl 2-CH3 - - 4-Cl 2-Cl 85-88.6°C - 4-Cl 2-Cl - - 4-Cl 4-0CH3 - - 4-Cl 4-OCH3 - - 2,4-(Cl)2 4-F - - 2,4-(Cl)2 4-OCH3 - - 4-Cl 4-Cl 165°C - 4-Cl 4-Cl - a 2,4-(Cl)2 4-CH3 - b 2,4-(Cl)2 4-CH3 - - 2,4-(Cl)2 4-Cl - - 2,4-(Cl)2 4-Cl - b 2,4-(Cl) 2 2,4-(Cl)2 - - 2,4-(Cl)2 2,4-(Cl)2 - b 4-Cl 2,6-(Cl)2 - - 2,4-(Cl)2 2-CH3 - b Example XIX A mixture of 11.2 parts of 2,2',4'-trichloroacetophenone, 14.9 parts of 1-(2,4-dichlorophenoxy)-2,3propanediol, 3 parts of p-toluenesulfonic acid and 240 parts of benzene is stirred and refluxed for 20 hours in a four-necked, round-bottomed flask, equipped with a water-trap. The reaction mixture is washed successively with a diluted sodium hydroxide solution and twice with water. The solvent is removed in vacuo. The residue is triturated in methanol for 3 hours. The product is filtered off and crystallized from 2-propanol, yielding A-2-(chioromethyl)-4-(2,4-dichlorophenoxymethyl)-2-(2,4dichlorophenyl)-1,3-dioxolane; mp. 32.5°C.

Example XX A mixture of 6 parts of 2-bromo-21,4'-dichloroacetophenone, 6 parts of 3-(4-chloro-o-tolyloxy)-1,2-propanediol, 3 parts of £>-toluenesulfonic acid, 80 parts of nbutanol and 180 parts of benzene is stirred and refluxed for 24 hours with water-separator. The solvent is removed in vacuo and the residue is triturated in methanul. The product is filtered off and crystallized from petroleum ether, yielding A+B 2-(bromomethyl)-4-(4-chloro-2tolyloxymethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolane, Example XXI Following the procedure of Example XX and using equivalent amounts of the appropriate starting materials and the indicated solvent, the following dioxolanes are prepared: BrCH. // '2 - 76 31 87 aner r5 Melting Solvent Point 2.4- (Cl)2 2.4- (Cl) 2 2.4- (Cl)2 2,4-(Cl)2 2,4-(Cl)2 2,4-(Cl)2 2,4-(Cl)2 2,4-(Cl)2 2,4-(Cl)2 2,4-(Cl)2 2,4-(Cl)2 2,4-(Cl)2 2,4-(Cl)2 2,4-(Cl)2 4-CH3 4-C1 4-Br 2,4-(Cl)2 2,4-(Cl)2 2,4-(Cl)2 4-OCH3 2.4- (Cl)2 2.3.4- (Cl)3 2.4- (C3)2 2.4- (0) 2 2-Cl,4- Br 3,4,5- Cl)3 2.4- (Cl)2 2.4- (Cl) 2 C6H5 97.6°C benzene 3,4-(Cl)2-C6H3 - benzene 3-Cl-C6H4 benzene 3,5-(CH3)2,4-Cl-CgH2 115.8°C benzene 2,4-(Br)2-C6H3 - benzene 4-CN-C6H4 benzene 2-OCH3-CgH4 benzene 4-(CgH5)-CgH4 - benzene 4-/CH(CH3)2/-CgH4 90°C methylbenzene 3-CH3,4-Cl-CgH3 - methylbenzene 3,5-(Cl)2-CgH3 methylbenzene 4-/C(CH3)37-CgH4 methylbenzene 2-naphthyl 117.6°C benzene 2-F-C6H4 125.7°C benzene 4-Br-CgH4 121.1°C benzene 4-Br-CgH4 157.4°C benzene 4-Br-CgH4 158.7°C benzene 3-Br-CgH4 112.7°C benzene 3,5-(CH3)2-CgH3 118.7°C benzene 4-(CgH5-CH2)-CgH4 106.1°C benzene 4-Br-C6H4 117°C benzene 4-Br-CgH4 85.6°C benzene 4-Cl-l-naphthyl 122.7°C benzene 4-Br-C6H4 - methylbenzene 2-Br,4-CH3-CgH3 methylbenzene 1,6-(Br)2~2-naphthyl - methylbenzene 4-(CgH5)-CgH4 - dimethylbenzene 4-(C6H5)-c6H4 - dimethylbenzene 2-CN-CgH4 - dimethylbenzene 4-(nC4H9-OOC)-CgH4 - dimethylbenzene - 77 43157 Example XXII A mixture of 13.6 parts of 2-bromo-l-(2,4-dichlorophenyl)-1-ethanone, 12 parts of 3-(2,5-dimechylphenoxy)-1, 2-propanediol, 3 parts of 4-methylbenzenesulfonic acid, 80 parts of butanol and 180 parts of benzene is stirred and refluxed for 24 hours with water-separator. The reaction mixture is evaporated and the residue is dissolved in trichloromethane. The solution is stirred with silica gel for 30 minutes. The latter is filtered off and the filtrate is evaporated, yielding A+B-2-(bromomethyl)-2(2,4-dichlorophenyl)-4-(2,5-dimethylphenoxymethyl)-1,3dioxolane as a residue.

Example XXIII Following the procedure of Example XXII and using equivalent amounts of the appropriate starting materials and the indicated solvent, the following dioxolanes are obtained as a residue: Isomer R6 R5 Solvent A+B 2,4-(Cl)2 2-Cl-CgH4 benzene A+B 2,4-{Cl)2 2,6-(Cl)2-CgH3 benzene A+B 2,4-(Cl)2 2-Br-C6H4 benzene A+B 2-Br 4-Br-C6H4 benzene A+B 2,4-(Cl)2 2-Cl,6-CH3-CgH3 methylbenzene A+B 2,4-(Cl)2 2,3-(Cl)2-CgH3 roethylbenzene A+B 2,4-(Cl)2 2,4,6-(Cl)3-CgH2 benzene 157 Isomer R6 R5 Solvent A+B 2,4-(Cl)2 2-Cl,4-/C(CH,) ^7-CfiH, benzene A+B 2,4-(Cl)2 2,4,5-(Cl)3-CgH2 benzene A+B 2,4-(Cl)2 2,5-(Br),,4-CH,-CfiH, benzene A+B 2,4-(Cl)2 2,0C,Hq-CfiH4 benzene A+B 2-C1 4-Br-C6H4 benzene A+B 2,4-(Cl)2 2,6-(CH3)2-C6H3 methylbenzene A 2,4-(Cl)2 6-Br-2-naphthyl benzene - 2,4-(Cl)22-C6H4 dimethylbenzene Example XXIV Following the procedure of Example XXII and using equivalent amounts of the appropriate starting materials and methylbenzene as a solvent, the following dioxolanes are obtained after purification of the products by columnchromatography over silica gel using trichloromethane as eluent: 2-(bromomethyl)-4-(2-chloro-5-methylphenoxymethyl)-2-(2,4dichlorophenyl)-1,3-dioxolane as an oily residue; A+B-2- (bromomethyl) -2- (2,4-dichlorophenyl) -4- (3,4,5-trichlorophenoxy methyl)-1,3-dioxolane as a residue.

Example XXV A mixture of 222.5 parts of 2-bromo-l-(2,4-dichlorophenyl ) -1-ethanone, 250 parts of 3-(4-bromophenoxy)-1,2propanediol, 50 parts of 4-methylbenzenesulfonic acid and 3150 parts of benzene is stirred and refluxed in a fournecked, round-bottomed flask, equipped with a water-trap. After 16 hours the theoretical amount of water is evolved. The reaction mixture is allowed to cool to room temperature and washed successively with diluted sodium hydroxide solution and twice with water. The solvent is dried and removed in vacuo. The residue is triturated in methanol. 1ST The product is filtered off (the filtrate is set aside) and crystallized from butanol, yielding A-2-(bromomethyl)-4(£>-bromophenoxymethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolane.

The filtrate (see above) is evaporated. The residue is dissolved in 210 parts of 2,2'-oxybispropane and the solution is allowed to crystallize. The precipitated product is filtered off and discarded. The filtrate is evaporated and the residue is dissolved in 400 parts of a mixture of hexane and trichloromethane (3:1 by volume).

The undissolved part is filtered off and discarded. The filtrate is purified twice by column-chromatography over silica gel using a mixture of hexane and trichloromethane (3:1 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue solidifies on triturating in petroleum ether. The product, is filtered off and dried, yielding B-2-(bromomethyl)-4(4-bromophenoxymethyl)-2-(2,4-dichlorophenyl)-1,3dioxolane.

Example XXVI A mixture of 15.2 parts of 2-bromo-l-(2,4-dichlorophenyl) -ethanone, 16.7 parts of 3-(3-chloro/l,l'-biphenyl/4-yloxy)-1,2-propanediol, 3 parts of 4-methylbenzenesulfonic acid, 40 parts of butanol and 225 parts of dimethylbenzene is stirred and refluxed for 2 days with a water-separator. The reaction mixture is allowed to cool to room temperature and 2,2'-oxybispropane is added. The organic phase is washed with a diluted sodium hydroxide solution 5N and with water, dried, filtered and evaporated. The residue is triturated in a mixture of 2,2'-oxybispropane and petroleum ether. The product is filtered off (the filtrate is set aside) and dried, yielding 12.5 parts of A-2-(bromomethyl)-4-(3-chloro-/l,l1-biphenyl/-4-yloxymethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolane.

The filtrate (see above) is evaporated. The residue is dissolved in trichloromethane and the solution is stirred - 80 with silica gel. The latter is filtered off and the filtrate is evaporated, yielding 10 parts of A+B-2-(bromomethyl) -4-(3-chloro-/l,1’-biphenyl7~4-yloxymethyl)-2(2,4-dichlorophenyl)-1,3-dioxolane as a residue.

Example XXVII A mixture of 18.1 parts of 3-/4-(phenyImethyl)phenoxy/ -1,2-propanediol, 13.4 parts of 2-bromo-l-(2,4-dichlorophenyl) ethanone, 3 parts of 4-methylbenzenesulfonic acid, parts of butanol and 225 parts of methylbenzene is stirred and refluxed over week-end. The reaction mixture is evaporated and the oily residue is triturated in methanol. The product is filtered off (the filtrate is set aside), yielding 15 parts of A-2-(bromomethyl)-2-(2,4dichlorophenyl)-4-/4-(phenylmethyl)phenoxymethy17-1,3dioxolane; mp. 96°C.

The filtrate, which was set aside, is evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 20% of hexane as eluent. The pure fractions are collected and the eluent is evaporated, yielding 13 parts of B-2-(bromomethyl) -2-(2,4-dichlorophenyl)-4-/4-(phenylmethyl)phenoxymethyl7-l,3-dioxolane as an oily residue.

Example XXVIII A mixture of 14.9 parts of 3-(2-nitrophenoxy)-1,2propanediol, 13.4 parts of 2-bromo-l-(2,4-dichlorophenyl) -ethanone, 3 parts of 4-methylbenzenesulfonic acid, 40 parts of butanol and 225 parts of methylbenzene is stirred and refluxed over a week-end. The reaction mixture is evaporated and the oily residue is dissolved in trichloromethane. The solution is washed with a dilute sodium hydroxide solution 20% and with water, dried, filtered and evaporated. The oily residue is crystallized from 2,2'oxybispropane while stirring. The product is filtered off (the filtrate is set aside), yielding 8.5 parts of - 81 A-2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-(2-nitrophenoxymethyl) -1,3-dioxolane.

The filtrate which was set aside, is evaporated. The oily residue is purified twice by column-chromatography over silica gel using, first trichloromethane and second a mixture of trichloromethane and 20% of hexane as eluent.

The pure fractions are collected and the eluent is evaporated, yielding 14.5 parts of B-2-(brOmomethyI)-2-(2,4dichlorophenyl)-4-(2-nitrophenoxymethyl)-1,3-dioxolane as an oily residue.

