CS202001B2 - Process for preparing derivative of imidazole - Google Patents

Description

The invention relates to a process for the preparation of an imidazole derivative.

In U.S. Pat. No. 3,575,999 and 3,171,655 there are described some l- _(2-aryl-l) 3-dioxolan-2-ylmethyl) imidazoles. The compounds according to the invention differ from the previous ones mainly in the nature of the substituent R 1 located at the 4-position of the dioxolane group.

A process for preparing an imidazole derivative of the formula I,

where

Ar is phenyl, substituted phenyl, thienyl, or naphthyl and substituted phenyl is phenyl having 1 to 3 substituents such as halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms in the alkyl radical, nitro or cyano, and

R is alkyl of 2 to 10 carbon atoms, alkoxymethyl wherein the alkyl group has 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkenyloxymethyl wherein the alkenyl group has 2 to 10 carbon atoms, 2-propionyl oxymethyl, hydroxymethyl, halomethyl aryl, arylalkyl of 1 to 6 carbon atoms in the alkyl radical, aryloxymethyl, arylthiomethyl or arylmethoxymethyl, wherein aryl is in each case phenyl, substituted phenyl, naphthyl or mono- and dihalo-naphthyl and wherein the substituted phenyl is phenyl having 1 to 3 substituents such as halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms in the alkyl radical, cyanonitro, phenyl, phenylmethyl, benzoyl, halo-benzoyl, alkylcarbonyl of 1 to 6 carbon atoms in the alkyl radical, alkyloxycarbonyl of 1 to 6 atoms carbon in an alkyl radical or trifluoromethyl, provided that when there are more than one substituent, only one of them may be phenyl, phenylmethyl, benzoyl and halobenzoyl, or a therapist The acid addition salts and stereochemical isomeric forms are characterized by reacting a compound of formula II at a temperature of 100 to 200 ° C.

202 3

Π

H (ID or a metal salt of a compound of formula II with a compound of formula III,

WCH Air --------- --------- 1 ^R 1 _{(wherein llll}

W represents the function of the reactive ester, in an organic solvent such as dimethylformamide or dimethylacetamide, preferably in the presence of metal iodide, and when the compound of formula II is used in a reaction without preliminary salt formation, an excess of imidazole is preferably used or binding the liberated acid, such as sodium or potassium carbonate or bicarbonate, and optionally converting the obtained compound with an acid into a therapeutically acceptable acid addition salt, and optionally converting the obtained compound into stereochemical optical isomeric forms.

C 2 -C 10 alkyl includes straight and branched chain hydrocarbon radicals such as ethyl, propyl, 1-methylethyl, 1,1-dimethylethyl, butyl, pentyl, hexyl, heptyl, octyl, decyl and the like;

Alkyl group with 1. up to 10 carbon atoms in the definition of alkoxymethyl includes straight or branched chain hydrocarbon radicals such as methyl and the aforementioned alkyls; (C 1 -C 6) alkyl radical includes a straight or branched alkyl radical such as methyl, ethyl, propyl, N, N, N-dimethyl, 1,1-dimethylethyl, butyl, pentyl, hexyl C 2 -C 10 alkenyl represents straight and branched alkenyl radicals such as ethenyl, 2-propenyl, 2-butenyl,

3-butenyl, 2-pentenyl, 2-hexenyl, 2-decenyl and the like; . and the term "halogen" means halogens of. atomic. Weights of less than 127, for example. fluorine, chlorine, bromine and iodine.

Compounds of formula I are conveniently prepared by reacting an imidazole of formula II with an appropriate reactive ester of formula III wherein Ar and R are as defined above and wherein W represents a reactive ester group such as halogen, 4-methylbenzenesulfonate, methylsulfonate and the like.

Preferred reactive esters are halides, and especially bromides and chlorides.

In one method of reacting an imidazole of formula II with a compound of formula III, the imidazole is first converted by reaction with a suitable metallating agent such as a metal alkoxide such as sodium or potassium methoxide, or a metal hydride such as sodium hydride to a metal salt. The metal salt thus obtained is then reacted with a compound of formula III in a suitable organic solvent such as dimethylformamide or dimethylacetamide. A small amount of a metal iodide such as sodium or potassium iodide may be advantageously added to accelerate the reaction, especially when the reactive ester is chloride or bromide.

Alternatively, the reaction of the imidazole of formula II with the reactive ester of formula III can also be carried out without preliminary salt formation by reacting the reactants in a suitable organic solvent, such as dimethylformamide or dimethylacetamide. In these circumstances, it is convenient to use an excess of imidazole or to add a suitable base such as sodium or potassium carbonate or acid carbonate to the reaction mixture to bind the acid released during the reaction. However, it is preferred to use an excess of imidazole. It is further preferred to carry out the reaction in the presence of a metal iodide such as sodium or potassium iodide.

In each of these processes, a somewhat elevated temperature can be used to increase the reaction rate, and most preferably the reaction is carried out at the reflux temperature of the reaction mixture.

In these and subsequent preparations, the reaction products are isolated from the environment and optionally further purified by generally known methods such as extraction, trituration, crystallization, chromatography, etc.

The foregoing procedures may be illustrated by the following scheme:

¹¹¹¹ . шп ш

The imidazole derivatives of formula (I) obtained in the previous base form can be converted into therapeutically acceptable acid addition salts by reaction with a suitable acid, for example an inorganic acid such as a hydrohalic acid, i.e. hydrochloric, hydrobromic or hydroiodic acid; sulfuric, nitric or rhodic acid; phosphoric acid; an organic acid such as acetic, propionic, hydroxyacetic, α-hydroxypropionic, 2-oxopropionic, ethanedioic acid, propanedioic acid, 1,4-butanedioic acid, (Z) -2-butenedic acid, (E) -2-butenedic acid, 2-hydroxy-1, 4-butanedioic acid, 2,3-dihydroxy-1,4-butanedioic acid,

2-hydroxy-1,2,3-propanetricarboxylic acid, benzoic acid, 3-phenylpropenoic acid, α-hydroxybenzeneacetic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid,

4-methylbenzenesulfonic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic, 2-phenoxybenzoic or 2-acetyloxybenzoic acid. Conversely, the salts are converted to the corresponding free bases in a conventional manner, for example by reaction with an alkali such as sodium or potassium hydroxide.

Intermediates of formula III can be prepared from the corresponding ketone of formula IV, wherein Ar and W are as previously defined, by ketalization with a suitable diol of formula V.

Ketalization can be carried out according to analogous methods described in the literature, for example for the preparation of 2-bromomethyl-2,4-diphenyl-1,3-dioxolane [Synthesis, 1974 (1), 23].

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

The preceding reaction can be illustrated as follows:

OOH

IIII

W — CH2 — C — Ar + R — CH — CH2OH (IV) (V)

4-Methylbenzenesulfonic acid butanol / benzene (III)

Alternatively, intermediates of formula III are preferably prepared by trans-ketalizing a ketal derivative of ketone of formula IV, such as a lower alkyl ketal or cyclic lower alkylene ketal, with a glycol of formula V under similar conditions to the direct ketalization described above. The lower alkyl ketols and cyclic lower alkylene ketals used as starting material are readily obtained by ketalizing the ketone of formula IV with a lower alkanol or alkanediol according to known methods. These compounds and methods for their preparation are described in U.S. Patent Nos. 3,575,999 and 3,717,655.

Intermediates of formula III wherein Ar, R and W are as defined above, with the proviso that when Ar is phenyl, then R is different from phenyl, they are new compounds.

The glycol intermediates of formula (V) are known and all can be prepared according to known methods described in the literature.

It can be seen from Formula I that the compounds of the invention have two asymmetric carbon atoms in their structure, particularly located at the 2- and 4-position of the dioxoian nucleus, and therefore occur in different stereochemical ophthalmic isomeric forms. Stereochemical optical isomeric forms of the compounds of Formula I and therapeutically active acid addition salts are included within the scope of the invention.

Diastereomeric racemates of the compounds of formula I, designated as cis- and trans-forms, according to the "Naming and Indexing of Chemical Substances for Chemical Abstracts during the 9th Collective Period (1972-1976)" published in CA 1972, 76, Index Quide Section IV 85, can be obtained separately according to conventional methods, for example, selective crystallization and column chromatography, the stereochemical configuration has been determined experimentally for most compounds, and conventionally it is agreed to refer to the stereochemical form, which is initially isolated as "A" and then as "B", without further reference to the actual stereochemical configuration.

Since the asymmetric carbon atoms already exist in intermediates of formula III, it is also possible to separate the cis- and trans-forms, or generally the "A" and "B" forms, at this stage, after which the corresponding forms of the compounds of formula I can be obtained imidazole as previously described. Separation of the cis- and trans-forms of the compounds of formula III can be carried out by conventional methods as described previously for the resolution of the compounds of the formula I into their cis- and trans-forms.

When R is a hydroxymethyl group in intermediates of formula III, it is preferred to first esterify the hydroxymethyl group with a suitable acyl halide, for example benzoyl chloride, whereupon the esters thus obtained are cleaved to their cis and trans forms, from which the acyl group is hydrolytically cleaved under alkaline conditions. of the corresponding forms of the desired hydroxymethyl-substituted intermediates of formula III.

It will be appreciated that cis- and trans-diastereomeric racemates can further be resolved according to known methods into the optical isomers, cis (+), cis (-), trans (-f-) and transf-).

Compounds of formula I and their addition salts with

211001 acid are useful in combating fungi and bacteria. As such, they are important in the treatment of humans, animals and plants affected by pathogenic microorganisms and in attacking materials by microorganisms.

The broad spectrum of antifungal and antibacterial activity of the compounds of Formula I is illustrated in the following tests. The compounds in the tables are not given for the purpose of limiting the invention but merely to demonstrate the useful properties of all the compounds of the formula I according to the invention.

The antifungal activity test was performed using Sabouraud's liquid medium in test tubes containing 4.5 ml liquid medium, which were heated in an autoclave at 120 ° C for 15 minutes. Substances. were dissolved in 50% ethanol at a concentration of 20 mg / ml and then diluted with sterile distilled water to a concentration of 100 mg / ml. Subsequently, successive 10-fold dilutions were made to obtain a series of stock solutions. Into each tube containing

4.5 ml of Sabouraud's liquid medium, 0.5 ml of one of the stock solutions was added to obtain a drug concentration of 100 µg, 10 µg, 1, µg or 0.1 µg. per ml medium.

The filamentous fungi were incubated at 25 ° C for 2-3 weeks. Square plates of 2 mm side were cut and inoculated into a liquid medium. A three day old culture in a Sabouraud medium was used for yeast and the inoculum was 0.05 ml per tube. All cultures were incubated for 14 days at 25 ° C. Finally. values were obtained after 2 weeks and were summarized in the following tables A.

++++ = complete ^ g / ml inhibition growth at 0.1. -] —— = complete ^ g / ml inhibition growth at 1 -J -] - = complete , ug / ml, inhibition growth at 10 + = complete inhibition growth at 100 ALIGN!

/ zg / ml

0 = no effect, ie growth is observed at the highest concentration tested (100 µg / ml).

In the first sort, drugs against the following 11 fungi were tested:

1. Microsporum canis (M. c. In the tables),

2. Ctenomyces mentagrophytes (C. t. M. In the tables),

3. Trichophyton rubrum (Tr. R. In tables),

4. Phialophora verrucosa (Ph. V. In the tables),

5. Cryptococcus neoformans (Cr. N. In tables)

6. Candida tropicalis (C. tr. In the tables)

7. Candida albicans (C. alb. In tables),

8. Mucor species (Muc. In tables),

9. Aspergillus fumigatus (A. f. In tables),

10. Sporotrichum schenckii (Sp. S. In the tables),

11. Saprolegnia species (Sap. In the tables).

Many substances exhibiting an effect at a concentration of 10 µg / ml against Phycomycetes Mucor have also been tested against 4 other phycomycetes, in particular:

1. Absidia ramosa (Abs. R. In tables),

2. Basidiobolus meristosporus [Bas. m. in tables),

3. Mortierella species (Mort. In tables),

4. Rhizopus (Rhi, in tables).

The method used for further screening was exactly the same as described above, and the results are shown in Tables B.

Bactericidal tests were carried out on Difco culture media with phenolsulfonphthalein and dextrose. The same ten-fold dilution as described above was used. The inoculum consisted of platinum loops (5 mm diameter) from a 24-hour culture.

hours after incubation, subcultures were formed from each culture and, for the assessment of bactericidal efficacy of the drugs, after seven days of incubation, the presence or absence of growth was evaluated as described above.

The substances were tested against the following gram-negative bacteria:

1. Salmonella pullorum gallinarum (SPG in the table),

2. Escherichia coli (E. coli in the table) a

3. Pseudomonas auruginosa (Ps. Aer. In the table), and against the following gram-positive bacteria and cocci:

1. Erysipelothrix insidiosa (E. ins. In the table),

2. Staphylococcus hemolyticus (Staph. In the table) a

3. Streptococcus pyogenes (Strept. In the table).

The results are shown in Tables C.

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Ri R2 Abs. r. Bass. m. Mort. Rhi. 2,4- (01) 2 4-01 ++ ++ + 4-Br 2-C1 + + + ++ 4-Br 4-Br +++ ++ ++ ++ 4-СНз 4-C1 ++ + + ~ b 2,4- (01) 2 4-Br +++ ++ ++ H — h 4-01 4-Br +++ ++ ++ ++ 2-C1 4-Br ++ H — ь ++ 4-Br 4-СНз H — H ++ + ++ 4-01 4-F ++ ++ + + 4-Br 4-F ++ ++ + ++

Ri R2 Isomer Abs. r. Bass. m. Mort. Rhi. 4-C1 4-C1 в +++ + + + 4-01 4-F cis ++ + + + 4-C1 2-СНз AND H — l · + + 4-C1 2,4- (01) 2 В +++ ++ ++ + 2,4- (01) 2 2-СНз AND + + + + 2,4- (01) 2 4-C1 trance + ++ + 2,4- (01) 2 2-N, 4-C1 A + B ++ ++ + + 4-01 2.6- (01) 2 AND ++ + + + 2,4- (01) 2 2-СНз AND ++ ++ + + 2,4- (01) 2 4-СНз AND + ++ + + 2,4- (01) 2 4-ОСНз AND ++ ++ + + 2,4- (01) 2 4-С1 cis ++ ++ + + 2,4- (01) 2 4-Br AND Η 1 — h ++ ++ ++ 2,4- (01) 2 Η AND H — H H — H + + 2,4- (01) 2 3,4- (01) 2 AND +++ H 1 — l · + H — l · 2,4- (01) 2 3-C1 AND —H H — 1 — H ++ H — h 2,4- (01) 2 2-C1 AND H 1 — H ++ + + 2,4- (01) 2 2-Br cis Η h ++ + +

С 2 О О 1

Table С: Bacteriostatic and bacteriocidal activity

The table shows the efficacy against Gram positive bacteria

r, r ₂ Bacteriostatic activity Bacteriocidal activity

E. ins. Staph. Strept. E. ins. Staph. strept. 4-C1 4-C1 ++ 4 — l · H — h ++ ++ H — h 4-C1 H H — l · “I — h Η 1 H ++ + +++ 4-C1 2,4- (Cl) ₂ +++ ++ +++ ++ ++ +++ 4-Br 4-C1 +++ +++ +++ +++ + “1—1 — h 4-Br 2,4- (01) 2 +++ + I — 1 — l · +++ 4- 4—1 — h 2,4- (Cl) 2 H ++ 0 ++ ++ 0 + 4- ' 4-ОСНз 4-C1 ++ + “I h + + 4-4- H 2,4- (01) 2 ++ 4 — l · 4 1 H + + 4 — h 2,4- (01) 2 4-C1 +++ ++ +++ ++ + 4 h H 4-C1 +++ + 4—1 — l · + + ++ 4-C1 2-C1 H — 1 — l · 4 — l · +++ ++ + 4 H 2-C1 2,4- (01) 2 +++ ++ 4 1 l · H — l · + 4-4- + 4-Br 2-C1 +++ + 4 — h +++ + ++ 2-C1 4-C1 i — 1 — l · + +++ +++ + +++ 2,4- (Cl) 2 2,4- (01) 2 +++ ++ +++ +++ + +++ 4-Br H ~ 1 — H + 4—1 — h ++ 4- 4—1 — Η H 4-Br +++ 0 +++ +++ 0 +++ 4-СНз 2,4- (01) 2 +++ + 4 — h +++ +++ ++ +++ 4-Br 4-Br 4—1 — l · 4 — l · +++ +++ + +++ 2,4- (Cl) 2 2-C1 4—1 — l · 4—1 l · +++ +++ ++ +++ 4-СНз 4-C1 +++ ++ +++ И — 1 — h + +++ 2,4- (Cl) 2 4-Br 4—1 — Η ++ +++ H — h + 4 — H 4-C1 4-Br +++ ++ +++ +++ ++ +++ 4-СНз 4-Br 4—1 — h. ++ 4—1 h H — 1 — l · + +++ 3-C1 2,4- (01) 2 ++ + +++ ++ + +++ 2-C1 4-Br 4 — h 4 — l · ++ ++ + 4 — h 4-СНз 2-C1 +++ + +++ ++ + +++ 4-C1 4-СНз +++ + +++ —1_ + +++ 4-Br 4-СНз +++ ++ ++ ++ + 4 h 4-C1 4-F + 0 ++ + 0 ++ 4-Br 4-F ++ + 4—1 l · H — l · + +++

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Ri R isomer Bacteriostatic activity Bacteriocidal activity

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Alkyl Isomer Bacteriostatic activity Bacteriocidal activity

E. ins. Staph. Strept. E. ins. Staph. Strept.

СНз cis + 0 0 + 0 0 C2H5 trance 4—4 + ++ + 0 + ПСЗН7 cis ++ + + μ — μ 0 0 ПС4Н9 A + В +++ ++ H — 1 — H + 0 + ПС5Н11 cis 4-4-4- 4-4-4- 4—1 — H Η — 1 — h 0 ++ пСбН13 cis 4 1—4 4—4 —Μ —Μ + 4—4 ПС7Н15 cis +++ 4—1—4 —1 — μ —1 — μ + ++ nCeH17 cis +++ ++ —1 — μ ++ + +++

Aryl Isomer Bacteriostatic activity Bacteriocidal activity

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Aryl Bacteriostatic activity Bacteriocidal activity

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In the sense of the above-mentioned antifungal and antibacterial activity, the invention provides valuable mixtures containing the active ingredient 1,3-dioxolan-2-ylmethylimidazoles of the formula I or their acid addition salts in a solvent or solid, semi-solid or liquid diluent or carrier. combating the growth of fungi and bacteria using an effective antifungal or antibacterial amount of these ketals of formula I or salts thereof. The compounds may be used in a suitable solvent or diluent, in the form of an emulsion, suspension, dispersion or ointment, on a suitable solid or semi-solid carrier, in conventional or synthetic soaps, detergents or dispersion media, optionally together with other compounds having arachnicidal, insecticidal, ovicidal, fungicidal and / or bactericidal effects, or together with inactive ingredients.

