FI62081C - Process for the preparation of novel therapeutically useful 1- (1,3-dioxolan-2-ylmethyl) imidazole derivatives. - Google Patents

Description

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Beerse, Belgium-Belgium (BE) (72) Jan Heeres, Vosselaar, Belgium-Belgium (BE) (7I +) Oy Kolster Ab (5 ^) Method for the development of new therapeutically useful 1- (1,3-dioxolan-2-ylmethyl) - for the preparation of imidazole derivatives - For the preparation of therapeutically active compounds 1- (1,3-dioxolan-2-ylmethyl) - imidazole derivatives

The invention relates to a process for the preparation of novel 1- (1,3-dioxolan-2-ylmethyl) imidazole derivatives, their pharmaceutically acceptable acid addition salts and their optically active isomers. These compounds are useful as antifungal agents. The formula for the new imidazole derivatives is

'N

1 J

ΓΗ I

wherein Ar is phenyl, substituted phenyl, thienyl, chlorothienyl or naphthyl, wherein the substituted phenyl group has 1 to 3 substituents which may independently be halogen atoms, C 1-4 alkyl, N-alkoxy, nitro or cyano groups, and R is alkyl having 2 to 10 carbon atoms, alkoxymethyl having 1 to 10 carbon atoms in the alkoxy group 2,62081, ethenyl, propenyloxymethyl, 2-propynyloxymethyl, hydroxymethyl, halomethyl, aryl, aryl- C 1-4 alkyl, aryloxymethyl, arylthiomethyl or arylmethoxymethyl, wherein the aryl group is phenyl, substituted phenyl, naphthyl or mono- or dihalonaphthyl, and wherein the substituted phenyl group has 1 to 3 substituents which may independently be C 1-4 alkyl, alkoxy, cyano, nitro, phenyl, phenylmethyl, benzoyl, halobenzoyl, N-alkylcarbonyl, N-alkoxycarbonyl or trifluoromethyl groups, provided that when more than one substituent, only one of which may be phenyl, benzyl, benzoyl or chlorobenzoyl.

U.S. Patent No. 3,575,999 describes compounds of close structure which have in vitro antifungal activity comparable to that of the compounds of formula I. However, the compounds now described are considerably more active in vivo, especially against vaginal candidiasis, than the above-mentioned known compounds.

Imidazole derivatives of the formula I, their pharmaceutically acceptable acid addition salts and their optically active isomers can be prepared a) by reacting a compound of the formula - n 0

B

or an alkali metal salt thereof for reacting, preferably at an elevated temperature, with a compound of formula

W-CH- ^ Ar III

«X.

"Wherein W is halogen, in a suitable organic solvent, preferably in the presence of an alkali metal iodide, or b) ketalizing a compound of formula

[D IV

1 »CH2-C-Ar 3 62081 with a compound of formula

OH

i

r-ch-ch2-oh V

preferably in the presence of an alcohol and a suitable strong acid, or c) O-alkylating in a manner known per se a compound of formula I in which R is HOCH2- with a compound of formula

R1 - W VI

wherein R is alkyl, alkenyl, 2-propynyl or arylmethyl and W is halogen, preferably in the presence of a suitable organic solvent and a suitable strong base, to form a compound of formula I wherein R is R-O-CH 2, or d) by condensing a compound of formula I wherein R is HOCH 2 - with an alkanol of a suitable formula alkyl-OH, preferably in a suitable organic solvent in the presence of a suitable strong acid, to form a compound of formula I wherein R is alkyl-O-CH 2 -, or e) O-alkylation in a manner known per se a compound of formula o ^ N '0Ho Ar VI1 IX, w-ch2--1 wherein W is halogen, with a compound of formula

R2 - OH VIII

2 wherein R is alkyl, alkenyl, 2-propynyl, arylmethyl or aryl, preferably in the presence of a suitable organic solvent and a suitable strong base, to form a compound of formula I, 2 wherein R is R-O-CH 2, and if desired converting the resulting compound to pharmaceutically acceptable to an acid addition salt by reacting the compound with a suitable acid, and / or converting the compound optically to the 4,62081 active isomer in a manner known per se.

In process a) an imidazole of formula II or an alkali metal salt thereof is reacted with a compound of formula III / wherein W is halogen, preferably bromine or chlorine.

The imidazole can first be converted to the metal salt by treatment with a suitable metallizing agent such as a metal alkoxide, e.g. sodium or potassium methanolate, or a metal hydride such as sodium hydride. The metal salt thus obtained is then reacted with a compound of formula III in a suitable organic solvent such as dimethylformamide or dimethylacetamide. A small amount of alkali metal iodide, such as sodium or potassium iodide, may be advantageously added to promote the reaction. Alternatively, the reaction of imidazole with a compound of formula III may be carried out without prior salt formation by contacting the reactants with each other in a suitable organic solvent such as dimethylformamide or dimethylacetamide. Under these conditions, it is convenient to use an excess of imidazole or to add a suitable base such as sodium or potassium carbonate or bicarbonate to the reaction mixture to scavenge the acid liberated during the reaction. However, the use of an imidazole excess is more preferred. It is further preferred to carry out the reaction in the presence of a metal iodide such as sodium or potassium iodide.

In process a), an elevated temperature can be used to accelerate the course of the reaction, and the reactions are preferably carried out at the boiling temperature of the reaction mixture.

In this and the following process alternatives, the reaction products can be isolated from the medium and, if necessary, further purified by methods well known in the art, such as extraction, fine grinding, crystallization, chromatography, etc.

Method a) is more fully described below by means of a reaction scheme.

62081 imidazole W-CH0 ^ ^ .Ar I N NaOCHo sodium salt,> <| II ----> +

L - I

H R — 1-1 II m

DMF

V

II + III Nal_ I

DMF

The ketalization reaction of process b) can be carried out using analogous methods described in the literature, e.g. for the preparation of 2-bromoethyl-2,4-diphenyl-1,3-dioxolane (Synthesis, 1974 (I), 23).

When the reaction is preferably carried out, each reactant is boiled for several hours, azeotropically removed in a suitable organic solvent, preferably in the presence of a simple alcohol such as ethanol, propanol, butanol or pentanol, and a suitable strong acid such as 4-methylbenzenesulfonic acid. Suitable organic solvents include, for example, aromatic hydrocarbons such as benzene, methylbenzene and dimethylbenzene and saturated hydrocarbons such as cyclohexane.

The above reaction can be described as follows:

f-N

P jj 4-methylbenzene-O OH sulfonic acid

CH2-c-Ar + r - (!: h-ch2-oh -----------> I

butanol IV in benzene 6 62081

Process c) can be used to prepare compounds of the formula I in which R represents an alkoxymethyl, alkenyloxymethyl, 2-propynyloxymethyl or arylmethoxymethyl radical, in which O-alkylation is known in a manner known per se, in which R is a hydroxymethyl group with a compound of formula VI in formula W means the same as above. Preferably the reaction is carried out in a suitable organic solvent such as dimethylformamide or dimethylacetamide in the presence of a suitable strong metal base such as sodium hydride, sodium carbonate, potassium carbonate.

rj r ~ i I Ί i CH,, Ar + R -W NaH CH0 Ar X -> 2X "0 0, 7T DMF 0 Ό

VI, I

1 1 H0CH2- R -O-CH2-- 1 I-b I-a

In process d) compounds of formula I wherein R represents an alkyloxymethyl group are prepared by condensing a compound of formula I wherein R is hydroxymethyl with a suitable alkanol. Said condensation reaction may be carried out by boiling the reactants together under a reflux condenser and removing the water azeotropically in a suitable organic solvent such as an aromatic hydrocarbon, e.g. benzene, methylbenzene or dimethylbenzene, a saturated hydrocarbon such as cyclohexane, acid.

ii N

I ii

Nx '4-methylbenzenesulfonic acid I-b + alkyl-OH-7 TTT 7: /? 9 dxmethylbenzem 1 alkyl-O-CH2-1-1 I-c 7 62081

Process e) can be used to prepare compounds of the formula I in which R represents an alkoxymethyl, alkenyloxymethyl, 2-propynyloxymethyl, arylmethoxymethyl or aryloxymethyl group, O-alkylating the compound of the formula VII with a hydroxy compound of the formula VIII in a manner known per se.

li if n — N

L J iL J

l l CH2 Ar CH Ar

+ R -OH K „CO

o ^ 0 —— £ -> 0 '^ 0

j .7TTT DMP, I

w-ch2 - * - VI11 r2-o-ch2 ^ ------; VII I-d

The imidazole derivatives of formula I obtained in base form in the above processes can be converted into their pharmaceutically acceptable acid addition salts by reacting the compound with a suitable acid, suitable acids include inorganic acids such as hydrochloric, hydrobromic and hydroiodic acids; sulfuric, nitric, and thiocyanic acid; phosphoric acid; organic acids such as acetic, propane, hydroxyacetic, cis-hydroxypropane, 2-oxypropane, ethanedicarboxylic, propanedicarboxylic, 1,4-butanedicarboxylic, (Z) -2-butenedicarboxylic, (E) ) -2-butenedicarboxylic, 2-hydroxy-1,4-butanedicarboxylic, 2,3-dihydroxy-1,4-butanedicarboxylic, 2-hydroxy-1,2,3-propanetricarboxylic, benzoic, 3 -phenylpropene, o-hydroxybenzene vinegar, methanesulfone ethane sulfone, 2-hydroxyethanesulfone, 4-methylbenzenesulfone, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic, 2-phenoxybenzoic and 2- acetyloxybenzoic acid. The salts are in turn converted into the corresponding free bases in the usual manner, e.g. by reaction with a base such as sodium or potassium hydroxide.

Intermediates of formula III can be prepared by ketalizing a ketone of formula IX wherein Ar and W are as defined above with a suitable diol of formula V in the same manner as described above for the preparation of compounds of formula I from compounds IV and V.

O OH 4-methylbenzene- W-CH2-C-Ar + R-CH-CH2OH S —- f ° n, A *}. GPPS1 -> m butanol benzene

IX V

Alternatively, intermediates of formula III are prepared by transketalizing a ketal derivative of a ketone of formula IX, such as a lower alkyl ketal or a cyclic lower alkylene ketal, with a glycol of formula V under conditions similar to those described above for direct ketalization. The lower alkyl ketals and cyclic lower alkylene ketals used as starting materials herein are readily obtained by ketalization of a ketone of formula IX with a lower alkanol or alkanediol according to methods known in the art. A number of such 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 R is not phenyl when Ar is phenyl are novel compounds.

A number of precursor glycols of formula V are known and can all be prepared according to methods known from the literature.

In general, they can be derived from the corresponding 2-R-oxiranes of formula X by hydrolytic cleavage of the oxirane backbone with a suitable strong acid such as ethanedicarboxylic acid, sulfuric acid or hydrochloric acid.

(° C (C00H)) 9

R _Z \ - ± -> V

H-O / 1,4-dioxane X *

The oxiranes of formula X, in turn, can be obtained in a number of different ways.

3

Those compounds of formula X-a wherein R represents an alkyl or aryl-lower alkyl group may be prepared, for example, by oxidation of an appropriate alkene of formula XI or an arylalkene with a suitable oxidizing agent such as benzene peroxyacid, e.g. 3-chlorobenzeneperoxyacid.

9 62081 __ p

R3-CH = CH, ♦ HO-C-f \ -> R3-ZA

Cl xi X-a

Alternatively, intermediates of formula Xa may also be prepared by i) converting a suitable halide of formula XII having an alkyl or aryl-lower alkyl group having one carbon atom 3 less than the corresponding R into a Grignard complex with magnesium, ii) reacting said Grignard complex with a suitable halomethyloxirane of formula XIII to give an o-halomethyl alcohol compound of formula XIV; and iii) performing a ring closure reaction on XIV with a base treatment, e.g. sodium hydroxide in a suitable solvent such as 2,2'-oxybispropane.

The above reaction sequence is more fully illustrated by the following reaction scheme: 4 ~ “Λ R -halogen + Mg + halogen CH2- -> solvent

XII XIII

4 ° H NaOH 4 / ° \ R -CH2-CH-CH2halo -> R -CH2-L- ^ 2,2'-oxybispropane XIV X-a

Those intermediates of formula X wherein R is an alkyloxymethyl, alkenyloxymethyl, 2-propynyloxymethyl, arylmethoxymethyl or aryloxymethyl group, Xb, are readily obtained by reacting the appropriate hydroxy compound of formula XV wherein R is alkyl, alkenyl, 2 -propynyl, aryl or arylmethyl group, to react with a suitable 2-halomethyloxirane of formula XIII using O-alkylation methods well known in the art.

10 62081

Intermediates of formula X wherein R represents an arylthiomethyl group, X-c, can be prepared analogously by α-alkylating an arylthiol of formula XVI with a 2-halomethyloxirane of formula XIII.

The above reactions are described below: ° / ° \ R5-OH + halogen-CH2 / .. \ K2CO3 R5-0-CH2 L— \ 2-propanone XV XIII X-b

A

Aryl-SH + XIII --—--> aryl_s “CH2 ^: 2-propanone XVI X-c

Intermediates of formula V wherein R represents an alkenyl group may be prepared, for example, by starting from the appropriate hydroxyalkyl-substituted ethanediol by ketalizing the ethanediol group with a suitable ketone, e.g. 2-propanone, then converting the remaining hydroxy group to a with a base such as sodium hydride in a suitable solvent such as dimethylformamide and finally liberating the free diol from the ketal by treatment with a suitable strong mineral acid such as hydrochloric or sulfuric acid.

The above reactions are preferably carried out such that the ketone used in the ketalization step is an intermediate of formula IX, whereby the alkenyl-substituted dioxolanes of formula III are obtained directly during the above reaction sequence.

The precursor aryl ketones of formula IX are well known and can be prepared according to known methods described in the literature.

For example, bromides are readily obtained by bromination of the corresponding methylarylmethanone with bromine.

11 62081

Aroylmethyl-substituted imidazoles of formula IV, some of which are described in U.S. Patent Nos. 3,717,655 and 3,658,813, are conveniently prepared by reacting a compound of formula IX with imidazole in the same manner as described above for the preparation of compounds of formula I from imidazole and compounds of formula III.

Reactive esters of formula VII used as intermediates in the preparation of compounds of formula I-d are readily obtained by converting the corresponding alcohol of formula I-b to a reactive ester according to methods well known in the art. For example, methanesulfonates and 4-methylbenzenesulfonates are conveniently prepared by reacting the alcohol with methanesulfonyl chloride or 4-methylbenzenesulfonyl chloride, and halides can be prepared by reacting the alcohol with a suitable halogenating agent, such as sulfuryl chloride, phosphorus pent. When the reactive ester is iodide, it is preferably prepared from the corresponding chloride or bromide by replacing the halogen therein with iodine.

It appears from formula I that the compounds have two asymmetric carbon atoms in their structure, namely at the 2- and 4-positions of the dioxolane backbone and can therefore exist in different stereochemical optically isomeric forms.

Diastereomeric racemates of formula I, designated cis and trans forms according to the rules set forth in "Naming and Indexing of Chemical Substances for Chemical Abstracts during the 9th Collective Period (1972-1976)", C.A. 1972.76, Index Guide Section IV, p. 85, can be distinguished in a manner known per se. Suitable methods for this purpose include, for example, selective crystallization and column chromatography. For a number of compounds, the stereochemical configuration was determined experimentally. In the remaining cases, it has generally been agreed to designate the first isolated stereochemical form as A and the second as B, without further reference to the actual stereochemical configuration.

12 62081

Since asymmetric carbon atoms already exist in the intermediates of formula III, it is also possible to distinguish the cis and trans forms, or in general the "A" and "B" forms at this stage, after which the corresponding forms of the compounds of formula I can be obtained by reacting them with imidazole. after as described above. Separation of the cis and trans forms of the compounds of formula III can be carried out in a known manner, as described above for the separation of the compounds of formula I into their cis and trans forms.

When R in the intermediates of formula III represents a hydroxymethyl group, it may be advantageous to first esterify said hydroxymethyl group with a suitable acid halide, e.g. benzoyl chloride, after which the esters thus obtained are separated into their cis and trans forms. to give the corresponding forms of the desired hydroxymethyl-substituted intermediates of formula III.

It will be appreciated that cis- and trans-diastereomeric racemates may be further optically resolved into their isomers, cis (+) -, cis (-) -, trans (+) - and trans (-) - using methods known to those skilled in the art.

The compounds of formula I and their acid addition salts are useful agents for controlling fungi and bacteria. As such, they are valuable in treating humans and animals that suffer from disease-causing microorganisms.

The broad spectrum of fungicidal and bactericidal activity of the compounds of formula I is clearly illustrated by the experimental data presented below.

The fungicidal activity test was performed using a solution of Sabouraud liquid in test tubes each containing 4.5 ml of a liquid solution kept in an autoclave at 120 ° C for 15 minutes. The substances were dissolved in 50% ethanol to a concentration of 20 mg / ml and subsequently diluted with sterile distilled water to a concentration of 10 mg / ml. Subsequent decimal dilutions were then made by distillation of 13,62081! come with water to give a series of stock solutions. To each tube containing 4.5 ml of Sabouraud liquid solution was added 0.5 ml of one (stock solution) to give a concentration of 100 μg, 10 μg, 1 μg or 0.1 μg per ml of the test chemical.

Fibrous fungi were incubated at 25 ° C for 2-3 weeks. A rectangular body with a side of 2 mm was cut and implanted in the liquid solution. A three-day-old culture in Sabouraud's liquid solution was used for yeasts and the planting is 0.05 ml per tube. All cultures were incubated at 25 ° C for 14 days. Final readings were taken after two weeks and have been collected.

to Tables A in the following format: ++++ = complete growth inhibition at a concentration of 0.1 μg / ml + + + = complete growth inhibition at a concentration of 1 μg / ml ++ = complete growth inhibition at a concentration of 10 μg / ml + = complete growth prevention at a concentration of 100 μg / ml 0 = no effect, i.e. growth was observed at the highest concentration tested (100 ug / ml).