Example XXIX A mixture of 13.6 parts of 2-bromo-l-(2,4-dichlorophenyl)-1-ethanone, 15.8 parts of 3-(4-bromophenylthio)-l,2 -propanediol, 3 parts of 4-methylbenzenesulfonic acid, 180 parts of butanol and 90 parts of benzene is stirred and refluxed for 12 hours with water-separator. The reaction mixture is evaporated and the residue is dissolved in trichloromethane. The solution is stirred with silica gel for 30 minutes. The latter is filtered off and the filtrate is evaporated, yielding A+B 2-(bromomethyl)-4(4-bromophenylthiomethyl)-2-(2,4-dichlorophenyl)-1,3dioxolane as a residue.

Example XXX Following the procedure of Example XXIX and using equivalent amounts of the appropriate starting materials, the following dioxolanes are prepared: A+B-2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-(phenyIthiomethyl)-1,3-dioxolane as a residue A+B 2-(bromomethyl)-2-(2,4-dichlorophenyl)^-/-^-fluorophenyl) thiomethyl/-! , 3-dioxolane as a residue - 82 3157 Example XXXI A mixture of 19.8 parts of 3-(4-bromophenoxy)-1,2propanediol, 15.6 parts of 2-(bromomethyl)-2-(3,5-dichlorophenyl) -1,3-dioxolane, 4 parts of 4-methylbenzenesulfonic acid, 40 parts of butanol and 225 parts of benzene is stirred and refluxed for 2 days with water-separator. The reaction mixture is allowed to cool to room temperature and the solvent is removed by evaporation in Vacuo. The residue is triturated in methanol. The product is filtered off and crystallized from 2-propanol yielding 5.5 parts (22%) of A-2-(bromomethyl)-4-(4-bromophenoxymethyl)-2(3,5-dichlorophenyl)-1,3-dioxolane.

Example XXXII Following the procedure of Example XXXI and using equivalent amounts of the appropriate starting materials, the following dioxolanes are prepared by carrying out the reaction in the indicated solvent: Using methylbenzene as a solvent there are prepared: A-2-(bromomethyl)-4-(4-bromophenoxymethyl)-2-(4-chloro2-methylphenyl)-!, 3-dioxolane; mp. 155°C; A-2-(bromomethyl)-4-(4-bromophenoxymethyl)-2-(3-bromophenyl)-1,3-dioxolane; mp. 92.2°C; A-2-(bromomethyl)-2-(4-bromo-2-methylphenyl)-4-(4-bromophenoxymethyl )-3., 3-dioxolane; A-2-(bromomethyl)-2-(3-bromo-4-methylphenyl)-4-(4-bromophenoxymethyl) -1,3-dioxolane; mp. 100°C; A-4-/2-(bromomethyl)-4-(4-bromophenoxymethyl)-1,3-dioxolan2-yl7-benzontrile; A-2-(bromomethyl)-4-(4-bromophenoxymethyl)-2-(3-nitrophenyl)-1,3-dioxolane; and A-2-(bromomethyl)-4-(4-bromophenoxymethyl)-2-(2,3-dichloro - fi j phenyl)-1,3-dioxolane.

Using dimethylbenzene as a solvent there are prepared: A+B-4-(/1,1'-bipnenyi/-4-yloxymethyI)-2-(bromomethyl)2- (2-naphthalenyl)-1,3-dioxolane; mp. 160.8°C; A-4-(/1,1'-biphenyl7-4-yloxymethyl)-2-(bromomethyl)-2(2-chloro-4-methoxyphenyl)-1,3-dioxolane; A+B-2-(bromomethyl)-4-ethyl-2-(2,3,4-trichlorophenyl)-1, 3- dioxolane; bp. 145°C at 0.1 mm. pressure; A+B-4-(/1,1'-biphenyl/-4-yloxymethyl)-2-(bromomethyl)-2(2,4,5-trichlorophenyl)-1,3-dioxolane as a residue; A+B-2-(bromomethyl)-2-(2,3-dichlorophenyl)-4-ethyl-l,3dioxolane; bp. 131-133°C at 0.1 mm. pressure; A+B-2-(bromomethyl)-2-(2-chloro-4-methoxyphenyl)-4-ethyl1,3-dioxolane; bp. 142-144°C at 0.3 mm. pressure; A+B-2-(bromomethyl)-2-(4-chloro-2-methylphenyl)-4-ethyl1.3- dioxolane; bp. 118°C at 0.15 mm. pressure; A+B-2-(bromomethyl)-4-ethyl-2-(2-naphthalyl)-1,3dioxolane as a residue; and 2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-/2-(4-methylphenyl)-ethy1/-1,3-dioxolane as a residue.

Example XXXIII A mixture of 13.6 parts of 2-bromo-l-(2,4-dichlorophenyl) -1-ethanone, 14.1 parts of 1-/2-(2,4-dichlorophenyl) ethy l/ethanediol, 3 parts of 4-methyIbenzenesulfonic acid, 80 parts of butanol and 180 parts of benzene is stirred and refluxed for 24 hours. The reaction mixture is evaporated and the residue is stirred for 2 hours with 160 parts of methanol. The precipitated product is filtered off, yielding 2-(bromomethyl)2-(2,4-dichlorophenyl)-4-/2-(2,4-dichlorophenyl)ethy1/1.3- dioxolane. - 84 L57 Example XXXIV Following the procedure of Example XXXIII and using equivalent amounts of the appropriate starting materials, the following dioxolanes are prepared by carrying out the reaction in the indicated solvent.

Using benzene as a solvent there are prepared: 2-(bromomethyl)-4-/2-(2-chlorophenyl)ethy1/-2-(2,4dichlorophenyl)-1,3-dioxolane; 2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-/2-(2,6dichlorophenyl)ethy17-1,3-dioxolane; and A+B-2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-/2-(4methoxyphenyl)ethy1/-1,3-dioxolane.

In methylbenzene as a solvent are prepared: 2-(bromomethyl)-4-/2-(4-chlorophenyl)ethyl7~2-(2,4dichlorophenyl)-1,3-dioxolane as a residue; and 2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-(2-phenylethyl)1,3-dioxolane as a residue.

In dimethylbenzene as a solvent are prepared: A+B-2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-(phenylmethyl) -1,3-dioxolane as a residue; A+B-2-(bromomethyl)-4-(4-chlorophenylmethyl)-2-(2,4dichlorophenyl)-1,3-dioxolane; and A+B-2-(bromomethyl)-2-(2,4-dichlorophenyl) .-4-(4-methoxyphenyl methyl)-1,3-dioxolane as a residue.

Example XXXV A mixture of 13.5 parts of 1,2-butanediol, 37.5 parts 2-bromo-l-(2,4-dichlorophenyl)ethanone, 2 parts of 4-methylbenzenesulfonic acid, 40 parts of butanol and 225 - 85 parts of methyIbenzene is stirred and refluxed for 24 hours with water-separator. The reaction mixture is cooled, washed twice with a sodium bicarbonate solution, dried, filtered and evaporated. The residue is distilled, yielding 38 parts (80%) of A+B-2-(bromomethyl)2-(2,4-dichiorophenyl)-4-ethyl-l,3-dioxolane; bp. 125130°C at 0.1 mm. pressure.

Example XXXVI Following the procedure of Example XXXV and using 10 equivalent amounts of the appropriate starting materials, the following dioxolanes are prepared: R R6 boiling point c2h5 2-Cl 97-99°C at 0.05 mm. pressureC2H5 2-CH3 86-88°C at 0.05 mm. pressureC2H5 4-CH3 100°C at 0.05 mm. pressureC2H5 2-Br 114-115°C at 0.05 mm, pressureC2H5 3-Cl 140°C at 0.6 mm. pressureC2H5 2-Cl-4-Br - ^2^5 4-OCH3 122°C at 0.15 nun. pressureC2H5 3,4,5-(Cl)3 135°C at 0.05 mm. pressurenC3H7 2,4-(Cl)2 1O2-125°C at 0.05 mm. pressurenC4R9 2,4-(Cli2 137-139°C at 0.05 mm. pressure - 86 QSI57 R R6 -SH11 2,4-(Cl)2 '6H13 2,4-(Cl)2:7H15 2,4-(Cl)2 '8H17 2,4-(Cl)2 [2°h 2,4-(Cl)2 boiling point 140-145°C at 0.03 mm. pressure 163-17O°C at 0.1 mm. pressure 16O-165°C at 0.05 mm. pressure 18O-19O°C at 0.05 mm. pressure 145-150°C at 0.05 mm. pressure Example XXXVII To a stirred and warm solution of 6.5 parts of 1,2butanediol, 13 parts of l-(4-chloro-2-methoxyphenyl)~ ethanone and 40 parts of butanol are added dropwise (slowly) 5.7 parts of bromine at about 40°C. After stirring for 30 minutes, there are added 2 parts of 4methylbenzenesulfonic acid and 225 parts of methylbenzene and the whole is stirred and refluxed overnight with water-separator. The reaction mixture is cooled, washed with a potassium carbonate solution, dried,filtered and evaporated. The residue is distilled, yielding 17 parts (63%) of A+B-2-(bromomethyl)-2-(4-chloro-2-methoxyphenyl)4-ethyl-1,3-dioxolane; bp. 135-14O°C at 0.3 mm. pressure.

Example XXXVIII Following the procedure of Example XXXVII and using an equivalent amount of 1-(2,4,5-trichlorophenyl)ethanone in place of the 1-(4-chloro-2-methoxyphenyl)ethanone, there is obtained: A+B-2-(bromomethyl)-4-ethyl-2-(2,4,5-trichlorophenyl)-1,3dioxolane; bp. 145°C at 0.2 mm. pressure.

Example XXXIX To a stirred solution of 53 parts of l-(2,4-dibromo· phenyl)ethanone in 105 parts of l,l'-oxybisethane, are added dropwise, during a 2 hours-period, 32 parts of bromine. Then there are added carefully 68 parts of 1Himidazole and 135 pares of Ν,Ν-dimethylformamide ana the whole is stirred for 2 hours at 50°C. Upon the addition of water, the product precipitates. It is filtered off, washed with water and dissolved in trichloromethane. The solution is dried, filtered and evaporated.. The residue is converted into the hydrochloride salt in 2-propanone and 2-propanol. Upon the addition of 2,2'-oxybispropane, the product is crystallized. It is filtered off, washed with 2-propanone and recrystallized from a mixture of ethanol and 2,2'-oxybispropane, yielding 28.3 parts of 1-(2,4-dibromophenyl)-2-(IH-imidazol-l-yl)ethanone hydrochloride; mp. 204.7°C.

Example XXXX To a stirred solution of 78.7 parts of 2-bromo-l(2-chloro-4-fluorophenyl)ethanone in 140 parts of 1,1'oxybisethane are added carefully 106.4 parts of IHimidazole. Upon completion, there are added 180 parts of Ν,Ν-dimethylformamice and the whole is stirred for 2 hours at 50°C. After the addition of water, the product is extracted twice with trichloromethane. The combined extracts are washed three times with water, dried, filtered and evaporated. The residue is converted into the hydrochloride salt in 4-methyl-2-pentanone, 2,2'oxybispropane and 2-propanol. The salt is filtered off and crystallized from a mixture of ethanol and 2,2'oxybispropane, yielding 1.5 parts of 1-(2-chloro-4~fluorophenyl)-2-(IH-imidazol-l-yl)ethanone hydrochloride; mp. 1S7.4°C.

Example XLI A. To a stirred mixture of 67.2 parts of A+E-2(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolane-443157 - 88 _ methanol and 100 parts of pyridine are added dropwise 27.2 parts of benzoyl chloride while cooling at a temperature below 10°C. Upon completion, stirring is continued for 2.50 hours at room temperature. The reaction mixture is poured onto water and the product is extracted with trichioromethane. The extract is washed successively with a dilute hydrochloric acid solution, to remove the last traces of pyridine, and with water, dried,filtered and evaporated. The oily residue is triturated in methanol. The solid product is filtered off (the filtrate is set aside) and crystallized twice from ethanol, yielding 28 parts of cis 2-(bromomethyl)-2(2,4-dichlorophenyl)-1,3-dioxolan-4-yImethyl benzoate; mp. 118.3°C. The filtrate (see above) is evaporated.

The oily residue is purified by column-chromatography over silica gel using 2,21-oxybispropane as eluent. The pure fractions are collected and the eluent is evaporated.

The oily residue is triturated in methanol. The solid product is purified by column-chromatography over silica gel using trichioromethane and hexane (30:70) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 17.5 parts of trans-2-(bromomethyl)2-(2,4-dichlorophenyl)-l,3-dioxolan-4-yImethyl benzoate; mp. 68.6°C.