Solid carriers which are suitable for the preparation of mixtures in powder form include various inert, porous and powder formulations of inorganic or organic origin, such as calcium phosphate, calcium carbonate in the form of chalk or ground lime, kaolin, strain, bentonite, talc, diatomaceous earth and boric acid; pulverized cork, sawdust and other finely pulverulent materials of vegetable origin are also suitable carriers.

The active ingredient is mixed with the carrier, for example by grinding; or the inert carrier is impregnated with a solution of the active ingredient in a readily volatile solvent and the solvent is then removed by heating or filtration using a vacuum pump. By addition of a wetting agent and / or a dispersing agent, the powdered formulations can also become easily wettable with water so as to obtain suspensions.

The inert solvents used for the production of liquid preparations should preferably not be readily flammable and preferably odorless and non-toxic to warm-blooded animals or plants in the surrounding environment. Solvents suitable for this purpose include high-boiling oils, for example of vegetable origin and low-boiling solvents with a flash point of at least 30 ° C, such as polyethylene glycols, isopropanol, dimethylsulfoxide, hydrogenated naphthalenes and alkylated naphthalenes. However, it is also possible to use solvent mixtures. Solutions can be prepared in a conventional manner, optionally using a dissolution accelerator. Other liquid forms which may be used include emulsions or suspensions of the active compound in water or a suitable inert solvent, or else concentrates for preparing such emulsions which can be directly adjusted to the desired concentration. For this purpose, the active ingredient is mixed, for example, with a dispersing or emulsifying agent. The active ingredient may also be dissolved or dispersed in a suitable inert solvent and mixed simultaneously or later with the dispersing or emulsifying agent.

It is also possible to use a semi-solid carrier of cream, ointment, pasty or waxy nature into which the active ingredient may be incorporated, optionally with the aid of dissolution accelerators and / or emulsifiers. An example of a semi-solid carrier is petrolatum or other cream bases.

It is also possible to use the active ingredient in the form of aerosols. For this purpose, the active ingredient is dissolved or dispersed, optionally using a suitable inert solvent as a liquid carrier, such as difluorodichloromethane, which boils at atmospheric pressure at a temperature below room temperature, or in another volatile solvent. In this way, pressurized solutions are obtained and sprayed to provide aerosols which are particularly suitable for controlling or controlling molds and bacteria, for example in closed chambers or storage areas, or for use in eradicating or preventing infections caused by fungi or bacteria in plants.

The compounds of the invention and mixtures thereof can be administered by conventional methods. For example, the compounds of the invention or mixtures thereof can control the growth of fungi or bacteria or the infected material or to protect against fungal or bacterial attack, for example by dusting, spraying, rubbing, dipping, anointing, impregnating or other suitable means.

When the compounds of the invention are used in admixture with a suitable carrier, for example in a solution, suspension of a dust, powder, ointment, emulsion and other form, high efficiency is observed over a very wide dilution range. For example, in combating fungi or bacteria, effective concentrations of active ingredient in the range of 0.1 to 10 wt. % by weight of the mixture used. However, higher concentrations may be used depending on the situation.

The following examples illustrate the invention without limitation. All parts are by weight unless otherwise stated.

Example I

A mixture of 11.7 parts of 2-bromo-4'-chloroacetophenone, 9 parts of 1- (p-chlorophenyl) -1,2-ethanediol, 0.5 parts of p-toluenesulfonic acid and 80 parts of benzene is stirred and refluxed for 2 days. The reaction mixture is cooled and washed successively with 2X sodium bicarbonate solution and 1X 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, ice-cooled. The mixture was stirred in acetonitrile, filtered again and washed once more with acetonitrile to give 2- [bromomethyl (-2,4-bis) p-chlorophenyl] -1,3'-dioxolane.

2U2001

Example II

Example IV

A mixture of 11.6 mine of 2-bromo-4'-chloroacetophenone 8.4 parts of α- (hydroxymethyl) benzyl alcohol, 0.1 parts of p-toluenesulfonic acid, 210 parts of benzene and 40 parts of ethanol. The reaction mixture was evaporated and the residue was triturated in methanol. The product was filtered off and crystallized from methanol to give 2- [bromomethyl (-2-) p-chlorophenyl] -4-phenyl-1,3-dioxolane; mp 60 ° C.

Example III

A mixture of 11.6 parts of 2-bromo-4'-chloroacetophenone, 12.4 parts of 1- (2,4-dichlorophenyl) -1,2-ethanediol, 0.1 parts of p-toluenesulfonic acid, 80 parts of n-butanol and 160 parts. Parts of benzene were stirred and refluxed for 24 hours while separating the water, the solvent was removed in vacuo and the residue was triturated in methanol, and the precipitated product was filtered off and crystallized from petroleum ether to give 2- (bromomethyl (-2-) p). -chlorophenyl (-4-) 2,4-dichlorophenyl] -1,3-dioxolane, mp 82.7 ° C.

Using the procedure of Example III and equivalent amounts of the respective starting materials, the following dioxolanes were obtained, optionally after further purification using one of the following procedures:

(a) silica gel column chromatography using trichloromethane as the eluent; or

b) mixing the product with silica in trichloromethane, filtering off the silica gel and evaporating the solvent.

Re R7 Melting point cleaning 4-Br 4-01 101.3 ° C - 4-Br 2,4- (01) 2 99.9 ° C - 4-ОСНз 4-C1 115.6 ° C - - 4-C1 63.9 ° C - 4-CH1 2,4- (01) 2 89.9 ° C - 4-Br 4-Br 96.8 ° C - 4-СНз 4-C1 122 [deg.] C - 4-СНз 4-Br 118.6 ° C - 4-СНз 2-01 - - 2,4- (01) 2 - - and - 2,4- (01) 2 - and 24--01) 2 4-C1 - and 4-C1 2-01 - b 2-C1 2,4- (01) 2 - b 4-Br 2-C1 - b 2-C1 4-01 - b 2,4- (01) 2 2,4- (01) 2 - b 4-Br - 70 ° C b - 4-Br 71.3 ° C b 2,4- (01) 2 2-C1 - b 24 - (01) 2 4-Br - b 4-C1 4-Br 80.5 ° C b 3-C1 2,4- (01) 2 - b 2-C1 4-Br - b 4-01 4-CH3 - b 4-Br 4-CH3 - b 4-C1 4-F - b 4-Br 4-F - b 4-Br 4-C1 101.3 ° C - 4-Br 2,4- (01) 2 99.9 ° C - 4-OCH3 4-C1 115.6 ° C - - 4-C1 63.9 ° C - 4-CH3 2,4- (01) 2 89.9 ° C - 4-Br 4-Br 96.8 ° C - 4-CH3 4-C1 122 [deg.] C - 4-CH3 4-Br 118.6 ° C - 4-CH 2 2-C1  - - 2,4- (01) 2 - - · and

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a b b b b b b b b

Example V

To the Grignard complex, previously prepared from 98 parts of 1- (chloromethyl) -5,4-dichlorobenzene and 14 parts of magnesium in 70 parts of 1,1'-oxybisethane which is stirred and heated to reflux, a solution of 46.5 is added dropwise. The reaction mixture was cooled in an ice bath and quenched by the dropwise addition of 120 parts of a concentrated hydrochloric acid solution. The mixture was poured into a mixture of 2-chloromethyl-oxirane in 350 parts of 1,1'-oxybisethane. The organic phase was washed with 3 X water, the aqueous phase was extracted with 1,1'-oxybisethane, the combined phases were dried, filtered and evaporated.

2,4-dichloro-α- (chloromethyl) benzenepropanol; b. 130 ° C at 0.04 mm pressure.

Example VI

Using the procedure of Example V and equivalent amounts of the respective starting materials, the following compounds were prepared:

R boiling point

2-Cl 118 ° C at 0.01 mm pressure

2.6- (01) 2136 ° C at 0.2 mm pressure

4-ОСНз 140 ° C at 0.2 mm pressure

4-Cl 130-135 ° C at 0.3 mm pressure

Example VII

A solution of 87 parts of 2,4-dlchloro-α- (chloromethyl) benzenepropanol in 144 parts of concentrated sodium hydroxide solution and 350 parts of 2,2'-oxybispropane was stirred at room temperature overnight. The product is extracted with 2,2'-oxybispropane. The extract was washed with water, dried, filtered and evaporated. The oily residue was distilled to give [2- (2,4-dichlorophenyl) ethyl] oxirane; b. 90 DEG-98 DEG C. at 0.01 mm pressure.

Example VIII

Using the procedure of Example VII and equivalent amounts of suitable starting materials, the following oxirane derivatives were obtained:

R boiling point

2-C1 66—70 ° C at 0.01 mm pressure

2.6- (01) 2 85-89 ° C at 0.01 mm pressure

4-ОСНз 80—90 ° C at 0.05 mm pressure

4-Cl 106-115 ° C at 0.03 mm pressure

Example IX

To the Grignard complex previously prepared from 89 parts of 4- (chloromethyl) -1,1-biphenyl and 12.5 parts of magnesium in 350 parts of 1,1'-oxybisethane, which is stirred and heated to reflux, solution 60 is added dropwise. parts of 3-bromo-1-propene in 180 parts of tetrahydrofuran. Stirring is continued for 2.5 hours at reflux temperature. The reaction mixture was cooled and poured into water. The layers were separated and the aqueous phase was extracted with 1,1'-oxybisethane. The combined organic phases were washed with water, dried, filtered and evaporated. The residue was filtered off and the filtrate was evaporated to give 60 parts of 4- (3-butenyl) -1,1'-biphenyl as a residue.

To a stirred mixture of 88 parts of 3-chloroperbenzoic acid and 650 parts of dichloromethane was added dropwise 60 parts of 4- (3-butenyl) -1,1'-biphenyl, then stirring was continued over the weekend at room temperature. 50 parts of potassium carbonate solution are then added dropwise at 200 L. The organic phase was separated, washed with sodium bisulfite solution and water, dried, filtered, and evaporated to give 63.5 parts [70.87%] [2 - ([1,1'-biphenyl] -4-yl] ethyl of oxoxane as an oily residue.

Example X

To a stirred mixture of 86 parts of 3-chloroperbenzoic acid and 650 parts of dichloromethane was added dropwise (slowly) 53 parts of 1-fluoro-4- (2-propenyl) benzene. Stirring is then continued overnight. at room temperature. 92 parts of potassium carbonate solution are then added dropwise and the layers are separated. The organic phase was washed with sodium bisulfite solution, dried, filtered and evaporated to give 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-1-naphthalenol and II5 parts of 2- (chloromethyl) oxirane was added portionwise 17.1 parts of potassium hydroxide (exothermic reaction). When the exothermic reaction ceases, the mixture is heated to -ref lux and stirred at this temperature for 2 hours. Water was added and the mixture was extracted twice with 3: 1 (1: 1). The combined extracts were washed with X3X water, dried and evaporated. The residue was distilled to give 45.3 parts of 2 - ((4-chloro-naphthalenyloxy) methyl ixirane; b. V. 150-155 ° C at 0.2 mm pressure).

EXAMPLE I a d X II

To a stirred solution of I39 parts of 2-nitrophenol and 138 parts of potassium carbonate in 640 parts of 2-propanone are added dropwise with 2.05 parts of -2- (chloromethyl-oxirane) and then stirring is continued for 2 hours under reflux. washed with 2-propanone. - the filtrate -se - evaporated. the residue - was crystallized from a mixture - _.2! 2'-o.xybispropanu and - petroleum ether (1: I v O. j. - the product was filtered off and dried, yielding N with 38 parts (20%) of 2- (2-nitrophenoxymethyl) oxirane, mp 56 ° C.

P-river ice XII

Following the procedure of Example XII and using an equivalent amount of appropriately substituted phenol or naphthalenol in place of 2-nitrophenol, the following 2-aryloxymethyloxiranes are obtained:

2 - [(2-chloro-5-methylphenoxy) methyl] oxirane, b. At 15 ° C at 0.05 mm pressure;

2- (3,4,5-trichlorophenoxymethyl) oxirane - as an oily residue;

2- (3-chloro- [1,1'-biphenyl] oxirane as a residue;

2 - [(1,6-dibromo-2-naphthalene-7-oxo) methyl-oxirane as a solid residue.

Example XIV

To a stirred solution of 38 parts of 2- (2-phenoxyphenoxy) -dioxide in 10 parts of ethanedioic acid and 3-0 parts of 1,4-dioxane was added 100 parts of water, stirred and refluxed for 2 days. and - the residue crystallizes from a mixture of 2,2'-oxyblspropane and petroleum ether, and the product is filtered off and recrystallized from 2,2'-oxybispropane to give 29.5 parts (13%) of 3- (2-diaminophenotexy) -1,2-propanediol; mp 96 ° C.

Example XV

Following the procedure of Example XIV, the following diols are obtained by using an equivalent amount of a suitably substituted oxirane in place of 2 - [(2-nitrophenoxy) methyl] oxirane:

3- (4-chloro-1-naphthalenyloxy) -1,2-propanediol; b. mp 120 ° C;

3- (2-ChloroCi-5-methylenoxy-1,2-propanediol m.p. 59 ° C);

3- (4- (phenoxy) phenoxy] -1,2-piperidiol; b. mp 70 ° C;

3- (3,4,2-trichlorophedoxy) -1,2-azaadadiol; m.p. - 64 ° C;

3- (3-chloro- [1,1'-biphenyl] -4-yloxy) -1,2-propanediol; b. mp 60 ° C;

3- (1,6-dibromo-2-naphthaloyloxy) -1,2-propanediol; -b.’t. 139 [deg.] C .;

3- (4'-Bromophen-11-2-propanediol) mp 60.6 ° C;

3- (4-fluorophedyl) -1,2-propopadiol; b. 125 ° C at 0.05 mm pressure;

4 - ((1,1'-biphenyl] -4-yl) trihutadiol; mp 125.9 ^° C.

1- (2- (N, 4-dichlorophenyl) ethyl) ethanediol; mp 83.2 ° C;

1- (2- (2-chlorophenyl) ethyl) ethanediol; b.

63.1 ° C; '

4- (2-6-chloro-1- (2-yl) -1,2-baranol);

mp 111.7 ° C; and l- (2- (4-chlorophedyl) ethyl) ethanediol; b. 150 degrees Celsius at 0.02 mm pressure.

Example XVI

To the stirred solution. (hot 50 ° C) 64 thoxyphenyl) ethyl] oxioad in 1.8 parts sulfuric acid and 160 parts 2-aroaadad were added 100 parts water. The mixture was stirred for 2 days at room temperature. The reaction mixture was stirred with sodium bicarbonate solution and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated to give - -1- (2- (4-methoxyphenyl) ethyl] -1,2-erhaddiol) as a residue.