The chemicals tested in the first screen were tested on the following 11 fungi: 1. Microsporum canis (Tables Mc) i 2. Ctenomyces mentagrophytes (Tables Ct.m.) 3. Trichophyton rubrum (Tables Tr.r.) 4. Phialophora verrucosa (Ph.v 5. Cryptococcus neoformans (in tables Cr.n.) 6. Candida tropicalis (in C.tr. tables) 7. Candida albicans (in tables C.al.) 8. Mucor species (in tables Muc.) 9. Aspergillus fumigatus ( in tables Af) 10. Sporotrichum schenckii (in tables Sp.s.) 11. Saprolegnia species (in tables Sap.)

A set of substances that proved to be effective

Phycomycetes Mucor at a concentration of 10 μg / ml was also tested on four other phycomycetes species, namely: 1. Absidia ramosa (in the tables Abs.r.) 2. Basidiobolus meristosporus (Bas.m. in the tables) 3. Mortieralla species (in the tables Mort.) 4. Rhizopus (in the tables Rhi.).

14 62081 The method used in this second screening was exactly the same as described above and the results are given in Tables B.

Bactericidal experiments were performed on cultures in phenol red dextrose medium in Difco medium. The same decimal dilution technique as described above was used. The implantation consisted of a platinum loop (5 mm diameter) taken from 24-hour medium culture.

48 hours after incubation, subcultures were made from each culture and the presence or absence of growth was measured after 7 days of incubation to determine the bactericidal activity of the test chemicals as described above.

The substances were tested on the following gram-negative bacilli: 1. Salmonella pullorum gallinarum (in the SPG table) 2. Ascherichia coli (in the E. coli table) and 3. Pseudomonas aeruginosa CPs. aer. in the table); and the following gram-positive bacilli and cooks: 1. Erysipelothrix insidiosa (R. ins. in the table), 2. Staphylococcus hemolyticus (Staph, in the table), and 3. Streptococcus pyogenes (Strept. in the table).

The results are summarized in Tables C.

15 62081

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- Effect on phyccmycetes 26 62081 cl

V

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Rj K2 Iscmeeri Abs.r. Bae.m Mort. Rhi.

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Table C Bacteriostatic and bactericidal effect

The effect on gram-positive bacteria is collected in the table.

2? 62061 ΰ B ^ k ^ erostatic bactericidal effect j R1 'R2 E. ins. Staph.- Strcpt. E. ins. Staph. Strcpt. | 4-Cl 4-Cl 44 ++ ++ - ++ 44 ++ | 4-C1 I-Ι i 44 44 +++ ++ + +++ \ 4-Cl 2,4- (Cl) 2 444 44 4 + 4 ++ ++ 44+ j 4-Br 4-Cl · 4 +4 +++ +++ * 444 + +++!

4-Br 2,4- (Cl) _ 44+ + +++ +++ + +++ I

2.4- (Cl)? H ^ +4 0 ++ ++ 0 ++ 4-OCH- '4-Cl ++ + ++ + + ++ H · 2,4- (Cl) 2 +4 44 +++ + + ++.

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Table C Bacteriostatic and bacterial activity 2

O R

—L v

Isomer Bacteriostatic active bactericidal effect R1 R2 Π - E. ins, Staph. Strept, E. in *. Staph. Strcpt.

Η-Cl 2-CH «, 4-Ci ci · ++++ 0 ++++ ++++ 0 ++++ Η-Cl 4-CH, trans +++ 4+ +++ ++ 4 + +++ 14-Cl 2-CH ,, 4-Cl trans 4444 ++ ++++ ++++ + +++ 4-Cl 4-CH_ cis +++ ++ 44+ +4+ + 1 4 ++

LfCl 4-C1 A 44 + 4 + 444 ++++ + 4 ++ 1 H-Cl 4-C1 B ++++ +4 +++ 4 + 44 4 44+! kCl 2,4- (Cl), A 0 0 ++ 0 0 44 4-C14-F cis +44 0 444 444 0 444 4-Cl 2-CH. A 4444 ++ ++++ 44 + 4 4 ++++ 4 “Cl 2-C1 A 4 + 4 0 +4+ +++ 0 44+ 14-Cl 2-CH B 444+ +4 444 +4 + + +++ ^ -Cl 2,4- (Cl), B 444+ 4+ f + 4 + 4 ++++ 4+ ++++ 4-Cl 4-OCH- A +44 0 * 44+ 4+ 0 ++ - «- 4-Cl 4-F trans 44. 4 44 4 4 44 4-Cl 4-OCH- B 44 4 44 4 4 44 j 4-Cl 2,6- (C I). A '44+ 0 ++++ 4+ 0 4 + 4 +.

4-Cl 2-Cl B 44+ 4 44 +4+ + ++ I

4 -Cl 2,6- (0) - .B 4 + 4 4+ 4 + A ++ 4 4 +4+ * 2.4- (Cl), 4-CH. B! 4+ 44 44 44 4 4+ 2.4- (Cl) f 4-F * A +4 +4 +4 4+ 0 4+ 2, 4- (Cl), 2-CH »A 4 + 4 4 4 + 4 +4+ 4 +4+ »4- (θ), 4-CH- A 4 + 4 44 444 +4+ 4 +44 2.4- (0), 4-OCH- A 44 4 44 4+ 4 ++ 2.4 - (d), 4-C1 ci · 44 4 44 44 4 4+ 2.4- (Cl) 2-CH B 444 4 +4+ +4+ 4 +4+ 2.4- (Cl) 2 2,4- (Cl ) 2 A 444 0 44+ +4+ 0 +4+ 2.4- (Cl) 2 4-C1 trans' 44+ 4+ +4+ ++ 4 +4 444 2.4- (0), 4-Br ·· A 444 4 44+ +44 4 +4+ j 2 | 4- (C1), 2,4- (Ci), B 44+ 44 444 44 4 +4+ 2.4- (0), HA 44+ 4 444 4+ 4 + +44 j 2.4- (Cl) “3, .4- (0) - A 444 4+ +4+ 4 + 4 4 4 + 4 j 2» 4— (Cl) 2 3-0 A 444 4+ 444 4 + 4 4+ +44 j 7.4- (0), 2-0 A 44+ 4+ +4+ +4+ 4 444! 2 »4- (Cl), 2-CH 2. 4-0 A 4 B 4 + 4 4+ 444 4+ 4 +4+ 1 2, 4- (OJ 2-0 B 4 + 4 + 44+ 4+ 4 +4+ 2 14- (Cl), 2, 6- (0), A 444 +4 44+ 4+ + 4+ 2.4- (Clf 3, S * (OL) f, 4-QA 44+ O 444 +44 O 4 + 4!

2.4- (0), 2.4- (Brf, A 4 + 4 O 444 4 + 4 O +4+ S

2.4- (Cl) 2 4-CN CA 44+ 4 44 OO 4+] 2, 4- (Cl) 2 2-Br cis +4+ +4 +44 444 4 444 j 2, 4- (Cl) 2 2 -OCH-, A. 444 4 +44 +4+ 4 +4+! 2, 4- (0), 2-Br trans +4+ 4+ 4+ 4+ 4 4+. ! 2 .4- (Gl), 2,4,6- (0) - A +4+ O +4+ 4+ O 4+ 2, 4- (Cl), 2,5- (CH,), A 4 +4 +4 +44 4 + 4 4 +4+ 2 »4- (G1) 2 2,5- (CHj) 2 B 4 + 4 4+ 4 + 4 +4+ 4 +44 _______________________________________________ i

Table C

2 (continued) Bacteriostatic and bacterial activity.

29 620 81

The rheostostatic or bactericidal active ingredient is the isomer. Staph, Strept. E. ine. Staph. Strep.

2.4- (Cl) 2 2-Cl, 4-tert. but. A 444 44 +44 4+ 0 ++ 2.4- (Cl) 2 2,4,5- (Cl) 3 A ++++ 0 ++ +4+ 0 ++ · j 2, 4- (01) 2 2-C1,4-tert. but. B ++++ ++ ++++ +4+ 4 +++ j 2.4- (0) 2 2,4, 5- (0) 3 B +++ + +++ 4+ + +4 '2.4 - (0) 2 2, 5- (Br) 2,4-CH3 A +++ + +4+ ++ + -H- 2.4- (Cl '£ 2-FA +4+ .4 ++++ + + + 1 +++ 4-CH, 4-Br A 444 ++ 4 + 44 ++ + +++ i $ -Cl 4-Br A ++++ ++ +44+ 4 + 4 + +++ 4-Br 4-Br A 4 + 44 + 4444 +++ + ++ 4 £, 4- (0) 2 2-OC2H5 A 444+ 0 ++++ +4+ 0 4 + 4 <1.-0 4-Br A 4 B 4444 ++ ++++ +4+. + +++ (Ä.-Cl 4-Br B 444 44 444+ ++ + +++ 1 H 4-Br A +++ + + ++++ + 0 4 + 4 j ft.-Br 4-Br A ++++ +++ ++++ +4+ ++ - ++ t a-Br 4-Br B ++++ 4+ 4 * 44 444 4 4444 \% 4- (C \) z 4-C6H5 A 4 B 4444 0 44 444 0 44 j

Qj 4- (0) 2 4-G £, H§ B 0 0 4444 0 0 444 $ (, 4- (0) 2 2,6- (013) 2 A 4444 44 4 + 44 +4+ 4+ + 4+ 4- (Cl) 2 4-Br B +4+ +4+ 4/4 4+ 4 4+ ^, 4- (Cl) 2 2,6- (013) 2 A 4 B +4+ 4+ +4+ 4+ 4 4+ X, 4τ (0) 2 3, 5- (013) 2 A +4+ 4+ +4+ +++ 4 +4+% 4- (0) 2 4-1C3H7 A 4 B +4 4+ 44+ 4+ 4 +4 2 .. 4- (0) 2 2-0, 6-CH3 A 4+ +4 +4 4+ 4 + 4 3 .. 4- (0) 2 4-tert-but A 4 + 4 4+ 4+ +4 4 4+ X, 4- (Cl) 2 3, 5- (0) 2 A +4 +4+ + 4 + 4 4+ 4+ + 4+ 4- (0) 2 3-CH3, 4-0 A 44+ 44 +4 4+ 4+ 4 -1 _________ 1

Table C

3 Bacteriostatic and bactericidal effect 30 6208 1

O "R

'R, ^ cr ^ o ^>. Λ | "* E. ine. Staph. Strept. E. ins. Staph. Strcpt. J

2.4- (0) 2 4-Br A + B +++ ++ 4444 ++ + 444 J

2.4- (0) 2 H A 4 B 4444 44 4444 444 4 444 'J

Table C

4 r; -N

• ^^ CH2-CHz- ^ J

gajCi; er | os ^; aa ^^ nen deficient bacteriocidal activity- R R2 Isomer _use__I__tus__ * E. ins. Staph. Strep. E. ins. Staph. Strcpt.

2.4- (0) 2 2-0 ++++ +++ +++ 4 +++ ++ 444 2.4- (0) 2 2,4- (0) 2 '++++ +++ ++ ++ +++ ++ +++ 2.4- (0) 2 2, 6- (0) 2 A 4 B 4444 444 4444 44+ 44 444 2.4- (0) 2 4-OCH3 A 4 B 4444 4 444 444 4 44 2.4τ (θ) 2 4-0 4444 44 4444 444 4 444 2.4- (0) 2 II 4444 44 444 444 O 44 31 62 Cc

Table C

5 Bacteriostatic and bactericidal effect

- - —N

u R-ϊ — 3 TI Bacteriostatic vqi- bacterium ios_udiritof. ; A- R iso ". Kutus___kutus_ -; E, ine. Staph, Strept. E. ine. Staph. Strept.

^ 4 '(Cl) 2'CgHj C2Hg A + B +++ ++ +++ ++ o ++ - $ -Cl-C6H4 C2H5 A + B ++ + o ++ +! o C2H ,. A + B ++ o ++ o o ς.

4-CH3-C6H4 C2H5 A + B ++ + ++ ++ o: + -.- ^, 3,4- (Cl) 3-C6H2 C2H5 A + B +++ ++ +++ +++ + + -Ϊ- +, «1-Br-C6H4 C2H5 A + B ++ + ++ ++ o% 3- (Cl) 2“ C6H3 C2H5 A + B ++ + + -t ++ o + ·, etc. -Cl, 4-F-C6H C2II5 A + B ++ o ++ ++ o 4- Br-C / H C_H_ A + B '++ o + ++' oo 4 2 5 3-Cl-C, H . C, H_ A + B ++ o ++ ++ o 6 4 2 5 ä-Cl, 4-Br-C6H3 C2H5 A + B +++ + ++ +++ i + a, 4- (Br) ^ -C6H3 C2H5 A + 13 +++ + ++ +++; -r 1- och3-c6h4 c2h5 A + B + o + to% -thienyl C2H5 A + D + o + 0 0 gL-CH3,4-Cl-C6H3 C2Hg A + B +++ + + '++ * · + <£ -Cl, 4-OCl-13 CzH5 A + B ++ + ++ + c <j_naphthyl C_H A + B '+++ + ++ + A + B ++ + ++ 0 0 c 2- OCH3,4-Cl-C6H3 C2II5 A + B + o. + + O 4- (Cl) 2-C6H3 nC3H7 AH B +++ ++ +++, > + * iv Ä.4- (C1) 2-C6H3 nC4H9 A + D χ ++ +++ + 1v I +++ \ * · '* · 4- (Cl) 2-C ^ H3 i nC ^ Hj j A + B +++ ++ +++ +++ + - ^ 4 «(G1) 2“ G £ H3! nC ^ lI ^ 3 A + B +++ +++ +++ +++ i -t- + ---.- t 4- (Cl) 2 ~ C ^ IT, 'nC ^ IIjg A + B +++ +++ ++ - r +++ + v.

S ^, 4- (C1) 2-C6H3 j nCgH17 A + B +++ ++ +++ +++! r + · T,., - X, 4- (Cl), - C, H. i CI-I-Cl A + B + o + + 'o ^ L · kj -s Ct e, 2, 4- (Ci) .- C, K. | CH-, ΟΗ trans +,: o +: o r

At 4- (Cl) 2-C6 il'3 _; CH./OH At3 i ++. ; o · j rv T, 4- (C1) 2-C6H3 j CM OH "• -is + · cooj c. '3.4,5nCl;, - C.II, j C_7i ^ Ark +++ ++ <. - - --ti - 1 _ "b 2 1 2 5. ______j_L______i · I____. _ 32 62081

Table C

6 Bacteriostatic and bacterial residual effect

_OF

O?

Ah2] T ~ 'Vei

alkyyli__0-CH2-3-J

'bacteriostatic effect of er ios and sleep

Alkyl Isomee- ——------ p ± __E ». Staph. Strcpt. E. ins. Staph. Strep.

CH 2 ele + o o + o o C ^ Hg tr an e. ++ + ++ + o + nCjH ^ cis ++ + + ++ o o nC ^ H ^ A + B +++ ++ +++ + o; + nCgHj j cie +++ +++ +++ +++ o ++ nCgHjg .cie +++ ++ Ί + ++ + ++ nC ^ H ^ g cie + ++ +++ +++ + ++ + ++ nCgH17 cie +++ ++ +++ ++ + +++

__OF

Table C y1 7 ^ 'X'O01 o ^ o N—'

-alkyl - OCH-O-CH ^ -J

A ^. τ ^ Bacteriostatic or bactericidal effect |

mer E. ins. Staph. Strep. E. ins. Stapa. Strep. J

4- (C * H_) -C ,, H cis f ++ +++ +++ +++ + -1 · ++ '6 5 6 4 4- (C ^ Hg) -C ^ H ^ trans ++ * ++ +++ Ht ++ ++ f 4-Br-CH cis +++ ++ +++ ++ f + +++ 6 4?., 4- (Cl) 2-C6H cie +++ +++ +++ ++ + ++ 2,4- (Cl ) 2-C6H3 trans +++ ++ +++ +++ + ++ 33 620θ 1

Table C Bacteriostatic and bactericidal activity 8

,_OF

O vC1 aryl-CH2-I-1

BaJcter ^ g ^ static antibacterial effect ^ YY E. ine. Staph. Strep. E. ins. Staph. Strep.

c6k5 +++ ++ ++. +++ + ~~ n 4-Cl-C ^ H ^ +++ t + ++ +++ ++ ++ 4-F-C6H4 +++ ++ ++ ++ + · ++ 4-Clij- C ^ H ^ +++ ++ +++ +++ ++ +++ 4-Br-C ^ H ^ +++ ++ | +++ +++ ++ +++ 4-OCH3-C6H4 +++ + +++ +++ + + -H- 4- (C ^ Hg) -C ^ H4 +++ ++ +++ ++ + ++ 34 62031

Vaginal candidiasis test in rats

Female rats (weight 100 g) were ovariectomized. Three weeks later and weekly thereafter, during the experiment, each rat was injected subcutaneously with 100 μg of estradiol undecylate in sesame oil. The induced pseudochrome was detected by microscopic examination of a vaginal sample. Only animals found to be psendokimic were used in the experiment.

Animals were infected intravaginally with a suspension containing 8.10 ^ C.F.U. (colomy forming units) Candida albians in 0.2 ml saline. Animals were then treated orally once daily for the next 14 days, starting from the day of infection, either as a solvent (PEG 200) or with a solution of the test compound PEG 200. Vaginal samples were taken from all animals 24 hours after the last treatment and cultured on Sabourand agar containing penicillin (20 I.U./ml) and streptomycin (40 μg / ml), after which the number of Candida colonies was counted. Results are expressed as ED 2 Q values (mg / kg). The ED 2 Q values of some of the compounds of formula I are shown in the following table.