B. A mixture of 12 parts of cis-2-(bromomethyl)2-(2,4-dichlorophenyl)-l,3-dioxolan-4-yImethyl benzoate, 7.5 parts of sodium hydroxide solution 60%, 100 parts of water and 200 parts of 1,4-dioxane is stirred and refluxed for 1 hour. The reaction mixture is cooled, poured onto water and the product is extracted with trichioromethane. The extract is washed with water, dried, filtered and evaporated. The oily residue is purified by columnchromatography over silica gel using a mixture of trichioromethane, hexane and methanol (50:49:1) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 4.5 parts of cis-2-(bromomethyl)-243157 (2,4-dichlorophenyl)-l,3-dioxoiane-4-rnethanol as a residue.

Following the procedure of Example XLI-B and using an equivalent amount of trans-2-(bromomethyl)-2-(2,4dichlorophenyl)-1,3-dioxolan-4-ylmethyl benzoate in place of the cis-2-(bromomethyl)-2-(2,4-dichlorophenyl)-1,3dioxolan-4-ylmethyl benzoate, there is obtained: trans-2-(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolane -4-methanol as a residue.

Example XLII A mixture of 4.5 parts of methanesulfonyl chloride, 10 parts of cis-2-(2,4-dichlorophenyl)-2-(1H-Imldazol-1ylmethyl)-1,3-dioxolane-4-methanol and 50 parts of pyridine is allowed to stand for 3 hours at room temperature. The reaction mixture is poured onto water. The precipitated product is filtered off and crystallized from benzene, yielding 10.3 parts (87%) of cis-2-(2,4dichlorophenyl)-2-(IH-imidazol-l-ylmethyl)-1,3dioxolan-4-ylmethyl methanesulfonate; mp. 111.7°C.

Example XLIII A mixture of 32 parts of 1,2,4-butanetriol, 60 parts of 2-bromo-l-(2,4-dichlorophenyl)ethanone, 2 parts of 4-methylbenzenesulfonic acid, 40 parts of butanol and 225 parts of methylbenzene is stirred and refluxed overnight with water-separator. The reaction mixture is cooled, washed with a potassium carbonate solution, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (99:1) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 34 parts (43.) of A+B-2-(bromomethyl)-2-(2,4dichlorophcnyl)-l,3-di.oxolane-4-ethgnol as a residue. 3157 - 90 _ To a stirred mixture of 20 parts of A+B-2-(bromomethyl) -2-(2,4-dichlorophenyl)-1,3-dioxolane-4-ethanol and 50 parts of pyridine are added dropwise 6.9 parts of methanesulfonyl chloride. Upon completion, stirring at room temperature is continued for 2 hours. The reaction mixture is poured onto water and the product is extracted twice with l,l'-oxybisethane. The combined extracts are washed successively twice with a dilute hydrochloric acid solution and once with water, dried, filtered and evaporated, yielding 25 parts (100%) of A+B{2-/2-(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4 -yl/ethyl} methanesulfonate as a residue.

To a stirred mixture of 25 parts of A+B-{2-/2-(bromo methyl)-2-(2,4-dichlorophenyl)-1,3-dioxalan-4-yl/ethyl·} methanesulfonate and 100 parts of dimethylsulfoxide are added 2.2 parts of sodium hydride dispersion 78% at room temperature. Stirring is continued for 3 hours at 50°C. The reaction mixture is poured onto water and the product is extracted twice with 2,21-oxybispropane.

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 eluent. The pure fractions are collected and the eluent is evaporated, yielding 15 parts (79%) of A+B-2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-ethenyl-l, 3-dioxolane as a residue Example XLIV A mixture of 1.1 parts of imidazole, 1 part of 2(bromomethyl)-2,4-bls(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 1,1'-oxybisethane. The extract is washed twice with water, dried, filtered and evaporated. The residue of l-/2,4-bis(4 chlorophenyl)-l,3-dioxolan-2-ylmethyl/imidazole is 431S7 converted into the nitrate salt. The crude salt is filtered off and crystallized from a mixture of 2propanol and 2,2'-oxybispropane, yielding l-/2,4-bis(4-chlorophenyl)-1,3-dioxolan-2-ylmethyl/imidazole nitrate; mp. 192.3°C.

Example XLV A mixture of 7 parts of imidazole, 7.5 parts of 2(bromomethyl)-2-(4-chlorophenyl)-4-phenyl-l,3-dioxolane, 2 parts of sodium iodide and 100 parts of N,N-dimethylformamide is stirred and refluxed for 48 hours. The reaction mixture is allowed to cool to room temperature and is poured into water. The product is extracted twice with benzene. The extract is washed twice with water and the solvent is removed in vacuo. The residue of 1-/2-(4-chlorophenyl)-4-phenyl-l,3-dioxolan-2ylmethyl/imidazole is converted into the nitrate salt in 4-methyl-2-pentanone and 2,2'-oxybispropane. The crude salt is filtered off and crystallized from 4-methyl-220 pentanone, yielding 1-/2-(4-chlorophenyl)-4-phenyl-l,3dioxolan-2-ylmethyl/imidazole nitrate; mp. 153.2°C.

Example XLVI Following the procedure of Example XLV and using equivalent amounts of the appropriate starting materials 25 the following imidazole acid addition salts are prepared: i- N ,7 - 92 6 43137 Acid Salt Melting Point of Salt Cl 2,4-(Cl)2 HN03 Br 4-Cl Br 2,4-(Cl)2 hno3 4-(Cl) 2 - 2(COOH) och3 4-Cl hno3 2,4-(Cl)2 hno3 4-(Cl) 2 4-Cl 11/2(COOH 4-Cl hno3 Cl 2-Cl hno3 Cl 2,4-(Cl)2 hno3 4-(Cl)2 2-Cl HNO3 Br 2-Cl hno3 4-(Cl)2 2,4-(Cl)2 hno3 Br - hno3 4-Br hno3 0H3 2,4-(Cl)2 hno3 Br 4-Br hno3 2H3 4-C1 hno3 21 4-Br hno3 2H3 4-Br hno3 21 2,4-(Cl)2 hno3 21 4-Br hno3 2H3 2-Cl hno3 21 4-CH3 hno3 Br 4-CH3 hno3 21 4-F hno3 Br 4-F HNO, 196.6°C 152.6°C 205.3°C 107.7°C 196.3°C 163.8°C 119.9°C 134,7°C 183.8°C 164.2°C 151°C 194.7°C 161.2°C 156.5°C 131.1°C 193.6°C 144.3°C 200.8°C 145.2°C 210.5°C 165.4°C 184.1°C 207.5°C 144.3°C 140.2°C 163.2°C 179.3°C Example XLVII A mixture of 13.6 parts of imidazole, 18.5 parts of 2-(bromomethyl)-2-(o-chlorophenyl)-4-(£~chlorophenyl) -1,3-dioxolane, 4 parts of sodium iodide and 150 parts of dimethylformamide is stirred and refluxed for 72 hours.

Water is added and the product is extracted twice with diisopropylether. 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 eluent. The pure fractions are collected and the eluent is evaporated. The residue of 1-/2-(o-chlorophenyl)-4-(^-ehlorophenyl)-1,3-dioxolan2-ylmethyl/imidazole is converted into the nitrate salt in 2-propanol and diisopropylether. The salt is filtered off and crystallized from a mixture of ethanol and diisopropylether, yielding 1-/2-(o-chlorophenyl)-4(p-chlorophenyl)-1,3-dioxolan-2-ylmethylTimidazole nitrate; mp. 183.1°C.

Example XLVIII Following the procedure of Example XLVII and using an equivalent amount of 2-(bromomethyl)-4-(4-bromophenyl) -2- (2 , 4-dichlorophenyl) -1, 3-dioxolane in place of the 2-(bromomethyl)-2-(2-ehlorophenyl)-4-(4-chlorophenyl)1,3-dioxolane used therein, there is prepared: 1-/4-(4-bromophenyl)-2-(2,4-dichlorophenyl)-1,3-dioxolane -2-ylmethyl/imidazole nitrate; mp. 141.9°C.

Example IL To a stirred solution of 2.3 parts of sodium in 80 parts of methanol are added 6.8 parts of imidazole, followed by the addition of 100 parts of dimethylformamide and the methanol is removed at atmospheric pressure till an internal temperature of 130°C is reached. Then there are added 7 parts of A-2-(bromomethyl)-2-(^-ehlorophenyl)4-(4-chloro-o-tolyloxymethyl)-1,3-dioxolane and the mixture is stirred and refluxed for 3 hours. The reaction mixture is poured onto water and the product is extracted with benzene. The extract is dried and evaporated in vacuo. The residue of A-1-/2-(p-chloro157 phenyl)-4-(4-chloro-o-tolyloxymethyl)-l,3-dioxolan-2yImethyl/imidazole is converted into the nitrate salt in 2-propanol. Upon the addition of 2,2'-oxybispropane ether, the salt is precipitated. It is filtered Off and crystallized from a mixture of methanol and 2,2’oxybispropane yielding ois 1-/2-(p-chlorophenyl)-4(4-chloro-o-tolyloxymethyl)-1,3-dioxolan-2-ylmethy1/imidazole nitrate; mp. 164.3°C.

Example L ) Following the procedure of Example IL and using equivalent amounts of the appropriate starting materials, the following imidazoles and imidazole acid addition salts are prepared: R.

O-CH, ‘6 IsomerR6 r7 Acid Salt Melting Point · Salt trans 4-Cl 4-Cl,2-CH 3 hno3 190 - 190.7° cis 4-Cl 4-CH3 HN03 140.2° trans 4-Cl 4-CH3' HNO3 160° trans 4-Cl 4-Cl hno3 171.8 - 176.9° cis 4-Cl 4-Cl hno3 165.8 - 169.6° B 4-Cl 2,4-Cl HN03 160 - 165.3° cis 4-Cl 4-P hno3 172.3 - 174.5° trans 4-Cl 4-P HN03 175.9° A 4-Cl 2-CH3. hno3 134.6 - 145.4° B 4-Cl 2-CH3 HN03 156.6 - 161.6° B 4-Cl 2-Cl HNO3 170.5° B 4-Cl 4-OCH3 h»03 133.2° Isomc.rR6 Ry base Melting Point A 4-Cl 2,4-(Cl)2 base 175.4-179.5°C A 4-Cl 2-Cl base 140.8-143.6°C A 4-Cl 4-0CH3 base 111.1°C Example LI To a stirred solution of 4.6 parts of sodium in 160 parts of methanol are 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 till an internal temperature of 130°C is reached. Then there are added 25.9 parts of A + B-2-(bromomethyl)-2-(g-chlorophenyl)-4-(2,6-dichloro10 phenoxymethyl)-1,3-dioxolane and the whole is stirred at reflux temperature for 2 hours. The reaction mixture is allowed to cool to room temperature and poured onto water. The product is extracted twice with benzene. The combined extracts are washed twice with water, dried and evaporated in vacuo. The residue, containing the A" - 96 Example LI1 Following the procedure of Example LI and using equivalent amounts of the appropriate starting materials, the following imidazoles and imidazole acid addition salts are prepared: A-1-/2-(2,4-dichlorophenyl)-4-(o-tolyloxymethyl)-1,3dioxolan-2-ylmethyl/imidazole nitrate; mp. 156.2°C; B-1-/2-(2,4-dichlorophenyl)-4-(o-tolyloxymethyl)-1,3dioxolan-2-ylmethyl7imidazole sesquioxalate; mp. 138.5°C; A-1-/2-(2,4-dichlorophenyl)-4-(2,6-dimethylphenoxymethyl)-l,3-dioxolan-2-ylmethyl/-lH-im:>-^azole nitrate; mp. 155.6°C; A + B-1-/2-(2,4-dichlorophenyl)-4-(2,6-dimethylphenoxymethyl)-l,3-dioxolan-2-ylmethyl7-lH-imidazole nitrate; m.p. 134.5°C.

Example LIII A mixture of 6.8 parts of imidazole, 7.8 parts of A-2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-(phenoxymethyl)-1,3-dioxolane, 4 parts of sodium iodide and 150 parts of dimethylformamide is stirred and refluxed for 431S7 - 97 3 days. The reaction mixture is allowed to cool to room temperature, poured into water and the product is extracted twice with 2,2'-oxybispropane. The combined extracts containing A-1-/2-(2,4-dichlorophenyl)-45 (phenoxymethyl)-l,3-dioxolan-2-ylmethyl7imidazole are washed twice with water and acidified with an excess of a concentrated nitric acid solution. The salt is filtered off and crystallized from a mixture of ethanol and 2,2'-oxybispropane yielding 5.6 parts of A-l-/2-(2,410 dichlorophenyl)-4-(phenoxymethyl)-1,3-dioxolan-2-ylmethyl/" imidazole nitrate; mp. 180.5°C.