Example XVII

To a stirred solution (hot 50 ° C, 64 parts of 1- (3-bromo-4-methylphenyl) -1-ethanone in 160 parts of 1-butanol) was added dropwise over one hour 48 parts of bromine without external heating. 21.7 parts of 1,2-ethanediol, 6 parts of 4-methylbenzenesulfonic acid and 720 parts of benzene were added sequentially, and the mixture was stirred and refluxed overnight with water separation, the reaction mixture was evaporated and the residue dissolved in 2.2. The resulting solution was washed successively with one dilute sodium hydroxide solution and three times with water, dried, filtered and evaporated, and the residue was distilled to give 57 parts (57%) of 2- (bromomethyl) -2- (3-bromo-). 4-methylphenyl) -1,3-dioxolane, bp 126-130 ° C at 0.1 mm pressure.

Example XVIII

Following the procedure of Example XVII and using an equivalent amount of the appropriate 1-aryl-1-ethanone in place of 1- (3-bromo-4-methylphenyl) -1-ethanone, the following 2-aryl-2- (bromomethyl) -1 was prepared, 3-dioxolanes:

2- (bromomethyl) -2- (4-chloro-2-methylphenyl) -1,3-dioxolane;

2- [bromomethyl- (2-) 3,5-dichlorophenyl] -1,3-dioxolane; mp 58 ° C;

2- [bromomethyl (-2-) 2,3-dichlorophenyl] -1,3-dioxolane, mp 135-137 ° C at 0.1 mm pressure;

2- [bromomethyl [-2-] 2,4,5-trichlorophenyl] -1,3-dioxolane; b. 146-147 ° C at 0.3 mm pressure; and

2- [bromomethyl (-2-) 2-chloro-4-methoxyphenyl] -1,3-dioxolane, mp 53 ° C.

Example XIX

To a stirred solution of 112 parts of 4- (2-bromoacetyl) benzonitrile in 320 parts of butanol, 5 parts of 4-methylbenzenesulfonic acid and 360 parts of benzene are added, followed by dropwise addition of 46.5 parts of 1,2-ethanediol. The reaction mixture was evaporated The oily residue crystallized from 2,2'-oxybispropane The product was filtered off and recrystallized from methanol to give 95.12 parts

4- [2- (bromomethyl) -1,3-dioxolan-2-yl] benzonitrile; mp 92.4 ° C.

Example XXi of an equivalent amount of the corresponding 1-aryl-2-bromo-1-ethanone in place of 4- (2-bromoacetyl) benzonitrile, the following 2-aryl-2- (bromomethyl) -1,3-dioxolanes are prepared:

2- [bromoethyl (-2-) 2-naphthalenyl] -1,3-dioxolane; b. mp 64 ° C;

2- [bromomethyl (-2-) 4-bromo-2-methylphenyl] -1,3-dioxolane; b. mp 86 ° C;

2- [bromomethyl (-2-) 3-bromophenyl] -1,3-dioxolane; m.p. 50 ° C;

2- [bromoethyl (-2-) 3-nitrophenyl] -1,3-dioxolane; mp 88 ° C.

Example XXI

A mixture of 11.7 parts of 2-bromo-4'-chloroacetophenone,

11.9 parts of 1- (4-chloro-o-tolyloxy) -2,3-propanediol, 2.5 parts of p-toluenesulfonic acid and 240 parts of benzene are stirred and refluxed for 24 hours in a four-necked round-bottomed flask, equipped with a water separator. The benzene solution is washed successively with dilute sodium hydroxide solution and water. The solvent was removed in vacuo. The residue crystallized from methanol and the less pure fraction was recrystallized from diisopropyl ether to give N-2- [bromomethyl (-2-) p-chlorophenyl (-4-) 4-chloro-o-tolyloxymethyl] -1,3-dioxolane mp 102.5 ° C. The methanol filtrate was evaporated in vacuo to give B-2- (bromomethyl) -2- (p-chlorophenyl) -4- (4-chloro-o-tolyloxymethyl) -1-dioxolane. like the rest.

Example XXII

Following the procedure of Example 21, and using equivalent amounts of the respective starting materials, the following dioxolanes, respectively. after cleaning the product as follows:

(a) silica gel column chromatography using trichloromethane as the eluent; or

b) stirring the product with silica gel in trichloromethane, filtering off the silica gel and evaporating the solvent.

Following the procedure of Example XIX and using the R6 isomer

R7 melting point cleaning

AND 4-С1 4-СНз - В 4-С1 4-СНз - AND 4-С1 2,4- (01) 2 87—89 ° С В 4-С1 2,4- (01) 2 - AND 4-С1 • 4-F 102 ° С В 4-С1 4-F - AND 4-С1 2-СНз 82.2—85 ° С В 4-С1 2-СНз - AND 4-С1 2-С1 85—88.6 ° С В 4-С1 2-С1 - AND 4-С1 4-ОСНз - В 4-С1 4-ОСНз - AND 2,4- (01) 2 4-F - AND 2,4- (01) 2 4-ОСНз - AND 4-С1 4-С1 165 ° С В 4-С1 4-С1 - а В 2,4- (01) 2 4-СНз - b А 2,4- (01) 2 4-СНз - А 2,4- (01) 2 4-С1 - В 2,4- (01) 2 4-С1 - b А 2,4- (01) 2 2,4- (01) 2 - В 2,4- (01) 2 2,4- (01) 2 - b А + В 4-С1 2.6- (01) 2 - А + В 2,4- (С1) 2 2-СНз - b

Example XXIII

A mixture of 11.2 parts of 2.2 ´, 4´-trichloroacetophenone,

14.9 parts of 1- (2,4-dichlorophenoxy) -2,3-propanediol, 3 parts of p-toluenesulfonic acid and 240 parts of benzene were stirred and refluxed for 20 hours in a four-neck round bottom flask equipped with a water trap. . The reaction mixture was washed successively with dilute sodium hydroxide solution and 2 X water. The solvent was removed in vacuo. The residue was triturated in methanol over 3 hours. The precipitated product is filtered off and crystallized from 2-propanol to give A-2 (chloromethyl) -4- (2,4-dichlorophenoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolane; b. 92.5 ° C.

Example XXIV

Mixture of 6 parts 2-bromo-2 ', 4'-dichloroacetophenone, 6 parts 3- (4-chloro-o-tolyloxy) -1,2-propanediol, 3 parts p-toluenesulfonic acid, 80 parts n-butanol and 180 parts of benzene was stirred and refluxed for 24 hours while separating the water. The solvent was removed in vacuo and the residue was triturated in methanol. The product was filtered off and crystallized from petroleum ether to give N-B 2- (bromomethyl) -4- (4-chloro-2-tolyloxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolane.

Example XXV

Following the procedure of Example XXIV and using equivalent amounts of the appropriate starting materials and a particular solvent, the following dioxolanes were prepared:

Isomer R6 R5 melting point solvent AND 2,4- (Cl) 2 C6H5 97.6 ° C benzene AND 2,4- [Cl] 2 3,4- (Cl) 2 -C 6 H 3 -. benzene AND 2,4- (Cl) 2 B-H-CeH- - benzene AND 2,4- (01) 2 3,5- (CH3) 2,4-01-CeH2 115.8 ° C benzene AND 2,4- (Cl) 2 - (Br 2 -Celfc -. benzene AND 2,4- (Cl) 2 4-0N-C6H4 - benzene AND 2,4- (01) 2 2-00Hз-06H3 -, benzene A + B 2,4- (Cl) 2 4- (C 6 H 5) -C 5 H 4 - benzene A-j-B 2.4 · ^!) 2 4- (OHCH 2) 2 - C 6 H 4 90 ° C methylbenzene AND 2,4- (01) 2 3OHs-, 4-Gl · CeHs - methylbenzene AND 2,4- (Cl) 2 3,5- (1) 2-06 ^ 3 - methylbenzene AND 2,4- (Cl) 2 4- (C (CH 3) 3] -C 6 H 4 - methylbenzene AND 2,4- (01) 2 2-Naphthalenyl 117.6 ° C benzene AND 2,4 - (31) 2 2-F-C 6 H 4 125.7 ° C benzene A + B 4-CH 2 4-Br-C6H4 121.1 ° C benzene A-j-B 4-C1 4-Br-C6H4 157.4 ° C benzene A-j-B 4-Br --Br-CeH- 158.7 ° C benzene AND 2,4- (01) 2 3-Br-C 6 H 4 112.7 ° C benzene AND 2,4- (Cl) 2 з, 5- (c5) 2-α 118.7 ° C benzene A + B 2,4- (01) 2 4 - (-: 6H5-o2) oe4 106.1 ° C benzene A-j-B 4-OCH3 4-Br-CeH- 117 ° C benzene AND - 4-Br * -C6 H4 85.6 ° C benzene A + B 2,4- (Cl) 2 4-C11-naphthalenyl 122.7 ° C benzene AND 2,3,4- (01) 3 4-Br-CeH- - methylbenzene AND 2,4- (G1) 2 2-Bi'41Cl2: 5-C6H3 - methylbenzene A + B 2,4- (01) 2 1,6- (Br) 2-2-naphthalenyl - methylbenzene A-j-B 2-01,4-Br - dimethylbenzene A-J-B 3,4,5- (Cl) 3 4- - dimethylbonzen AND 2,4- (01) 2 2-0N-OcH4 - dimethylbenzene AND 2,4- (01) 2 - (nC-Ha-ODCi-Cell- - dimethylbenzene

Example X ^ VII

Example XXVI

A mixture of 13.6 parts of 2-bromo-1- (2,4-dichlorophenyl) -1-ethanone, 12 parts of 3- [2,5-dimethylphenoxy) -1,2-propanediol, 3 parts of 4-methylbenzenesulfonic acid, 80 parts butanol and 180 parts of benzene are stirred and refluxed for 24 hours while separating the water. The reaction mixture was evaporated and the residue was dissolved in dichloromethane. The solution was stirred with silica gel for 30 minutes. Filter and evaporate the filtrate to give A + B - 2- (bromomethyl) -2- (2,4-dichlorophenyl) -4- (2,5-dimethylphenoxymethyl) -1,3-dioxolane as a residue.

Isomer Re Rs

Following the procedure of Example XXVI and using equivalent amounts of the appropriate starting materials and a particular solvent, the following dioxolanes were obtained as a residue:

solvent

A-j-B 2,4- (01) 2 2-01-06H4 A + B 2,4- (CD2 2,6- (01) 2-0643 A + B 2,4- (01) 2 2-Br-C 6 H 4 A + B 2-Br 4-Br-C6H4 A-j-B 2,4- (Cl) 2 2-Cl, 6-H 3 -C 6 H 3 A + B 2,4- (01) 2 2,3- (0122-06113) A + B 2,4- (01) 2 2,4,6- (01) 5-06 ^ 2 A-j-B 2,4- (Cl) 2 2-01, 4- (C (C13) A + B 2,4- (01¼ 2 4,5- (C) 3-S? ^A-j-B 2,4- (01) 2 2,5- (Br) 2, 4-OH-06H2 A + B 2,4- (031) 2 2-002H5-06H4 A-j-B 2-01 --Br-CeH- A-j-B 2,4- (01) 2 2,6- (CH 2 - ^ C 6 H 2 -) AND 2,4- (Cl) 2 6-Br-2-naphthalenyl - 2,4- (01) 2 2- (06½) -06½

benzene benzene benzene benzene methylbenzene methyl, benzene benzene benzene benzene benzene benzene benzene methylbenzene benzene dimethylbenzene

Example XXVIII.

Following the procedure of Example XXVI and using equivalent amounts of the appropriate starting materials and methylbenzene as solvent, the following dioxolanes were obtained after purification of the products by column chromatography on silica gel using trichloromethane as eluent:

2- (bromomethyl) -4- (2-chloro-5-methylphenoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolane as an oily residue;

N- (2- (bromomethyl) -2- (2,4-dichlorophenyl) -4- (3,4,5-trichlorophenoxymethyl) -1,3-dioxolane) as a residue.

Example XXIX

A mixture of 222.5 parts of 2-bromo-1- (2,4-dichlorophenyl) -1-ethanone, 250 parts of 3- (4-bromophenoxy) -1,2-propanediol, 50 parts of 4-methylbenzenesulfonic acid and 3150 parts of benzene is stirred After 16 hours, the theoretical amount of water was released, the reaction mixture was allowed to cool to room temperature, and washed successively with dilute sodium hydroxide solution and twice with water. The product was filtered off (the filtrate was set aside) and crystallized from butanol to give A-2 (bromomethyl) -4- (p-bromophenoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolane.

The filtrate was evaporated. The residue was dissolved in 210 parts of 2,2'-oxybispropane and the solution was allowed to crystallize. The precipitated product is filtered off and discarded. The filtrate was evaporated and the residue was dissolved in 400 parts of a mixture of hexane and trichloromethane (3: 1 by volume). The undissolved portion was filtered and discarded. The filtrate was purified 2X by silica gel column chromatography using hexane / trichloromethane (3: 1 v / v) as eluent. The pure fractions were collected and the eluent was evaporated. The residue solidifies while being purged in light petroleum. The product was filtered off and dried to give B-2- (bromomethyl) -4- (4-bromophenoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolane.

Example XXX

A mixture of 15.2 parts of 2-bromo-1- (2,4-dichlorophenyl) -ethanone, 16.7 parts of 3- (3-chloro- [1,1'-biphenyl] -4-yloxy) -1,2-propanediol 3 parts of 4-methylbenzenesulfonic acid, 40 parts of butanol and 225 parts of dimethylbenzene were stirred and refluxed for 2 days while separating the water. The reaction mixture was allowed to cool to room temperature and 2,2'-oxybispropane was added. The organic phase was washed with dilute 5N sodium hydroxide solution, water, dried, filtered and evaporated. The residue is eluted in a mixture of 2,2´-oxybispropane and petroleum ether. The product was filtered off (the filtrate was set aside) and dried, yielding 12.5 parts of A-2-

- (bromomethyl) -4- (3-chloro- [1,1'-biphenyl] -4-yloxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolane.

The filtrate was evaporated. The residue was dissolved in trichloromethane and stirred with silica gel. Filter and evaporate the filtrate to give 10 parts of A + B-2- (bromomethyl) -4- (3-chloro- [1,1'-biphenyl] -4-yloxymethyl) -2- (2,4-dichlorophenyl) - 1,3-dioxolane as a residue.

Example XXXI

A mixture of 18.1 parts of 3- [4- (phenylmethyl) phenoxy] -1,2-propanediol, 13.4 parts of 2-bromo-1- (2,4-dichlorophenyl) -ethanone, 3 parts of 4-methylbenzenesulfonic acid, 40 parts of butanol and 225 parts of methylbenzene were stirred and refluxed over the weekend. The reaction mixture was evaporated and the oily residue was triturated in methanol. The product was filtered off (the filtrate was set aside) to give 15 parts of A-2 (bromomethyl) -2- (2,4-dichlorophenyl) -4- [4- (phenylmethyl) phenoxymethyl] -1,3-dioxolane, bt 96 degrees Celsius. .

The filtrate left aside is evaporated. The oily residue was purified by silica gel column chromatography using a mixture of trichloromethane and 20% hexane as eluent. The pure fractions were collected and the eluent was evaporated to give 13 parts of B-2 (bromomethyl) -2- (2,4-dichlorophenyl) -4- (4- (phenylmethyl) phenoxymethyl] -1,3-dioxolane as an oil-yellow residue.

Example XXXII

A mixture of 14.9 parts of 3- (2-nitrophenoxy) -1,2-propanediol, 13.4 parts of 2-bromo-1- (2,4-dichlorophenyl jethanone), 3 parts of 4-methylbenzenesulfonic acid, 40 parts of butanol and 225 parts The reaction mixture was evaporated and the oily residue was dissolved in trichloromethane and the solution was washed with dilute 20% sodium hydroxide solution and water, dried, filtered and evaporated. The product was filtered off (the filtrate was set aside) to give 8.5 parts of A-2-oxybispropane.

- (bromomethyl) -2- (2,4-dichlorophenyl) -4- (2-nitrophenoxymethyl) -1,3-dioxolane.

The filtrate left aside is evaporated. The oily residue was purified by 2X silica gel column chromatography using first trichloromethane and then a mixture of trichloromethane and 20% hexane as eluent. The pure fractions were collected and the eluent was evaporated to give 14.5 parts of B-2-

- (bromomethyl) -2- (2,4-dichlorophenyl) -4- (2-nitrophenoxymethyl) -1,3-dioxolane as an oily residue.

Example XXXIII

A mixture of 13.6 parts of 2-bromo-1- (2,4-dichlorophenyl) -1-ethanone, 15.8 parts of 3- (4-bromophenylthio) -1,2-propanediol, 3 parts of 4-methylbenzenesulfonic acid, 180 parts of butanol and 90 parts of benzene are stirred and refluxed for 12 hours while separating the water.

The reaction mixture was evaporated and the residue was dissolved in trichloromethane. The solution was stirred with silica gel for 30 minutes. The filtrate was evaporated to give N + 2- (bromomethyl) -4- (4-bromophenylthiomethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolane as a residue.