Ar K Vaginal candidiasis EDgQ value (mg / kg) (orally) 2.4- Cl2-C6H3 CH2OH 10 j 2.4- Cl2-C6H3 CH2OC2H5 10 2.4- Cl2-C6H3 CH20n.C4H9 10 | i 2,4-Cl2-C6H3 CH2OCH2C = CH8 j 2.4- Cl2-C6H3 CH2OCH2 "C6H4" 10 i (4-Br) j | 2'4 "c12 ~ C6H3 CH2OC6H5 5 i 2.4- Cl2-C6H3 CH2OC6H3 (2- C, 5 and 4-t.C4H9); 2.4- Cl2-C6H3 CH2OC6H4 (4_C6H5) 10 2.4- Cl2-C6H3 CH2O- (2-naphthyl) 10 i 2.4- Cl2-C6H3 | CH2S-C6H4 (4-Br) .5 j 2-Cl-C6-H4 CH2CH2_C6H5 <1 °! 4 "CH3_C5H4 C6H4 (4-CH3) 10 i j4_Br_C6H4 C6H4 (4-F) 2.5 j4" C1 "C6H4 C6H4 (2-Cl) i _______________________________________ _ _; 35 6 2 0 81

Table continues ...

2.4- Cl2-C6H3 C6H3 (2,4-Cl2) <10 4-Cl-C6H5 C6H4 (4-Br) <10 2.4- Cl2-C6H3 CgH3 (2,6-Cl2) 10 2r4-Cl2 "C6H3 CgH4 (4 -OCH3) 10 and 2,4-Cl2-C6H3 C6H4 (4-Cl) 10 and 2,4-Cl2-C6H3 C8H4 (4-CN) 10

The following table compares the vaginal candidiasis activities of some of the compounds of formula I with that of the compound described in U.S. Patent No. 3,575,999.

ΓΊ] Cl \ __ “2 / \ _C1 Xu R—- - \

Vaginal candidiasis of formula I Compound of rats studied in rats, ED 2 q (mg / kg) number R (orally) c2h5 10 10 n-C3H? 10 6 n-C4H9 10 6 | n-CgH ^ ^ 5 6 j ί - - - 11 I I - I I. I I ... I I -} R = CH-, (US 3575999) 40 10 | 3 j {{

The table shows that the compounds of the formula I having an alkyl substituent having 2 to 10 carbon atoms in the 4-position of the dioxolane group are considerably more active than the corresponding known methyl-substituted compound.

36 62081

The following examples illustrate the invention. Unless otherwise indicated, all parts are by weight.

Preparation of starting material

Example I

11.7 parts of a mixture containing 2-bromo-4'-chloroacetophenone, 9 parts of 1- (p-chlorophenyl) -1,2-ethanediol, 0.5 part of p-toluenesulfonic acid and 80 parts of benzene were stirred and heated to reflux. with a water separator for 2 days. The reaction mixture was cooled and next washed twice with sodium bicarbonate solution and once with water. The organic phase was dried and evaporated. The residue was triturated in petroleum ether and cooled with ice. The precipitated product was filtered off, crystallized from methanol, stirred in acetonitrile under ice-cooling, filtered again and washed once more with acetonitrile to give 2- (bromomethyl) -2,4-bis (p-chlorophenyl) -1,3-dioxolane.

Example II

11.6 parts of a mixture of 2-bromo-4'-chloroacetophenone, 8.4 parts of oC- (hydroxymethyl) benzyl alcohol, 0.1 part of p-toluenesulfonic acid, 210 parts of benzene and 40 parts of ethanol were stirred and heated under reflux for 24 hours. I drive. The reaction mixture was evaporated and the residue was triturated with methanol. The product was filtered and crystallized from methanol to give 2- (bromomethyl) -2- (p-chlorophenyl) -4-phenyl-1,3-dioxolane; mp. 60 ° C.

Example III

11.6 parts of a mixture containing 2-bromo-4 * -chloroacetophenone, 12.4 parts of 1- (2,4-dichlorophenyl) -1,2-ethanediol, 0.1 part of p-toluenesulfonic acid, 80 parts of n-butanol and 160 parts of benzene was stirred and heated under reflux for 24 hours with a water separator. The solvent was removed in vacuo and the residue was triturated with methanol. The precipitated product was filtered off and crystallized from petroleum ether to give 2- (bromomethyl) -2- (p-chlorophenyl] -4- [2,4-dichloroethyl) -1,3-dioxolane] m.p. 82.7 ° C.

Example IV

Following the procedure of Example III and using equivalent amounts of the appropriate starting materials, the following dioxolanes were finally purified after one of the following methods: a) column chromatography through silica gel using trichloromethane as eluent; or b) mixing the product with silica gel in trichloromethane, filtering off the silica gel and evaporating the solvent.

BrCH2 0ÖW · R7 4 • · .- »38 62081 R‘ r7 Melting point Purification- c procedure

4-Br 4-Cl 101.3 * C I

4-Br 2,4- (Cl) 2 99.9 * C

4-OCH3 4-C1 115.6’C

4-C1 63.9 * C

4-CH3 2,4- (Cl) 2 89.9 * C

4-Br 4-Br 96.8 * C

4-CH3 4-C1 122 * C

4-CH3 4-Br 118.6 * C

4-CH3 2-C1 - - 2.4- (Cl) 2 - - a 2.4- (Cl) 2 - a 2.4- (Cl) 2 4-C1 - a 4-C1 2-C1 - b 2-C1 2.4 - (Cl) 2 - b 4-Br 2-Cl - b 2- C1 4-Cl - b 2.4- (Cl) 2 2,4- (Cl) 2 b 4-Br - 70 * C b 4-Br 71.3 * C b 2.4- (Cl) 2 2-Cl - b 2.4- (Cl) 2 4-Br - b 4-C1 4-Br 80.5 * C b 3- C1 2,4- (Cl) 2 - b 2- C1 4-Br - b 4- C1 4-Ch3 - b 4-Br 4-ch3 - b 4-C1 4-F - b 4-Br 4-F - b 39 62031

Example V

To a stirred and boiling Grignard complex, previously prepared from 98 parts of 1- (chloromethyl) -2,4-dichlorobenzene and 14 parts of magnesium in 70 parts of 1,1'-oxybisethane, was added dropwise a solution containing 46 parts of 5 parts of 2- (chloromethyl) oxirane in 350 parts of 1,1'-oxybisethane. After the dropwise addition, stirring at the boiling point was continued overnight. The reaction mixture was cooled in an ice bath and quenched by dropwise addition of 120 parts of concentrated hydrochloric acid solution. This was all poured into water and the layers were separated. The organic phase was washed three times with water. The aqueous phase was extracted with 1,1'-oxybisethane. The combined organic phases were dried, filtered and evaporated. The residue was distilled to give 2,4-dichloro-ol (chloromethyl) benzene-propanol; tr. 130 ° C at 0.04 mm.

Example VI

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

OH

^ J ^ 7 ^ ch2-ch2 - <!: h-ch2ci R Boiling point # Z-Cl 118 * C. at 0.01 mm. at 2, 6- (Cl) 2 136 ° C. at 0. 2 mm. at 4-OCH 2 140 ° C. at 0. 2 mm. paijieess ^ 4-Cl 130-135eC. at 0. 3 mm.pressure ho 62G31

Example VII

87 parts of 2,4-dichloro-β-chloromethylbenzenepropanol in 144 parts of concentrated sodium hydroxide solution and 350 parts of 2,2'-oxybispropane solution were stirred overnight at room temperature. The product was extracted with 2,2'-oxybispropane. The extract was washed with water, dried, filtered and evaporated. The oily residue was distilled to give N, 2- (2,4-dichlorophenyl) ethyl, 7-oxirane; tr. 90-98 ° C at a pressure of 0.01 mm.

Example VIII

Following the procedure of Example VII and using equivalent amounts of the appropriate starting materials, the following oxirane derivatives were prepared: Boiling point 2-Cl 66-70 ° C. at 0. 01 mm. at Z $ 6- (Cl), 85-89 ° C. at 0. 01 mm. at a pressure of £ 4-OCH 2 80-90 ° C. at 0.05 mm. at a pressure of 4_C1 106-115 * C. at 0. 03 mm.pressure

Example IX

To a stirred and boiling 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, was added dropwise a solution containing 60 parts of part of 3-bromo-1-propylene in 180 parts of tetrahydrofuran. After completion of the dropwise addition, stirring was continued for 2.50 hours at the boiling point. The reaction mixture was cooled and poured into water. The layers were separated and the aqueous phase was extracted with 1,1'-oxybisethanil. The combined organic phases were washed with water, dried, filtered and evaporated. The residue was filtered and the filtrate was evaporated to give 60 parts of 4- (3-butenyl) -1,1'-biphenyl as a residue. To a stirred mixture of XLII1 containing 88 parts of 3-chlorobenzeneperoxyacid and 650 parts of dichloromethane was added dropwise 60 parts of 4- (3-butenyl) -1,1'-biphenyl 62081 yl. After the dropwise addition, stirring was continued over the weekend at room temperature. Then 50 parts of potassium carbonate solution were added dropwise. The organic phase was separated, washed with sodium bisulfite solution and water, dried, filtered and evaporated to give 63.5 parts (70, 87%) of [2- (Q, 1'-biphenyl-7 + +) yl] ethyl] oxirane as an oil. residue.

* i-

Example X

To a stirred mixture of 86 parts of 3-chlorobenzeneperoxyacid and 650 parts of dichloromethane was added dropwise (slowly) 53 parts of 1-fluoro-4- (2-propenyl) benzene. After completion of the dropwise addition, stirring was continued overnight at room temperature.

Then 92 parts of potassium carbonate solution were added dropwise and the layers were 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 oils.

Example XI

To a stirred mixture of 44.5 parts of 4-chloro-1-naphthalenol and 115 parts of 2- (chloromethyl) oxirane was added portionwise 17.1 parts of potassium hydroxide (exothermic reaction). When the exothermic reaction was complete, the mixture was heated to reflux and stirred at reflux for 2 hours. Water was added and the mixture was extracted twice with trichloromethane. The combined extracts were washed three times with water, dried and evaporated. The residue was distilled to give 45.3 parts of 2- (4-chloro-1-naphthalenyloxy) methyl-4-oxirane; tr. 150-151 ° C at 0.2 mm.

Example XII

To a stirred mixture of 139 parts of 2-nitrophenol and 138 parts of potassium carbonate in 640 parts of 2-propanone was added dropwise 215 parts of 2- (chloromethyl) oxirane. After the dropwise addition, stirring was continued for 2 days at the boiling point. The precipitate formed was filtered off and the filter mass was washed with 2-propanol. The filtrate was evaporated. The residue was crystallized from a mixture of 2,2'-oxybispropane and petroleum ether (1: 1 by volume). The product was filtered off and dried, yielding 38 parts (20%) of 2- (2-nitrophenoxymethyl) oxirane; mp. 56 ° C.

12 62C81

Example XIII

Following the procedure of Example XII and using an equivalent amount of appropriately substituted phenol or naphthalenol instead of the 2-nitrophenol used therein gave the following 2-aryloxymethyloxiranes: At a pressure of .05 mm; 2- (3,4,5-trichlorophenoxymethyl) oxirane as an oily residue; 2- (3-chloro-E, 1,1'-biphenyl] -4-yloxymethyl) oxirane as a residue; 6-Dibromo-2-naphthalenyloxy) methyl] oxirane as a solid residue.

Example XIV

To a stirred solution of 38 parts of 2- (2-nitrophenoxymethyl) oxirane in 10 parts of ethanedicarboxylic acid and 300 parts of 1,4-dioxane was added 100 parts of water. The mixture was stirred and heated under reflux for 2 days. The reaction mixture was evaporated and the residue was crystallized from a mixture of 2,2'-oxybispropane and petroleum ether. The product was filtered and recrystallized from 2,2'-oxybispropane to give 29.5 parts (13%) of 3- (2-nitrophenoxy) -1,2-propanediol; mp. 96 ° C.

Example XV

Following the procedure of Example XIV and using an equivalent amount of an appropriately substituted oxirane instead of the 2- (2-nitro-phenoxy) methyl, 7-oxane used therein gave the following diols: 3- (4-chloro-1-naphthalenyloxy) -1,2-propanediol; mp. 120 ° C; 3- (2-chloro-5-methylphenoxy) -l, 2-propanediol; mp. 5S ° C; 3- £ 4- (phenylmethyl) fenoksi7 ~ l, 2-propanediol; mp. 7G ° C; 3- (3,4,5-trichlorophenoxy) -1,2-propanediol; mp. 64 ° C;

3- (3-chloro-11 bifenyyli7-4-yloxy) -l, 2-propanediol; mp. 60 ° C

* 362081 3- (C 1-6-dibromo-2-naphthalenyloxy) -1,2-propanediol; mp. 139 ° C; 3- (4-bromophenyl) -1,2-propanediol; mp. 60.6 ° C; 3- (4-fluorophenyl) -1,2-propanediol; tr. 125 ° C at 0.05 mm; and 4- (N, 1,1'-biphenyl-4-yl) -1,2-butanediol; mp. 125.9 ° C.

1- [1- (2,4-dichlorophenyl) ethyl] ethanediol; mp. 83.2 ° C; 1- [2- (2-chlorophenyl) ethyl] ethanediol; mp. 64.1 ° C; 1- (4-chlorophenyl ethyl) ethanediol, b.p. 150 ° C at 0.02 mm

Example XVI

To a stirred solution of 12 parts of 2-O- (4-methoxyphenyl) ethyl, 7-oxirane in 1.8 parts of sulfuric acid and 160 parts of 2-propanone was added 100 parts of water. The mixture was stirred for 2 days at room temperature. The reaction mixture was mixed with sodium bicarbonate solution and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated to give 1- [2- (4-methoxyphenyl) ethyl] -4-1,2-ethanediol as a residue.

Example XVII

To a stirred and hot (50 ° C) solution of 64 parts of 1- (3-bromo-4-methylphenyl) -1-ethanone in 160 parts of 1-butanol was added dropwise over 1 hour 48 parts of bromine without external heating. After stirring for one hour at room temperature, 21.7 parts of 1,2-ethanediol, 6 parts of 4-methylbenzenesulfonic acid and 720 parts of benzene were successively added thereto, and the whole mixture was stirred and heated under reflux overnight with a water separator. The reaction mixture was evaporated and the residue was taken up in 2,2'-oxybispropane. The resulting solution was washed successively once with dilute sodium hydroxide solution and three times with water, dried, filtered and evaporated. The residue was distilled to give 57 parts (57%) of 2-bromoethyl) -2- (3-bromo-4-methylphenyl) -1,3-dioxolane; tr. 126-130 ° C at 0.1 mm.

* „„ 62031

Example XVIII

Following the procedure of Example XVII and using an equivalent amount of the appropriate 1-aryl-ethanone in place of 1- (3-bromo-4-methylphenyl) -1-ethanone used therein, the following 2-aryl-2- (bromomethyl) -1,3- dioxolanes: 2- (bromomethyl) -2- (4-chloro-2-methylphenyl) -1,3-dioxolane; 2- (bromomethyl) -2- (3,5-dichlorophenyl) -l, 3-dioxolane; mp. 58 ° C; 2- (bromomethyl) -2- (2,3-dichlorophenyl) -l, 3-dioxolane; tr. 135-137 ° C at 0.1 mm; 2- (bromomethyl) -2- (2,4,5-trichlorophenyl) -l, 3-dioxolane; tr. 146-147 ° C at 0.3 mm; and 2- (bromomethyl) -2- (2-chloro-4-methoxyphenyl) -1,3-dioxolane; mp. 5 3 ° C.

Example XIX

112 parts of 4- (2-bromoacetyl) benzonitrile To 320 parts of a stirred solution containing butanol were added 5 parts of 4-methylbenzenesulfonic acid and 360 parts of benzene. 46.5 parts of 1,2-ethanediol were then added dropwise. The final stirring of the drip was continued for 4 hours under a condenser. The reaction mixture was evaporated. The oily residue was crystallized from 2,2'-oxy-bispropane. The product was filtered and recrystallized from methanol to give 95.12 parts of 4- [2- (bromomethyl) -1,3-dioxyano-2-yl] benzonitrile; mp. 92.4 ° C.

Example XX

Following the procedure of Example XIX and using an equivalent amount of the appropriate I-aryl-2-bromo-1-ethanone instead of the 4- (2-bromoacetyl) -benzonitrile used therein, the following 2-aryl-2- (bromomethyl-1,3-dioxolanes were prepared: 2 - (bromomethyl) -2- (2-naphthalenyl) -1,3-dioxolane, mp 6h C, 2- (bromomethyl) -2- (4-bromo-2-methylphenyl) -1,3-dioxolane, m.p. 86 ° C, 2- (bromomethyl) -2- (3-bromophenyl) -1,3-dioxoane, mp 50 ° C, and 2- (bromomethyl) -2- (3-nitrophenyl) -1,3- dioxano, mp 8 8 ° C.

1 + 5 6 2 C 3 1

Example XXI

11.7 parts of a mixture containing 2-bromo-4'-chloroacetophenone, 11.9 parts of 1- (4-chloro-tolyloxy) -2,3-propanediol, 2.5 parts of p-toluenesulfonic acid and 240 parts of benzene stirred and heated under reflux for 24 hours in a four-necked round bottom flask equipped with a water collector. The benzene solution was washed successively with dilute sodium hydroxide solution and water. The solvent was removed in vacuo. The residue was crystallized from methanol and the less pure fraction was recrystallized from diisopropyl ether to give A-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) -1,3-dioxolane as a residue.