Example LIV Following the procedure of Example LIII and using equivalent amounts of the appropriate starting materials, the following imidazoles and imidazole acid addition salts are prepared: R R Melting Point Acid 1 or Base 2,4-(Cl)2 3,4-(Cl)2-CgH3 152.1°C HNO3 2,4-(Cl)2 3,C1-C6H4 120.9°C hno3 2,4-(Cl)2 2-CH3,4-Cl~C6H3 121.9°C HNOj 2,4-(Cl)2 2,4-(Br)2-CgH3 164.9°C hno3 2,4-(Cl)2 2-F-CgH4 135.9°C hno3 - 4-Br-C6H4 167.6°C hno3 2,4-(Cl)2 4-Br-CgH4 131.1°C hno3 2,4-(Cl)2 4-F-C6H4 151-152°C HNO3 2,4-(Cl)2 4-CH3-cgH4 141.8°C -hno3 2,4-(Cl)2 4-CH3-CgH4 145.1°C (COOH). 2,4-(Cl)2 4-OCH3-CgH4 184.7°C (COOH) 2,4-(Cl)2 4-Cl-CgH4 152.7°C hno3 2,4-(Cl)2 2,4-(Cl)2-CgH3 146.5° hno3 2,4-(Cl)2 4-Br-C6H4 158.9°C hno3 2,4-(Cl)2 3,5-(CH3)2,4-Cl-CgH2 185.7°C hho3 2,4-(Cl)2 4-CN-CgH4 2O8°C hno3 2,4-(Cl)2 2-OCH3-CgH4 110.6°C 2(COOH), 2,4-(Cl)2 6-Br-2-naphthalenyl 195.5°C hno3 2,4-(Cl)2 2-naphtha leiiyl 156.3°C hno3 2,4-(Cl)2 4-Cl-2-naphthalenyl 136.7°C hno3 2,4-(Cl)2 4-Br-CsH4 121.8°C base Example LV A mixture of 13.6 parts of imidazole, 22.2 parts of - 95 _ A + B-2-(bromethyl)-4-(o-chlorophenoxymethyl)-2-(2,4-dichlorophenyi)-1,3-dioxolane, 4 parts of potassium iodide, and 150 parts of dimethylformamide is 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 2,2'-oxybispropane. The combined extracts are washed twice with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using chloroform as eluent, yielding two fractions.

The first fraction is evaporated and the residue of A-1-/4-fo-chlorophenoxymethyl)-2-(2,4-dichlorophenyl)-1, 3-dioxolan-2-ylmethyl/imidazole is dissolved in a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane. The solution is acidified with an excess of a concentrated nitric acid solution. The nitrate salt is filtered off and crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane, yielding A-1-/4-(o-chlorophenoxymethyl) -2-(2,4-dichlorophenyl)-1,3-dioxolan-2-ylmethyl/20 imidazole nitrate; mp. 136.2°C.

T ie second fraction is evaporated and the residue of B-1-/3-(o-chlorophenoxymethyl)-2-(2,4-dichlorophenyl)-1, 3-dioxo!.an-2-y Imethyl/imidazole is dissolved in a mixture of 4-mcthyl-2-pentanone and 2,2'-oxybispropane. The soluti' n is acidified with an excess of oxalic acid. The oxalati salt is filtered off and crystallized from 4methyl- i-pentanone, yielding 4 parts of B-l-/4-(ochloropuenoxymethyl)-2-(2,4-dichlorophenyl)-1,3dioxolan-2-yImethyl/imidazole diethanedioate; mp. 103.5°C Example LVI Following the procedure of Example LV and using equivalent amounts of the appropriate starting materials, the following imidazoles and imidazole acid addition 1S7 salts are prepared. Where only one isomer is listed, no second fraction was obtained from chromatography. mer Rg 2,4-(Cl)2 2,4-(Cl)2 ns 2,4-(Cl)2 2,4-(Cl)2 2,4-(Cl)2 2,4-(Cl)2 2,4-(Cl)2 2,4-(Cl)2 2,4-(Cl)2 2,4-(Cl)2 2,4-(Cl)2 2,4-(Cl)2 2,4-(Cl)2 B 2-Cl 2-Cl 2-Br 2-Br 2,4-(Cl)2 2.6- (Cl)2 2-Br 2-Br 2,5-(CH3)2 2.5- (CH3)2 2.4.6- (Cl)3 2,4,6-(Cl)3 2-Cl,4-C(CH3)3 2-Cl,4-C(CH3)3 2.4.5- (Cl)3 2.4.5- (Cl)3 2.5- (Br)2,4-CH3 2OC2H5 4-Br 4-Br 4-Br 4-Br 2-Cl,6-CH3 Acid Melting Salt Point of Salt HNO3 159° HNO3 142.2° 2(COOH)2 151.3° HN03 180.9° 1.5(COOH)2 142.7° HNO3 181.6° 2(COOH)2 143.9° HNO3 141.2° HNO3 141.1° HNO3 196.1° 1.5(COOH)2 173.6° HNO3 175.4° HN03 117.7° HNO3 145.3° HNO3 152.7° HNO3 149.9° HNO3 169.3° HN03 154.2° - 101 Example LVII A mixture of 9.7 parts of 1H-imidazole, 12.5 parts of A + B 2-(bromomethyl)-4- (4-bromophenoxymethyl) -2-(4methylphenyl)-1,3-dioxolane, '3 parts of potassium iodide and 135 parts of Ν,Ν-dimethylformamide is stirred and refluxed for 72 hours. The reaction mixture is poured into water and the product is extracted twice with 1,1'oxybisethane. The extract containing A-1-/4-(4-bromophenoxymethyl) -2-(4-methylphenyl)-1,3-dioxolan-2-ylmethyl/ -ΙΗ-imidazole is washed twice with water, and an excess of a concentrated nitric acid solution and 2,21-oxybispropane are added. The formed salt is filtered off and crystallized from a mixture of ethanol and 2,2'-oxybispropane, yielding 5.6 parts of A 1-/4-(4-bromophenoxymethyl)-2(4-methylphenyl)-l,3-dioxolan-2-ylmethyl/~lN-imidazole nitrate; mp. 175.5°C.

Example LVIII Following the procedure of Example LVII but substituting for the A+B-2-(brctnomathy 1 )-4-(4-bromophenoxymethyl)-2-(4-methylphenyl)-1,3-dioxolane used therein equivalent amounts of A+B-2-(bromomethyl)-4-(4-bromophenoxymethyl)-2-(4-chlorophenyl)-1,3-dioxolane and A+B2-(branamethyl)-4-(4-bromophenoxymethyl)-2-(4-bromophenyl)1,3-dioxolane there are prepared A-1-/4-(4-bromophenoxymethyl)-2-(4-chlorophenyl)-l,3-dioxolan-2-ylmethy!7"lHimidazole and its nitrate salt (mp. 158°) and A-l-/4-(4bromophenoxymethyl)-2-(4-bromophenyl)-l,3-dioxolan-2ylmethyl7-lii-imidazolG and its nitrate salt (mp. 170.8°).

Example LIX A mixture of 7.9 parts of IH-imidazole, 11.5 parts of A + B 2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-/l,l'bipheny!7-4-ylmethyl)-1,3-dioxolane, 4 parts of potassium 157 - 102 iodide and 135 parts of Ν,Ν-dimethylformamide is stirred and refluxed for 3 days. The reaction mixture is poured onto water and the product is extracted twice with 1,1'oxybisethane. 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 into the nitrate salt in 4-methyl-2-pentanone and 2,2'-oxybispropane. The salt is filtered off and crystallized from a mixture or ethanol and 2,2'-oxybispropane, yielding A + Β 1 - /2-(2,4 dichlorophenyl)-4- /~l,l'-biphenylJ7-4-ylmethyl)-1,3dioxolan-2-ylmethyl7-lH-imidazole nitrate; mp. 187.9°C.

The second fraction is collected and the eluent is evaporated. The residue Is crystallized from 4-methyl-2pentanone, yielding trans-l-/2-(2,2-dichlorophenyl)-4(/1,11-bipheny17-4-ylmethyl)-1,3-dioxolan-2-ylmethyl7"lHimidazole; mp. 155.7°C.

Example LX A mixture of 6.8 parts of imidazole, 8.5 parts of B-2-(bromomethyl)-4-(g-chlorophenoxymethyl)-2-(2,4dichlorophenyl)-l,3-dioxolane, 2 parts of sodium iodide and 100 parts of dimethylformamide is 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 is removed in vacuo. The residue is purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated. The residue of B-l-/4-(gchlorophenoxymethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan2-ylmethyl/imidazole is converted into the oxalate salt - 103 in 4-mcthyl-2-pentanone: upon the addition of 2,2'oxybispropane the salt is precipitated. It is filtered off and crystallized from 4-methyl-2-pentanone, yielding 3.1 parts of trans-l-/4-£-chlorophenoxymethyl)-2-(2,4dichlorophenyl) -l,3-dioxolan-2-ylmethy17imidazole sesquiethanedioate mp. 101°C.

Example LXI Following the procedure of Example LX there is prepared: B-1-/4-(2,4-dichlorophenoxymethyl)-2-(2,4-dichlorophenyl)l,3-dioxolan-2-ylmethyl_7imidazole sesquiethanedioate; mp. 121.2°C. by the reaction of B-2-(bromomethyl)-4-(2,4-dichlorophenoxymethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan with imidazole.

Example LXII A mixture of 8.6 parts of lH-imidazole, 11.3 parts of A-2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-(3,5dimethylphenoxymethyl)-1,3-dioxolane, 4 parts of potassium iodide and 135 parts of Ν,Ν-dimethylacetamide is stirred and refluxed for 3 days. The reaction mixture is poured onto water and the product is extracted twice with 2,2'oxybispropane. The combined extracts are Washed twice with water and an excess of a concentrated nitric acid solution is added. The formed nitrate salt is filtered off and crystallized from a mixture of 2-propanol and 2,2'-oxybispropane. The product is filtered off again and recrystallized from 4-methy1-2-pentanone, yielding A-1-/2-(2,4-dichlorophenyl)-4-(3,5-dimethylphenoxymethyl)l,3-dioxolan-2-ylmethyl7-lH-imidazole nitrate hydrate; mp. 122.6°C. 3157 - 104 Example LXIII Following the procedure of Example LXIX and using equivalent amounts of the appropriate starting materials, tho following imidazoles and imidazole acid addition salts are prepared: omer R6 R7 Acid Salt Melting Point of Salt A 2-CH3-4-Cl 4-Br hno3 159.3°C cis 2-CH3"4-Br 4-Br ™°3 164.3°C cis 3-Br 4-Br HN03 158.7°C cis 3-Br-4-CH3 4-Br hno3 201.1°C cis 4-CN 4-Br hno3 190.1°C 2,4-(Cl)2 4-(c6h5-ch2) ΗΝΟ,.Η,Ο 110.3°C cis 3,5-(Cl)2 4-Br hno3 167.1°C is 3-NO2 4-Br hno3 148.8°C cis 2,4-(Cl)2 2-N°2 2(COOH)2 95.2°C trans 2,4-(Cl)2 2-NO2 (COOH)2 157.2°C trans 2,4-(Cl)2 4-(C6h5-CH2) (COOH)2 137°C 3 2,4-(Cl)2 2-(CsH5) hno3 109.3°C 3 2,4-(Cl)2 4-/ch3-ch(ch3 )7hno3 115.2°C 2,4-(Cl)2 4-/CH.,-C(CH ,,),7 hno3 169.5°C 2,4-(Cl)2 3,5-(Cl) 2 ΗΝΟ,.Η,Ο 136.7°C 2,4-(Cl)2 3-CH3,4-Cl hno3 142.8°C 2,3,4-(Cl)3 4-Br hno3 174.4°C 2,4-(Cl)2 2-Br,4-CH3 hno3 137.1°C - 105 Example LXIV A mixture of 42 parts of lH-imidazole, 63 parts of A+B-4-(/I,1'-biphenyl7-4-yloxymethyl)-2-(bromomethyl)-2(2,4-dichlorophenyl)-1,3-dioxolane, 20 parts of potassium iodide and 675 parts of N,N-dimethylformamide is stirred and refluxed for 3 days. The reaction mixture is poured onto water and the product is extracted with 2,2'-oxybispropane. The extract is dried, filtered and evaporated. The residue is converted into the nitrate salt in 4methyl-2-pentanone and 2,2'-oxybispropane. The product is separated as an oil. The supernatant phase is decanted and the residual oil solidifies on triturating in 4methyl-2-pentanone. The nitrate salt is filtered off and crystallized from ethanol, yielding 5 parts of cis-1-/4(/1,1'-biphenyl/-4-yloxymethyl)-2-(2,4-dichlorophenyl)-1, 3-dioxolan-2-ylmethyl/~lH-imidazole nitrate; mp. 186.5°C.