Example XXXIV

Following the procedure of Example XXXIII and using equivalent amounts of the respective starting materials, the following dioxolanes were prepared:

A + B-2- (bromomethyl) -2- (2,4-dichlorophenyl) -4- (phenylthiomethyl) -1,3-dioxolane as a residue;

A + B-2- (bromomethyl) -2- (2,4-dichlorophenyl) -4 - [(4-fluorophenyl) thiomethyl] -1,3-dioxolane as a residue.

Example XXXV

A mixture of 19.8 parts of 3- (4-bromophenoxy) -l, 2-propanediol, 15.6 parts of 2- (bromomethyl) -2- (3 _{5-dichlorophenyl)} -l, 3-dioxolane, 4 parts of acetic

The 4-methylbenzenesulfonic acid, 40 parts butanol and 225 parts benzene were stirred and refluxed for 2 days while separating the water. The reaction mixture was allowed to cool to room temperature and the solvent was removed by evaporation in vacuo. The residue is eluted in methanol. The product was filtered off and crystallized from 2-propanol to give 5.5 parts (22%) of A-2-

- (bromomethyl) -4- (4-bromophenoxymethyl) -2-

- (3,5-dichlorophenyl) -1,5-dioxolane.

Example XXXVI

Following the procedure of Example XXXV and using equivalent amounts of the appropriate starting materials, the following dioxolanes were prepared by reaction in a particular solvent.

Using methylbenzene as solvent, prepare:

N-2- (bromomethyl) -4- (4-bromophenoxymethyl) -2- (4-chloro-2-methylphenyl) -1,3-dioxolane; mp 155 ° C;

N-2- (bromomethyl) -4- (4-bromophenoxymethyl) -2- (3-bromophenyl) -1,3-dioxolane;

mp 92.2 ° C;

N-2- (bromomethyl) -2- (4-bromo-2-methylphenyl) -4- (4-bromophenoxymethyl) -1,3-dioxolane;

N-2- (bromomethyl) -2- (3-bromo-4-methylphenyl) -4- (4-bromophenoxymethyl) -1,3-dioxolane; b. mp 100 ° C;

N-4- (2-) bromomethyl- [4- (4-bromophenoxymethyl) -1,3-dioxolan-2-yl] -benzonitrile;

N-2- (bromomethyl) -4- (4-bromophenoxymethyl) -2- (3-nitrophenyl) -1,3-dioxolane;

N-2- (bromomethyl) -4- (4-bromophenoxymethyl) -2- (2,3-dichlorophenyl) -1,3-dioxolane.

Using dimethylbenzene as solvent, prepare:

A + B-4 - [[1,1'-biphenyl) -4-yloxymethyl] -2- (bromomethyl) -2- (2-naphthalenyl) -1,3-dioxolane; mp 160 ° C;

N-4 - [(1,1'-biphenyl) -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;

b. 145 ° C at 0.1 mm pressure;

N + B-4 - [(1,1'-biphenyl) -4-yloxymethyl] -2- (bromomethyl) -2- (2,4,5-trichlorophenyl) -1,3-dioxolane as a residue;

4- 4-B-2- (bromomethyl) -2- (2-, 3-dichlorophenyl) -4-ethyl-1,3-dioxolane; b. 131-133 ° C at 0.1 mm pressure;

N 4 'B-2- (bromomethyl) -2- (2-chloro-4-methoxyphenyl) -4-ethyl-1,3-dioxolane;

b. 142-144 ° C at 0.3 mm pressure;

N + B-2- (bromomethyl) -2- (4-chloro-2-methylphenyl) -4-ethyl-1,3-dioxolane;

b. 118 ° C at 0.15 mm pressure;

N-β-2- (bromomethyl) -4-ethyl-2- (2-naphthalenyl) -1,3-dioxolane as a residue;

2- (bromomethyl) -2- (2,4-dichlorophenyl) -4- [2- (4-methylphenyl) ethyl] -1,3-dioxolane as a residue.

Example XXXVII

A mixture of 13.6 parts of 2-bromo-1- (2,4-dichlorophenyl) -1-ethanone, 14.1 parts of 1- (2- (2,4-dichlorophenyl) ethyl) ethanediol, 3 parts of 4-methylbenzenesulfonic acid, 80 parts of butanol and 180 parts of benzene were stirred and refluxed for 24 hours, the reaction mixture was evaporated and the residue was stirred with 160 parts of methanol for 2 hours, and the precipitated product was filtered off to give 2- (bromomethyl) -2- (2,4 -dichlorophenyl) -4- (2- (2,4-dichlorophenyl) ethyl] -1,3-dioxolane.

Example XXXVIII

Following the procedure of Example XXXVII and using equivalent amounts of the appropriate starting materials, the following dioxolanes were prepared in a particular solvent for the reaction. Using benzene as solvent, prepare:

2- (bromomethyl) -4- [2- (2-chlorophenyl) ethyl] -2- (2,4-dichlorophenyl) -1,3-dioxolane;

2- (bromomethyl) -2- (2,4-dichlorophenyl) -4- [2- (2,6-dichlorophenyl) ethyl] -1,3-dioxolane; A + B-2- (bromomethyl) -2- (2,4-dichlorophenyl-4- [2- (4-methoxyphenyl) ethyl] -1,3-dioxolane;

The following is prepared in methylbenzene as solvent:

2- (bromomethyl) -4- [2- (4-chlorophenyl) ethyl] -2- (2,4-dichlorophenyl) -1,3-dioxolane as a residue; and

2- (bromomethyl) -2- (2,4-dichlorophenyl) -4- (2-phenylethyl) -1,3-dioxolane as a residue.

The following is prepared in dimethylbenzene as solvent:

A B-2- (bromomethyl) -2- (2,4-dichlorophenyl) -4- (phenylmethyl) -1,3-dioxolane as a residue;

A + B-2- (bromomethyl) -4- (4-chlorophenylmethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolane;

A + B-2- (bromomethyl) -2- (2,4-dichlorophenyl) -4- (4-methoxyphenylmethyl) -1,3-dioxolane as a residue.

Example XXXIX

A mixture of 13.5 parts of 1,2-butanediol, 37.5 parts of 2-bromo-1- (2,4-dichlorophenyl Jethanone, 2 parts)

4-methylbenzenesulfonic acid, 40 parts

R Re C2H5 2-C1 C2H5 2-СНз C2H5 4-СНз C2H5 2-Br C2H5 3-C1 C2H5 2-Cl, 4-Br C2H5 4-ОСНз C2H5 3,4,5- (С1) з 11C3H7 2,4- (01) 2 ПС4Н9 2,4- (01) 2 ПС5Н11 2,4- (01) 2 пСбН1з 2,4- (01) 2 11C7H15 2,4- (01) 2 ПС & Н17 2,4- (01) 2 CH2OH 2,4- (01) 2

Example XLI

To the stirred and warm solution of 6.5 parts

1,2-butanediol, 13 parts of 1- (4-chloro-2-methoxyphenyl) ethanone and 40 parts of butanol were added dropwise (slowly) at 40 ° C with 5.7 parts of bromine, after stirring for 30 minutes, 2 parts of 4-methylbenzenesulfonic acid The reaction mixture was separated, washed with potassium carbonate solution, dried, filtered and evaporated. The residue was distilled to give 17 parts (63%) of AB- 2- (bromomethyl) -2- (4-chloro-2-methoxyphenyl) 4-ethyl-1,3-dioxolane, mp 135-140 ° C at 0.3 mm pressure.

Example XLII

Following the procedure of Example XLI and using an equivalent amount of 1- (2,4,5-trichlorophenyl) ethanone instead of 1- (4-chloro-2-methoxyphenyl) ethanone;

butanol and 225 parts of methylbenzene were stirred and refluxed for 24 hours while separating the water. The reaction mixture was cooled, washed 2X with sodium bicarbonate solution, dried, filtered and evaporated. The residue was distilled to give 38 parts (80%) of N -? - 2- (bromomethyl) -2- (2,4-dichlorophenyl) -4-ethyl-1,3-dioxolane; b. 125-130 ° C at 0.1 mm pressure.

Example X L

Following the procedure of Example XXXIX and using equivalent amounts of the appropriate starting materials, the following dioxolanes were prepared:

0 O-' R- ¹ - - ¹ д + в

boiling point up to 99 ° C at 0.05 mm pressure 86 to 88 ° C at 0.05 mm pressure 100 ° C at 0.05 mm pressure

114 to 115 ° C at 0.05 mm pressure 140 ° C at 0.6 mm pressure

122 ° C at 0.15 mm pressure 135 ° C at 0.05 mm pressure

102 to 125 ° C at 0.05 mm pressure 137 to 139 ° C at 0.05 mm pressure 140 to 145 ° C at 0.03 mm pressure 163 to 170 ° C at 0.1 mm pressure 160 to 165 ° C at 0.05 mm pressure 180 to 190 ° C at 0.05 mm pressure 145 to 150 ° C at 0.05 mm pressure

A + B-2- (bromomethyl) -4-ethyl-2- (2,4,5-trichlorophenyl) -1,3-dioxolane; b. 145 ° C at 0.2 millimeter pressure.

Example XLIII

To a stirred solution of 53 parts of 1- (2,4-dibromophenyl) ethanone in 105 parts of Ι, ol-olxybisethane, 32 parts of bromine are added dropwise over 2 hours, then 68 parts of 1H-imidazole with 135 parts of N, N-dimethylformamide are added carefully. The mixture was stirred for 2 hours at 50 DEG C. After the addition of water, the product precipitated, filtered, washed with water and dissolved in CHCl3, dried, filtered and evaporated, and the residue was converted to the hydrochloride salt in 2-propanone and 2-propanol. By adding 2,2'-oxybispropane, the product is crystallized, filtered, washed with 2-propanone and recrystallized from a mixture of ethanol and 2,2'-oxybispropane to give 28.3 parts of 1- (2,4-dibromophenyl) -2- (1H-imidazol-1-yl) -ethanone hydrochloride, mp 204.7 ° C.

2 (2ϋϋ1

3o

Example XLIV

To a stirred solution of 78.7 parts of 2-bromo-1- (2-chloro-4-fluorophenyl) ethanone in 140 parts of 1,1'-oxybisethane was carefully added 106.4 parts of 1H-imidazole. 180 parts of Ν, Ν-dimethylformamide and are then added. the mixture was stirred at 50 ° C for 2 hours. After addition of water, the product is extracted 2X with trichloromethane. The combined extracts were washed 3 times with water, dried, filtered and evaporated. The residue was converted to 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'-oxyblspropane. 1.5 'parts of 1- (2-chloro-4-fluorophenyl) -2- (1H-imidazolyl) ethanol are obtained; mp 197.4 ° C.

XLV example

A. To a stirred mixture of 67.2 parts of A-β-2- (2-methyl-2- (2 ', 2', 2 ', 2', 2 ', 3', 2 ', 3', 2 ', 2', 3 ', 3'). 3-1,3-dioxolane-4-methanol and 100 parts of pyridine were added dropwise with cooling at below 10 ° C 27.2 parts of benzoyl chloride, then stirred for another 2.50 hours at room temperature. The reaction mixture was poured into water and the product was extracted with CHCl3, and the extract was washed successively with dilute hydrochloric acid solution to remove the last pyridine residue, and water, dried, filtered and evaporated.

The oily residue is eluted in methanol. The solid product was filtered off (the filtrate was set aside) and crystallized 2X from ethanol to give 28 parts of cis-2- (bromomethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-4-ylmethylbenzoate; mp 118.3 ° C. The filtrate was evaporated. The oily residue was purified by silica gel column chromatography using 2,2'-oxybispropane as eluent. The pure fractions were collected and the eluent was evaporated. The oily residue is eluted in methanol. The solid product was purified by column chromatography on silica gel using trichloromethane and hexane (30:70) as eluent. The pure fractions were collected and the eluent was evaporated to give 17.5 parts of trans-2- (biomethyl) -2- (2,4- (dichlorophenyl) -1,3-dioxotan-4-ylmethylbenzoate); b. t.

68.6 ° C.

B. A mixture of 12 parts of cis-2- (bromoethyl) -4- (2,4-dichlorophenyl) -1S-dioxolar-1-ylmethylbenzone, 7.5 parts of 60% sodium hydroxide solution, 100 parts of water and 200 parts of 1.4 The dioxane was stirred and refluxed for one hour. The reaction mixture was quenched. The mixture was cooled, poured into water and the product was extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The oily residue was purified by column chromatograaií on silica gel ^tr IC fik ^ i ^ n ^ ^^ et anus, hexane and methanol (50: 49: 1) as eluant. The pure fractions were collected and the eluent was evaporated, yielding 4.5 parts of cis-2- (bromomethyl) -2- (2,4-phenoxy) -1,3-dioxolane-4-methanol as a residue.

Following the procedure of Example XLV-B and using an equivalent amount of trans-2- (bromomethyl) -2- (2,4-dihydroxy) -1,3-dioxoan-4-ylmethylbenzoate in place of cis -bromomethyl) - 2- (2,4-Dichlorophenyl) -1,3-dioxolan-4-ylmethylbenzoate gave:

trans-2- (bromomethyl) -2- (2,4-dichlorophenyl) -1,3-dioxanlan-4-methanol as a residue.

XLVI example

A mixture of 4.5 parts of methanesulfonyl chloride, 10 parts of c's-2- (2,4-dicolophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolane-4-methanol and 50 parts of pyridine is left to leave. The reaction mixture was poured into water and the precipitated product was filtered off and crystallized from benzene to give 10.3 parts (87%) of cis-2- (2,4-dicci ro) i - 1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethyl methanesulfonate, mp 111.7 ° C.

Example XLVII

A mixture of 32 parts of 1,2,4-blltanrriol, 60 parts of 2-bromo-1M 2,4-dichlorophenyl jethanone, 2 parts

Of 4-methylbenzenesulfonic acid, 40 parts of butanol and 225 parts of methylbenzene are stirred and heated. under reflux overnight while separating the water. The reaction mixture was cooled, washed with potassium carbonate solution, dried, filtered and evaporated. The residue was purified by silica gel column chromatography using a 99: 1 mixture of trichloromethane and methanol as eluent. The pure fractions were collected and the eluent was evaporated to give 34 parts (43%) of A4-B-2- (bromomethyl) -2- (2,4-dichlorophenyl) -1,3-dioxothall-4-ethanediol as a residue.

To a stirred mixture of 20 parts of N-B (4-bromomethyl) -2- (2,4-dichlorophenyl) -1'-dioxolane-ethanol and 50 parts of pyridine was added dropwise 6.9 parts of methanesulfonyl chloride. It is then stirred for a further 2 hours at room temperature. Pour the reaction mixture into water and extract the product 2X with 1,1'-oxybisethane. The combined extracts are washed successively with 2 * dilute acid solution. hydrochloric acid and 1X water, dried, filtered and evaporated to give 25 parts (100%) of A + B- [2- [2- (bromomethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan- 4-yl) ethyl methanesulfonate residue.

To a stirred mixture of 25 parts of N- [2- (2- (bromomethyl) -2- (2,4-dichloro-phenyl) -LS-dioxolan-yl) ethyl) methanesulfonate and 100 parts of dimethylsulfoxide was added to a stirred mixture. add 2.2 parts of a 78% sodium hydride dispersion at room temperature. Stirring is continued for 3 hours at 50 ° C. The reaction mixture was poured into water and the product was extracted 2X with 2,2'-oxybispropane. The combined extracts were washed twice with water, dried, filtered and evaporated. The residue was purified by silica gel column chromatography using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated. 15 parts (79%) of A + B-2- (bromomethyl) -2- (2,4202001) are obtained

(dichlorophenyl) -4-ethenyl-1,3-dioxolane as a residue.

Example XLVIII

A mixture of 1.1 parts of imidazole, 1 part of 2- (bromomethyl) -2,4-bis (4-chlorophenyl) -1,3-dioxolane, 0.4 parts of potassium iodide and 20 parts of dimethylformamide is stirred and heated to reflux. 12 hours. Water is added and the product is extracted with Ι, Γ-oxybisethane. The extract was washed with water 2X, dried, filtered and evaporated. The residue, 1- [2,4-bis (4-chlorophenyl) -1,3-dioixolan-2-ylmethyl] imidazole, was filtered off and crystallized from a mixture of 2-propanol and 2,2'-oxybispropane to give 1- [2,4-bis (4-chlorophenyl) -1,3-dioxolan-2-ylmethyl] imidazole disulfate; mp 192.3 ° C.

Example IL

A mixture of 7 parts of imidazole, 7.5 parts of 2-bromomethyl) -2- (4-chlorophenyl) -4-phenyl-1,3-dioxolane, 2 parts of sodium iodide and 100 parts of N, N-dimethylformamide is stirred and heated under The reaction mixture was allowed to cool to room temperature and poured into water, the product was extracted 2X with benzene, the extract was washed 2X with water and the solvent was removed in vacuo to give the residue, 1- [2- (4-chlorophenyl) - 4-Phenyl-1,3-dioxolan-2-ylmethyl] imidazole was converted to the nitrate in 4-methyl-2-pentanone and 2,2'-oxybispropane, and the crude salt was filtered and crystallized from 4-methyl-2. -pentanone to give 1- [2- (4-chlorophenyl) -4-phenyl-1,3-dioxolan-2-ylmethyl-imidazole-disulphate: mp 153.2 ° C.