Example XXII

Following the procedure of Example XXI and using equivalent amounts of the appropriate starting materials, the following dioxolanes were finally obtained after purification of the products: a) by column chromatography through silica gel using trichloromethane as eluent; or b) mixing the product with silica gel in trichloromethane, filtering off the silica gel and evaporating the solvent.

i 146 62081

BrCH,

_ oX ^ W

^ 0.O.CH2_l_3 R7 6 7. . R R Melting- Cleaning-

Isomer point method

A 4-C1 4-CH3 I I

B 4-Cl 4-CH 3

A 4-Cl 2 # 4- (Cl) 2 87-89 ° C

B 4-C1 2 „4- (Cl) 2

A 4-C1 4-F 102 * C

B 4-C1 4-F - - A 4-C1 2-CH 2 82.2-85 * C - B 4-C1 2-CH 3 A 4-C1 2-C1 85-88. 6 * C - B 4 -Cl 2 -Cl - - A 4-C14-OCH3 B 4-C14-OCH3 A 2,4- (Cl) 2 4-F - -.

A '2. 4- <Cl) 2 4-OCH3

A 4-C1 4-C1 165 * C

B 4 -Cl 4 -Cl - a B 2,4- (Cl) 2 4-CH 3 - b A 2,4- (Cl) 2 4-CH 3 -, - ^ A 2,4- (Cl) 2 4- C1 B 2,4- (Cl) 2 4-C1 - b A 2,4- {Cl) 2 2.4- (Cl) 2 B 2,4- (Cl) 2 2,4- (Cl) 2 - b A + B 4 -Cl 2,6- (Cl) 2 A + B 2,4- (Cl) 2 2-CH 3 - b 1.7 62081

Example XXIII

11.2 parts of 2,2 '' - 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 heated under reflux For 20 hours in a four-necked, round-bottomed flask equipped with a water separator. The reaction mixture was washed successively with dilute sodium hydroxide solution and twice with water. The solvent was removed in vacuo. The residue was triturated in methanol for 3 hours. The precipitated product was filtered off and crystallized from 2-propanol to give A-2- (chloromethyl) -4- (2,4-dichlorophenoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolane; mp. 92.5 ° C.

Example XXIV

6 parts of 2-bromo-2'-4'-dichloroacetophenone, 6 parts of 3- (4-chloro-o-tolyloxy) -1,2-propanediol, 3 parts of p-toluenesulfonic acid, 8 parts of n-butanol and 180 parts of benzene the mixture was stirred and heated under a condenser for 24 hours with a water separator. The solvent was removed in vacuo and the residue was triturated with methanol. The product was filtered off and crystallized from petroleum ether to give A + 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 solvent shown, the following dioxolanes were prepared:

r5-O-CH2-J-J

6 5 R Ra Melting _. point Solvent

Isomer.

A 2,4- (Cl) 2 C benzene A 2.4- (Cl) 2 3-Cl-C6H4. benzene A 2.4- (Cl) 2 3.5- (CH3) 2,4-CUC6H2 115.8 * C benzene, 8 62081 r6 j ^ 5 Melting point

Isomer point Solvent A 2,4- (Cl) 2 2,4- (Br) 2'C2 H2-benzene A 2,4- (01) 2 4-CN-C (01) 2 2-OCH3-C6H4 - benzene A + B 2,4- (Cl) 2 4- (C6H5) -C6H4 - benzene A + B 2,4- (01) 2 90 C methylbenzene A 2,4- (01) 2 S-CH 2, 4-Cl-C 1 H 3 -methylbenzene A 2,4- (01) 2 3,5- (Cl) 2-C 6 H 3 -methylbenzene A 2,4- (01) 2 4- (CH3) 37-C6H4 ”methylbenzene A 2,4- (01) 2 2-naphthalenyl 117.6 * C benzene A 2.4- (Cl) 2 2-F-C6H4 125.7 * C benzene A + B 4-CHL 4-Br- C, H. 121.1 * 0 benzene 3 0 4 A + B 4-C1 4-Br-C6H4 157.4 * 0 benzene A + B 4-Br 4-Br-C6H4 158.7 * 0 benzene A 2.4- (0¾ 3-Br-C6H4 112.7 * 0 benzene A 2,4- (Cl) 2 3,5- (0Η3) 2-06Η3 118.7 * C benzene A + B 2,4- (Cl) 2 4- (C6H5-CH2) -C6H4 106.1 * 0 benzene A + B 4-OCH3 4-Br-C6H4 117 * 0 benzene A - 4rBr-C6H4 85.6 * 0 benzene A + B 2,4- (01) 2 4-C1-1-naphthalenyl 122.7 * 0 benzene A 2,3 , 4- (Cl) 3 4-Br-O-H4-methylbenzene A 2,4- (Cl) 2 2-Br, 4-CH3-C6H3-methylbenzene A + B '2,4- (Cl) 2 l, 6- (Br) 2-2-Naphth-methylbenzene ,, lenyl A + B 2-Cl, 4-Br 4- (O, O) -N-dimethylbenzene * A + B 3,4.5- (Cl) 3 4- (C6H5) -C6H4-dimethylbenzene A 2,4- (Cl) 2 2-CN-C6H4 «dimethylbenzene A '2,4- (Cl) 2 4- (nC4H9-OOC) -C6H4 - dimethylbenzene

V

„62081

Example XXVI

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 a mixture of butanol and 180 parts of benzene was stirred and heated under a condenser for 24 hours with a water separator. The reaction mixture was evaporated and the residue was dissolved in trichloromethane. The solution was stirred with silica gel for 30 minutes. The latter was filtered off and the filtrate was evaporated to give A + B 2- (bromomethyl) -2- (2,4-dichlorophenyl) -4- (2,5-dimethylphenoxymethyl) -1,3-dioxolane as a residue.

Example XXVII

Following the procedure of Example XXVI and using equivalent amounts of the appropriate starting materials and solvent shown, the following dioxolanes were obtained as residues: i r5.0-CH2_1-1

Isomer> Solvent A + B 2,4- (Cl) 2 2-Cl-C6H4 benzene A + B 2.4- (Cl) 2 2f6- (Cl) 2-C6H3 benzene A + B 2,4- (Cl) 2 2 -Br-C6H4 benzene A + B 2-Br 4-Br-C 1 H 4 benzene. . - 50

OcUÖ J

Isomer 1 ** S Solvent A + B 2,4- (O1) 2-C1-10-CH2-CH2-methylbenzene A + B 2,4- (Cl) 2 2,3- (Cl) 2- C6H3 methylbenzene A + B 2.4- (Cl) 2 2,4,6- (Cl) 3-C6H2 benzene A + B 2,4- (Cl) 2 2 -Cl, 4- / C (ZHJJ-benzene N C6H3 A + B 2,4- (Cl) 2 2 »4,5- (C1) 3-C6H2 benzene A + B 2, 4- (Cl) 2 2,5- (Br) 2,4-CH3-C2H2benzene A + B 2,4- (Cl) 2 2rOC2Hg-C6H4 benzene A + B 2-C1 4-Br-CrH K + - 64 benzene 2t4- (Cl) 2 2,6- (CH3) 2-C methylbenzene A 2,4- (Cl) 2 6-Br-2-naphthalenyl benzene 2,4- (Cl) 2 2- (C6H5) -C6H4 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-methyls). enoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolane as an oily residue; A + B-2- (bromomethyl) -2- (2,4-dichlorophenyl) -4- (3,4,5-trichlorophenoxymethyl) -1,3-dioxolane as a residue.

Example XXIX

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 the mixture was stirred and heated under a condenser in a four-necked round bottom flask equipped with a water collector. After 16 hours, a theoretical amount of water had formed. The reaction mixture was allowed to cool to room temperature and washed successively with dilute sodium hydroxide solution and twice with water. The solvent was dried and removed in vacuo. The residue was triturated with methanol.

62081 51

The product was filtered off (the filtrate was collected) and crystallized from butanol to give A-2- (bromomethyl) -4- (p-bromophenoxymethyl) -2 - ((2,4-dichlorophenyl) -1,3-dioxolane.

The filtrate (see above) was evaporated. The residue was dissolved in 210 parts of 2,21-oxybispropane and the solution was allowed to crystallize. The precipitated product was 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 insoluble material was filtered off and discarded. The filtrate was purified twice by column chromatography through silica gel using a mixture of hexane and trichloromethane (3: 1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue solidified on trituration with petroleum ethers. The product was filtered off and dried, yielding B-2- (bromomethyl) -4- (4-bromophenoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolane.

Example XXX

15.2 parts of 2-bromo-1- (2,4-dichlorophenyl) ethanone, 16.7 parts of 3- (3-chloro-11,11-biphenyl-4-yloxy) -1,2-propanediol, A mixture of 3 parts of 4-methylbenzenesulfonic acid, 40 parts of butanol and 225 parts of dimethylbenzene was stirred and heated under reflux for 2 days with a water separator. 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 and water, dried, filtered and evaporated. The residue was triturated in a mixture of 2,21-oxybispropane and petroleum ether. The product was filtered off and dried, the filtrate was collected) to give 12.5 parts of A-2- (bromomethyl) -4- (3-chloro- {1,1'-biphenyl-4-yloxymethyl) -2- (2.4 -dichlorophenyl) -1,3-dioxolane.

The filtrate (see above) was evaporated. The residue was dissolved in trichloromethane and the solution was mixed with silica gel. The latter was filtered off and the filtrate was evaporated, yielding 10 parts of A + B-2- (bromoethyl) -4- (3-chloro-1,1'-biphenyl] -4'-yloxymethyl) -2- (2,4 -dichlorophenyl) -1,3-dioxolane as a residue.

52 62081 Example XXXI

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, A mixture of 40 parts of butanol and 225 parts of methylbenzene was stirred and heated under a condenser over the weekend. The reaction mixture was evaporated and the oily residue was triturated in methanol. The product was filtered (the filtrate was collected) to give 15 parts of A-2- (bromomethyl) -2- (2,4-dichlorophenyl) -4- [4- (phenylmethyl) phenoxymethyl] -1,3-dioxolane; mp. 96 ° C.

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

Example XXXII

14.9 parts of 3- (2-nitrophenoxy) -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 a portion of the methylbenzene-containing mixture was stirred and heated under a condenser over the weekend. The reaction mixture was evaporated and the oily residue was dissolved in trichloromethane. The solution was washed with dilute sodium hydroxide solution 20% and water, dried, filtered and evaporated. The oily residue was crystallized from 2,2'-oxybispropane with stirring. The product was filtered (the filtrate was collected) to give 8.5 parts of A-2- (bromomethyl) -2- (2,4-dichlorophenyl) -4- (2-nitrophenoxymethyl) -1,3-dioxolane.

The recovered filtrate was evaporated. The oily residue was purified twice by column chromatography through silica gel, eluting first with trichloromethane and secondly with a mixture of trichloromethane and 20% hexane. The pure fractions were collected and the eluent was evaporated, yielding 14.5 parts of B-2- (bromomethyl) -2- (2,4-dichlorophenyl) -4- (2-nitrophenoxymethyl) -1,3-dioxolane as an oily residue.

53 6ZUÖ l

Example XXXIII

13.6 parts of 2-bromo-1- (2, Η-dichlorovinyl) -1-ethanone, 15.8 parts of 3- (4-bromophenylthio) -1,2-propanediol, 3 parts of 4-methylbenzenesulfonic acid, 180 parts a mixture of butanol and 90 parts of benzene was stirred and heated under a condenser for 12 hours with a water separator. The reaction mixture was evaporated and the residue was dissolved in trichloromethane. The solution was stirred with silica gel for 30 minutes. The latter was filtered off and the filtrate was evaporated to give A + B 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 appropriate starting materials, the following dioxolanes were prepared: A + B 2- (bromomethyl) -2- (2,1-dichlorophenyl) -4- (phenylthiomethyl) -1,3-dioxolane as residue A + B 2- (bromomethyl) -2- (2,1-dichlorophenyl) -L- (H-fluorophenyl) -thiomethyl-1,3-dioxolane as a residue.

Example XXXV

19.8 parts of 3- (4-bromophenoxy) -1,2-propanediol. A mixture of 15.6 parts of 2- (bromomethyl) -2- (3,5-dichlorophenyl) -1,3-dioxolane, L part of M-methylbenzenesulfonic acid, 40 parts of butanol and 225 parts of benzene was stirred and heated under reflux for 2 days. equipped with a water separator. The reaction mixture was allowed to cool to room temperature and the solvent was removed by evaporation in vacuo. The residue was triturated in methanol. The product was filtered and crystallized from 2-propanol to give 5.5 parts (22%) of A-2- (bromomethyl) -4- (4-bromophenoxymethyl) -2- (3,5-dichlorophenyl) -1,3-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 the indicated solvent: A-2- (bromomethyl) -4- (4-bromophenoxymethyl) -2- (L-chloro-2-methylphenyl) -1, 3-dioxolanes; mp. 155 ° C; A-2- (bromomethyl) - * + - (4-bromophenoxymethyl) -2- (3-bromophenyl) -1,3-dioxolane; mp. 92.2; 54 62081 A-2- (bromomethyl) -2- (4-bromo-2-methylphenyl) -4- (4-bromophenoxymethyl) -1,3-dioxolane; A-2- (bromomethyl) -2- (3-bromo-4-methylphenyl) -4- (4-bromophenoxymethyl) -1,3-dioxolane; mp. 100 ° C; N- 4- [2- (bromomethyl) -4- (4-bromophenoxymethyl) -1,3-dioxolan-2-yl] -benzonitrile; A-2- (bromomethyl) -4- (4-bromophenoxymethyl) -2- (3-nitrophenyl) -1,3-dioxolane; and A-2- (bromomethyl) -4- (4-bromophenoxymethyl) -2- (3,3-dichlorophenyl) -1,3-dioxolane.

Using dimethylbenzene as a solvent, the following were prepared: A + B-4- (E, 1,1'-biphenyl-4-yloxymethyl) -2- (bromomethyl) -2- (2-naphthalenyl) -1,3-dioxolane; mp. 160.8 ° C; A 4- (£ i, 1, ^ biphenyl -4-yloxymethyl) -2- (bromomethyl) -2- (2-chloro-4-ri-metoksiienyyli) -l, 3-dioxolane; A + B-2- (bromomethyl) -4-ethyl-2- (2,3,4-trichlorophenyl) -1,3-dioxolane; tr. 145 ° C at 0.1 mm; A + B-4- (N, 1,1'-biphenyl-4-yloxymethyl) -2- (bromomethyl) -2- (2,4,5-trichlorophenyl) -1,3-dioxolane as a residue; A + B-2- (bromomethyl) -2- (2,3-dichlorophenyl) -4-ethyl-1,3-dioxolane; tr. 131-133 ° C at 0.1 mm; A + B-2- (bromomethyl) -2- (2-chloro-4-methoxyphenyl) -4-ethyl-1,3-dioxolane; tr. 142-144 ° C at 0.3 mm; A + B-2- (bromomethyl) -2- (4-chloro-2-methylphenyl) -4-ethyl-1,3-dioxolane; tr. 118 ° C at 0.15 mm; A + B-2- (bromomethyl) -4-ethyl-2- (2-naphthalenyl) -1,3-dioxolane as a residue; and 2- (bromomethyl) -2- (2,4-dichlorophenyl) -4- [2- (4-methylphenyl) ethyl] -1,3-dioxolane as a residue.

Example XXXVII

13.6 parts of 2-bromo-1- (2,4-dichlorophenyl) -1-ethanone, 14.1 parts of 1-2- (2,4-dichlorophenyl) ethylethanediol, 3 parts of 4-methyl-benzenesulfonic acid, 80 a mixture of one part butanol and 180 parts of benzene was stirred and heated under a vertical condenser for 24 hours. The reaction mixture was evaporated and the residue was stirred with 160 parts of methanol for 2 hours. The precipitated product was filtered to give 2- (bromomethyl) -2- (2,4-dichlorophenyl} -4- [2- (2,4-dichlorophenyl) ethyl 1,7-1,3-dioxolane.

62 08 1 55 1

Example XXXVIII

Following the procedure of Example XXXVII and using equivalent amounts of the appropriate starting materials, the following dioxolanes were prepared using the solvent shown in the reaction:

Using benzene as a solvent, the following were prepared: 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; and A + B-2- (bromomethyl) -2- (2,4-dichlorophenyl) -4- ^ 2- (4-methoxyphenyl-phenyl) etyyli7 ~ l, 3-dioxolane.

Using methylbenzene as a solvent, the following was prepared: 2- (bromomethyl) -4- (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.

Using dimethylbenzene as a solvent, the following was prepared: A + B-2- (bromomethyl) -2- (2,4-dichlorophenyl) -4- (phenylmethyl) -1,3-dioxolane as a residue; A + B-2- (bromomethyl) -4- (4-chlorophenylmethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolane; and A + B-2- (bromomethyl) -2- (2,4-dichlorophenyl) -4- (4-methoxyphenyl) methyl) -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) ethanone, 2 parts of 4-methylbenzenesulfonic acid, 40 parts of butanol and 225 parts of methylbenzene was stirred and heated. under a vertical condenser for 24 hours with a water separator. The reaction mixture was cooled, washed twice with sodium bicarbonate solution, dried, filtered and evaporated. The residue was distilled to give 38 parts (80%) of A + B-2- (bromomethyl) -2- (2,4-dichlorophenyl) -4-ethyl-1,3-dioxolane; tr. 125-130 ° C at 0.1 mm.