Example LXV E’ollowing the procedure of Example LXIV and using equivalent amounts of the appropriate starting materials, the following compounds are prepared: cis-l-/2-(2,4-dichlorophenyl)-4-(2-methoxyphenoxymethyl)-1, 3-dioxolan-2-ylmethyl7~lH-imidazole ethanedioate hemihydrate; mp. 123.6°C; and cis-l-/2-(2,4-dichlorophenyl)-4-(4-fluorophenoxymethyl)l,3-dioxolan-2-ylmethyl7-lH-imidazole; mp. 106.7°C.

Example LXVI A mixture of 6.4 parts of IH-imidazole, 10 parts of A+B-2-(bromomethyl)-4-(3-chloro-/l,l'-biphenyl7~4-yloxymethyl)-2-(2,4-dichlorophenyl)-l,3-dioxolane and 135 parts of Ν,Ν-dimathylacetamide is stirred and refluxed for 5 days. The reaction mixture is allowed to cool to room temperature and poured onto water. The product is 431S7 - 106 extracted twice with 1,1'-oxybisethane. The combined extracts are washed with water, dried, filtered and evaporated. The residue is crystallized from 4-methyl-2pentanone, yielding 2.2 parts (22%) of trans-l-/4-(3chloro-/!,1'-biphenyl7~4-yloxymethyl)-2-(2,4-dichlorophenyl)-l,3-dioxolan-2-ylmethy!7-lH-imidazole; mp. 140.8°C.

Example LXVII A mixture of 10.2 parts of ΙΗ-imidazole and 26.8 parts of sodium methoxide solution 30% is stirred and refluxed for 15 minutes. Then there are added 90 parts of Ν,Ν-dimethylformamide. The methanol is distilled off till internal temperature of about 130°C. After the addition of another 90 parts of N,N-dimethylformamide, 50 parts of A+B-4-(/1,l'-biphenyl7-4-yloxymethyl)-2-(bromomethyl) -2- (2, 4-dichlorophenyl) 1, 3-dioxolane are added portionwise at about 100°C. Upon completion, 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 a mixture of trichloromethane and 1% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. . The residue is crystallized from 2-propanol, yielding 9.3 parts of cis-l-/4-(/I,11-biphenyl7-4-yloxvinethyl)-2-(2,4dichlorophenyl)-1,3-dioxolan-2-ylmethyl7~lH-imidazole; mp. 150.7°C.

Example LXVIII A mixture of 17 parts of IH-imidazole, 27.4 parts of A+B-4-(/1,11-biphenyl7"4-yloxymethyl)-2-(bromomethyl)2-(3,4,5-trichlorophenyl)-1,3-dioxolane and 135 parts of Ν,Ν-dimethylacetamide is stirred and refluxed for 5 days. The reaction mixture is cooled and poured onto water. The - 107 43157 product is extracted twice with 1,1’-oxybisethane. The combined extracts are washed with water, dried, filtered and evaporated. The residue is purified by columnchromatography over silica gel using trichloromethane as eluent. The first fraction is collected and the eluent is evaporated. The residue is converted into the nitrate salt in 4-methyl-2-pentanone and 2,2'-oxybispropane. The salt is filtered off and crystallized from a mixture of acetonitrile and 2,2'-oxybispropane, yielding 3 parts of cis-l-/4-(/1,1'-biphenyl7"4-yloxymethyl)-2-(3,4,5-trichlorophenyl) -l,3-dioxolan-2-ylmethyl/-lH-imidazole nitrate; mp. 212.2°C. The second fraction is collected and the eluent is evaporated. The residue is converted into the nitrate salt in 4-methyl-2-pentanone and 2,2'-oxybispropane. The salt is filtered off and crystallized from a mixture of acetonitrile and 2,2'-oxybispropane, yielding 1.9 parts of trans-l-/4-(/1,11-biphenyl7"4-yloxymethyl)-2-(3,4,5trichlorophenyl)-1,3-dioxolan-2-ylmethyl7-lH-imidazole nitrate; mp. 158°C Example LXIX Following the procedure of Example LXVIII and using equivalent amounts of the appropriate starting materials, the following imidazoles and imidazole acid addition salts are prepared: cis-l-/4-(/1,1'-bipheny!7-4-yloxymethyl)-2-(4-bromo-2chlorophenyl)-l,3-dioxolan-2-ylmethyl7~lH-imidazole; mp, 161.8°C; trans-1-/4-- (/1,1'-biphenyl/-4-yloxymethyl)-2-(4-bromo-2chlorophenyl)-l,3~dioxolan-2-ylmethyl7-lH-imidazole; mp. 164.6°C; cis-l-/4-(/1,1'-biphenyl7-4-yloxymethyl)-2-(2-naphthalenyl)-1,3-dioxolan-2-ylmethyl7-lH-imidazole; mp. 152.6°C; - 108 Ϊ137 trans-l-/4- (/1,1' -biphenyl/-4-yloxymethyl) -2- (2-naphthal· enyl)-l,3-dioxolan-2-yImethy17-lH-imidazole nitrate; mp. 230.6°C; cis-l-/4-(/1,1'-biphenyl7-4-yloxymethyl)-2-(2,4,5trichlorophenyl)-1,3-dioxolan-2-yImethy17-lH-imidazole nitrate; mp. 199.2°C; and trans-l-/4-(/1,1'-biphenyl7"4-yloxymethyl)-2-(2,4,5trichlorophenyl)-1,3-dioxolan-2-yImethy17-1H-imidazole; mp. 139.2°C.

Example LXX A mixture of 11.5 parts of ΙΗ-imidazole, 17.5 parts of A+B-2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-(3,4,5trichlorophenoxymethyl)-1,3-dioxolane, 3 parts of potassium iodide and 180 parts of Ν,Ν-dimethylacetamide is stirred and refluxed over a week-end. The reaction mixture is poured onto water and the product is extracted four times with l,l'-oxybisethane. The combined extracts are washed a few times with water, dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using trichloromethane as eluent. The first fraction (A-isomer) is collected and the eluent is evaporated. The oily residue is converted into the nitrate salt in 4-methyl2-pentanone. The salt is filtered off and crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane, yielding, after drying, 7.5 parts (40%) of cis-l· /2-(2,4-dichlorophenyl)-4-(3,4,5-trichlorophenoxymethyl)-l,3-dioxolan-2-yImethy1/-1H-imidazole nitrate, hydrate; mp. 149.9°C.

The second fraction (B-isomer) is collected and the eluent is evaporated. The oily residue is converted into the nitrate salt in 4-methyl-2-pentanone. The salt is filtered off and crystallized from a mixture of 4-methyl2-pentanone and 2,2'-oxybispropane, yielding, after - 109 drying, 6.2 parts (27%) of trans-l-/2-(2,4-dichlorophenyl) -4-(3,4,5-trichlorophenoxymethyl)-1,3-dioxolan-2ylmethyl/-lH-imidazole nitrate; mp. 169.3°C.

Example LXXI Following the procedure of Example LXX and using equivalent amounts of the appropriate starting materials, the following imidazoles and imidazole acid addition salts are prepared. When only one isomer is listed, no second fraction was obtained from chromatography. cis-l-/4-(2-chloro-5-methylpnenoxymethyl)-2-(2,4-dichlorophenyl)-l,3-dioxolan-2-ylmethyl7-lH-imidazole; mp. 131.7°C; trans-l-/4-(2-chloro-5-methylphenoxymethyl)-2-(2,4dichlorophenyl)-l,3-dioxolan-2-ylmethyl/-lH-imidazole sesquiethanedioate; mp. 148.7°C; A—1-(4-/71,6-dibromo-2-naphthalenyloxy)methy1/-2-(2,4dlchlorophenyl)-1,3-dioxolan-2-ylmethyl}-lH-imidazole nitrate; mp. 179.4°C; A—1-/4-(2,3-dichlorophenoxymethyl)-2-(2,4-dichlorophenyl)1.3- dioxolan-2-ylmethyl7-lH-imidazole diethanedioate; mp. 151.1°C; and B-1-/4-(2,3-dichlorophenoxymethyl)-2-(2,4-dichlorophenyl)1.3- dioxolan-2-ylmethyl/-lH-imidazole sesquiethanedioate; mp. 156.3°C.

Example LXXII Following the procedure of Example LIII and using equivalent amounts of the appropriate starting materials, the following compounds are prepared: A+B-1-/4-(4-bromophenyIthiomethyl)-2-(2,4-dichlorophenyl)413157 - 110 l,3-dioxolan-2-ylmethyl7-lH-imidazole nitrate; mp. 17O°C; and A+B-1-/2-(2,4-dichlorophenyl)-4-(phenylthiomethyl)-1,3dioxolane-2-ylmethyl7-lH-imidazcle nitrate; mp. 122.3°C.

Example LXXIII A mixture of 4.5 parts of lH-imidazole, 6.5 parts of A-2-(bromomethyl)-4-(4-bromophenoxymethyl)-2-(2,3dichlorophenyl) -1,3-dioxolane and 125 parts of Ν,Νdimethylacetamide is stirred and refluxed for 2 days.

The reaction mixture is allowed to cool to room temperature, poured onto water and the product is extracted twice with 1,1'-oxybisethane. The combined extracts are washed twice with water ahd an excess of a concentrated nitric acid solution is added. The formed nitrate salt is filtered off and crystallized from 4-methyl-2-pentanone, yielding 5 parts (68¾) of cis-l-/4-(4-bromophenoxymethyl)2-(2,3-dichlorophenyl)-1,3-dioxolan-2-yImethyl7-1Himidazole nitrate; mp. 138.9°C.

Example LXXIV Following the procedure of Example LXXIII and using equivalent amounts of the appropriate starting materials, the following imidazole acid addition salts are prepared: cis-l~/4-(3-chloro-/l,l'-biphenyl7-4-yloxymethyl)-2-(2,4dichlorophenyl)-1,3-dioxolan-2-ylmethyl7-lH-imidazole nitrate; mp. 171.1°C; cis-l-/3-(/l,i‘-biphenyl7-4-yloxymethyl)-2-(2-chloro-4methoxyphenyl)-l,3-dioxolan-2-ylmethyl7~lH-imidazole nitrate; mp. 172.9°C; A+B-1-/7-(2,4-dichlorophenyl)-4-(phenylmethyl)-1,3dioxolan-2-ylmethyl7-lH-imidazole diethanedioate; mp. 117.1°C; - Ij I A+B-i-{2-(2,4-dichlorophenyl)-4-/74-fluorophenyl)thiomethyl7~l,3-dioxolan-2-ylmethyl}-lH-imidazole diethanedioate; mp. 129.8°C; A+B-1-/4-(4-chlorophenylmethyl)-2-(2,4-dichlorophenyl)-1, 3-dioxolan-2-ylmethyl7-lH-imidazole sesquiethanedioate; mp. 141.6°C.

A+B-1-/2-(2,4-dichlorophenyl-4-(4-methoxyphenylmethyl)-1, 3-dioxolan-2-ylmethyl7-lH-imidazole diethanedioate; mp. 94.2°C; cis-2-/2-(2,4-dichlorophenyl)-2-(lH-imidazol-l-ylmethyl)1.3- dioxolan-4-ylmethoxy7benzonitrile nitrate; mp. 162.1° C; and cis-butyl 4-/2-(2,4-dichlorophenyl)-2-(IH-imidazol-lylmethyl)-1,3-dioxolan-4-ylmethoxy7benzoate nitrate; mp. 9O.5°C.