Example L

Following the procedure of Example IL and using equivalent amounts of the appropriate starting materials, the following imidazole acid addition salts were prepared:

Re R7 acid salt melting point 4-C1 2,4- (01) 2 HNO3 196.6 ° C 4-Br 4-C1 HNO3 152.6 ° C 4-Br 2,4- (Cl) 2 HNOs 205.3 ° C 2,4- (Cl) 2 - 2 (COOH) 2 107.7 ° C 4-ОСНз 4-01 HN03 196.3 ° C - 2,4- (01) 2 HNOs - 163.8 ° C 2,4- (01) 2 4-C1 11 (2) COOH12 119.9 ° C - 4-C1 HNOs 134.7 ° C 4-C1 2-C1 HNOs 183.8 ° C 2-C1 2,4- (01) 2 HNO3 164.2 ° C 2,4- (01) 2 2-C1 HNOs 151 [deg.] C 4-Br 2-C1 HNO3 194.7 ° C 2,4- (Cl) 2 2,4- (01) 2 HN03 161.2 ° C 4-Br - HNOs 156.5 ° C - 4-Br HN.03 131.1 ° C 4-СНз 2,4- (Cl) 2 HNOs 193.6 ° C 4-Br 4-Br HNO3 144.3 ° C 4-СНз 4-C1 HNOs 200.8 ° C 4-C1 4-Br HNO3 145.2 ° C 4-СНз 4-Br HNO3 210.5 ° C 3-C1 2,4- (01) 2 HNOs 165.4 ° C 2-C1 4-Br HNOs 184.1 ° C 4-СНз 2-C1 HNO3 207.5 ° C 4-C1 4-СНз HNOs 144.3 ° C 4-Br 4-СНз HNO3 140.2 ° C 4-C1 4-F HNOs 163.2 ° C 4-Br 4-F HNO3 179.3 ° C

Example LI

A mixture of 13.6 parts of imidazole, 18.5 parts of 2- (bromomethyl) -2- (o-chlorophenyl) -4- (p-chlorophenyl) -1,3-dioxolane, 4 parts of sodium iodide and 150 parts of dimethylformamide was stirred. and heated at reflux for 72 hours. Water was added and the product was extracted 2X with diisopropyl ether. The combined extracts were washed 2X with water, dried, filtered and evaporated. The residue was purified by silica gel column chromatography using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated. The residue, 1- [2- (o-chlorophenyl) -4- (p-chlorophenyl) -1,3-dioxolan-2-ylmethyl] imidazole, was converted to the nitrate in 2-propanol and diisopropyl ether. The salt is filtered off and crystallized from a mixture of ethanol and diisopropyl ether. There was thus obtained 1- [2- (o-chlorophenyl) -4- (p-chlorophenyl) -1,3-dioxolan-2-ylmethyl] imidazole disulfate; mp 183.1 ° C.

Example LII

Following the procedure of Example LI and using an equivalent amount of 2-bromomethyl) -4- (4-bromophenyl) -2- (2,4-dichlorophenyl) -1,3-dioxolane instead of 2- (bromomethyl) -2- (2- chlorophenyl) -4- (4-chlorophenyl) -1,3-dioxolane was prepared by:

1- (4- (4-Bromophenyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl) imidazole disulfate, m.p.

141.9 ° C.

Example L 11 I

To a stirred solution of 2.3 parts of sodium in parts of methanol was added 6.8 parts of imidazole and then 100 parts of dimethylformamide and meth, the anol was removed at atmospheric pressure until an internal temperature of 130 ° C was reached. 7 parts of N-2- (bromomethyl) -2- (p-chlorophenyl) -4- (4-chloro-o-tolyloxymethyl) -1,3-dioxolane are then added and the mixture is stirred and refluxed for 3 hours. . The reaction mixture was poured into water and the product was extracted with benzene. The extract was dried and evaporated in vacuo. The residue, N - [2- (p-chlorophenyl) -4- (4-chloro-o-tolyloxymethyl) -1,3-dioxolan-2-ylmethyl] imidazole, was converted to the nitrate in 2-propanol. Addition of diisopropyl ether precipitates the salt. Filter and crystallize from a mixture of methanol and diisopropyl ether to give cis 1- [2- (p-chlorophenyl) -4-4 (4-chloro-tolyloxymethyl) -1,3-dioxolan-2-ylmethyl] imidazole disulfate; mp 164.3 ° C.

Example LI V

The following imidazoles and imidazole acid addition salts were prepared according to the procedure of Example IIIa and using an equivalent amount of the appropriate starting materials:

Isomer R6 R7 Salt with acid or base melting point of salt trance 4-С1 4-С1 2-СНз HNO3 Mp 190-190.7 ° C cis 4-С1 4-СНз HN03 140.2 ° C trance 4-С1 4-СНз HNOs 160 ° C trance 4-С1 4-С1 ΗΝΟ3 171.8-176.9 ° C cis 4-С1 4-С1 HNOs 165.8-169.6 ° C В 4-С1 2,4-С1 ΗΝ03 Mp 160-165.3 ° C cis 4-С1 4-F ΗΝ03 172.3-174.5 ° C trance 4-С1 4-F ΗΝΟ3 175.9 ° C AND 4-С1 2-СНз ΗΝ03 134.6-145.4 ° C В 4-С1 2-СНз . ΗΝ03 156.6-161.6 ° C В 4-С1 2-С1 ΗΝ03 170.5 ° C В 4-С1 4-ОСНз ΗΝ03 133.2 ° C А 4-С1 2,4- (С1) 2 base 175.4-179.5 ° C А 4-С1 2-С1 base 140.8-143.6 ° C А 4-С1 4-ОСНз base 111.1 ° C

Example · LV

To a stirred solution of 4.6 parts of sodium in 160 parts of methanol was added successively 13.6 parts of imidazole, 300 parts of dimethylformamide and 4 parts of sodium iodide. Methanol was distilled off at atmospheric pressure until an internal temperature of 130 ° C was reached. Then add

25.9 parts of A + B-2- [bromomethyl-4-p-chlorophenyl) -4- [2,6-di-lindenomethoxymethyl] -1,3-dioxanolan and the mixture was stirred at reflux. 2 hours. The reaction mixture was allowed to cool to room temperature and poured into water. The product was extracted 2X with benzene. The combined extracts were washed with 2X water, dried and evaporated in vacuo. The residue containing the "A" and "B" isomers is chromatographed on silica gel using chloroform as eluent. The "A" - isomer is collected as an oily free base and converted to the nitrate salt in 2-propanol. The crude salt crystallized from 2-propanol to give 3.8 parts of Al- [2- (p-chlorophenyl) -4- (2,6-dichlorophenoxymethyl) -1,3 (dioxolane (2 (yimethylimidazob nitrate); bt 145) 8 ° C. The "B" isomer is also collected as an oily free base and converted to the nitrate salt in 2-propanol · diisopropyl ether. The crude salt crystallizes from 2-propanol to give 2.2 parts of B1- [2]. - (PCH) -4- (2,6-di-chlorophenoxonoyl) -1,3-di-slan-2-ylmethyl-imidazole-dilane, mp 197-200.5 ° 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 salts were prepared:

N- [2- (2,4-Dichloro) phenyl] -4- (o-tolyloxymethyl) -1,3-dioxolan-2-ylmethyl] imidazole disulfate; mp 156.2 ° C;

B-1- [2- (2,4,4-bis (4-chloro-piperidin) -4- (o-tolyloxymethyl) -1,3-d-cyclolan-2-ylmethyl) imidazolesesquicoxalate; mp 138.5 ° C;

N-1- [2- (2,4-dichlorophenyl) -4- (2,6-dimethylphenyl) -1,3-dloxolan-2-ylmethyl] m.p. 155.6 ° C;

N-β-1- [2- (2,4-dichlorophenyl) -4- (2,6-dimethylphenoxymethyl) -1,3-disulphonan-2-ylmethyl] -1H-imidazole disulfate;

mp 134.5 ° C.

Example · LVU

Mixture · 6.8 parts of imidazole, 7.8 parts · A-2- (brпптеШу i) -2- (2,4-dichlorophenyl) -4- (phenoxymethyl) -1,3-dioxolane, 4 parts iodide sodium and 150 parts of dimethylformamide were stirred and refluxed for 3 days. The reaction mixture was allowed to cool to room temperature, poured into water and the product was extracted 2 times with diisopropyl ether. The combined extracts containing Al- [2- (2,4-dichlorophenyl) -4- (fluoro-methoxyl) -1,3-dioxolan-2-ylmethyl] imidazole are washed 2X with water and acidified with an excess of concentrated acid solution. nitric. The salt was filtered off and crystallized from a mixture of ethanol and diisopropyl ether to give 5.6 parts of A-1- [2- (2-chloro-phenyl) -4- (phenoxymethyl) -1,3-disulfolan-2-ylmethyl] imidazole nitrate; mp 180.5 ° C.

Example LVIII

Following the procedure of Example LVII and using equivalent amounts of the appropriate starting materials, the following imidazoles and imidazole acid addition salts were prepared.

melting point acid or base salt

Isomer Rs

Rs

AND 2,4- (01) 2 3,4- (С) -2-С6 152.1 ° C HNO3 AND 2,4- (01) 2 3-Cl-C6H4 120.9 ° C HNO3 A + B 2,4- (01) 2 2-CH 3, 4-C 1 -C 6 H 3 121.9 ^O C HN03 AND 2,4 - (31) 2 2,4- (Br) -C 6 H 3 164.9 ° C HNO3 cis 2,4- [CI] 2 2-F-C 6 H 4 135.9 ° C HNO3 AND - 4-Вг-СбШ 167.6 ° C HNO3 (B) 2,4- (01) 2 4-Br-CeHU 131.1 ° C HNO3 cis 2,4- (01) - 4-F-C 6 H 4 Mp 151-152 ° C HNO3 AND 2,4- (01) - 4-CH3-C & H4 141.8 ° C HN03 (B) 2,4- (01) 2 4-CH 3 -C 6 H 4 145.1 ° C (COOH) 2 cis 2,4- (031) 2 4-O) CH 3 -C 6 H 4 184.7 ° C ^ 00 ^ 2 cis 2,4- (01) - 4-Cl-C6H4 152.7 ° C HNO5 AND 2,4- (01) 2 2,4- (01) 12-C6H3 146.5 ° C HN03 AND 2,4- (01) - 4-Br-C6H4 158.9 ° C HN03 AND 2,4- (01) - 3,5- (CH 3) 2 4-Cl-C6H2 185.7 ° C HN03 AND 2,4- (031) 2 4-CN-C 6 H 4 208 ° C HN03 AND 2,4- (01) - 2-OCH 3 -C 6 H 4 110.6 ° C 2 (COOH) 2 AND 2,4- (01) 2 6-Br-2-naphthalenyl 195.5 ° C HN03 cis 2,4- (031) 2 2-Naphthalenyl 156.3 ° C HN03 A + B 2,4- (01) - 4-Cl-2-naphthalenyl 136.7 ° C HN03 cis 2,4- (01) 2 4-Вг-СбИ4 121.8 ° C base

Example LIX

A mixture of 13.6 parts imidazole, 22.2 parts AJB -2- (bromomethyl) -4- (o-chlorophenoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolane, 4 parts potassium iodide and 150 parts dimethylformamide was stirred and refluxed for 3 days. The reaction mixture was allowed to cool to room temperature, poured into water, and the product was extracted 2X with diisopropyl ether. The combined extracts were washed twice with water, dried, filtered and evaporated. The residue was purified by silica gel column chromatography using chloroform as eluent to give 2 fractions.

The first fraction was evaporated and the residue, A-1- [4-

- (o-Chlorophenoxymethyl) -2- (2,4-isophenyl) -1,3-dioxolan-2-ylmethyl] imidazole was dissolved in a mixture of 4-methyl-2-pentanone and diisopropyl ether. The solution was acidified with excess concentrated nitric acid solution. The nitrate salt is filtered off and crystallized from a mixture of 4-methyl-2-pentanone and diisopropyl ether. There was thus obtained N-1- [4- (o-chlorophenoxymethyl) -2- (2,4-difluoro-η 1) -1,3-dioxolan-2-ylmethyl] imidazole dilateate; mp 136.2 ° C.

The second fraction was evaporated and the residue, B-1- [4-

- (r-Chlorophenylmethyl) -2- (2,4-dichlorophenyl)

1,3-dioxolan-2-ylmethyl] imidazole was dissolved in a mixture of 4-methyl-2-pentanone and diisopropyl ether. The solution was acidified with excess oxalic acid. The oxalate is filtered off and crystallized from 4-methyl-2-pentanone to give 4 parts of B-1- [4- (1-chlorophenoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxrlan-2-ylmethyl] imidazole dioxolate; mp 103.5 ° C.

Example LX

Following the procedure of Example LIX and using equivalent amounts of the appropriate starting materials, the following imidazoles and their acid addition salts were prepared. Where only one isomer is given, no second fraction was obtained by chromatography.

2 (2001

Isomer Re R7 acid salt melting point AND 2,4- (Cl) 2 2.6- (01) 2 HNO3 159 [deg.] C cis 2,4- (01) 2 2-Bo HNO3 142.2 ° C trance 2,4- (01) 2 2-Bo 2 (COOH) 2 151.3 ° C AND 2,4- (01) 2 2,5- (CH 3) 2 HNO3 180.9 ° C (B) 2,4- (01) 2 2,5- (CH 3) 2 1.5 (COOH) 2 142.7 ° C AND 2,4- (01) 2 2,4,6- (01) 3 HNOs 181.6 ° C (B) 2,4- (01) 2 2,4,6- (01) 3 2 (COOH) 2 143.9 ° C AND 2,4- (01) 2 2-C1 4-C (CH 3) 3 HN03 141.2 ° C (B) 2,4- (01) 2 2-C1 4-C (CH 3) 3 HNOs 141.1 ° C AND 2,4- (01) 2 2,4,5- (01) 3 HNO3 196.1 ° C (B) 2,4- (01) 2 2,4,5- (01) 3 1.5 (COOH) 2 173.6 ° C cis 2,4- (01) 2 гл-вгк 4-CH3 HNO3 175.4 ° C AND 2,4- (01) 2 2OC2H5 HNO3 117.7 ° C a + b 2-C1 4-Br HNO3 145.3 ° C (B) 2-C1 4-Bo HNO3 152.7 ° C AND 2-Bo 4-Bo HNO3 149.9 ° C (B) 2-Bo 4-Bo HNO3 169.3 ° C AND 2,4- (O ^ 1) 2 2-Cl, 6-CH 3 HNOs 154.2 ° C

Example LIX

A mixture of 9.7 parts 1H-imidazole, 12.5 parts AjB 2- (bromomethyl) -4- (4-bromophenoxymethyl) -2- (4-methylphenyl) -2,3-dioxolade, 3 parts potassium iodide and 135 parts N The N-dimethylformamide was stirred and refluxed for 72 hours. The reaction mixture was poured into water and the product was extracted 2X with 1,1'-oxybiserane. The extract containing [alpha] - [4- (4-methoxyphenyl) methyl] -2- (4-thienyl) -1,3-dioxolad-2-ylmethyl] -1H-imidazole was passed through 2X and washed with excess concentrated solution. nitric acid and 2,2'-oxybisaoopane. The formed salt is filtered off and crystallized from a mixture of ethanol and 2,2'-oxybispooaad to give 5.6 parts of A 1- [4-thromophedoxymethyl] -2t

- (4-methylphenyl) -1,3 (10 &lt; 101 &gt; -2-2H-ylmethyl) -1H-imidazole-disulfide; mp 175.5 ° C.

Example LXII

Following the procedure of Example LXI, but using equivalent amounts of A-j-B-2-

- (4-methylmethyl) -4- (4-bromophenoxymethyl) -2- (4-chlorophedyl) -1,3-dioxolane and AjB-2- (bromomethyl) -4- (4-bromophenoxymethyl) -2- (4-bromophenyl) - ,, 3-010x040 instead of N - 2- (bromomethyl) -4- (bromophenoxymethyl) -2- (4-methylphenyl) -2,3-dioxolade was prepared by Al- [4- (4-Bromo-phenoxymethyl) -2- (4-chloro-phenyl) -1,3-dioxolan-2-ylmethyl-1H-imidazole and its nitrate salt (mp 158 ° C) and Al- (4- (4 (Bromophenyl) -2- (4-bromophenyl) -1,3-dioxolan-2-ylmethyl-1H-imidazole and its nitrate salt (mp 170.8 ° C).

Example LXIII

A mixture of 7.9 parts of lH-imidazole, 11.5 parts of A- | -B 2- _{(bromomethyl)} -2- (2) 4-dich1orfenyl) -4- (4-fedylfedoxymethyl) tl, 3-dioxolane, 4 parts of iodide potassium and 135 parts of N, N-dimethyl formamide were stirred and refluxed for 3 days. The reaction mixture was poured into water and the product was extracted 2X with 1,1'-oxybisethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by silica gel column chromatography using trichloromethane as the eluent.