Example XL

Following the procedure of Example XXXIX and using equivalent amounts of the appropriate starting materials, the following dioxolanes were prepared: 56 62081

Br "^^ CH 2 /" VR6

y ^ p \ == / A + B

Boiling point C0H_ 2-C1 97-99eC at 0.05 mm. at a pressure of 1 5 C, H_ 2-CH. 86-88 * 0 at 0.05 mm. At a pressure of 2 5 3 4 »CHj 100 * 0 at 0.05 mm. at pressure C, H_ 2-Br 114-115 * 0 at 0.05 mm. at a pressure of Δ 5 C H 3-C1 I 140 eC at 0.6 mm. at a pressure of C 2 H 2 2 -Cl 2 -BR CH 4 -OCH, 122 * 0 at 0.15 mm. at a pressure of 2 5 3 S 3,4,5- (Cl) ^ 135 * C at 0 05 mm, at a pressure of

nC-H_ 2,4- (Cl), 102 -125 * 0 at 0.05 mm.pressure I

3 7 IC4H'2, 4- (Cl) 2 137-139eC at 0.05 mm. at pressure nC H 2,4- (01), 140-145eC at 0.03 mm, at pressure 5 11.2 nC, H 2,4- (01), 16-170eC at 0.1 mm. at a pressure of 6 13 * · ηρ h 2,4- (Cl) 2 160-165 “C at 0. 05 mm at a pressure. ncH 2,4- (01), 180-190 ° C at 0.05 mm. pressure

V17 V v2 CH2OH 2,4- (Cl) 2 145-150 * 0 at 0.05 mm. pressure

Example XLI

To a stirred and warm solution containing 6.5 parts of 1,2-butanediol, 13 parts of 1- (U-chloro-2-methoxyphenyl) ethanone and 40 parts of butanol was added dropwise (slowly) 5.7 parts of bromine at about 40 ° C: in. After stirring for 30 minutes, 2 parts of 4-methylbenzenesulfonic acid and 225 parts of methylbenzene were added and the mixture was stirred and heated under reflux overnight with a water separator. The reaction mixture was cooled, washed with potassium carbonate solution, dried, filtered and evaporated. The residue was distilled to give 17 parts (63%) of A + B-2-ό '·) r> ο ί 2 u o i. (Bromomethyl) -2- (4-chloro-2-methoxy-phenyl) -4-ethyl-l, 3-Dickson silane; tr. 135-140 ° C at a pressure of 0.3 mm.

Example XLII

Following the procedure of Example XLI and using an equivalent amount of 1- (2,4,4,5-trichlorophenyl) ethanone instead of 1- (4-chloro-2-methoxyphenyl) ethanone gave: A + B-2- (bromomethyl) - 14-ethyl-2- (2,4,5-trichlorophenyl) -1,3-dioxolane · b.p. 145 ° C at 0.2 mm.

Example XLIII

To a stirred solution of 53 parts of 1- (2,4-dibromophenyl) ethanone in 105 parts of 1,1'-oxybisethane was added dropwise 32 parts of bromine over 2 hours. Then, 68 parts of 1H-imidazole and 135 parts of Ν, Ν-dimethylformamide were carefully added thereto, and the mixture was stirred for 2 hours at 50 ° C. Upon addition of water, the product precipitated. It was filtered, washed with water and dissolved in trichloromethane. The solution was dried, filtered and evaporated. The residue was converted to the hydrochloride salt in 2-propanone and 2-propanol. Upon addition of 2,2'-oxybispropane, the product crystallized. It was 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-dibromo-phenyl) -2- (1H-imidazol-1-yl ) ethanone hydrochloride; mp. 204.7 ° C.

Example XLIV

To a stirred solution of 78.7 parts of 2-bromo-1- (2-chloro-4-fluorophenyl) ethanone in 140 parts of 1,11-oxybisethane was carefully added 106.4 parts of 1H-imidazole. After the addition was complete, 180 parts of Ν, Ν-dimethylformamide were added thereto, and the mixture was stirred for 2 hours at 50 ° C. After addition of water, the product was extracted twice with trichloromethane. The combined extracts were washed three times with water, dried, filtered and evaporated. The residue was converted to the hydrochloride salt in 4-methyl-2-pentanone, 2,21-oxybispropane and 2-propanol. The salt was filtered and crystallized from a mixture of ethanol and 2,2'-oxybispropane to give 1.5 parts of 1- (2-chloro-4-fluorophenyl) -2- (1H-imidazol-1-yl) ethanone hydrochloride; mp. 197.4 ° C.

58 62081

Example XLV

A. To a stirred mixture of 67.2 parts of A + B-2- (bromomethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolane-4-methanol and 100 parts of pyridine was added dropwise 27.2 parts of benzoyl chloride. slide with cooling below 10 ° C. After the addition was complete, stirring was continued for 2.50 hours at room temperature. The reaction mixture was poured into water and the product was extracted with trichloromethane. The extract was washed successively with dilute hydrochloric acid solution to remove residual pyridine and with water, dried, filtered and evaporated. the oily residue was triturated in methanol. The solid product was filtered (the filtrate was collected) and crystallized twice from ethanol to give 28 parts of cis-2- (bromomethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-4-ylmethyl benzoate; mp. 118.3 ° C.

The filtrate (see above) was evaporated, the oily residue was purified by column chromatography through silica gel using 2,2 * - oxybispropane as eluent. The pure fractions were collected and the eluent was evaporated, the oily residue was triturated in methanol. The solid product was purified by column chromatography through silica gel using a mixture of trichloromethane and hexane (30:70) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 17.5 parts of trans-2- (bromomethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-4-ylmethyl benzoate; mp. 68, S ° C.

B. 12 parts of cis-2- (bromomethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-4-ylmethyl benzoate, 7.5 parts of sodium hydroxide solution 60%, 10 parts of water and 200 parts of 1, The mixture containing 4-dioxane was stirred and heated under a condenser for 1 hour. The reaction 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 chromatography through silica gel using a mixture of trichloromethane, hexane and methanol (50: 49: 1) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 4.5 parts of cis-2- (bromomethyl) -2- (2,4-dichlorophenyl) -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-dichlorophenyl) -1,3-dioxo-59,620San-4-ylmethyl benzoate cis-2- (bromomethyl) -2 Instead of - (2,4-dichlorophenyl) -1,3-dioxolan-4-ylmethylbenzoate, the following was obtained: trans-2- (bromomethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolane-4-methanol residue.

Example XLVI

A mixture of 4.5 parts of methanesulfonyl chloride, 10 parts of cis-2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolane-4-methanol and 50 parts of pyridine was administered stand for 3 hours at room temperature. The reaction mixture was poured into water. The precipitated product was filtered and crystallized from benzene to give 10.3 parts (87%) of cis-2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethylmethanesulfone -naattia; mp. 111.7 ° C.

Example XLVII

A mixture of 32 parts of 1,2,4-butanetriol, 60 parts of 2-bromo-1- (2,4-dichlorophenyl) ethanone, 2 parts of 4-methylbenzenesulfonic acid, 40 parts of butanol and 225 parts of methylbenzene was stirred and heated. under a vertical condenser overnight with a water separator. The reaction mixture was cooled, washed with potassium carbonate solution, dried, filtered and evaporated. The residue was purified by column chromatography through silica gel using a mixture of trichloromethane and methanol (99: 1) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 34 parts (43%) of A + B-2- (bromomethyl) -2- (2,4-dichlorophenyl-1,3-dioxolane-4-ethanol as a residue).

To a stirred mixture of 20 parts of A + B-2- (bromomethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolane-4-ethanol and 50 parts of pyridine was added dropwise 6.9 parts of methanesulfonyl chloride. After the addition was complete, stirring at room temperature was continued for 2 hours. The reaction mixture was poured into water and the product was extracted twice with 1,1'-oxybisethane. The combined extracts were washed successively twice with dilute hydrochloric acid solution and once with water, dried, filtered and evaporated to give 25 parts (100%) of A + B-2-O · - (bromomethyl) -2- (2,4-dichlorophenyl) -1 , 3-dioxolan-4-yl-ethyl methanesulfonate as a residue.

To a stirred mixture of 25 parts of A + B- (2- {2- (bromomethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-4-yl} ethyl) methanesulfonate and 100 parts of dimethyl sulfoxide was added 2 , 2 parts of sodium hydroxide dispersion 78% at room temperature. Stirring was continued for 3 hours at 50 ° C. The reaction mixture was poured into water and the product was extracted twice with 2,2'-oxybispropane. The combined extracts were washed twice with water, dried, filtered and evaporated. The residue was purified by column chromatography through silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated, yielding 15 parts (79%) of A + B-2- (bromomethyl) -2- (2,4-dichlorophenyl) -4-ethenyl-1,3-dioxolane as a residue.

Preparation of final products "Example ΐ_ 1.1 parts imidazole, 1 part 2- (bromomethyl) -2,4-bis- (4-chlorophenyl) -1,3-dioxolane, 0.4 parts potassium iodide and 20 parts The mixture containing dimethylformamide was stirred and refluxed for 12 hours, water was added and the product was extracted with 1,1'-oxybisethane, the extract was washed twice with water, dried, filtered and evaporated. The residue was converted to a salt, and the crude salt was filtered and crystallized from a mixture of 2-propanol and 2,2'-oxy-bis-propane to give 1- (2,4-bis- (4-oxy-bis-propane)). -chlorophenyl) -1,3-dioxolan-2-ylmethyl <7-imidazoline nitrate mp 192.3 ° C.

Example .2 7 parts of imidazole, 7.5 parts of a mixture containing 2- (bromomethyl) -2- (4-chlorophenyl) -4-phenyl-1,3-dioxolane, 2 parts of sodium iodide and 100 parts of N, N-dimethylformamide stirred and heated under reflux for 48 hours. The reaction mixture was allowed to cool to room temperature and poured into water. The product was extracted twice with benzene. The extract was washed twice with water and the solvent was removed in vacuo. 1- [2- (4-Chlorophenyl) -4-phenyl-1,3-dioxolan-2-ylmethyl] -imidazole residue was converted to the nitrate salt in 4-methyl-2-pentanone and 2,2'-oxybispropane. The crude salt was filtered and crystallized from 4-methyl-2-pentanone to give 1- [12- (4-chlorophenyl) -4-phenyl-1,5-dioxolan-4-ylmethyl] -imidazoline nitrate; mp. 153.2 ° C.

no 62081

Example 3

Following the procedure of Example 2 and using equivalent amounts of the appropriate starting materials, the following imidazole acid addition salts were prepared:

__OF

O

A 7 Salt The melting point of the salt

4-Cl 2,4- (Cl) 2 HNO3 196.6eC

4-Br 4-Cl HNO 3 152. 6 * C

4-Br 2,4- (Cl) -HNO, 205.3eC

2.4- (Cl) 2 - 2 (COOH) 2 107.7eC

4-OCH 3 4-Cl HNO 3 196.3eC

2, i- (Cl) 2 HNO 3 163.8eC

2.4- (Cl) 2 4-Cl 11/2 (COOH) 2 119.9 * C

4-C1 hn ° 3 134.7eC

4-C1 2-Cl HNO3 183.8eC

2-Cl 2,4- (Cl) 2 HNO 3 164.2eC

2.4- (Cl) 2 2-Cl HNCLj 151 eC

4-Br 2-Cl, HNO 3 194.7eC

2.4- (Cl) 2 2,4- (Cl) 2 HNO3 v 161.2eC

4-Br - HNO 3 156.5 ° C.

4-Br HN03 131.1 ° C

4-CH3 2,4- (Cl) 2 HNO3 193.6eC

4-Br 4-Br HNO 3 144. 3 ° C

4-CH 3 4-Cl HN ° 3 200.8eC

4-C1 4-Br HN03 145.2eC

. %

62 6 2 0 SI

6 τ> 7 R R Salt Salt melt- _______. happo_ mispiste

4-CH 3 4-Br HN ° 3 210.5eC

3- C1-2,4- (Cl) 2 HNO3 165.4eC

2-C1 4-Br HN ° 3 184. leC

4- CH3 2-Cl HNO3 207.5 ° C

4-Cl 4-CH 3 HNC> 3 144.3 * C

4-Br 4-CH 3 mp 3 140.2 * C

4-C1 4-F HN03 163.2eC

4-Br 4-F HN (> 3 179.3 ° C

Example 14 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 a mixture of a portion of dimethylformamide was stirred and refluxed for 72 hours, water was added and the product was extracted twice with diisopropyl ether, the combined extracts were washed twice with water, dried, filtered and evaporated. The residue of 1- [2- (o-chlorophenyl) -4- (p-chlorophenyl) -1,3-dioxolan-2-ylmethyl] imidazole was converted into the nitrate salt in 2-propanol and diisopropyl ether to give 1 2- (o-chlorophenyl) -H- (p-chlorophenyl) -1,3-dioxolan-2-ylmethylimidazoline nitrate, mp 183.1 ° C.

Example F>

Following the procedure of Example 4 and using an equivalent amount of 2- (bromomethyl) -4- (4-bromophenyl) -2- (2,4-dichlorophenyl) -1,3-dioxolane used therein 2- (bromomethyl) -2- (2- instead of chlorophenyl) -4- (p-chlorophenyl) -1,3-dioxolane, the following was prepared: 1- (4 - [(4-bromophenyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-yl -methyl ^ imidatsolinitraatti; mp. 141.9 ° C.

63 62081

Example 6 To a stirred solution of 2.3 parts of sodium in 80 parts of methanol was added 6.8 parts of imidazole, followed by the addition of 100 parts of dimethylformamide, and the methanol was removed under normal atmospheric pressure until an internal temperature of 130 ° C was reached. Then, 7 parts of A-2- (bromomethyl) -2- (p-chlorophenyl) -4- (4-chloro-o-tolyloxymethyl) -1,3-dioxolane was added thereto, and the mixture was stirred and heated under reflux 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. A-1- [2- (p-chlorophenyl) -4- (4-chloro-o-tolyloxymethyl) -1,3-dioxolan-2-ylmethyl] imidazole was converted to the nitrate salt in 2-propanol. Upon addition of diisopropyl ether, the salt precipitated. It was filtered and crystallized from a mixture of methanol and diisopropyl ether to give cis-1- [2- (p-chlorophenyl) -4- (4-chloro-o-tolyloxymethyl) -1,3-dioxolan-2-ylmethyl] imidazoline nitrate; mp. 164.3 ° C.

Example 7_

Following the procedure of Example 6 and using equivalent amounts of the appropriate starting materials, the following irnidazoles and imidazole acid addition salts were prepared: o R J ° 7 - ^ '' .f ''} 62081 64

Hydrochloric acid Salt or. base melting point

IffOfflfifiri R 6 R7 _ ---- trans 4-Cl 4-Cl, 2-0¾ HNO3. 190 - 190.7 ° cie 4-Cl. 4-0¾ HN03 l40.2 * trans 4-Cl 4-0¾ ΗΜ®3 l6o ° trans 4-Cl 4-Cl HN ° 3 171.8-176.9 ° cie 4-ci 4-ci hno3 165.8-169.60 B 4-Cl 2,4-Cl HNO3 160-165.3 ° cie 4-ci 4-f hno3 172.3 - 17¾.5 * trans 4-Cl 4-F HNC> 3 175-9 ° A 4-Cl . 2-0¾ HN03 134.6 - 145.4 ° B 4-Cl 2-0¾ hn03 156.6 - 161.6 * B '4-Cl 2-Cl HN03 170.5 ° B 4-Cl 4r0CH3 HN03 133.2 *

A 4-Cl 2,4- (Cl) 2 base 175.4-179.5eC

A '4-Cl 2-C1 base 140.8-143.6eC

A 4-Cl 4-OCH 2 base 111.1 * C

Example .8 4.6 parts of sodium To 160 parts of a stirred solution containing methanol were added successively 13.6 parts of imidazole, 300 parts of dimethylformamide and 4 parts of sodium iodide. The methanol was distilled off at normal atmospheric pressure until an internal temperature of 130 ° C was reached. 2S, 9 parts of A + B-2- (bromomethyl) -2- (p-chlorophenyl) -4- (2,6-dichlorophenoxymethyl) -1,3-dioxolane were then added thereto, and the mixture was stirred at reflux for 2 hours. The reaction mixture was allowed to cool to room temperature and poured into water. The product was extracted twice with benzene. The combined extracts were washed twice with water, dried and evaporated in vacuo. The residue containing the "A" and "B" isomers was chromatographed on silica gel eluting with chloroform. The "A" isomer was collected as an oily free base and converted to the nitrate salt in 2-propanol. The crude salt was crystallized from 2-propanol to give 3.3 parts of A-1- [2- (p-chlorophenyl) -4- (2,6-dichlorophenoxymethyl) -1,3-dioxan-2-ylmethyl] imidazoline nitrate, m.p. 145.8 ° C. The "B" isomer was also collected as an oily free base and converted to the nitrate LXXXIII salt in 2-propanol and diisopropyl ether. The crude salt., 62031 6 5 was crystallized from 2-propanol to give 2.2 parts of B1- [2- (p-chlorophenyl) -4- (2,6-dichlorophenoxymethyl) -1,3-dioxolan-2-ylmethyl ^ -imidatsolinitraattia; mp. 197 to 200.5 ° C.

Example 9;

Following the procedure of Example 8 and using equivalent amounts of the appropriate starting materials, the following imidazoles and imidazole acid addition salts were prepared:

N- 1- [2- (2,4-dichlorophenyl) -4- (o-tolyloxymethyl) -1,3-dioxolan-2-ylmethyl] imidazoline nitrate; mp. 156.2 ° C

B-L-£ 2- (2,4-dichlorophenyl) -4- (o-tolyloxymethyl) -1,3-dioxo-lan-2-yylimetyyli7imidatsoliseskvioksalaatti; mp. 138.5 ° C; A-1- [2- (2,4-dichlorophenyl) -4- (2,6-dimethylphenoxymethyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazoline nitrate; mp. 155.6 ° C and A + B-1- (2- (2,4-dichlorophenyl) -4- (2,6-dimethylphenoxymethyl) -1,3-dioxolan-2-ylmethyl, -1H-imidazoline nitrate; mp. 134.5 ° C.

Example 10 6.8 parts of imidazole, 7.8 parts of A-2- (bromomethyl) -2- (2,4-dichlorophenyl) -4- (phenoxymethyl) -1,3-dioxolane, 4 parts of sodium iodide and 150 parts of the mixture containing dimethylformamide was stirred and heated under reflux for 3 days. The reaction mixture was allowed to cool to room temperature, poured into water and the product was extracted twice with diisopropyl ether. The combined extracts containing A-1- [2- (2,4-dichlorophenyl) -4- (phenoxymethyl) -1,3-dioxolan-2-ylmethyl] imidazole were washed twice with water and acidified using an excess of concentrated nitric acid. The salt was filtered and crystallized from a mixture of ethanol and diisopropyl ether to give 5.6 parts of Al- [2- (2,4-dichlorophenyl) -4- (phenoxymethyl) -1,3-dioxolan-2-ylmethyl]. 'imidazo-methylnitrate; mp. 180.5 ° C.