Example LXXV A mixture of 14.4 parts of IH-imidazole, 18.5 parts of A+ B 2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-/2-(4methoxyphenyl)ethy1/-1,3-dioxolane, 5 parts of potassium· · iodide and 135 parts of Ν,Ν-dimethylacetamide is stirred and refluxed for 2 days. The reaction mixture is allowed to cool to room temperature and poured onto water. The product is extracted twice with 2,2'oxybispropane. The combined extracts are washed with water, dried, filtered and evaporated. The residue is converted into the ethanedioate salt in 4-methyl-2-pentanone and 2,2'oxybispropane. The salt is filtered off and crystallized from a mixture of 2,2'-oxybispropane and ethanol, yielding A+B l-{2-(2,4-dichlorophenyl)-4-/2-(4-methoxyphenyl)ethyi7 1.3- dioxolan-2-ylmethyl}-IH-imidazole sesquiethanedioate; mp. 130./°C. - 112 Example LXXVI Following the procedure of Example LXXV and using equivalent amounts of the appropriate starting materials, the following imidazoles and imidazole acid addition salts are prepared: 1-(4-/2-(4-chlorophenyl)ethyl7~2-(2,4-dichlorophenyl)-1, 3-dioxolan-2-ylmethyl}-lH-imidazole diethanedioate; mp. 131.9°C. ; 1- /2-(2,4-dichlorophenyl)-4-(2-phenylethyl)-1,3-dioxolan2- yl-methyl7-lH-imidazole sesquiethanedioate; mp. 117.8°C and A + B l-{2-(2,4-dichlorophenyl)-4-/2-(4-methylphenyl)ethyl/ 1.3- dioxolan-2-ylmethyl}-lH-imidazole sesquiethanedioate hydrate? mp. 123.8°C. 1-(4-/2-(2-chlorophenyi)ethy1/-2-(2,4-dichlorophenyl)-1,3dioxolan-2-ylmethyl}-lH-imidazole nitrate; mp. 98.8°C; 1-(2-(2,4-dichlorophenyl)-4-/2-(2,4-dichlorophenyl)ethyl7~ 1.3- dioxolan-2-ylmethyl}-lH-imidazole nitrate; mp. 158.1°C? Example LXXVII To a stirred sodium methoxide solution, prepared starting from 3.8 parts of sodium in 40 parts of methanol are added 11 parts of ΙΗ-imidazole and 225 parts of N,Ndimethylformamide. The methanol is distilled off until the internal temperature is 150°C. Then there are added 19 parts of A+B-2-(bromomethyl)-2-(2,4-dichlorophenyl)4-ethyl-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 onto water. The product is extracted three times with 1,1’-oxybisethane. The combined extracts are washed with water, dried, - 113 filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 1% of methanol as eluent. The first fraction is collected and the eluent is evaporated. The residue is converted into the nitrate salt in 2,2'oxybispropane. The salt is filtered off and crystallized from a mixture of 2-propanol and 2,2'-oxybispropane, yielding 12 parts (56%) of A+B-l-/2-(2,4-dichlorophenyl)4-ethy1-1,3-dioxolan-2-yImethyl7"lH-imidazole nitrate; mp. 149.1°C.

Example LXXVIII To a stirred sodium methoxide solution, prepared starting from 2.8 parts of sodium in 40 parts of methanol, are added 8 parts of ΙΗ-imidazole and 225 parts of N,Ndimethylformamide. The methanol is distilled off until the temperature is 150°C. Then there are added 30 parts of A+B-2-(-4-bromo-2-chlorophenyl)-2-(bromoethyl)-4ethyl-1,3-dioxolane and stirring is continued for 1 hour at reflux temperature. The reaction mixture is cooled and poured onto water. The product is extracted twice with 2,2'-oxybispropane. The combined extracts are washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 2% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted into the nitrate in 2,21-oxybispropane. The salt is filtered off and crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane, yielding 8.5 parts (26%) of A+B-1-/2(4-bromo-2-chlorophenyl)-4-ethyl-l,3-dioxolan-2-yImethy17lH-imidazole nitrate; mp. 162.2°C.

Example LXXIX Following the procedure of Example LXXVIII and using equivalent amounts of the appropriate starting materials, 157 - 114 the following imidazole acid addition salts are prepared: R A+B Ar R Acid Salt Melting Point ’-ci-c,h4C2H5 ^3 147.6°C >-ch3-c6h4C2S5 HNO3 117.5°C 1-CH3-C6H4C2H5 hno3 172.7°C !,3,4-(Cl)3-C6H2C2H5 HMO3 176.4°C !-Br-C6H4C2a5 HNOs 135.3°C !,3-(C1)2-c6H3 Ο,Ηξ hn°3 140.3°C i-ci-c6h4C2H5 hno3 151.6°C -och3-c6h4C2H5 hno3 157.1°C -CH3-4-Cl-CgH3C2H5 HNO3 126.8°C -Cl-4-OCH3-CgH3 c2h5 hno3 117.7°C ,4,5-(Cl)3-CgH2C2H5 hno3 195.8°C -naphthylC2H5 ™°3 195.1°C ^-OCIi3-4-Cl-CgH3C2l5 HNO3 131.8°C ,4,5-(Cl)3-CgH2 C,Hc; hno3 180.1°C ,4-(Cl)2-CgH3nC3H7 hno3 119.2°C ,4-(Cl)2-CgH3 *c4h9 hno3 113.1°C ,4-(cl)2-C6H3nC5Hll hno3 128.3°C ,4-(Cl)2-C6H3nCSH13 hno3 99.4°C ,4-(Cl)2-CgH3nC7a!5 2(COOH) 2 131°C ,4-(Cl)2-CgH3nC8H17 2(COOH) 2 132.8°C - 115 Example LXXX A mixture of 32 parts of 1-(2,4-dichlorophenyl)-2(IH-imidazol-l-yl)ethanone, 55 parts of 1,2,3-propanetriol, 35 parts of 4-methylbenzenesulfonic acid, 96 parts of butanol and 360 parts of dimethylbenzsne is stirred and refluxed for 5 days with water-separator. The reaction mixture is cooled, washed with a potassium carbonate solution and with water, dried, filtered and evaporated.

The residue is dissolved in a diluted ethanedioic acid solution. The resulting solution is washed twice with 1,1' -oxybisethane. 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% of methanol as eluent. The first fraction is collected and the eluent is evaporated. The residue is converted into the nitrate salt in 2,2’-oxybispropane. The salt is filtered off and crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane, yielding 5.5 parts (9.8%) of A+B-1-/4-(butoxymethyl)-2-(2,4-dichlorophenyl) -l,3-dioxolan-2-ylmethyl7-lH-imidazole nitrate; mp. 101.8°C. The second fraction is collected and the eluent is evaporated. The residue is triturated in 1,1'-oxybisethane The product is filtered off and crystallized from a mixture of 4-methyl-2~pentanone and petroleum ether, yielding 9.75 parts of A+B-2-(2,4-dichlorophenyl)-2-(lH-imidazol-lylmethyl)-1,3-dioxolane-4-methanol; mp. 128.1°C.

Example LXXXI A mixture of 7.7 parts of ΙΗ-imidazole. 8 parts of cis-2-(bromomethyl)-2-(2,4-dichlorophenyl)-1,3d:oxolane-4-methanol, 1 part of potassium iodide and 180 parts of Ν,Ν-dimethylacetamide is stirred and refluxed for 3 days. The reaction mixture is cooled and 157 - 116 evaporated. Then there are added 50 parts of water and 300 parts of trichloromethane to the residue. The whole is washed three times with water, dried, filtered and evaporated. The residue is purified by column-chromography over silica gel using a mixture of trichlbromethane and 2% of methanol as eluent. The pure fractions are collected and the eluent is evaporated, yielding 9.2 parts of cis-2-(2,4-dichlorophenyl)-2-(lH-imidazol-1ylmethyl)-1,3-dioxolane-4-methanol; mp. 140°C.

Example LXXXII Following the procedure of Example LXXXI and using an equivalent amount of trans-2-(bromomethyl)-2-(2.4dichlorophenyl)-l,3-dioxolane-4-methanol as a starting material, there is obtained: trans-2-(2,4-dichlorophenyl)-2-(IH-imidazol-l-ylmethyl)l,3-dioxolane-4-methanol; mp. 129°C.

Example LXXXIII To a stirred mixture of 4 parts of cis-2-(2,4dichlorophenyl)-2-(IH-imidazol-l-ylmethyl)-1,3-dioxolane -4-methanol, 2.2 parts of iodomethane and 90 parts of Ν,Ν-dimethylformamide are added 0.5 parts of sodium hydride dispersion 78%. Stirring is continued for 2 hours at room temperature. The reaction mixture is poured onto water and the product is extracted three times with l,l'-oxybisethane. The combined extracts are washed with water and acidified with a nitric acid solution in 1,1’oxybisethane. The formed nitrate salt is filtered off and crystallized from 4-methyl-2-pentanone, yielding 2.2 parts (45%) of cls-l-/2-(2,4-dichlorophenyl)-4-(methoxymethyl)-1,3-dioxolan-2-ylmethyl7"lH-imidazole nitrate; mp. 140°C. - 117 Example LXXXIV To a stirred mixture of 4 parts of cis-2-(2,4dichlorophenyl)-2-(IH-imidazol-l-ylmethyl)-1,3-aioxolane4-methanol, 1.7 parts of bromoethane and 90 parts of N,N-dimethylformamide are added 0.5 parts of sodium hydride dispersion 78%. The whole is stirred for 1 hour at room temperature. The reaction mixture is poured onto water and the product is extracted three times with 2,2'-oxybispropane. The combined extracts are washed with water and acidified with a nitric acid solution in 2,2'oxybispropane. The formed nitrate salt is filtered off and crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane, yielding 4.7 parts (93%) of cis-l-/2-(2,4-dichlorophenyl)-4-(ethoxymethyl)-1,3dioxolan-2-ylmethyl7-lH-imidazole nitrate; mp. 134.7°C.

Example LXXXV Following the procedure of Example LXXXIV and using an equivalent amount of an appropriate bromoalkane or bromoalkene in place of the bromoethane used therein, the following imidazole acid addition salts are prepared: ,. cis-1-/?-(2,4-dichlorophenyl)-4-(propoxymethyl)-1,3dioxolan-2-ylmethyl7-lH-imidazole nitrate; mp. 131.7°C; cis-l-/2-(2,4-dichlorophenyl)-4-(pentyloxymethyl)-1,3dioxolan-2~ylmethyl7_lH-imidazole nitrate; mp. 78.6°C; cis-1-/2-(2,4-dichlorophenyl)-4-(hexyloxymethyl)-1,3dioxolan-2-ylmethyl7-lH-imidazole nitrate; mp. 87.1°C; cis-l-/2-(2,4-dichlorophenyl)-4-(heptyloxymethyl)-1,3dioxolan-2-ylmethyl7_lH-imidazole nitrate; mp. 8O.7°C; cis-l-/3-(2,4-dichlorophenyl)-4-(octyloxymethyl)-1,3dioxolan-2-ylmethyl7-lH-imidazole nitrate; mp. 73.4°C; and 157 - 118 cis-1-/2-(2,4-dichlorophenyl)-4-(2-propenyloxymethyl)-1,3dioxolan-2-ylmethyy-lH-imidazole nitrate; mp. 116.3°C.

Example LXXXVI To a mixture of 4 parts trans-2-(2,4-di.chl.oropiienyl·)-2-(lHimidazol-l-y lmethyl)-1,3-dioxolane-4-methanol, 1.7 parts of bromoethane and 90 parts of N,N-dimethylformamide are added 0.5 parts of sodium hydride dispersion 78% and the whole is stirred for 2 hours at room temperature. The reaction mixture is poured onto water and the product is extracted twice with 2,2'-oxybispropane. The combined extracts are washed with water and taken up in 2,2'oxybispropane. The solution is acidified with nitric acid The formed nitrate salt is filtered off and crystallized from 4-methyl-2-pentanone, yielding 3.5 parts (69%) of trans-l-/2-(2,4-dichlorophenyl)-4-(ethoxymethyl)-1,3dioxolan-2-ylmethyl7-lH-imidazole nitrate; mp. 151.4°C.