The first fraction was collected and the eluent was evaporated. The residue was converted to the nitrate salt in 4-methylt-2-a.edtadone and 2,2'-oxybisaoopane. The salt was filtered off and crystallized from a mixture of ethanol and 2,2'-oxybispoopad to give AjB 1- [2- (2,4-Isophenyl) -4- (4-phenylphenoxymethyl) -1,3-dloxoalkylethylmethyl] -1H -imidazolium nitrate; mp 187.9 ° C.

The second fraction was collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-tetrahydro-piperidine to give trans- [2- (2,4-dichlorophenyl) -4- (4-phenylphenoxymethyl) -1,3,4,10x0,4- 2 - ylmethyl-1H-imidazole; mp 155.7 ° C.

Example LXIV

A mixture of 6.8 parts of imidazole, 8.5 parts of B-2- (bromomethyl) -4- (p-chlorophenoxymethyl) -2- (2,4-dichlorophedyl) -2,3-dioxolade, 2 parts of sodium iodide and 100 parts. of dimethylformamide was stirred and refluxed for 36 hours. The reaction mixture was allowed to cool to room temperature and poured into water. The product was extracted 2X with benzene. The combined organic layers were washed 2X with water, dried and the solvent removed in vacuo. The residue was purified by silica gel column chromatography using chloroform as eluent. The pure fractions were collected and the eluent was evaporated. The residue, B-1- (4-Chloro-phenoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolad-2-ylmethyl] -imidazole, is converted to oxalate in 4-methyl-2-pentanedione; addition of diisopropyl ether precipitates the salt. It is filtered off and crystallized from 4-methylt-2-ena-nitrate to give 3.1 parts of trads- (4-a-chlorophenoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolane-2- ylmethyl] imidazolesquioxalate; mp 111 ° C.

LXV example

Following the procedure of Example LXIV, the following were prepared:

B-1- [4- (2,4-dichlorophenoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl] imidazolesquioxalate; b. m.p. 121.2 ° C by reacting B-2- (bromomethyl) -4- (2,4-dichlorophenoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolane with imidazole.

nitric acid. The formed nitrate salt is filtered off and crystallized from a mixture of 2-propanol and 2,2 &apos; -oxybispropane. The product was filtered again and recrystallized from 4-methyl-2-pentanone to give Al- [2- (2,4-dichlorophenyl) -4- (3,5-dimethylphenoxymethyl) -1,3-dioxolane-2. -ylmethyl] -1H-imidazole disulfate hydrate; mp 122.6 ° C.

Example LXVII

Following the procedure of Example LXVI and using equivalent amounts of the respective starting materials, the following imidazoles and their acid addition salts were prepared:

LXVI example

A mixture of 8.6 parts of 1H-imidazole, 11.3. parts of A-2- (bromomethyl) -2- (2,4-dichlorophenyl) -4- (3,5-dimethylphenoxymethyl) -1,3-dioxolane, 4 parts of potassium iodide and 135 parts of N, N- The reaction mixture was poured into water and the product was extracted 2X with 2,2'-oxybispropane, the combined extracts were washed with 2X water and excess solution of conc.

Isomer Re R7 acid salt melting point AND 2-CH3-4-C1 4-Br HNO3 159.3 ° C A = cis 2-CH3-4-Br 4-Br HNO3 164.3 ° C A = cis 3-Br 4-Br HNO3 158.7 ° C A = cis 3-P-4 CH3 4-Br HN03 201.1 ° C A = cis 4-Cn 4-Br HNO3 190.1 ° C AND 2,4- (01) 2 4- (C 6 H 5 -CH 2) HNO3.H2O 110.3 ° C A = cis 3,5- (01) 2 4-Br HNO3 167.1 ° C A = cis 3-NOž 4-Br HNO3 148.8 ° C A = cis 2,4- (01) 2 2-NO2 2 (COOH) 2 95.2 ° C B = trans 2,4- (01) 2 2-NO2 (COOH) 2 157.2 ° C B = trans 2,4- (01) 2 4- (C6H5-CH2) (C00H2 137 ° C A-j-B 2,4- (01) 2 2- (CeH5) HNO3 109.3 ° C A- | -B 2,4- (01) 2 4- [CH 3 -CH (CH 3)] HNO3 115.2 ° C AND 2,4- (01) 2 4- [CH 3 -C (CH 3) 1] HNO3 169.5 ° C AND 2,4- (O ^ 1) 2 3,5- (01) 2 HNO3.H2O 136.7 ° C AND 2,4- (O ^ 1) 2 3-CH 3, 4-Cl HNO3 142.8 ° C AND 2,3,4- (С1) з 4-Br HNO3 174.4 ° C AND 2,4- (01) 2 2-Br, 4-CH 3 HNO3 137.1 ° C

Example LXVIII

A mixture of 42 parts of 1H imidazole, 63 parts of AjB-4 - [[1,1'-diphenyl] -4-yloxy] trans} -2- (bromomethyl) -2- (2,4-dichlorophenylH-1,3) Dioxolane, 20 parts of potassium iodide and 675 parts of N, N-dimethylformamide were stirred and refluxed for 3 days, the reaction mixture was poured into water and the product was extracted with 2,2'-oxybispropane, dried, filtered and evaporated. The residue is converted to the nitrate salt in 4-methyl-2-pentanone and 2,2'-oixybispropane, the product is collected as an oil, the upper phase is decanted and the residual oil solidifies on trituration in 4-methyl-2-pentanone. filtered and crystallized from ethanol to give 5 parts of cis-1- [4- / [1,1'-biphenyl] -4-yloxymethyl] -2- (2,4-dichlorophenyl) -1,3-di oxolan-2-ylmethyl] -1H-imidazole nitrate;

mp 186.5 ° C.

Example LXIX Following the procedure of Example LXVIII and using equivalent amounts of the appropriate starting materials, the following compounds were prepared:

cis-1- [2- (2,4-dichlorophenyl) -4- (2-methoxyphenoxymethyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazolethanedioate hemihydrate, mp 123.6 ° C, cis-1- [2- (2,4-difluorophenyl) -4- (4-fluorophenoxymethyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole, mp 106.7 ° C .

Example LXX

A mixture of 6.4 parts of ΙΗ-imidazole, 10 parts of β-2- (bromomethyl) -4- (3-chloro- [1,1'-biphenyl] -4-yloxymethyl) -2- (2,4- dichlorophenyl) -1,3-dioxolane and 135 parts of N, N-dimethylacetamide were stirred and refluxed for 5 days. The reaction mixture was allowed to cool to room temperature and poured into water. The product is extracted 2X with 1,1'-oxybisethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue crystallized from 4-methyl-2-pentanone to give 2.2 parts (22%) of trans-1 - [[4 ((4-chloro [1,1,1-biphenyl] -4-yloxymethyl)) -2- (2 ', 4', 4 ', 4', 4 ', 5', 5 ', 5', 1 ', 3'-dioxolan-2-ylmethyl, 14'-imidazole, mp 140.8 ° 0.

Example LXXI

A mixture of 10.2 parts of 1H-imidazole and 26.8 parts of 30% sodium methoxide solution was stirred and refluxed for 15 minutes. Then 90 parts of N, N-dimethylformamide are added. The methanol was distilled off to an internal temperature of 130 ° C. After addition of another 90 parts of N-dimethylformamide, 50 parts of Α + Β-4 - ([1,4,4-4,11] -4-ε-χικ + θ-Ι) -2- (bromomethyl) is added in portions at 100 ° C. -2- (2,4-dichlorophenyl) 11,3-dioxolane. It is then stirred for 5 hours at reflux temperature. The reaction mixture was poured into a mixture of water and methylbenzene. The organic phase was separated and stirred with activated carbon. Filter and evaporate the filtrate. The residue was purified 2X by silica gel column chromatography using a mixture of trichloromethane and 1% methanol as eluent. The pure fractions were collected and the eluent was evaporated. The residue crystallized from 2-propanol to give 9.3 parts of cis-1- (4 - ([1,1'-biphenyl] -4-yloxymethyl) -2- (2,4-dichlorophenyl) -1, 3-dioxolan-2-ylr + ethyl] -1H-imidazole;

150.7 ° C.

Example LXXII ·

A mixture of 17 parts of 1H-imidazole, 27.4 parts of A- + 4-B-4 - ([1,1'-biphenyl] -4-ylmethyl) -2- (bromomethyl) -2- ( 3,4,5-trichlorophenyl) -1,3-dioxolane and 135 parts of N, N-dimethylacetamide were stirred and refluxed for 5 days. The reaction mixture was cooled and poured into water. The product was extracted 2X with Ι, Γ-olkoxybisethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by silica gel column chromatography using trichloromethane as eluent. The first fractions were collected and the eluent was evaporated. The residue was converted to the nitrate salt in 4-methyl-2-pentanone and bispropane 2,2'toxyl. The salt is filtered off and crystallized from a mixture of aceeonilrile and 2,2'-oxybispropane to give 3 parts of cis-1- [4 - ([1,1'-biphenyl] -4-yloxymethyl) -2- (3,4,5- tert-chlorophenyl) -1,3-dioxollan-2-yl-1-ethyl] -1H-imidazole disulfate; mp 212.2 ° C. The second fraction was collected and the eluent was evaporated. The residue was converted to the nitrate salt in 4-methyl-2-pentanone and 2,2'-oxy bispropanone. The salt is filtered off and crystallized from a mixture of aceeonitrile and 2,2'-dibisbispropane to give 1.9 parts of trans-1- [4 - ((1,1'-biphenyl) -4-yloxymethyl) -2- (3,4) Mp 158 ° C, 5-thichlorophenyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole-disulphate;

Example LXXIII

Following the procedure of Example LXXII and using equivalent amounts of the appropriate starting materials, the following imidazoles and their acid addition salts were prepared:

cis-1- [4- ([1,1'-biphenyl] -4'-biphenyl-4-yl) -2- (4-bromo-4-chlorophenyl) -1S-dioxolane -ylmethyl] -4H-imidazole; mp 161.8 ° C;

trans-1- [4 - ((1,1'-biphenyl) -4-yloxymethyl) -2- (4-methyl-2-methylphenyl) -1,3-dioxolan-2-ylmethyl] -H-imic mp 164.6 ° C;

cis-1- (4 - ((1,1'-biphenyl) -4-yloxymethyl) -2- (2-naphthalenyl) -1,3-dixoxo-2-ylmethyl] -1H-imidazole; bt 152, 7 ° C;

trans-1- [4- ([1,1 &apos; -biphenyl] -4'-yloxymethyl) -2- (2-naphthalenyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazolium nitrate; mp 230.6 ° C;

cis-1- [4- ([1,1'-biphenyl] -4-yloxymethyl) -2- (2, -

4,5-dichlorophenyl) -5,3-dioxolan-2-ylmethyl] -1H-imidazole disulfate; mp 199.2 ° C; and trans-1- [4 - ([1,1'-biphenyl] -4-yloxymethyl) -2- (2,4,5-thichlorophenyl) -1,3-dioxolan-2-ylmethyl] -4Himimidazole ; mp 139.2 ° C.

Example LXXIV

A mixture of 11.5 parts of 1H-imidazole, 17.5 parts of BB-2- (bromomethyl) -2- (2,4,4-bisphenyl) -4- (3,4,5-trichlorophenoxymethyl) -1,3-di-oxolane, 3 parts of potassium iodide and 180 parts of N, N-dimethylacetamide were stirred and refluxed over the weekend. The reaction mixture was poured into water and the product was collected. Extract 4X with 1,1'-oxybutethane. The combined extracts were washed several times with water, dried, filtered and evaporated. The oily residue was purified by silica gel column chromatography using trichloromethane as eluent. First fraction. The (4-isomer) was collected and the eluent was evaporated. The oily residue was converted to the nitrate salt in 4-methyl-2-pentanone. The salt was filtered off and crystallized from a mixture of 4- + 2-pent-2-pentanone and 2,2'-oxybispropanone, and after drying 7.5 parts (40%) of cis-2- [2,4-dichlorophenyl] were obtained. ) -4- (3,4,5-trichlorophenoxymethyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole disulfate nanhydrate; mp 149.9 ° C.

The second fraction (B-isomer) was collected and the eluent was evaporated. The oily residue was converted to the nitrate salt in 4-methyl-2-pentanone. The salt was filtered off and crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane, and after drying, 6.2 parts (27%) of trans-1- [2- (2,4-dichlorophenyl) were obtained. ) -4- (3,4,5-trichlorophenoxymethyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazolidinedioate; mp 169.3 ° C.

Treasure LXXV

Following the procedure of Example LXXIV and using equivalent amounts of the respective starting materials, the following imidazoles and theirs were prepared. acid addition salts. When one isomer has been reported to have difficulty, no second fraction was obtained by chromatography.

Cis-1- (4- (2-methyl-5-methyl-6-methyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole, mp 131.7 ° C ;

trans-1- [4- (2-6-chloro-5-θ6θιγί ίίηοχγιηβΟιγΙ) -2- (4-chlorophenyl) -1,3-110x01- (2-dimethylamino) -1H-imiazrolesquiethanedioate; b. t.

148.7 ° C;

N-1,4 - [(1,6-dibromo-2-naphthalenyloxy) methyl] -2- (2,4-dichlorophenyl) -1,3-dihydroxolan-2-ylmethyl] -1H-imidazoidonate; mp 179.4 ° C;

A-1- [4- (2,3-dicethoxybutyl). -2- (2,4-dichlorophenyl) -1,3-dioxolanlan-2-ylmethyl] -1H-imidazole diethioate; mp 151.1 ° C;

B-1- [4- (2,3-Dichlorophenoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazolesquiethanedioate, mp 156.3 ° C.

Example LXXVI

Following the procedure of Example LVU and using equivalent amounts of the appropriate starting materials, the following compounds were prepared:

N + -1- [4- (4-bromophenylthiomethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole disulfate; mp 170 ° C;

N- [1- [2- [] -4- (phenylthiomethyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole disulfate; mp 122.3 ° C.

Example LXXVII

A mixture of 4.5 parts of 1H-imidazole, 6.5 parts of A-2- (4-bromophenoxy) -4- (4-bromophenoxymethyl) -2- (2,3-dichlorophenyl) -1,3-dioolanlane and 125 parts of N, N-dimethylacetamide were stirred and refluxed for 2 days, the reaction mixture was allowed to cool to room temperature, poured into water and the product was extracted 2X with 1,1'-oxybisethane. concentrated nitric acid solution, the formed nitrate salt was filtered off and crystallized from 4-methyl-2-pentanone to give 5 parts (68%) of cis-1- [4-44-bromophenoxymethyl) -2- (2,3-dichlorophenyl) -1,3-dioxolan-2-ylmethyl] -1'-imidazolyl disulfate; mp 138.9 ° C.

Example LXXVIII

Following the procedure of Example LXXVII and using equivalent amounts of the appropriate starting materials, the following imidazole acid addition salts were prepared:

cis-1- [4- (3-chloro- [1,1'-biphenyl] -4-yloxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole di-nitrate; mp 171.1 ° C;

cis-1- [4- ((1,1'-biphenyl) -4-yl-trifluoromethyl) -2-chloro-4-methoxyphenyl) -1,3-110x0-4-1-2-methyl] -1Hlimidazoidusulfate; b. mp 172.9 ° C;

N-β-1- [2- (2,4-dichlorophenyl) -4- (phenylmethylthiyl) -1,3-dioliolan-2-ylmethyl] -1H-imidazole diethioate; mp 117.1 ° C;

A | B-1- (2- (2,4-dichlorophenyl) -4 - ((4-fluorophenyl) thiomethyl) -1,3-dioxolan-2-ylmethyl} -1H-imidazole diethioate, mp 129.8 ° C;

AJB1- (4- (4-11-ο1 ^ ^ ^γγββ ^ ^ιγ)))) -2- (2,4-ichichlorophenyl) -1,3-dioxolan-2-ylmethyl) -1H-imidazolesquiethanedioate; 6 ° C;

N-β-1- [2- (2,4-dichlorophenyl-4-) 4-methoxyphenylamino] -1,3-dioxolan-2-ylmethyl] -1 H -imidazole diethane diate; mp 94.2 ° C;

cis-2- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl) -1,3-dioxolan-4-ylmethoxy] benzonitrile sulphate; mp 162.1 ° C; and cis-butyl 4- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl-1,3-dioxolan-4-ylmethoxy] benzoanedioate, mp 90.5 ° C.