66. 6 2 0 81

Example 11 Following the procedure of Example Ϊ0 "and using equivalent amounts of the appropriate starting materials, the following imidazoles and imidazole acid addition salts were prepared:

,_OF

«" -0-OH.-0

Salt 6 5 Melting acid or

Isomer ^ ”point base A 2,4- (Cl) 2 3, 4- (C1) 2-C6H3“ 152. 1 eC "hNO3 A 2,4- (Cl) 2 3-Cl-C6H4 120.9'C HNO3 A + B 2,4- (Cl) 2 2-CH3,4-Cl-C6H3 121.9eC HNC> 3 A 2,4- (Cl) 2 2,4- (Br) 2-C6H3 164.9eC HNC> 3 cis 2.4 - (Cl) 2 2-F-C6H4 135.9eC HNC> 3 A - 4-Br-C6H4 167. 6 * C HNC> 3 B 2,4- (Cl) 2 4-Br-C6H4 131.1 * C HNC> 3 cis 2,4- (Cl) 2 4-F-C6H4 151-152eC HNC> 3 A 2,4- (Cl) 2 4-CH3-C6H4 141.8 * C HNO3 B 2,4- (Cl) 2 4-CH3 -C6H4 145.1 * C (COOH) 2 cis 2t4- (Cl) 2 4-OCH3-C6H4 184. 7eC (COOH) 2

Cis 2,4- (Cl) 2 4-Cl-C6H4 152.7eC HNO3 A 2,4- (Cl) 2 2,4- (Cl) 2-C6H3 146.5 * C HNC> 3 A 2,4- (Cl) 2 4-Br-C6H4 158.9eC .HNOj A 2,4- (Cl) 2 3t5- (CH3) 2> 4-Cl ^ 6H2 185. 7 ° C HNC> 3 A 2,4- (Cj) 2 4- CN-C6H4 208 ° C hno3 A 2,4- (Cl) 2 2-OCH3-C6H4 110.6 ° C 2 (COOH) 2 A 2,4- (Cl) 2 6-Br-2-naphthalenyl 195.5eC HNC> 3 cis 2,4- (Cl) 2 2-naphthalenyl 156.3eC HNC> 3 A + B 2,4- (Cl) 2 4-Cl-2-naphthalenyl J36.7eC KNO.

gesture 2,4- (Cl) 2 4-Br-C6H4 121.8eC base 67 620 ϋΛ

Example 12 13.6 parts of imidazole, 22.2 parts of A + B-2- (bromomethyl) -4- (o-chlorophenoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolane, 4 parts of potassium iodide, and a mixture of 150 parts of dimethylformamide was stirred and heated under a condenser for 3 days. The reaction mixture was allowed to cool to room temperature, poured into water and the product was extracted twice with diisopropyl ether. the combined extracts were washed twice with water, dried, filtered and evaporated. The residue was purified by silica gel column chromatography eluting with chloroform to give 2 fractions.

The first fraction was evaporated and the residue of Ali (4- (o-chlorophenoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl} imidazole was dissolved in 4-methyl-2-pentanone and di The nitrate salt was filtered and crystallized from a mixture of 4-methyl-2-pentanone and diisopropyl ether to give Al- [1 · - (o-chlorophenoxymethyl) -2- (2, isopropyl ether). 4-Dichloro-phenyl) -1,3-dioxolan-2-ylmethyl-imidazoline nitrate, mp 135.2 ° C.

The second fraction was evaporated and the residue of B1- (N4- (o-chlorophenoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl-imidazole was dissolved in 4-methyl-2-pentanone. and diisopropyl ether The solution was acidified using an excess of oxalic acid and the oxalate salt was filtered and crystallized from 4-methyl-2-pentanone to give 4 parts of B1- [4- (o-chlorophenoxymethyl) -2- (2,4-dichlorophenyl) - 1,3-dioxolan-2-ylmethylimidazolidiooxalate, mp 103.5 ° C.

Example 13

Following the procedure of Example 12 and using equivalent amounts of the appropriate starting materials, the following imidazoles and imidazole acid addition salts were prepared. Where only one isomer is labeled, the other fraction was not chromatographed.

56 6 2 C S 1 O ^

Salt Salt melt

Isomer R,> R7. acidity point A 2,4- (Cl) 2 2; 6- (Cl) 2 HNO -; '- 159 ° ele 2,4 ~ (Cl) 2 2-Br HNO3 142.2 ° Trane 2,4- (Cl) 2 2-Br 2 (C00H) 2151.3 ° A 2,4- (ci) 2 2,5- (ch3) 2 hno3 180.9® B 2,4- (Cl) 2 2,5- (CH3) 2 1.5 (COOH ) 2. 142.7 ° A 2,4- (Cl) 2 2,4,6- (Cl) 3 HNO 3 181.6 ° B 2,4- (O) 2 2,4,6- (Cl) 3 2 (COOH) 2 -43.9 ° A 2,4- (Cl) 2 2-01.4-0 (ΟΗ3) 3 HNO3 14l.2 ° B 2,4- (Cl) 2 2-Cl, 4-C (CH3) 3 HNO314l. ° A 2,4- (Cl) 2 2,4,5- (Cl) 3 HNO3 196.1 ° B 2,4- (0l) 2 2,4,5- (Cl) 3 1.5 (COOH) 2 173-6 ° de 2,4- (Cl) 2 2,5- (Br) 2,4-CH3 HNO3 175.4 ° A 2,4- (Cl) 2 20C2H5 HNO3 117-7 ° K + B 2-Cl4-Br HNO3 145.3 ° B 2-Cl 4-Br HNO3 152.7 * A 2-Br 4-Br HNO3 149. 9 * B 2-Br * 4-Br HNO3 169. 3 * A 2,4- (01) 2 2-Cl, 6-CH3 HNO3 154.2 * 62081 69

Example 14 9.7 parts of 1H-imidazole, 12.5 parts of A + B-2- (bromomethyl) -4- (4-bromo-phenoxymethyl) -2- (4-methylphenyl) -1,3-dioxolane, A mixture of 3 parts of potassium iodide and 135 parts of N, N-dimethylformamide was stirred and heated under reflux for 72 hours. The reaction mixture was poured into water and the product was extracted twice with 1,1'-oxybisethane. The extract containing Al - [- (4-bromophenoxymethyl) -2- (4-methylphenyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole was washed twice with water and an excess of concentrated nitric acid solution was added thereto, and 2, 2'-oxybispropane. The resulting salt was filtered and crystallized from a mixture of ethanol and 2,21-oxybispropane to give 5.6 parts of A 1- [4- (4-bromophenoxymethyl) -2- (4-methylphenyl) -1,3-dioxolan-2- ylmethyl} -lH-imidatsolinitraattia; mp. 175.5 ° C.

Example 15

Following the procedure of Example 14, but substituting the equivalent amounts of A + B-2- for the substitution of A + B-2- (bromomethyl) -4- (4-bromophenoxymethyl) -2- (4-methylphenyl) -1,3-dioxolane used therein. - (bromomethyl) -4- (4-bromophenoxymethyl) -2- (4-chlorophenyl) -1,3-dioxolane and A + B-2- (bromomethyl) -4- (4-bromophenoxymethyl) -2- ( 4-Bromophenyl) -1,3-dioxolane was prepared from N- (4- (4-bromophenoxymethyl) -2- (4-chlorophenyl) -1,3-dioxolan-2-ylmethyl) -1H-imidazole and its nitrate salt (m.p. 158 ° C) and N 1 - (4- (4-bromo-phenoxymethyl) -2- (4-bromophenyl) -1,3-dioxolan-2-ylmethyl-C 1-6 methyl? -1H-imidazole and its nitrate salt (m.p. 170.8 ° C).

Example .16 7.9 parts of 1H-imidazole, 11.5 parts of A + B-2- (bromomethyl) -2- (2,4-dichlorophenyl) -4- (4-phenylphenoxymethyl) -1,3-dioxolane, 4 a mixture of part of potassium iodide and 135 parts of N, N-dimethylformamide was stirred and heated under reflux for 3 days. The reaction mixture was poured into water and the product was extracted twice with 1,1'-oxybisethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane as eluent.

The first fraction was collected and the eluent was evaporated.

7C 62081 The residue was converted to the nitrate salt in 4-methyl-2-pentanone and 2,2'-oxybispropane. The salt was filtered and crystallized from a mixture of ethanol and 2,2'-oxybispropane to give A + B1- [2- (2,4-dichlorophenyl) -4- (4-phenylphenoxymethyl) -1,3-dioxolan-2-ylmethyl] -1H -imidazoline nitrate ·, m.p. 187.9 ° C.

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

Example 17 6.8 parts of imidazole, 815 parts of B-2- (bromomethyl) -4- (p-chlorophenoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolane, 2 parts of sodium iodide and 100 parts of the mixture containing dimethylformamide was stirred and heated under reflux for 36 hours. The reaction mixture was allowed to cool to room temperature and poured into water. The product was extracted twice with benzene. The combined organic layers were washed twice with water, dried and the solvent removed in vacuo. The residue was purified by silica gel column chromatography eluting with chloroform. The pure fractions were collected and the eluent was evaporated. The N-4- (p-chlorophenoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl 13.7-imidazole residue was converted to the oxalate salt of 4-methyl- 2-pentanone; the precipitate precipitated on addition of diisopropyl ether. It was filtered off and crystallized from 4-methyl-2-pentanone to give 3.1 parts of trans-β- (4-p-chlorophenoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolane. 2-ylmethyl imidazole sesquioxalate m.p. pi ° C.

Example i h

Following the procedure of Example 17, the following were prepared: B-1- [4- (2,4-dichlorophenoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl] imidazole sesquioxalate; mp 121.2 ° C uXXXVx B-2- (bromomethyl) -4- (2,4-dichlorophenoxymethyl) -2- (2,4-chlorophenyl) -1,3-dioxolane and imidazole .

Example 19 8.6 parts of 1H-imidazole, 11.3 parts of A-2- (bromomethyl) -2- (2,4-chlorophenyl) -4- (3,5-dimethylenoxymethyl) -1,3 A mixture of 71,62081 containing -d dioxolane, 4 parts of potassium iodide and 135 parts of N, N-dimethylacetamide was stirred and heated under reflux for 3 days. The reaction mixture was poured into water and the product was extracted twice with 2,21-oxybispropane. The combined extracts were washed twice with water and an excess of concentrated nitric acid solution was added. The nitrate salt formed was filtered and crystallized from a mixture of 2-propanol and 2,2'-oxybis-propane. The product was again filtered and recrystallized from H-methyl-2-pentanone to give N-1- [2- (2,4-dichlorophenyl) - * + - (3,5-dimethylphenoxymethyl) -1,3- dioxolan-2-ylmethyl ^ -lH-imidatsolinitraattihydraattia; mp. 122.6 ° C.

Example 20

Following the procedure of the example and using equivalent amounts of the appropriate starting materials, the following imidazoles and imidazole acid addition salts were prepared: ci '