Example LXXXVII To a stirred mixture of 2.5 parts of l-chloro-4(chloromethyl·)benzene, 4 parts of cis-2-(2,4-dichlorophenyl) -2-(lH-imidazol-l-ylmethyl)-1,3-dioxolane-4methanol 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 onto water and the product is extracted twice with 2,2'-oxybispropane. The combined extracts are washed with water, dried, filtered and acidified with nitric acid. The formed nitrate salt is filtered off and crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane. The product is filtered off and recrystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane, yielding 3.5 parts (56%) of ois-1/4-(4-chlorophenylmethoxymethyl)-2-(2,4-dichlorophenyl)l,3-dioxolan-2-ylmethyl7_lH-imidazole nitrate; mp. 131.7° C. 3157 - 119 Example p:xxVIII By repeating the procedure of Example LXXXVII and using an equivalent amount of an appropriate (chloromethyl) benzene 'in place of the l-chloro-4-(chioromethyl) benzene used therein, there are obtained: cis-1-{4-/7 4-bromophenyl)methoxymethyl7-2-(2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl}-IH-imidazole nitrate; mp. 101.4°C; and cis-l-{2-(2,4-dichlorophenyl)-4-/74-1luorophenyl)methoxymethy1/-1,3-dioxolan-2-ylmethyl}-IH-imidazole nitrate; mp. 107°C.

Example LXXXIX To a stirred mixture of 3.3 parts of 2.4-dichloro-l(chioromethyl)benzene, 5 parts of A+B-2-(2,4-dichlorophenyl) -2-(IH-imidazol-l-ylmethyl)-1,3-dioxolane-4-methanol and 90 parts of Ν,Ν-dimethylformamide are added 0.5 parts of a sodium hydride dispersion 78% and stirring is continued for 3 hours at room temperature. The reaction mixture is poured onto water and the product is extracted three times with 2,2'-oxybispropane. 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 (A-isomer) is collected and the eluent is evaporated. The residue is converted into the nitrate salt in 4-methyl-2-pentanone and 2,2'-oxybispropane. The salt is filtered off and recrystallized from a mixture of 4-methyl-2-pentanone and 2,2-oxybispropane at 0°C, yielding 2.9 parts (35%) of cis-1-{2- (2,4-dichlorophenyl) -4-/'(2,4dichlorophenyl)methoxymethy1/-1,3-dioxolan-2-ylmethyl}ΙΗ-imidazole nitrate; mp. 96.9°C, The second fraction (B-isomer) is collected and the eluent is evaporated. The residue is converted into the - 120 ~ nitrate salt in 4-methyl-2-pentanone and l,l'-oxybisethane The salt i:; filtered off and recrystallized from a mixture of 4-methyI-2-pentanone and 2,2’-oxybispropane, yielding 1.6 parts (19%) of trans-l-{2-(2,4-dichlorophenyl)-4/12,4-dichiorophenyl)methoxymethyl/-!,3-dioX0lan-2-ylmethyl}-iH-imidazole nitrate; mp. 131.9°C.

Example XC By repeating the procedure of Example LXXXIX and using an equivalent amount of 4-(chloromethyl)-1,1·biphenyl in place of the 2,4-dichloro-l-chloromethylbenzene used therein, there are obtained; cis-I-/4-(/1,1'-biphenyl7~4-ylmethoxymethyl)-2-(2,4dichlorophenyl)-1,3-dioxolan-2-yImethy17-lH-imidazole diethanedioate; mp. 107.6°C; and trans-l-/4-(/1,1'-biphenyl7-4-ylmethoxymethyl)-2-(2,4dichlorophenyl)-1,3-dioxolan-2-yImethy17-lH-imidazole nitrate; mp. 168°C.

Example XCI A mixture of 2.2 parts of (4-hydroxyphenyl) phenyl methanone, 4.2 parts of cis-2-(2,4-dichlorophenyl)-2(lH-imidazol-l-ylmethyl)-l,3-dioxolan-4-ylmethyl methanesulfonate, 2 parts of potassium carbonate and 68 parts of N,N-dimethylformamide is stirred overnight at 100°C. The reaction mixture is cooled and poured onto water. The product is extracted twice with 1,1'oxybisethane. The conbined extracts are washed with water, dried, filtered and evaporated. The residue is converted into the nitrate salt in 4-methyl-2-pentanone and 2,2'-oxybispropane, yielding 4.5 parts (78%) of cis{4-/2-»(2,4-dichlorophenyl) -2- (IH-imidazol-l-ylmethyl)-1,3dioxolan-4-ylmethoxy7phenyl}-phenyl methanone nitrate; mp 179°C. - 121 Example XCIX 43137 Following the procedure of Example XCI and using an equivalent amount of an appropriate phenol in place of the (4-hydroxyphenyl) phenyl methanone used therein, the following imidazoles and imidazole acid addition salts are prepared; cis-5-chloro-2-/2-(2,4-dichlorophenyl)-2-(IH-imidazol-lylmethyl) -l,3-dioxolan-4-ylmethoxy7-4-methylphenyl phenyl methanone ethanedioate; mp. 170.8°C; cis-methyl 4-/2-(2,4-dichlorophenyl)-2-(lH-imidazol-lylmethyl)-l,3-dioxolan-4-ylmethoxy7benzoate nitrate; mp. 167.8°C; cis-ί2-/2-(2,4-dichlorophenyl)-2-(lH-imidazol-l-ylmethyl) -1,3-dioxolan-4-ylmethoxy7"5-methylphenyl}phenyl methanone nitrate; mp. 145.4°C; T cis-(4-chlorophenyl){2-/2-(2,4-dichlorophenyl)-2-(1Himidazol-l-ylutethyl)-1,3-dioxolan-4-ylmethoxy7~4-methoxyphenyllmethanone; mp. 168.3°C; cis-{2-/2-2,4-dichloroFhenyl ) -2- (IH-imidazol-l-ylmethyl) -1, 3-dioxolan-4-ylmethoxy7_4-methoxyphenyl}phenyl methanone; mp. 149.2°C; cis l-{2-(2,4-dichlorophenyl)-4-/5-(trifluoromethyl)phenoxymethy17~1,3-dioxolan-2-ylmethyl}-lH-imidazole nitrate; mp. 152.6°C; cis-l-f 4-/2-(2,4-dichlorophenyl)-2-(IH-imidazol-lylmethy1)-1,3-dioxolan-4-yImethoxy/pheny1}ethanone nitrate; mp. 182.6°C; cis-methyl 2-/2-(2,4-dichlorophenyl)-2-(lH-imidazol-1ylmethyl)-l,3-dioxolan-4-ylmethoxy7benzoate nitrate; mp. 140.5°C; and - 122 cis-l-{4-/2-(2,4-dichlorophenyl)-2-(lH-imidazol-1ylmethyl)-l,3-dioxolan-4-ylmethoxy7phenyl}-l-propanone nitrate; mp. 176.2°C.

Example XCIII A mixture of 12.5 parts of 1,2-butanediol, 19 parts of 1-(2-chloro-4-fluorophenyl)-2-(lH-imidazol-l-yl)ethanone hydrochloride, 16 parts of 4-methylbenzenesulfonic acid, 40 parts of 1-butanol and 225 parts of dimethylbenzene is stirred and refluxed for 6 days with waterseparator. After cooling, the reaction mixture is filtered and the filtrate is washed with a diluted sodium hydroxide solution and with water. After the addition of 2,21-oxybispropane, the whole is acidified with a nitric acid solution. The formed nitrate salt is filtered off and crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane, yielding 5.7 parts (22%) of A+B-l -/2-.(2-chloro-4-fluorophenyl)-4-ethyl-l,3-dioxolan-2ylmethyl7~lH-imidazole nitrate; mp. 132.4°C.

Example XCIV Following the procedure of Example XCIII and using equivalent amounts of the appropriate starting materials, the following imidazoles and imidazole acid addition salts are prepared: A+B-l-/2-(4-bromophenyl)-4-ethyl-l,3-dioxolan-2-ylmethyr7 -IH-imidazole nitrate; mp. 194.7°C; A+B-1-/2-(2,4-dibromophenyl)-4-ethyl-l,3-dioxolan-2ylmethyl7~lH-imidazole nitrate; mp. 149.7°C; A+B-l-/4-ethyl-2-(2-thienyl)-l,3-dioxolan-2-ylmethyl7IH-imidazole nitrate; mp. 135.4°C; A+B—l—/2— (r>—chloro—2—thienyl)-4-ethyl-l,3-dioxolan-2ylmethyl7~bH-imidazole nitrate; mp. 164,3°C; 315 7 - 123 Λ+Β-1-/4-(chloromethyl)-2-(2,4-dichlorophenyl)-1,3dioxolnri-2-ylmethyl7-iH-imidazole nitrate; mp. 166.1°C; A+B-1-/4-(/1,1'-biphenyl/_4-ylmethyl)-2-(2,4-dichloro phenyl)-1,3-dioxolan-2-ylmethyl/-lH-imidazole diethanedioate; mp. 116.8°C A+B-1-/2-(2,4-dichlorophenylj-4-(4-fluorophenylmethyl)1.3- dioxolan-2-ylmethyi7-lH-imidazole sesquiethanedioate; mp. 153.1°C; A+B-l-(2-(2,4-dichlorophenyl)-4-/74-methyIphenyDmethy1/1.3- dioxolan-2-ylmethyl3-lH-imidazole sesquiethanedioate; mp. 123.1°C.

A+B-1-/3-(4-bromophenylmethyl)-2-(2,4-dichlorophenyl)-1,3dioxolan-2-ylmethyl7~lH-imidazole diethanedioate; mp. 128.8°C; A+B-l-f 4-/2-(/1,1'-biphenyl/_4-yl)ethy1/-2-(2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl]-lH-imidazole sequiethanedioate hemihydrate; mp. 143.9°C; and A+B-l-f2-(2,4-dichlorophenyl)-4-/2-(phenylmethyl)phenoxymethy17-1,3-dioxolan-2-ylmethyl?-ΙΗ-imidazole sesquiethanedioate, hemihydrate; mp. 113°C.

Example XCV A mixture of 13.8 parts of 1-(2-chloro-4-fluorophenyl) -2- (ΙΗ-imidazol-l-yl) ethanone hydrochloride, 14.6 parts of 3-(/1,1'-biphenyl7-4-yloxy)-1,2-propanediol, 16 parts of 4-methylbenzenesulfonic acid, 40 parts of butanol and 225 parts of dimethylbenzene is stirred and refluxed for one week with water-separator. After cooling, 1,1'oxybisethane is added and the whole is washed successively with a diluted sodium hydroxide solution and with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using trichloro -methane as eluent. The first fraction (A-isomer) is collected and the eluent is evaporated. The residue is converted into the nitrate salt in 4-methyl-2-pentanone - 124 and 2,2'-oxybispropane. The product is filtered off and crystallized from a mixture of acetonitrile and 2,2'oxybispropane, yielding 5 parts of cis-l-/4-(/1,1'biphenyl/-4-yloxymethyl)-2-(2-chloro~4-fluorophenyl)-1,3dioxolan-2-ylmethyl/-lH-imidazole nitrate; mp. 185.7°C.

The second fraction (B-isomer) is collected and the eluent is evaporated. The residue is converted into the nitrate salt in 4-methyl-2-pentanone and 2,2'-oxybispropane.

The salt is filtered off and crystallized from a mixture of acetonitrile and 2,2'-oxybispropane, yielding 5.9 parts of trans-l-/4-(/1,1'-biphenyl/-4-yloxymethyl)-2-(2-chloro4-fluorophenyl)-1,3-dioxolan-2-ylmethyl/-lH-imidazole nitrate; mp. 156.9°C.