Example LXXIX

A mixture of 14.4 parts of 1H-imidazole, 18.5 parts of A [beta] 2- (bromomethyl) -2- (2,4-dichlorophenyl) -4- (2- (4-methoxyphenylene)) ethyl] - Of 1,3-dioxolane, 5 parts of potassium iodide and 135 parts of N, N-dimethylacetamide were stirred and refluxed for 2 days, the reaction mixture was allowed to cool to room temperature and poured into water. The combined extracts were washed with water, dried, filtered and evaporated, the residue was converted to the ethanedioate in 4-methyl-2-pentanone and 2,2'-Oxybispropane, and the salt was filtered off and crystallized from the 2,2'-mixture. of oxybispropane and ethanol to give AfB 1- (2- (2,4-dichlorophenyl) -4- (2- (4-methoxylenyl) ethyl) -1,3-dioxolan-2-ylmethyl) -1H-im- mp 130.7 ° C.

Example LXXX

Following the procedure of Example LXXIX and using equivalents. the following imidazoles and their acid addition salts are prepared in amounts of the appropriate starting materials:

1- {4- [2- (4-Chloro-phenyl) -ethyl] -2- (2,4-dichloro-20-yl-phenyl) -1,3-dioxolan-2-ylmethyl) -1H-imidazolyl-ethanedioate; mp 131.9 ° C;

1- (2- (2,4-dichlorophenyl) -4- (2-phenylethyl) -1,3-dioxolan-2-ylmethyl) -1H-imidazolesquiethanedioate, mp 117.8 ° C;

A + B 1- {2- (2,4-Dichloro-phenyl) -4- [2- (4-methyl-phenyl) -ethyl] -1,3-dioxolan-2-ylmethyl) -1H-imidazolesquiethanedioate hydrate; mp 123.8 ° C.

1- {4- [2- (2-Chloro-phenyl) -ethyl] -2- (2,4-dichloro-phenyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole-disulphate, mp 98.8 ° C;

1- {2- (2,4-Dichloro-phenyl) -4- [2- (2,4-dichloro-phenyl-ethyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole-disulphate, mp 158.1 ° C;

A + B 1- (2- (2,4-dichloro-phenyl) -4- [2- (2,4-dichloro-phenyl) -ethyl] -1,3-dioxolan-2-ylmethyl) -1H-imidazole-disulphate, mp 140.1 ° C.

Example LXXXI

To a stirred solution of sodium methoxide prepared from 3.8 parts sodium in 40 parts methanol was added 11 parts 1H-imidazole and 225 parts 225, Ν-dimethylformamide. The methanol was distilled off until the internal temperature was 150 ° C. Then, 19 parts of N -? - 2- (bromomethyl) -2- (2,4-dichlorophenyl) -4-ethyl-1,3-dioxolane are added and the mixture is stirred and refluxed for 1 hour. The reaction mixture was allowed to cool to room temperature and poured into water, the product was extracted 3X with 1,1'-oxybisethane, the combined extracts were washed with water, dried, filtered and evaporated, and the residue was purified by silica gel column chromatography using a mixture of trichloromethane and The first fraction was collected and the eluent was evaporated, the residue was converted to the nitrate salt in 2,2'-oxybispropane, and the salt was filtered off and crystallized from a mixture of 2-propanol and 2,2'-oxybispropane to give 12 g. parts (56%) of A + B1- [2- (2,4-Dichlorophenyl) -4-ethyl-1,3-dioxolan-2-ylmethyl] -1H-imidazole disulfate, mp 149.1 ° C.

Example LXXXII

To a stirred solution of sodium methoxide prepared from 9.8 parts sodium in 40 parts methanol was added 8 parts 1H-imidazole and 225 parts Ν, Ν-dimethylformamide. The methanol was distilled off until the internal temperature was 157 ° C. Then 30 parts of N -? - 2- (4-bromo-2-chlorophenyl) -2- (bromomethyl) -4-ethyl-1, 3-dioxolane are added and stirred for 1 hour at reflux temperature. The reaction mixture was cooled and poured into water. The product is extracted 2X with 2,2'-oxybispropane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by silica gel column chromatography using a mixture of trichloromethane and 2% methanol as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted to the nitrate salt in 2,2'oixybispropane. The salt was filtered off and crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane to give 8.5 parts (26%) of A + + B-1- [2- (4-bromo-2-chlorophenyl) (4-ethyl-1,3-dioxolan-2-ylmethyl) -1H-imidazole disulfate; mp 162.2 ° C.

Example LXXXIII

Following the procedure of Example LXXXII and using equivalent amounts of the appropriate starting materials, the following imidazole acid addition salts were prepared:

O *) A + B

R = 1 ---- J

Ar R 2-C 1 -C 6 H 4 C2H5 2-CH 3 -C 6 H 4 C2H5 4-CH 3 -C 6 H 4 C2H5 2,3,4- (C 1 -C 6 H 2) C2H5 2-ΒΓ-α4 C2H5 2,3- (Cl) C6H [3 C2H5 3-Cl-C6H4 C2H5 4-OCH 3 -C 6 H 4 C2H5 2-CH 3 -4-C 1 -C 6 H 3 C2H5 2-01-4-0011-C6H3 C2H5 3,4,5- (C1) 3 -C6H2 C2H5 2-nayl C2H5 2-OCH3-4-C1-C6H3 C2H5 2,4,5- (С)) - СбН2 C2H5 2,4- (C1-C6H5 nCiH7 2,4- (Cl) 2 -C 6 H 3 nC4H9 2,4- (Cl) 2 -C 6 H 3 nCsHn 2,4- (Cl) 2 -C 6 H 3 nC6Hi3 2,4- (Cl) 2 -C 6 H 8 nC7H15 2,4- (Cl) 2 -C 6 H 3 nCeHi7

acid salt 50 melting point HNO3 147.6 ° C HNO3 117.5 ° C HNO3 172.7 ° C HNO3 176.4 ° C HNO3 135.3 ° C HNO3 140.3 ° C HNO3 151.6 ° C HNO3 157.1 ° C HNO3 126.8 ° C HNO3 117.7 ° C HNO3 195.8 ° C HNO3 195.1 ° C HNO3 131.8 ° C HNO3 180.1 ° C HNO3 119.2 ° C HNO3 113.1 ° C HNO3 128.3 ° C HNO3 99.4 ° C 2 (COOH) 2 131 ° C 2 (COOH) 2 132.8 ° C

Example LXXXIV

A mixture of 32 parts of 1- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl-ethanone), 55 parts of 1,2,3-propanetriol, 35 parts of 4-methylbenzenesulfonic acid, 96 parts of butanol and 360 parts of dlmethylbenzene is added. Stir and reflux for 5 days while separating the water.

The reaction mixture was cooled, washed with potassium carbonate solution and water, dried, filtered and evaporated. The residue was dissolved in a dilute solution of ethanedioic acid. The resulting solution was washed 2X with Ι, Γ-oxybisethane. The aqueous phase was separated and neutralized with potassium carbonate. The product was extracted. The extract was dried, filtered and evaporated. The residue was purified by silica gel column chromatography using a mixture of trichloromethane and 2% methanol as eluent. The first fractions were collected and the eluent was evaporated. The residue was converted to 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. ·. It is obtained

5.5 parts (9.8%) of N-hB-1- [4- (butoxymethyl) -2- (2,4-dimethyl-4-yl) -phenyl] -1H-diH-4-ol; (R) - (2R) -2-methyl-1H-imidazole nitrate; b. -t. 101.8 ° C.

The second fraction was collected and the eluent was evaporated. The residue is covered with 1,1'-oxybisethane. The product was filtered off. and - crystallized from a mixture of 4-methyl-2-pentanone and petroleum ether to give 9.75 parts of A - (- B-2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolane- 4-methanol, mp 128.1 ° C.

Example LXXXV

A mixture of 7.7 parts of 1H-imidaol, 8 parts of cis-2- (bromomethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolane-4-methanol, 1 part of potassium iodide and -180 parts Ν, The Ν-dimethylacetamide was stirred and refluxed for 3 days. The reaction mixture was cooled and evaporated. 50 parts of water and 300 parts of trichloromethane are then added to the residue. Mixture with 3X. washed with water, dried, filtered and evaporated. The residue was purified by silica gel column chromatography using a mixture of - trichloromethane and. 2% methanol as eluent. The pure fractions were collected and the eluent was evaporated. 9.2 parts of cis-2423-dichlorophenyl) -2- are obtained.

- (11 H -imidazol-4-ylmethyl) -1,3-dioxolane-4-methanol; mp 140 ° C.

example LXXXVI

Following the procedure of Example LXXXV and using an equivalent amount of trans-2-

- (bromomethyl) -2- (2,4-dichlorophenyl) -1,3'-dioxolane-4-methanol as a starting material.

trans-2- (2,4-Dichloro-phenyl) -2- (1H-imidazole-

4-chloro-11,3,3-dioxolane-4-methanol; mp 129 ° C.

Example LXXXVII

To a stirred mixture of 4 parts of cis-2- (2,4-dichlorophenyl) -2- (1H-haloidaollylmethyl) -1,3-dioxolane-4-methanol, 2.2 parts of iodomethane and 90 parts of Ν, Ν-dimethylformamide is added 0, 2-dimethylformamide. 5 parts of a 78% sodium hydride dispersion. Stir for 2 hours at room temperature. The reaction mixture was poured into water and the product was extracted 3X with Ι, Γ-oxybisethane. The combined extracts were washed with water and acidified with a solution of nitric acid in Ι, Γ-oxybisethane. The formed nitrate salt is filtered off and crystallized from 4-methyl-2-pentanone. It is obtained

2.2 parts (45%) of cis-1- [2- (2,4-dichlorophenyl) -4- (methoxyphenyl) -1H-dioxolan-4-ylmethyl] -1H-imidazoidonate; mp 140 ° C.

Example LXXXVI I.I

To a stirred mixture of 4 parts of cis-2- (2,4-dichlorophenyl) -2- (N-nitrophenyl) -1,3-dio202001 xolan-4-methanol, 1.7 parts of bromoethane and 90 parts of Ν, Ν Dimethylformamide was added 0.5 parts of a 78% sodium hydride dispersion. The mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and the product was extracted three times with 2,2'-oxybispropane. The combined extracts were washed with water and acidified with a solution of nitric acid in 2,2'-oxybispropane. The formed nitrate salt was filtered off and crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane to give 4.7 parts (93%) of cis-1- [2- (2,4-dichlorophenyl) -4 - (ethoxymethyl) -1,3-dioxolan-2-ylmethyl-1H-imidazole-dilate, mp 134.7 ° C.

Example LXXXIX

Following the procedure of Example LXXXVIII and using an equivalent amount of the appropriate hypobromite or bromelkene instead of bromoethane, the following imidazole acid addition salts were prepared:

cis-1- [2- (2,4-dichlorophenyl) -4- (propoxymethyl) -1,3-dloxolan-2-ylmethyl] -1H-imidazole-butyrate; mp 131.7 ° C;

cis-1- [2- (2,4-dichlorophenyl) -4- (pentyloxymethyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazolyl: mp, mp 78.6 ° C;

cis-1- [2- (2,4-dichlorophenyl) -4- (hexyloxymethyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole disulfate, mp 87.1 ° C;

cis-1- [2- (2,4-dichlorophenyl) -4- (heptyloxymethyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole disulfate; mp 80.7 ° C;

* cis-1- [2- (2,4-dichlorophenyl) -4- (octyloxymethyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole disulfate; mp 73.4 ° C;

cis-1- [2- (2,4-dichlorophenyl) -4- (2-propenyloxymethyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole-disulphate, mp 116 ° C.

Example XC

To a mixture of 4 parts trans-2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) 1,3-dioxolane-4-methanol, 1.7 parts bromoethane and 90 parts Ν, Ν-dimethylformamide 0.5 parts of a 78% sodium hydride dispersion was added and the mixture was stirred at room temperature for 2 hours.

The reaction mixture was poured into water and the product was extracted 2X with 2,2'-oxybispropane. The combined extracts were washed with water and 2,2'-oxybispropane was added. The solution was acidified with nitric acid. The formed nitrate salt is filtered off and crystallized from 4-methyl-2-penanone. 3.5 parts (69%) of trans-1- (2- (2,4-dichlorophenyl) -4- (ethoxymethyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole disulfate are obtained; bt 151.4 Deň: 32 ° C.

Example X С I

To a stirred mixture of 2.5 parts of 1-chloro-4- (chloromethyl) benzene, 4 parts of cis-2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3- dioxolane-4-methanol and 90 parts of N, N-dimethylformamide were added 0.5 parts of a 78% sodium hydride dispersion. Stirring is continued for 5 hours at room temperature. The reaction mixture was poured into water and the product was extracted 2X with 2,2'-oxybispropane. The combined extracts were washed with water, dried, filtered and acidified with nitric acid. The nitrate salt formed is filtered off and crystallized from a mixture of 4-methyl-2-pentanone and 2,2 &apos; -xybispropane. The product is filtered off and recrystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane to give

3.5 parts (56%) of cis-1- [4- (4-chlorophenylmethoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazolylsulphate;

131.7 ° C.

Example X С 11

By repeating the procedure of Example XCI and using an equivalent amount of the appropriate (chloromethyl) benzene instead of 1-chloro-4- (chloromethyl) benzene, the following is obtained:

cis-1- {4 - [(4-bromophenyl) methoxymethyl] -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole-disulphate; mp 101.4 ° C; and C 1-9 - {2- (2,4-dichlorophenyl) -4 - ((4-fluorophenyl) methoxymethyl] -1,3-dioxolan-2-ylmethyl | -1H-imidazole disulfate, mp 107 ° C.

Example X С 111

To a stirred mixture of 3.3 parts 2,4-dichloro-1- (chloromethyl) benzene, 5 parts AjB-2- (2,4-dichlorophenyl) -2- [1H-imidazol-1-ylmethyl) -1,3 -dioxolane-4-methanol and 90 parts of Ν, Ν-dimethylformamide were added 0.5 parts of a 78% sodium hydride dispersion and stirred at room temperature for 3 hours. The reaction mixture is poured into water and the product is extracted 3 times with 2,2'-oxybispropane. The combined extracts were washed with water, dried, filtered and evaporated.

The residue was purified by silica gel column chromatography using trichloromethane as eluent.

The first fraction (A-isomer) was collected and the eluent was evaporated. The residue is converted to the nitrate salt in 4-methyl-2-pentanone and 2,2'-oxybispropane. The salt was filtered off and recrystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane at 0 ° C. 2.9 parts (35%) of cis-1- (2- (2,4-dichlorophenyl) -4 - [(2,4-dichlorophenyl) methoxylmethyl] -1,3-dioxolan-2-ylmethyl) - were obtained. 1H-imidazole disulfate; melting point

96.9 ° C.

The second fraction (B-isomer) was collected and the eluent was evaporated. The residue was converted to the nitrate salt in 4- (4-methyl-2-pentanone) and 1,1-oxybsethanes. The salt was filtered off and recrystallized from a mixture of .alpha.-methyl-.beta.-pentanone and 2,2 &apos; -xybisproppan to give 1.6 parts (19%) of trans- {2- (2,4-tetraisyl) -4 - ((2) Mp 131.9 ° C, 4-dichlorophenyl) methoxymethyl] -1,3-dioxolan-2-ylmethyl] -1H-imidazole disulfate;

Example XCIV

By repeating the procedure of Example XCIII and using an equivalent amount of 4- (chloromethyl) -, n-biphenyl instead of 2,4-dichloro-1-chloromethylbenzenes:

cis-1- [4- ([Ι, Γ-biphenyl] -4-ylmethylamino) -2- (2,4-dimethoxyphenyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazolediethanedioate ;

mp 107.6 ° C; and trans-1- [4 - ([1,1'-biphenyl-4-ylmethoxymethyl) -2- (2,4-difluorophenyl) -1,3-dioxolan-2-ylmethyl] -1-H-imidazole disulfate;

mp 168 ° C.

Example XCV

A mixture of 2.2 parts of (4-hydroxyphenyl) phenylmethanone, 4.2 parts of cis-2- (2,4-dichloro-phenyl) -2- (1H-imidazoill-ylmethyl) -1,3-dioxolan-4-ylmethyl-methanesulfonate, 2 parts potassium carbonate and 68 parts of Ν, Ν-dimethylformamide were stirred overnight at 100 ° C. The reaction mixture was cooled and poured into water. The product was extracted 2X with 1,1-oxybisethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue is converted to the nitrate salt in 4-methyl-2-pentanones and 2,2'-oxyblspropane. 4.5 parts (78%) of cis (4- [2,4-dichlorophenyl) -2- (1H-imidazolil-ylmethyl) -1,3-dioxolan-4-ylmethoxy] phenyl] phenylmethanone nitrate are obtained; mp 179 ° C.