Isomers 71 V "" Salt melting

~~~ Ä! 2-CH3-4-Cl 4-Br * HNC> 3 159.3eC

A 2-CH3-4-Br 4-Br HN ° 3 164. 3 ° C

A position 3 — Br. 4-Br HNO ^ ”158. TC

Ascis 3-Br-4-CH3 4-Br HNO3 201.1 * C

72, 62081. Isomer, y Salt Salt melt- R&'R acid mispiste

A = cie 4-CN ~ 4-Br. 190 ^ 1 * C

A 2.4- (Cl) 2 4- (C6H5-CH'2) HNOj. H 2 O 110. 3 ° C

A = cie 3.5- (Cl) 2 4-Br HNC> 3 167.1 * C *

A = cis 3-NO 2 4-Br HNO 3 148. 8 * C

A * cis 2,4- (Cl) 2 2 ”νο2. 2 (C00H) 2 95.2 * C

B = trans 2,4- (Cl) 2 2 "N ° 2 (COOH) 2 157.2 ° C

B = Trani 2.4- (Cl) 2 4- (C6H5-CH2) (COOH) 2 137 * C ·

A + B 2,4- (Cl) 2 2- (C6H5) 'HNO3 109.3 * C

A + B 2,4- (Cl) 2 4-i / CH3-CH (CH3i / ΗΝΟβ 115.2 * C

2,4- (Cl) 2 4- [fHH3-C (CH3 ^ HNC> 3 169.5'C

A 2.4- (Cl) 2 3.5- (Cl) 2 HNO3.H2O 136.7 * C

A 2,4- (Cl) 2 3-CH 2, 4-Cl HNO 3 142.8 ° C

2,3,4- (Cl) 34 4-Br HN ° 3 174.4 ° C

A 2,4- (Cl) 2 2-Br, 4-CH3 HNC> 3 137.1 * C

Example 21 42 parts of 1H-imidazole, 63 parts of A (1'-biphenyl-4-yloxymethyl) -2- (bromomethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolone, 20 parts of potassium iodide and 675 parts of the mixture containing N, N-dimethylformamide were stirred and heated under a condenser for 3 days. The reaction mixture was poured into water and the product was extracted with 2,2'-oxybispropane. The extract was dried, filtered and evaporated. The residue was converted to the nitrate salt in 4-methyl-2-pentanone and 2,2'-oxybispropane. The product was isolated as an oil. The liquid phase was poured off and the residual oil solidified on trituration in 4-methyl-2-pentanone. The nitrate salt was filtered and eluted from ethanol to give 5 parts of cis-1- [4 - (, i, biphenyl-4-yloxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolane- 2-yl-N-methyl-1H-imidazoline nitrate; mp. 186.5 ° C.

Example 22

Following the procedure of Example 21 and using equivalent amounts of the appropriate fertilizers, the following compounds were prepared; 73 62031 cis-1- [2- (2,4-dichlorophenyl) -4- (2-methoxyphenoxymethyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazoleethanedicarboxylate hemihydrate; mp. 123.6 ° C; and cis-1- [2- (2,4-dichlorophenyl) -4- (4-fluorophenoxymethyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole; mp. 106.7 ° C.

Example 23 6.4 parts of 1H-imidazole, 10 parts of A + B-2- (bromomethyl) -4- (3-chlorine, 1'-biphenyl-4-yloxymethyl) -2- (2,4-dichlorophenyl) -1 A mixture of 3-dioxolane and 135 parts of N, N-dimethylacetamide was stirred and heated under reflux for 5 days. The reaction mixture was allowed to cool to room temperature and poured into water. The product was extracted twice with 1,1'-oxybisethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was crystallized from 4-methyl-2-pentanone to give 2.2 parts (22%) of trans-1- [4- (3-chloro-1,1'-biphenyl] -4-yloxymethyl ) -2- (2,4-dichlorophenyl) -1,3-dioxoan-2-ylmethyl-1H-imidazole; mp. 140.8 ° C.

Example 24 A mixture of 10.2 parts of 1H-imidazole and 26.8 parts of sodium methoxide solution was stirred and heated under a condenser for 15 minutes. A portion of N, N-dimethylformamide was then added. Methanol was distilled off until the internal temperature was about 130 ° C. After the addition of another 90 parts of N, N-dimethylformamide, 50 parts of A + B-4- (, 1'-biphenyl] -4-yloxymethyl) -2-bromomethyl) -2- (2,4 -dichlorophenyl) -1,3-dioxolane was added portionwise at about 100 ° C. After the addition was complete, stirring was continued for 5 hours at reflux temperature. The reaction mixture was poured into a mixture of water and methylbenzene. The organic phase was separated and mixed with activated carbon. The latter was filtered off and the filtrate was evaporated. The residue was purified twice by column chromatography through silica gel using a mixture of trichloromethane and 1% methanol as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanol to give 9.3 parts of cis-1- [4 - (, 11-biphenyl] -4-yloxymethyl) -

OF

2- (2,4-Dichloro-phenyl) -1,3-dioxolan-2-ylmethyl-1H-imidazole; mp. 150.7 ° C.

™ 62081

Example 25 17 parts of 1H-imidazole, 27.4 parts of A + B-4- (E, 11-biphenyl-4-yloxymethyl) -2- (bromomethyl) -2- (3,4,5-trichlorophenyl) -1 A mixture of 3-dioxolane and 135 parts of N, N-dimethylacetamide was stirred and heated under reflux for 5 days. The reaction mixture was cooled and poured into water. The product was extracted twice with 1,11-oxybisethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography through silica gel eluting with trichloromethane. The first fraction was collected and the eluent was evaporated. The residue was converted to the nitrate salt in 4-methyl-2-pentanone and 2,2'-oxybispropane. The salt was filtered and crystallized from a mixture of acetonitrile and 2,2'-oxybispropane to give 3 parts of cis-1- [+ - (E, 1,1'-biphenyl-4-yloxymethyl) -2- (3,4,5 -trikloorife-phenyl) -1,3-dioxolan-2-yylimetyyli7-H imidatsolinitraartia; 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-bispropane, the salt was filtered and crystallized from a mixture of aceaonitrile and 2,2'-oxybispropane to give 1.9 parts of xrans-1- [4- ( (1'-Biphenyl-4-yloxymethyl) -2- (3,4,5-trichlorophenyl) -1,3-dioxolan-2-ylmethyl-1H-imidazoline nitrate, mp 158 ° C.

Example 26_

Following the procedure of Example 25 and using equivalent amounts of the appropriate starting materials, the following imidazoles and imidazole acid addition salts were prepared: cis-1- [4- (1,1'-biphenyl-4-yloxymethyl) -2- (4-bromo-2-chlorophenyl) ) -1,3-dioxolan-2-yylimetyylO-H-imidazole; mp. brought to 8 ° C; Trans-1- [4 - ((1,1'-biphenyl-4-yloxymethyl) -2- (4-bromo-2-chlorophenyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole; 16.6 ° C; cis-1- [4- (N, 1,1'-biphenyl) -4-yloxy] methyl) -2- (2-naphthene or phenyl) -1.3 ° C; - dioxolan-2-ylmethyl-1H-imidazole, mp 152.6 ° C, trans-1-4-4 ((1,1'-biphenyl-4-yloxymethyl) -2- (2-naphthalenyl) ) - 1,3-dioxolan-2-yl imidate sol nitrate, mp 2 30.6 ° C, 75 62081 cis-1- [4- (E, 1,1'-biphenyl-4-yloxymethyl) -2- (2,4,5-trichlorophenyl) -1,3-dioxolan-2-ylmethyl-1H-imidazoline nitrate, mp 199.2 ° C and trans-1- [4- (Q, 1'-biphenyl) 4-Yloxymethyl) -2- (2,4,5-trichloro-phenyl) -1,3-dioxolan-2-ylmethyl-1H-imidazole mp 139.2 ° C.

Example 27 11.5 parts of 1H-imidazole, 17.5 parts of Δ + B-2- (bromomethyl) -2- (2,4-dichlorophenyl) -4- (3,4,5-trichlorophenoxymethyl) -1,3- a mixture of dioxolane, 3 parts of potassium iodide and 180 parts of N, N-dimethylacetamide was stirred and heated under a condenser over the weekend. The reaction mixture was poured into water and the product was extracted four times with 1,1'-oxybisethane. The combined extracts were washed several times with water, dried, filtered and evaporated. The oily residue was purified by column chromatography on silica gel eluting with trichloromethane. The first fraction (isomer A) was collected and the eluent was evaporated, the oily residue was converted into the nitrate salt in 4-methyl-2-pentanone. The salt was filtered and crystallized from a mixture of 4-methyl-2-pentanone and 2,2 * -oxybispropane to give, after drying, 7.5 parts (40%) of cis-1- {2- (2,4-dichlorophenyl) -4- ( 3,4,5-trichlorophenoxymethyl) -1,3-dioxolan-2-ylmethyl-1H-imidazoline nitrate dihydrate; mp. 149.9 ° C.

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

Example 28

Following the procedure of Example 27 and using equivalent amounts of the appropriate starting materials, the following imidazoles and imidazole acid addition salts were prepared. Where only one isomer is labeled, no other fraction was obtained chromatographically.

76 * 6208 1 cis-1- [4- (2-chloro-5-methylphenoxymethyl) -2- (2, M-chlorophenyl) -1,3-dioxolan-2-ylmethyl ? LIJ -lH-imidazole; mp. 131.7 ° C; Trans -1- (4- (2-chloro-5-methylphenoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl) -1H-imidazole esquidium i-carboxylate; mp. 148.7 ° C; N- 1- (4- (1,6-dibromo-2-naphthalenyloxy) methyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl) -1H-imidazoline nitrate; mp. 17.9.4 ° C; A-1-6 + - (2,3-dichlorophenoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl) -lH-imidatsolidietaanidikarboksylaat-phosphate; mp. 151.1 ° C; and B-1-6 + - (2,3-dichlorophenoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl) -1H-imidazole cisquanethanecarboxylate; mp. 156.3 ° C.

Example 29

Following the procedure of Example 10 and using equivalent amounts of the appropriate starting materials, the following compounds were prepared: A + B-1-6 + - (4-bromophenylthiomethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl *? -1H-imidazoline nitrate isp. ± 7 DEG C. and CXVIII A + B-1- [2- (2,4-dichlorophenyl) -4- (phenylthiomethyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazoline nitrate; mp. 122.3 ° C.

Example 30 4.5 parts of 1H-imidazole, 6.5 parts of A-2- (bromomethyl) -4- (4-bromophenoxymethyl) -2- (2,3-dichlorophenyl) -1,3-dioxolane and 125 parts of N, The mixture containing N-dimethylacetamide was stirred and heated under reflux for 2 days. The reaction mixture was allowed to cool to room temperature, poured into water and the product was extracted twice with 1,1'-oxybisethane. The combined extracts were washed twice with water and an excess of concentrated nitric acid solution was added. The formed nitrate salt was filtered and crystallized from 4-methyl-2-pentanone to give 5 parts (68%) of cia-i- (4- (4-bromophenoxymethyl) -2- (2,3-dichlorophenyl) -1,3- cyloxolan-2-ylmethyl N-1H-imidazoline nitrate, mp 138.9 ° C.

77 6 2 0 81

Example 31_

Following the procedure of Example 30 and using equivalent amounts of the appropriate starting materials, the following imidazoles and imidazole acid addition salts were prepared: cis-1- {+ + (3-chloro- (±, 1'-biphenyl-4-yloxymethyl) -2- ( 2,4-dichloro-phenyl) -1,3-dioxolan-2-ylmethyl-1H-imidazoline nitrate, mp 171.1 ° C;

cis-1- [+ + (1,1'-biphenyl-4-yloxymethyl) -2- (2-chloro-U-methoxy-phenyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazoline nitrate; . 172.9 ° C

A + B1- (2- (2,4-dichlorophenyl) -4- (phenylmethyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazolidiethanedicarboxylate, mp 117.1 ° C; - (2,4-dichlorophenyl) -4- (4-fluorophenyl) thiomethyl-1,3-dioxolan-2-ylmethyl N-1H-imidazolidiethanedicarboxylate, mp 129.8 ° C; 4-Chloro-phenylmethyl) -2- (2,4-dichloro-phenyl) -1,3-dioxolan-2-ylmethyl-1H-imidazole-cis-danecarboxylate, mp 141.6 ° C.

A + B1- 3- (2,4-dichlorophenyl-4- (4-methoxyphenylmethyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazolidiethanedicarboxylate, mp 94.2 ° C; 2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy-7-benzonitrile nitrate, mp 162.1 ° C, and cis-butyl 2- N- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy benzoate nitrate, mp 90.5 ° C.

Example 32 14.4 parts of 1H-imidazole, 18.5 parts of A + B-2- (bromomethyl) -2- (2,4-dichlorophenyl) -4- [2- (4-methoxyphenyl) ethyl] -1, A mixture of 3-dioxolane, 5 parts of potassium iodide and 135 parts of N, N-dimethylacetamide was stirred and heated under reflux for 2 days. The reaction mixture was allowed to cool to room temperature and poured into water. The product was extracted twice with 2,2'-oxy-bispropane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was converted to the ethanedicarboxylate salt in 4-methyl-2-pentanone and 2,2'-oxybispropane.

7 8 6 2 O 8 1

The salt was filtered and crystallized from a mixture of 2,2'-oxybispropane and ethanol to give A + B1- (2- (2,4-dichlorophenyl) -4- [2- (4-methoxyphenyl) ethyl] -1,3-dioxolan-2- ylmethyl) -lH-imidazo-liseskvietaanidikarboksylaattia; mp. 130.7 ° C.

Example 33

Following the procedure of Example 32 and using equivalent amounts of the appropriate starting materials, the following imidazoles and imidazole acid addition salts were prepared: 1- (4-C1- (4-chlorophenyl) ethyl] -2- (2,4-dichlorophenyl) -1,3-dioxo- lan-2-ylmethyl) -lH-imidatsolidietaanidikarboksylaatii; mp. 131.9 ° C; 1- {2- (2H-dichlorophenyl) -4- (2-phenylethyl) -1,3-dicolol-2-ylmethyl] -1H-imidazole sesquicanedicarboxylate; mp. 117.8 ° C; and A + B-1- (2- (2,4-dichlorophenyl) -4- [2- (4-methylphenyl) ethyl] -1,3-dioxolan-2-ylmethyl) -1H-imidazolesecketanedicarboxylate dihydrate , sp. 123.8 ° C.

1- (4 -, (1- (2-chlorophenyl) ethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl) -1H-imidazoline nitrate mp 98.8 ° C 1- (2- (2,4-dichlorophenyl) -4- [1- (2,4-dichlorophenyl) ethyl] -1,3-dioxolan-2-ylmethyl) -1H-imidazolinitrate m.p. 158.1 ° C; CVI2 and A + B1- (2- (2,4-dichlorophenyl) -4- [2- (2,4-dichlorophenyl) ethyl] -1,3-dioxolan-2-ylmethyl) -1H-imidazoline nitrate, mp 140.1 ° C.

Example 34

To a stirred sodium methoxide solution prepared from 3.8 parts of sodium in 40 parts of methanol was added 11 parts of 1H-imidazole and 225 parts of N, N-dimethylformamide. Methanol was distilled off until the internal temperature was 150 ° C. Then, 19 parts of A + B-2- (bromomethyl) -2- (2,4-dichlorophenyl) -4-ethyl-1,3-dioxolane were added thereto, and the mixture was stirred and heated under a vertical condenser for 1 hour. The reaction mixture was allowed to cool to room temperature and poured into water. The product was extracted three times with 1,1 * -oxybisethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography through silica gel using a mixture of trichloromethane and 1% methanol as eluent. The first fraction was collected and the eluent was evaporated. The residue was converted to the nitrate salt in 2,2'-oxybispropane. The salt was filtered and crystallized from a mixture of 2-propanol and 2,21-oxybispropane to give 12 parts (56%) of A + B1- [2- (2,4-dichlorophenyl) -4-ethyl-1,3-dioxolan-2- ylmethyl} '- H imidatsolinitraattia; mp. 149.1 ° C.

Example 35_

To a stirred sodium methoxide solution prepared from 2.8 parts of sodium in 40 parts of methanol was added 8 parts of 1H-imidazole and 225 parts of N, N-dimethylformamide. The methanol was distilled off until an internal temperature of 150 ° C was reached. 30 parts of A + B-2- (4-bromo-2-chlorophenyl) -2- (bromomethyl) -4-ethyl-1,3-dioxolane were then added thereto, and stirring was continued for 1 hour at reflux temperature. The reaction mixture was cooled and poured into water. The product was extracted twice with 2,21-oxybispropane. The combined extracts were washed with water, dried, filtered, and evaporated. The residue was purified by column chromatography through silica gel 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'-oxybispropane. The salt was filtered and crystallized from a mixture of 4-methyl-2-pentanone and 2,2,2-oxybispropane to give 8.5 parts (26%) of A + B1- [2- (4-bromo-2-chlorophenyl) -4- ethyl-l, 3-dioxolan-2-ylmethyl -lH-imidatsolinitraattia?; mp. 162.2 ° C.

Example 36

Following the procedure of Example 35 and using equivalent amounts of the appropriate starting materials, the following imidazole addition salts were prepared: i.e. 6 2 0 8 1 Ψ CH, Ar

A + B

rXj ”” * Ar R Hydrochloric acid Melting point.

2-Cl-C6H4 'C2H5 HNO3 147.6 * C

2-CH3-C6H4 C2H5 HNO3 117.5 * C

4-CH3-C6H4 C2H5 HNO3 172. 7 * C

2.3.4- (Cl) 3-C6H2 C2H5 HNO3 176. 4 * C

2- Br-C6H4 C2H5 HNC> 3 135. 3 * C

2.3- (Cl) 2-C6H3 C2H5 HNO3 140.3 * C

3- Cl-C6H4 C2H5 HN ° 3 151.6 * C

4- OCH3-C6H4 C2H5 HNO3 157.1 * C

2-CH3-4-Cl-C6H3 C2Hg HNO3 126.8 * C

2-Cl-4-OCH3-C6H3 C2H5 HNO3 117.7 * C

. 3,4,5- (Cl) -C 2 H C 2 H 5 HNO 3 195.8 * C

2_naphthyl in C2H5 HN03 195.1 * C

2-OCH3-4-Cl-C6H3 C2H5 HNO3 131.8'C

2.4.5- (Cl) 3-C6H2 C2H5 ‘HNO3 180.1 * C.

2.4- (Cl) 2-C6H3 nC3H7 HNC> 3 119.2 * C

2.4- (Cl) 2-C6H3 nC4H9 HN ° 3 - 113.1 * C

2.4- (Cl) 2-C6H3 nC5H11 HN ° 3 128.3 * C

2.4- (Cl) 2-C6H3 dC6H13 HNO3 99.4 * C

2.4- (Cl) 2-C6H3 aC7K15 2 (COOH) 2131 ° C

2.4- (Cl) 2-C6H3 nC8H17 2 (COOH) 2 132.8 * C

81 62081

Example 37 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 a mixture of butanol and 360 parts of dimethylbenzene was stirred and heated under a condenser for 5 days with a water separator. The reaction mixture was cooled, washed with potassium carbonate solution and water, dried, filtered and evaporated. The residue was dissolved in dilute ethanedicarboxylic acid solution. The resulting solution was washed twice with 1,1'-oxybisethane. The aqueous phase was separated and neutralized with potassium carbonates. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography through silica gel using a mixture of trichloromethane and 2% methanol as eluent. The first fraction was collected and the eluent was evaporated. The residue was converted to the nitrate salt in 2,2'-oxybispropane. The salt was filtered and crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane to give 5.5 parts (9.8%) of A + B1- (1- (butoxymethyl) -2- (2, 4-dichlorophenyl-yl) -1,3-dioxolan-2-ylmethyl ^ -lH-imidatsolinitraattia; mp. 101.8 ° C. The second fraction was collected and the eluent was evaporated. The residue was triturated in 1,1'-oxybisethane. The product was filtered 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 38 7.7 parts of 1H-imidazole, 8 parts of cis-2- (bromomethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolane-4-methanol, 1 part of potassium iodide and 180 parts of N, The mixture containing N-dimethylacetamide was stirred and heated under reflux for 3 days. The reaction mixture was cooled and evaporated. Then 50 parts of water and 300 parts of trichloromethane were added to the residue. The mixture was washed three times with water, dried, filtered and evaporated. The residue was purified by column chromatography through silica gel using a mixture of trichloromethane and 2% methanol as eluent. The pure fractions were collected and the eluent was evaporated, yielding 9.2 parts of cis-2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolane-4-methanol; mp. 140 ° C.

ί 1 82 6208 1

Example ^ 9

Following the procedure of Example 38 and using an equivalent amount of trans-2- (bromomethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolane-4-methanol as starting material gave: trans-2- (2,4-dichlorophenyl) - 2- (lH-imidazol-l-ylmethyl) -l, 3-dioxolane-4-methanol; mp. 129 ° C.

Example 40 4 parts of cis-2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolane-4-methanol, 2.2 parts of methyl iodide and 90 parts of N, To the stirred mixture containing N-dimethylformamide was added 0.5 part of a 78% sodium hydride dispersion. Stirring was continued for 2 hours at room temperature. The reaction mixture was poured into water and the product was extracted three times with 1,1'-oxybisethane. The combined extracts were washed with water and acidified with a solution of nitric acid in 1,1'-oxybisethane. The formed nitrate salt was filtered and crystallized from 4-methyl-2-pentanone to give 2.2 parts (45%) of cis-1- {2- (2,4-dichlorophenyl) -4- (methoxymethyl) -1,3-dioxolane. yylimetyyli7-2-H-imidazole nitrate; mp. 140 ° C.