Example XCVI Following the procedure of Example XCV and using equivalent amounts of the appropriate starting materials the following imidazoles and imidazole acid addition salts are prepared. When only one isomer is listed, no second fraction was obtained from chromatography. cis-l-/4-(/1,11-biphenyl7-4-yloxymethyl)-2-(2-thienyl)-1, 3-dioxolan-2-ylmethyl7-lH-imidazole; mp. 149.5°C; trans-l-/4-(/1,1'-biphenyl7-4-yloxymethyl)-2-(2-thienyl)1,3-dioxolan-2-ylmethyl/-lH-imidazole; mp.>300°C; cis-l-/4-(/1,1'-biphenyl/-4-yloxymethyl)-2-(2,4-dibromophenyl)-l,3-dioxolan-2-ylmethyl/-lH-imidazole nitrate; mp. 174.4°C; trans-1-/4-(/1,1'-biphenyl/-4-yloxymethyl)-2-(2,4dibromophenyl)-1,3-dioxolan-2-ylmethyl/-lH-imidazole nitrate; mp. 141.8°C; and cis-l-/4-(/1,1'-biphenyl/-4-yloxymethyl)-2-(5-chloro-2thienyl)-l,3-dioxolan-2-ylmethyl/-lH-imidazole nitrate; mp. 170°C. - 125 Example XCVI To a stirred mixture of 1.1 parts of 3-chloro-lpropyne, 4 parts of cis-2-(2,4-dichlorophenyl)-2-(1Himidazol-l-yImethyl)-l,3-dioxolane-4-methanol and 90 parts of Ν,Ν-dimethylformamide are added 0.5 parts of sodium hydride dispersion 78%. Stirring is continued for 3 hours at room temperature. The reaction mixture is poured onto water and the product is extracted twice with 1,11-oxybisethane. The combined extracts are washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichioromethane and methanol (98:2) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted into the ethanedioate salt in 4-methyl-2-pentanone and 2,2'oxybispropane. The salt is filtered off and crystallized from 4-methyl-2-pentanone, yielding 3.6 parts (55%) of cis-l-/2-(2,4-aichiorophcnyl)-4-(2-propynyloxymethyl)-1, 3,dioxolan-2-ylmethyl7~lH-imidazole diethanedioate? mp. 145.6°C.

Example XCVIII A mixture of 17 parts of IH-imidazole, 16 parts of A+B-2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-ethenyl-l, 3-dioxolane and 225 parts of Ν,Ν-dimethylformamide is stirred and refluxed for 3 days. The reaction mixture is cooled, poured onto water and the product is extracted twice with 1,1'-oxybisethane. The combined extracts are washed with water, dried filtered and evaporated. The residue is purified by column-chromatography over silica gel using trichioromethane as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted into the nitrate salt in 4-methyl-2-pentanone and 2,2'-oxybispropane. The salt is filtered off and crystallized from 4-methyl-2-pentanone, yielding 2.4 parts (13%) of A+B-1-/2-(2,4-dichlorophenyl)-4-ethenyl)-1,3dioxolan-2-ylmethyiy-lH-imidazole nitrate; mp.l5O.9°C.

Claims

1. An imidazole derivative having the formula: Ar (I) or the therapeutically acceptable acid addition salts and stereochemical and optical isomeric forms thereof, wherein Ar is phenyl, thienyl, halothienyl or naphthyl group, or a phenyl group substituted with from 1 to 3 substituents which are independently halo, lower-, alkyl, loweralkyloxy, nitro or cyano; and R is an alkyl group having from

2. - 2.27 2. Cis-l-/2-(2,4-dichlorophenyl)-4-(4-fluorophenoxymethyl)-1,3-dicsxolan~2-ylmethyl7imidazole. 2 to 10 carbon atoms, an alkyloxymethyl group wherein the alkylgroup has from 1 to 10 carbon atoms, an alkenyl or alkenyloxymethyl group wherein the alkenylgroup has from 2 to 10 carbon atoms, a 2-propynloxymethyl, hydroxymethyl, halomethyl, aryl, aryllower alkyl, aryloxymethyl, arylthiomethyl or arylmethoxymethyl group, wherein the aryl group is a phenyl, naphthyl, mono- or di-halonaphthyl group or a phenyl group substituted with from 1 to 3 substituents which are independently halo, loweralkyl, loweralkyloxy, cyano, nitro, phenyl, phenylmethyl, benzoyl, halobenzoyl, loweralkylocarbonyl, loweralkyloxvcarbonyl or trifluoromethyl, provided that when more than one substituent is present only one substituent may be phenyl, phenyImethyl, benzoyl or halobenzoyl. 431S7

3. 1-/4-(4-Bromophenoxymethyl)-2-(2,4-dich]orophenyl)-l,3-dioxolan-2-yImethy17imidazole.

4. Cis-l-Z.2- (2,4-dichlorophenyl) -4- (4-methoxyphenoxymethvl)-1,3-dioxolan-2-yImethyl/Tmidazole. 5. Formula: in which Ar and R are as defined above and, if desired, preparing therapeutically useful acid addition salts of the above products by reaction with an appropriate acid; 5 wherein R is as defined in claim 1; or c) reacting a compound of the formula: (X-b) wherein Ar is as defined in claim 1 with a compound of the formula:

5. Cis-l-/2-(2,4-dichlorophenyl)-4-(2-fluorophenoxymethyl)-1,3-dioxolan-2-ylmethyl/-lH-imidazole.

6. 1-/4-(4-Bromophenoxymethyl)-2-(4-chlorophenyl)1,3-dioxolan-2-ylmethyl7-lB-imidazole.

7. 1-/J- (/1,1'-Biphenyl7-4-yloxymethyl)-2-(2,4-dichlorophenyl) -l,3~dioxolan-2-yImethy17-lH-imidazole.

8. 1-/2-(2,4-Dichlorophenyl)-4-ethyl-l,3-dioxolan2-ylinethyl7-Hl-imidazole.

9.· Cis-l-/4-(/1,1'-biphenyl/-4-yloxymethyl)-2-(2,4dichlorophenyl)-1,3-dioxolan-2-yImethy17-lH-imidazole. 10. And further, if desired, preparing stereochemical and optical isomeric forms of the above products by standard procedures. 10 R 1 - W (VI) wherein k' is a C^_ 30 alkyl, C 2 _ 10 alkenyl, 2-propynyl or arylmethyl group and W is a reactive ester group, in accordance with known O-alkylating procedures, in order to prepare a compound of the formula: - 130 is? in which Ar and are as defined above or d) condensing a compound of the formula (I-b) with an appropriate alkanol of the formula C 2__j_ 0 alkyl-OH in order to prepare a compound of the formula: in which Ar is as defined above or e) reacting a compound of the formula: wherein Ar is as defined in claim 1, with a compound of the formula: - 131 R 2 - OH (VIII) wherein R is a alkyl, C 2_io a3 - ken Y 1 ' 2-propynyl, arylmethyl or aryl group in accordance with known O-alkylating procedures in order to prepare a compound of the

10. 1-/2 -- (2-Chloro-4-fluorophenyl)-4-ethyl-l,3dioxolan-2-ylmethy]J'-lH-imidazole.

11. 1-/2 - - (4-Bromo-2-chlorophenyl)-4-ethyl-l,3dioxolan-2-yImethy17-lH-imidazole.

12. Cis-l-/4-(/'l,1'-biphenyl7-4-yloxymethyl)-2-(2chloro-4-fluorophenyl)-1,3-dioxolan-2-yImethy17-lHimidazole.

13. A compound of Formula (I) as defined in claim 1 substantially as hereinbefore described with reference to any one of Examples XLIV to XCVIII.

14. A therapeutically acceptable acid addition salt of a compound as claimed in any one of Claims 2 to 13. - 128 15. A process for preparing an imidazole derivative having the formula: R -1-1 (I) or the therapeutically acceptable acid addition salts and stereochemical and optical isomeric forms thereof, wherein Ar and R are as defined in claim 1, which comprises a) reacting a compound of the formula: H or a metal salt of the compound of formula (II) with a compound of the formula: W-CH 2 •Ar (III) wherein Ar and R are as defined in claim 1 and W is a reactive ester group, in an organic solvent; or b) ketalizing a compound of the formula: - 129 - (IV) wherein Ar is as defined in claim 1 with a compound of the formula: OH . I R-CH-CII 2 -OH (V)

15. (II) and (III) is carried out at elevated temperature.

16. A process as claimed in claim 15 wherein in process (a) the reaction between the compounds of formulae

17. A process as claimed in claim 15 or claim 16 wherein in process (a) the reaction between the compounds of formulae (II) and (III) is carried out in the presence of a metal iodide. 20

18. A process as claimed in any one of claims 15 to 17 wherein in process (a) when compound II is used without previous salt formation the reaction between the compounds of formulae (II) and (II) is carried out using an excess of imidazole or in the presence of a base.

19. A process as claimed in claim 15 wherein iri 157 - 132 process (b) the ketalization reaction is carried out by refluxing compounds IV and V together with azeotropic water removal in an organic solvent, in the presence of an alcohol and a strong acid.

20. A process as claimed in claim 15 wherein in process (c) the reaction between the compound of formula (I-b) with the compound of formula (VI) is carried out in the presence of an organic solvent and a strong base.

21. A process as claimed in claim 15 wherein in process (d) the reaction between the compound of formula (I-b) with the alkanol, alkyl-OH, is carried out by refluxing the reactants together in an organic solvent, in the presence of a strong acid.

22. A process as claimed in claim 15 wherein in process (e) the reaction between the compounds of formula (VII) and (VIII) is carried out in the presence of an organic solvent and a strong base.

23. A process for preparing 1-/4-(4-bromophenoxymethyl) -2-(2,4-dichlorophenyl)-1,3-dioxolan-2-ylmethyl7imidazole or a therapeutically acceptable acid addition salt thereof, which comprises reacting imidazole or a metal salt thereof with 2-(bromomethyl)-2-(2-,4-dichlorophenyl) -4-(p-bromophenoxymethyl)-1,3-dioxolane, and if desired preparing a therapeutically acceptable acid addition salt of the product thereof.

24. A process for preparing 1-/T-(4-bromophenoxymethyl)-2-(4-chlorophenyl)-l,3-dioxolan-2-ylmethy1/-IHimidazole or a therapeutically acceptable acid addition salt thereof, which comprises reacting IH-imidazole or a metal salt thereof with 2-(bromomethyl)-2-(4-chlorophenyl)· 4-(p-bromophenoxymethyl)-1,3-dioxolane, and,if desired preparing a therapeutically acceptable acid addition salt of the product thereof. - 133

25. A process for preparing 1-/3-(/1,1'-bipheny1/4-yloxymethyl)-2-(2.4-dichlorophenyl)-1,3-dioxolan-2ylmethyl/-lH-imidazole or a therapeutically acceptable acid addition salt thereof, which comprises reacting 1Himidazole or a metal salt thereof with 4-(/T,-l 1 -bipheny1/4-yloxymethyl)-2-(bromomethyl)-2-(2,4-dichlorophenyl)-1,3dioxolane and, if desired preparing a therapeutically acceptable acid addition salt of the product thereof.

26. A process for preparing 1-/2-(2,4-dichlorophenyl) -4-ethyl-l,3-dioxolan-2-ylmethy]J r -lH-imidazole or a therapeutically acceptable acid addition salt thereof, which comprises reacting lH-imidazole or a metal salt thereof with 2-(2,4-dichlorophenyl)-2-(bromomethyl)-4ethyl-1,3-dioxolane and, if desired preparing a therapeutically acceptable acid addition salt of the product thereof.

27. A process for preparing l-/T-(2-chioro-4f luorophenyl) -4-ethyl-l, 3-dioxolan-2-ylmethyl/-lH-iiitidazole or a therapeutically acceptable acid addition salt thereof, which comprises reacting ΙΗ-imidazole or a metal salt thereof with 2(2-chloro-4-fluorophenyl)-2-(bromomethyl)4-ethyl-l,3-dioxolane, and, if desired preparing a therapeutically acceptable acid addition salt of the product thereof.

28. A process for preparing 1-/2-(4-bromo-2-chlorophenyl)-4-ethyl-l,3-dioxolan-2-ylmethyi7“lH-imidazole or a therapeutically acceptable acid addition salt thereof, which comprises reacting ΙΗ-imidazole or a metal salt thereof with 2-(4-bromo-2-chlorophenyl)-4-ethyl-l,3dioxolane, and, if desired preparing a therepeutically acceptable acid addition salt of the product thereof.

29. A process for the preparation of a compound as claimed in claim 1 substantially as hereinbefore described.

30. A process for the preparation of a compound as - 134 claimed in claim 1 substantially as hereinbefore described with reference to any one of Examples XLIV to XCVIII.

31. A compound of Formula (I) as claimed in claim 1 whenever prepared by a process as claimed in any one of claims 15 to 30.

32. A composition for combatting the growth of a fungus or a bacterium which comprises an inert carrier or diluent and an effective amount of at least one compound as claimed in any one of claims 1 to 11 or claim 31, or a salt as claimed in claim 14.

33. A process for combatting the growth of a fungus or a bacterium which comprises treating the fungus or bacterium with a composition as claimed in claim 32.