Example XCVI

Following the procedure of Example XC V and using an equivalent amount of a suitable phenol instead of (4-hydroxymethyl) phenylmethanone, the following imidazoles and their acid addition salts are obtained:

cis-5-chloro-2- [2- (2,4-bisphenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] --- meithylphenylphenylmethanone ethanedioate ; mp 170.8 ° C;

cis-methyl --- [2- (2 ', 4', 1 ', 1', 1 ', 1', 2 ', 1', 1 ', 2', 2 ', 2', 2 ', 2', 2 ', 2', 2 ' dioxolan-4-ylmethoxy] benzoanedioate;

mp 167.8 ° C;

cis- {2- [2- (2 '^ - ^ ii ^ 1 ^ 1 i ^ ⁱ ^ i ^{^,} ^ ¹ ^ ¹ ^ ¹⁾ -2- (lH-imidazoill-ylmethy1) -1,3-dioxolane

4-ylmethoxy] 15-methylphenyl | 11. 145.4 ° C;

cis- (4-C-phenyl) {2- [2- (2,1) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] -4-methoxyphenyl] methanone; mp 168.3 ° C;

cis - {2- [2- (2'-Dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] -1,2-methoxyphenyl] phenylmethanone; mp 149.2 ° C;

cis-1- [2- (2,4-bis-naphthyl) -4- [3- (trifluoromethyl) phenoxymethyl] -1,3-dioxoian-2-ylmethyl] -1H-imidazole disulfate;

mp 152.6 ° C; Cis-1- [4- (2- (2'-biphenyl) -1,4,1-biphenyl] -4- (1H-imidazolil-ylmethyl) + dloxolan-4-ylmethoxy) ] lfenyiJethanondusičnan;

mp 182.6 C;

cis-methyl-2- [2- (2,4-difluorophenyl) -2- (1H-indazol-1-ylmethyl) -1,3-dioxolall-4-ylmethoxy] benzoan disulfate;

mp 140.5 ° C; and cis-1- {4-] 2- (2,4-ethoxyphenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] phenyli-1 -propanone nitrate; mp 176.2 ° C.

Example XCV II

A mixture of 12.5 parts of 4-methylphenol, 19 parts of 1- (2-chloro-4-fluorophenyl) -2- (1H-imidazolyl) ethanone hydrochloride, 16 parts of 4-methylbenzenesulfonic acid, 40 parts of butanol, and 225 parts of dimethylbenzene were stirred and refluxed for 6 days while separating the water. After cooling, the reaction mixture was filtered and the filtrate was washed with dilute sodium hydroxide solution and water. After adding 2,2'loxybispropane, the mixture is acidified with a nitric acid solution. The formed nitrate salt is filtered off and crystallized from the mixture

4-methyl-2-pentanone and 2,2'-10-oxybispropanes. 5.7 parts (22%) of N-B-1- [2- (2-chloro-4-fluorophenyl) -1,4-ethyl-1,3-dioxolyl-2-yl] ethyl] -1H-imidazoidonate are obtained; mp 132.4 ° C.

Example XC VIII

Following the procedure of Example XCVII and using equivalent amounts of the respective starting materials, the following imidazoles and their addition salts were prepared:

BB-1- [2- (4-bromophenyl) --- ethyl-1,3-dioxolanyl-2-ylmethyl] -1H-imidazole-disulphate; 11. 194.7 ° C; _;

N-β-1- [2- (2,4-dibromophenyl) -4-ethyl-1,3-dioxoan-12-ylmethyl] -1H-imidazole disulfate; mp 149.7 ° C;

N-β-1- [4-ethyl-2- (2-thienyl p1-dioxoian-2-ylmethyl) -1H-imidazole-disulphate;

mp 135.4 ° C;

Ч 55

AJB-1- {2 - {: 5-methyl-2-1: 1-methyl-4-ethyl-, -1,3,3-dioxolane-2 - [(4-methyl-1,3-dioxolane)] -: N-H-microcyclohexyl nitrate; 11. 164.3 ° C;

A + B-1- [4- (chloromethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazolicrate; Mp, 166.1 ° C;

N + -B1- {4 - [(1,1'-biphenyl) -4-ylmethyl] -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl} -1H -imidazoldiethandioate;

mp 116.8 ° C;

N -} - B-1- [2,4-Dichlorophenyl) -4- (4-fluorophenylmethyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazolesquiethandioate;

mp 153.1 ° C;

A4-B-1- (2- (2,4-dichlorophenyl) -4 - [(4-methylphenylmethyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazolesesethanedioate, mp 123.1 degrees Celsius;

N + B-1- [4- (4-bromophenylmethyl) -2- (2,4-didhoophenyl) -1,3-iodo-oxolan-2-ylmethyl] -1H-imidazolyl diethanedioate;

mp 128.8 ° C;

N + -B-4- {4- [2 - ([1,1'-biphenyl] -4-yl) ethyl] -2- (2,4-dichlorophenyl) -1,3-kioxolan-2-ylmethyl] - 1H-imidazolesquiethandioate hemihydrate; mp 143.9 ° C; and

N + -B-1- {2- (2,4-Dichlorophenyl) -4- [2- (phenylmethyl) phenoxymethyl] -1,3,3-dioxolan-2 H -ylmethyl] -1 H -imidazolesesethanedioate hemihydrate; mp 113 ° C.

Treasure IC

A mixture of 13.8 parts of 1- (2-chloro-4-fluorophenyl) -2- (1H-imidazol-1-yl) ethanone hydrochloride,

14.6 parts of 3 - [(1,1'-biphenyl) -4-yloxy] -1,2-propanediol, 16 parts of 4-methylbenzenesulfonic acid, 40 parts of butanol and 225 parts of dimethylbenzene are stirred and refluxed for 1 week water separation. After cooling, 1,1'-oxybisethane is added and the mixture is washed successively with dilute sodium hydroxide solution and water, dried, filtered and evaporated. The residue was purified by silica gel column chromatography using trichloromethane as eluent.

The first fraction (A-isomer) was collected and the eluent was evaporated. The residue was converted to the nitrate salt in 4-methyl-2-pentanone and 2,2'loxyblspropane. The product was filtered off and crystallized from a mixture of acetoniiril and 2,2'-oxybispropane to give 5 parts of cis-1- {4 - [(1,1'-biphenyl) -4-yloxymethyl] -2- (2-chloro-4- (fluorophenyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole disulfate; mp 185.7 ° C.

The second fraction (B-isomer) was collected and the eluent was evaporated. The residue was converted to the nitrate salt in 4-methyl-2-pentanone and 2,2'-oxybispropane. It is filtered off and crystallized from a mixture of acetoniiril and 2,2'loxyb-spro56 pan. 5.9 parts of trans-1- {4 - [(1,1'-biphenyl) -4-yloxymethyl] -2- (2-chloro-4-fluorophenyl) -1,3-dioxolane-2- are obtained. ylmethyl-1H-imidazole disulfate; mp 156.9 ° C.

Ex

Following the procedure of Example IC and using equivalent amounts of the appropriate starting materials, the following imidazoles and their acid addition salts are obtained. If only one isomer is given, the second fraction was not obtained by chromatography.

cis-1- (4 - [(1,1'-biphenyl) -4- (1-methyl) -4- (2-thienyl) -1,3-dioxolane-2 mp 149.5 ° C;

trans-1- {4 - [(1,1'-biphenyl) -4-ylxymethyl] -2- (2-thienyl) -1,3-dioxolan-2-ylmethyl | -1H-imidazole; mp &gt; 300 ° C;

cis-1 - 4 - [(1,1'-biphenyl) -4-yldxymethyl) -2- (2,4-dibromophenyl) -1,3-dioxolan-2-ylmethyl z ^ olc ^ i ^ si ^ ^ an; mp 174.4 ° C;

trans-1- {4 - [(1,1'-biphenyl] -4-yioxymethyl] -2- (2,4-dibromophenyl) -1,3-kioxolan-2-ylmethyl-4 H -imidazole; mp 141.8 ° C; and cis-1- (4 - [(1,1'-biphenyl-4-yloxymethyl) -2- (5-chloro-2-thienyl) m.p. 1,370-C, 1,3-dioxolan-2-ylmethyl-1H-imidazolium sulphate;

Example C1

To a stirred mixture of 1.1 parts of 3-chloro-1-propyne, 4 parts of cis-2- (2,4-dichlorophenyl) -2- (1H-imi-2-yl) -1,3- of dioxolane-4-methanol and 90 pounds of Ν, k-kimethylformamide were added dropwise to 0.5 parts of a 78% sodium hydride dispersion. Stirring is continued for 3 hours at room temperature. The reaction mixture was poured into water and the product was extracted 2X with Ι, Γ-oxybisethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by silica gel column chromatography using a mixture of trichloromethane and methanol (98: 2) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted to the ethanedioic acid salt in 4-methyl-2-pentanone and 2,2'-oxybispropane. The salt was filtered off and crystallized from 4-methyl-2-pentanone with a particle size of 3.6 kilograms (55%) of cis --- [2- (2,4-dichlorophenyl) -4- (2-propionyloxymethyl) -1,3- dioxolane-2- (2-chlorophenyl) -1H-microcyclohexyl ankioate; t. t.

145.6 ° C.

Example Cil

A mixture of 17 parts of 1 H-imidazole, 16 parts of A4-B-2- (bromomethyl) -2- (2,4-thiophenyl) -4-phenyl-1,3-dioxolane and 225 parts of Ν, Ν-dimethylformamide Stir and heat at reflux for 3 days. The reaction mixture was cooled, poured in, and the product was extracted 2X with Ι, b-oxybisethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by silica gel column chromatography using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted to the nitrate salt in 4-methyl-2-pentanone a

2,2'-oxybispropane. The salt was filtered off and crystallized from 4-methyl-2-pentanone. 2.4 parts (13%) of A + B-1- [2 - [[2,4-dichlorophenyl) -4-ethenyl] -1,3-dioxolan-2-ylmethyl] -1H-imidazolium nitrate are obtained; mp 150.9 ° C.

Claims (12)

OBJECT OF THE INVENTION A process for the preparation of an imidazole derivative of the Formula I wherein: Ar is phenyl, substituted phenyl, thienyl, halothienyl, or naphthyl, and substituted phenyl is phenyl having 1 to 3 substituents such as halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms in the alkyl radical, nitro or cyano, and R is alkyl of 2 to 10 carbon atoms, alkoxymethyl wherein the alkyl group has 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkenylQxymethyl wherein the alkenyl group has 2 to 10 carbon atoms, 2-propionyloxymethyl, hydroxymethyl, halomethyl, aryl, arylalkyl of 1 to 6 carbon atoms in the alkyl radical, aryloxymethyl, arylthiomethyl or arylmethoxymethyl, wherein aryl is in each case phenyl, substituted phenyl, naphthyl or mono- and dihalo-naphthyl and wherein the substituted phenyl is phenyl having 1 to 3 substituents such as halogen, alkyl C 1 -C 6 alkoxy, C 1 -C 6 alkoxy, cyano-nitro, phenyl, phenylmethyl, benzoyl, halo-benzoyl, C 1 -C 6 alkylcarbonyl, alkyloxycarbonyl; Having 1 to 6 carbon atoms in the alkyl radical or trifluoromethyl, provided that when there are more than one substituent, only one of them may be phenyl, phenylmethyl, benzoyl and halobenzoyl, or therapeutically acceptable acid addition salts and stereochemical isomeric forms thereof; by reacting a compound of formula II at a temperature of 100 to 200 ° C WCH ^^ A ^ R .................. J where W represents the function of the reactive ester, in an organic solvent such as dimethylformamide or dimethylacetamide, preferably in the presence of metal iodide, and when the compound of formula II is used in a reaction without preliminary salt formation, an excess of imidazole is preferably used or binding the liberated acid, such as sodium or potassium carbonate or bicarbonate, and optionally converting the obtained compound with an acid into a therapeutically acceptable acid addition salt, and optionally converting the obtained compound into stereochemical optical isomeric forms. 2. The process of item 1 for preparing an imidazole derivative of the Formula Ia, wherein Ar ¹ is phenyl, mono-, di- and trihalophenyl, C 1 -C 6 alkyl-phenyl and C 1 -C 6 alkoxyphenyl, Ar ² is phenyl, substituted phenyl, naphthyl and halo-naphthyl, and wherein the substituted phenyl is phenyl having 1 to 3 substituents such as halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms in the alkyl radical, cyano, phenyl and benzyl , X is oxygen, sulfur and CH 2 and n is an integer of 0 or 1 and therapeutically acceptable acid addition salts and stereochemical isomeric forms, characterized in that a compound of formula II or a metal salt of formula II is reacted with a compound of formula III, H (U) or a metal salt of a compound of formula II with a compound of formula IIIa, W-C -------- 1 _(lfl6 j where W is as defined in item 1, in an organic solvent such as dimethylformamide or dimethylacetamide, and when the compound of formula II is used in a reaction without preliminary salt formation, an excess of imidazole is preferably used or a base is added to bind the liberated acid such as sodium or potassium carbonate or bicarbonate. A process for the preparation of the chemical compound cis-1- [2- (2,4-dichlorophenyl) -4- (4-fluorophenoxymethyl) -1,3-dioxolan-2-ylmethyl] imidazole or a therapeutically suitable addition compound. an acid salt, characterized in that imidazole or its metal salt is reacted with 2- (bromomethyl) -2 (2,4-dichlorophenyl) -4- (p-bromophenoxymethyl) -1,3-dioxolane, and optionally to prepare a therapeutically acceptable acid addition salt of the product. A process for the preparation of the chemical compound 1- [4- (4-bromophenoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl] imidazole or a therapeutically acceptable acid addition salt thereof, by reacting imidazole or a metal salt thereof with 2- (bromomethyl) -2 (2,4-dichlorophenyl) -4- (p-bromophenoxymethyl) -1,3-dioxolane, and optionally preparing a therapeutically acceptable acid addition salt product. A process for the preparation of the chemical compound cis-1- [2- (2,4-dichlorophenyl) -4- (4-methoxyphenoxymethyl) -1,3-dioxodan-2-ylmethyl] imidazole or a therapeutically acceptable acid addition salt, characterized by: by reacting imidazole or a metal salt thereof with 2- (bromomethyl) -2- (2,4-dichlorophenyl) -4- (p-methoxyphenoxymethyl) -1,3-dioxolane, and optionally preparing a therapeutically acceptable addition salt of the product with an acid. A process for preparing the chemical compound cis-1- [2- (2,4-dichlorophenyl) -4- (2-fluorophenoxymethyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole or a therapeutically acceptable addition salt with acid, characterized in that 1H-imidazole or its metal salt is reacted with 2- (bromomethyl) -2- (2,4-dichlorophenyl) -4- (O-fluorophenoxymethyl) -1,3-dioxolane and optionally prepared a therapeutically acceptable acid addition salt of the product. 7. A process for the preparation of the chemical compound 1- (4- (4-bromophenoxymethyl) -2- (4-chlorophenyl) -1,3-dioxolan-2-ylmethyl) -1H-imidazole or a therapeutically acceptable acid addition salt, characterized by: by reacting ΙΗ-imidazole or a metal salt thereof with 2- (bromomethyl) -2- (4-chlorophenyl) -4- (p-bromophenoxymethyl) -1,3-dioxolane, and optionally preparing a therapeutically suitable addition salt; an acid salt of the product. A process for preparing the chemical compound 1- {4 - [(1,1'-biphenyl) -4-yloxymethyl] -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl) -1H -imidazole or a therapeutically acceptable acid addition salt thereof, characterized in that ΙΗ-imidazole or its metal salt is reacted with 4 - [(1,1'-biphenyl) -4-yloxymethyl] -2- (bromomethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolane, and optionally therapeutically suitable an acid addition salt of the product. A process for the preparation of the chemical compound 1- [2- (2,4-dichlorophenyl) -4-ethyl-1,3-dioxolan-2-ylmethyl] -1H-imidazole or a therapeutically acceptable acid addition salt thereof, by reacting-imidazole or a metal salt thereof with 2- (2,4-dichlorophenyl) -2- (bromomethyl) -4-ethyl-1, 3-dioxolane and optionally preparing a therapeutically acceptable acid addition salt of the product. A process for preparing the chemical compound cis-1- {4 - [(1,1'-biphenyl) -4-yloxymethyl] -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl | -1H -imidazole or a therapeutically acceptable acid addition salt thereof, characterized in that ΙΗ-imldazole or its metal salt is reacted with 4 - [(Ι, Γ-biphenyl) -4-yloxymethyl-2-bromomethyl] -2- (2) (4-dichlorophenyl) -1,3-dioxolane and optionally a therapeutically acceptable acid addition salt of the product is prepared. 11. A process for preparing a chemical compound 1- (2- (2-chloro-4-fluorophenyl) -4-ethyl-1,3-dioxolan-2-ylmethyl) -1H-imidazole or a therapeutically acceptable acid addition salt, characterized by reacting 1H-imidazole or its metal salt with 2- (2-chloro-4-fluorophenyl) -2- (bromomethyl) -4-ethyl-1, 3-dioxolane, and optionally a therapeutically acceptable acid addition salt of the product is prepared. - A process for the preparation of the chemical compound 1- (2- (4-bromo-2-chlorophenyl) -4-ethyl-1,3-dioxolan-2-ylmethyl) -1H-imidazole or a therapeutically acceptable acid addition salt thereof, The process of claim 1, wherein the 1H-imidazole or a metal salt thereof is reacted with 2- (4-bromo-2-chlorophenyl) -4-ethyl-1,3-dioxolane and optionally a therapeutically acceptable acid addition salt of the product is prepared.