Example 41 4 parts of cis-2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolane-4-methanol, 1.7 parts of ethyl bromide and 90 parts of N, To the stirred mixture containing N-dimethylformamide was added 0.5 part of the sodium hydride dispersion 78%. The mixture was stirred for 1 hour at room temperature. 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 nitrate salt formed was filtered and crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybis-propane to give 4.7 parts (93%) of cis-1- [2- (2,4-dichlorophenyl) - 4- (ethoxymethyl) -1,3-dioxolan-2-ylmethyl 1H-imidazoline nitrate; mp. 134.7 ° C.

83 6 2 0 81

Example 42_

Following the procedure of Example 41 and using an equivalent amount of the appropriate bromoalkane or bromoalkene instead of the ethyl bromide used therein, the following imidazole acid addition salts were prepared: cis-1- [2- (2,4-dichlorophenyl) -4- (propoxymethyl) -1,3-dioxolane -2-yylimetyyli7 ~ H imidatsolinitraatti; mp. 131.7 ° C; cis-1- [3- (2,4-dichlorophenyl) -4- (pentyloxymethyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazoline nitrate; mp. 78.6 ° C; cis (2,4-dichlorophenyl) -4- (hexyloxymethyl) -1,3-dioxolan-2-ylmethyl-1H-imidazoline nitrate; mp. 87.1 ° C; cis-1- {2- (2,4-dichlorophenyl) -4- (heptyloxymethyl) -1,3-dioxolan-2-ylmethyl, -1H-imidazoline nitrate; mp. 80.7 ° C; cis-1- [2- (2,4-dichlorophenyl) -4- (octyloxymethyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazoline nitrate; mp. 116.3 ° C. £ L-cis-2- (2,4-dichlorophenyl) -4- (2-propenyloxymethyl) -l, 3-di-oxolan-2-ylmethyl ^ -lH-imidatsolinitraatti; mp. 116.3 ° C.

Example 43 4 parts of trans-2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolane-4-methanol, 1.7 parts of ethyl bromide and 90 parts of Ν, To the mixture containing Ν-dimethylformamide was added 0.5 part of the sodium hydride dispersion 78%, and the mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into water and the product was extracted twice with 2,2'-oxybispropane. The combined extracts were washed with water and taken up in 2,21-oxybispropane. The solution was made acid-acid with nitric acid. The formed nitrate salt was filtered and crystallized from 4-methyl-2-pentanone to give 3.5 parts (69%) of trans-1- (2- (2,4-dichlorophenyl) -4- (ethoxymethyl) -1,3-dioxo- lan-2-ylmethyl-1H-imidazoline nitrate, mp 151.4 ° C.

Example 44 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 To a stirred mixture of -4-methanol and 90 parts of Ν, Ν-dimethylformamide was added 0.5 parts of a 78% sodium hydride dispersion. Stirring was continued for 5 hours at room temperature. The reaction mixture was poured into water and the product was extracted twice 84. 62 O S1 with 2,2'-oxybispropane. The combined extracts were washed with water, dried, filtered and acidified with nitric acid. The nitrate salt formed was filtered and crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane. The product was filtered 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-chlorophenyl-1-methoxymethyl) -2- (2 (4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl 1H-imidazoline nitrate; mp. 131.7 ° C.

Example 45

By repeating the procedure of Example 44 and using an equivalent amount of the appropriate (chloromethyl) benzene instead of the 1-chloro-4- (chloromethyl) benzene used therein, the following was obtained: cis-1- (4- (4-bromophenyl) methoxymethyl) -2- (2,4 (dichlorophenyl) -1,3-dioxolan-2-ylmethyl) -1H-imidazoline nitrate; mp. 101.4 ° C; and cis-1- (2- (2,4-dichlorophenyl) -4-4-fluorophenyl) methoxymethyl] -1,3-dioxan-2-ylmethyl) -1H-imidazoline nitrate; mp. 10 7 ^ 0.

Example 46 3.3 parts of 2,4-dichloro-1- (chloromethyl) benzene, 5 parts of A + B-2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1.3 To a stirred mixture of -dioxolane-4-methanol and 90 parts of N, N-dimethylformamide was added 0.5 parts of a 78% sodium hydride dispersion and stirring was continued for 3 hours at room temperature. 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, dried, filtered and evaporated. The residue was purified by column chromatography through silica gel eluting with trichloromethane. 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'-oxy-bispropane. The salt was filtered and recrystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane at 0 ° C to give 2.9 parts (35%) of cis-1- (2- (2,4- dichlorophenyl) -4- (2,4-dichlorophenyl) methoxymethyl (1,3-dioxolan-2-ylmethyl) -1H-imidazoline nitrate; mp. 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-methyl-2-pentanone and 1,1 * -oxybisethane. The salt was filtered and recrystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane to give 1.6 parts (19%) of trans-1- (2- (2,4-dichlorophenyl) -4 - [( f (2,4-dichlorophenyl) -methoxymethyl (-1,3-dioxolan-2-ylmethyl) -1H-85 62 0 81 imidazoline nitrate, mp 131.9 ° C.

Example 47

By repeating the procedure of Example 46 and using an equivalent amount of 4- (chloromethyl) -1,1 * -biphenyl instead of the 2,4-dichloro-1'-chloromethylbenzene used therein, the following was obtained: cis-1- [4- (E, 1,1'-biphenyl) 4-ylmethoxymethyl) -2- (2,4-dichloro-phenyl) -1,5-dioxolan-4-ylmethyl-1H-imidazolidiethanedicarboxylate; mp. 107.6 ° C; and trans-1- {4 - (. (1,1'-biphenyl-4-ylmethoxymethyl) -2- (2,4-dicione-phenyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazoline nitrate ; mp. 168 ° C.

Example 48 2.2 parts of (4-hydroxyphenylphenylmethanone, 4.2 parts of cis-2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethyl methanesulfonate, 2 A mixture of 1 part of potassium carbonate and 68 parts of N, N-dimethylformamide was stirred overnight at 100 [deg.] C. The reaction mixture was cooled and poured into water, the product was extracted twice with 1,11-oxybisethane, and the combined extracts were washed with water, dried, filtered and evaporated. In 4-methyl-2-pentanone and 2,2'-oxybis-propane to give 4.5 parts (78%) of cis- (4- {5- (2,4-dichlorophenyl) -2- (1H-imidazole). 1-ylmethyl) -1,3-dioxolan-4-ylmethoxy (phenyl) phenylmethanone nitrate, mp 179 ° C.

.Example ..49

Following the procedure of Example 48 and using an equivalent amount of the appropriate phenol instead of the (4-hydroxymethyl) phenylmethanone used therein, the following imidazoles and imidazole acid addition salts were prepared: cis-5-chloro-2- [2- (2,4-dichlorophenyl) -2 - (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy-2- (4-methylphenylphenylmethanone ethane dicarboxylate; mp. 170.8 ° C; cis-methyl-4- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] benzoate initiator; mp. 167.8 ° C; cis- (2- [1- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] -5-methylphenyl] phenylmethanonitrate; mp. 145.4 ° C; cis- (4-chlorophenyl) (2- {2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] -4-methoxyphenyl) -methano-ni; mp. 168.3 ° C; * 86 62081 cis- (2- {2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] -4-methoxyphenyl) phenylmethanone; mp. 149.2 ° C; cis-1- (2- (2,4-dichlorophenyl) -4- [3- (trifluoromethyl) phenoxymethyl] -1,3-dioxolan-2-ylmethyl) -1H-imidazoline nitrate; mp. 152.6 ° C; cis-1- (4- {2- (2,4-dichlorophenyl) -2- (ΙΗ-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxyphenyl) ethanone nitrate; mp. 182.6 ° C; cis-Methyl 2- (2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy-benzoate nitrate, mp 140.5 ° C and cis-1- (4- {2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy) phenyl) -1-propanenitrate; mp. 176.2 ° C.

Example at] 12.5 parts of 1,2-butanediol, 19 parts of 1- (2-chloro-4-fluorophenyl) -2- (1H-imidazol-1-yl) ethanone hydrochloride, 16 parts of 4-methylbenzenesulfonic acid, 40 parts A mixture of 1-butanol and 225 parts of dimethylbenzene was stirred and heated under a condenser for 6 days with a water separator.

After cooling, the reaction mixture was filtered and the filtrate was washed with dilute sodium hydroxide solution and water. After the addition of 2,2'-oxybispropane, the mixture was acidified with nitric acid solution. The formed nitrate salt was filtered and crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane to give 5.7 parts (22%) of A + B1- 2- (2-chloro-4-fluorophenyl) -4- ethyl-1,8-dioxolan-2-ylmethyl ^ -lH-imidatsolinitraattia; mp. 132.4 ° C.

For example 51

Following the procedure of Example 50 and showing the equivalent amounts of the appropriate starting materials, the following imidazoles and imidazole acid addition salts were prepared: A + B1- [2- (4-bromophenyl) -4-ethyl-1,3-dioxolan-2-ylmethyl] -1H -imidatsolinitraatti; mp. 194.7 ° C; A + B-1- [2- (2,4-dibromophenyl) -4-ethyl-1,3-dioxolan-2-ylmethyl] -1'-imidazoline nitrate m.p. 149.7 ° C; 87 62081 A + B-1- [4-ethyl-2- (2-thienyl) -1,3-dioxolan-2-ylmethyl] -1-imidazoline nitrate; mp. 135.4 ° C; A + B-1- [2- (5-chloro-2-thienyl) -H-ethyl-1,3-dioxolan-2-ylmethyl] -1H-imidazoline nitrate; mp. 164.3 ° C; A + B-1- [4- (chloromethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazoline nitrate; mp. 166.1 ° C; A + B-1- [4- (N, 1,1'-biphenyl-4--ylmethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazolidiethanedicarboxylate; mp. 116.8 ° C; A + B-1- [5- (2,4-dichlorophenyl) -4- (4-fluorophenylmethyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole sesquicanedicarboxylate; mp. 153.1 ° C; A + B-1- [2- (2,4-dichlorophenyl) -4- (4-methylphenyl) methyl-1,3-dioxan-2-ylmethyl} -1H-imidazole-sesquetanedicarboxylate; mp. 123.1 ° C; A + B-1- [1- + (4-bromophenylmethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazolidiethanedicarboxylate; mp. 128.8 ° C; A + B-1- (4- (2- (N, 1,1'-biphenyl) -4-yl) ethyl 47-2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl ) -1H-imidazole sesquicanedicarboxylate human hydrate, mp 143.9 ° C, and A + B-1- (2- (2,4-dichlorophenyl) -4- [2- (phenylmethyl) phenoxymethyl] -1, 3-dioxolan-2-ylmethyl) -1H-imidazole sesquanidane dicarboxylate hemihydrate, mp 113 ° C.

Example 52 13.8 parts of 1- (2-chloro-4-fluorophenyl) -2- (1H-imidazol-1-yl) ethanone hydrochloride, 14.6 parts of 3- (E, 1,1'-biphenyl-4-yloxy) A mixture of 1,2-propanediol, 16 parts of 4-methylbenzenesulfonic acid, 40 parts of butanol and 225 parts of dimethylbenzene was stirred and heated under reflux for one week with a water separator. After cooling, 1,1'-oxybisethane was added thereto, and it was washed successively with dilute sodium hydroxide solution and water, dried, filtered and evaporated. The residue was purified by column chromatography through silica gel eluting with trichloromethane. 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'-oxybispropane. The product was filtered and crystallized from a mixture of acetonitrile and 2,2'-oxybispropane to give 5 parts of cis-1- [4- (1,1'-biphenyl] -4-yl-88,62081 oxymethyl) -2- (2-chloro-N- (fluorophenyl) -1,3-dioxolan-2-ylmethyl-1H-imidazoline nitrate; 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 k-methyl-2-pentanone and 2,2'-oxybispropane. The salt was filtered and crystallized from a mixture of acetonitrile and 2,2'-oxybispropane to give 5.9 parts of trans-1- [k- (ζ ±, 1'-biphenyl] -4-yloxymethyl) -2- (2-chloro-k fluorophenyl) -l, 3-dioxolan-2-ylmethyl-imidazo ^ -lH-nitrate in; mp. 156.9 ° C.

Example 53

Following the procedure of Example 52 and using equivalent amounts of the appropriate starting materials, the following imidazoles and imidazole acid addition salts were prepared. When only one isomer is labeled, the second fraction was not chromatographically obtained.

cis-1- [E - (((1,1'-biphenyl) -k-yloxymethyl) -2- (2-phenyl) -1,3-dioxolan-2-ylmethyl] - H-imidazole; mp. 9.5 ° C · trans-1 H - (N, 1,1'-biphenyl-4-yloxymethyl) -2- (2-thienyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole mp. 300 ° C; cis-1- {4 - ((1,1'-biphenyl'-k-yloxymethyl) -2- (2,2-dibromophenyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazoline nitrate; mp 17 k, k ° C; Trans-1- (b - (1,1'-biphenyl-7-k-yloxymethyl) -2- (2, k-dibromophenyl) -1,3-dioxolan-2-ylmethyl N-1H-imidazoline nitrate; mp Iki, 8 ° C; and cis-1- [E - (”(1,1'-biphenyl-1'-yloxymethyl) -2- (5-chloro-2-thienyl) -1,3-dioxolan-2-ylmethyl 1 H -imidazoline nitrate mp 17u ° C.

Example 5k 1.1 parts of 3-chloro-1-propyne, k parts of cis-2- (2, k-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolane-k- To a stirred mixture of methano-1 and 90 parts of N, N-dimethylformamide was added 0.5 parts of a 78% sodium hydride dispersion. Stirring was continued for 3 hours at room temperature. The reaction mixture was poured into water and the product was extracted twice with 1,1'-oxybisethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography through silica gel 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 ethanedicarboxylate salt in 4-methyl-2-pentanone and 2,2'-oxybispropane. The salt was filtered and crystallized from 4-methyl-2-pentanone to give 3.6 parts (55%) of cis-1- {2- (2,4-dichlorophenyl) -4- (2-propynyloxymethyl) -1,3 -dioxolan-2-ylmethyl-1H-imidates solid ethanedicarboxylate; mp. 145.6 ° C.

Example 55 A mixture of 17 parts of 1H-imidazole, 16 parts of A + B-2- (bromomethyl) -2- (2,4-dichlorophenyl) -4-ethenyl-1,3-dioxolane and 225 parts of N, N-dimethylformamide was stirred. and heated under reflux for 3 days. The reaction mixture was cooled, poured into water and the product was extracted twice with 1,1'-oxybisethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography through silica gel 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 and 2,2'-oxybispropane. The salt was filtered and crystallized from 4-methyl-2-pentane to give 2.4 parts (13%) of A + B1- (2- (2,4-dichlorophenyl) -4-ethenyl) -1,3- dioxolan-2-ylmethyl / -1 H-imidazoline hydrate; mp. 150.9 ° C.

Example. 56 33 parts cis-2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolane-4-methanol, 35 parts 4-methylbenzenesulfonic acid, 80 part of pentanol and 360 parts of toluene were stirred and refluxed for 10 days while separating water. The reaction mixture was cooled, washed with dilute sodium hydroxide solution, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel 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'-oxybispropane. The nitrate salt formed was crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane to give 10.6 parts of cis-1- [2- (2,4-dichlorophenyl) -4- (pentyloxy). i-methyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazoline nitrate, m.p.

77.9 ° C.

Claims (2)

A process for the preparation of therapeutically useful 1- (1,3-dioxolan-2-ylmethyl) -imidazole derivatives of the formula I, their pharmaceutically acceptable acid addition salts and their optically active isomers, wherein R 1 is Ar-phenyl; substituted phenyl, thienyl, chlorothienyl or naphthyl, wherein the substituted phenyl group has 1 to 3 substituents which may independently be halogen atoms, C 1-4 alkyl, C 1-4 alkoxy, nitro or cyano groups, and R is 2- Alkyl of 10 carbon atoms, alkoxymethyl having 1 to 10 carbon atoms in the alkoxy group, ethenyl, propenyloxymethyl, 2-propynyloxymethyl, hydroxymethyl, halomethyl, aryl, aryl-C 1-4 alkyl, aryloxymethyl, arylthiomethyl or arylmethoxymethyl, wherein the aryl group is phenyl, substituted phenyl, naphthyl or mono- or di-halonaphthyl, and wherein the substituted phenyl group has 1 to 3 substituents eluents which may independently be halogen atoms, C 1-4 alkyl, C 1-4 alkoxy, cyano, nitro, phenyl, phenylmethyl, benzoyl, halobenzoyl, C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl or trifluoromethyl groups, provided that when more than one substituent is present, only one of them may be phenyl, benzyl, benzoyl or chlorobenzoyl, characterized in that a) a compound of formula IH or an alkali metal salt thereof is reacted, preferably at elevated temperature, with a compound with the formula 91 62081! W-CH 2, Ar III XR J- wherein VJ is halogen, in a suitable organic solvent, preferably in the presence of an alkali metal iodide, or b) ketalizing a compound of formula QI 5 CH 2 -C-Ar with a compound of formula OH V r-ch- ch 2 -oh preferably in the presence of an alcohol and a suitable strong acid, or c) O-alkylating in a manner known per se a compound of the formula I in which R is HOCH 2 - with a compound of the formula R 1 to W VI in which R is alkyl, alkenyl, 2-propynyl or arylmethyl and W is halogen, preferably in the presence of a suitable organic solvent and a suitable strong base, to form a compound of formula I wherein R is R 1 -O-CH 2 -, or d) condensing a compound of formula I wherein R is HOCH 2 with an alkanol of alkyl-OH, preferably in a suitable organic solvent in the presence of a suitable strong acid to form a compound of formula I wherein R is alkyl-O-CH 2 -, or 92 6 2 0 31 e) O-alkylation in a manner known per se; a compound of formula I-N CH 2 Ar W-CH 2 -I-1 wherein W is halogen, with a compound of formula R 2 to OH VIII 2 wherein R is alkyl, alkenyl, 2-propynyl, arylmethyl or aryl, preferably a suitable organic solvent and in the presence of a suitable strong base to form a compound of formula I wherein R is R-O-CH 2 - and, if desired, converting the resulting compound into a pharmaceutically acceptable acid addition salt by reacting the compound with a suitable acid and / or converting the compound to an optically active isomer known per se. 93 62081 For the preparation of a therapeutically active compound 1 (1,3-dioxolan-2-ylmethyl) -imidazole with the formula I, a pharmaceutical form of a syringe addition and an optically active isomeric compound, U d: H «, Ar oXo or phenyl R_J_I substituents phenyl, thienyl, chlorothienyl or naphthyl, colors having 1 to 3 substituents on the phenyl group, optionally substituted with a halogen atom, C 1-4 alkyl-, alkoxy-, nitro- or cyangroup, and 2- 10 cholatomers, alkoxymethyl, copper alkoxy groups 1-10 cholatomers, ethenyl, propenyloxymethyl, 2-propynyloxymethyl, hydroxymethyl, halomethyl, aryl, aryl-C1-4-alkyl, aryloxymethyl, arylthiomethyl or arylmethoxymethyl, colored aryl groups, phenyl, phenyl or mono- and di-halohaphthyl, with various substituents on the phenyl group having 1 to 3 substituents, optionally substituted with a halogen atom, C 1-4 alkyl, C 1-4 alkoxy, cyano, nitro, phenyl, phenylmethyl , benzoyl, halobenzoyl, alkyl R, butyl, 4-alkoxycarbonyl, or trifluoromethyl groups, which are substituted with the same substituents as the phenylphenyl, benzyl, benzoyl or halogenobenzoyl, with the aid of the same, (a) these are used in the form of A 111 J_J 62081 94 color W is halogen, which is a warm organic organ, alkali metal is used in the form of w-ch2 ^^. ketal series and compounds of formula I Ni J o iv I "CH2-C-Ar with compounds of formula OH R-CH-CH2-OH V derivative of the mixture with alcohol and warm Stark syrup, or c) O-alkyler and in the case of compounds of formula I, from R to HOCH2 ~, with to R1 - W VI color R to alkyl, alkenyl, 2-propynyl or arylmethyl and W to halogen, to give a mixture of the same organic leachate and warm stark bas, for bil this is a compound of formula I, wherein R is R 1 -O-CH 2 -, or d) a condenser of the form of I, wherein R is HOCH 2 -, is a preferred alkanol with alkyl alkyl-OH, which is a warm organic compound The solution of the mixture in the form of a starch, for the purpose of the formulation of Form I, with R is alkyl-OH-CH2 ~, or (e) O-alkylation of the form of the formulation - NI Ij VII XX ! CH0 Ar Xo W-CH2- ^ 1