AT296289B

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

Abstract

This record has no abstract on file.

AT296289B, drawing sheet 1 — Sheet 1 of 8

Term

Term ended

Expired 18 August 1989, 37.1 years ago.

1 claim: 1 independent, 0 dependent

1
CLAIMS:1. Process for the preparation of new imidazole derivatives of the general formula, -N R 3) | l R »| l. R 1 -CC-NH-CCHj ^ -Ar'te wherein R x and Rj independently of one another are hydrogen atoms or lower alkyl radicals} n is zero, 1 or 2;Ar is phenyl, substituted phenyl, thienyl or halogenthienyl, wherein the substituted phenyl radical contains at least 5 substituents from the group halogen atoms, lower alkyl radicals and lower alkoxy} Ar 'phenyl, substituted phenyl or α-tetralyl, wherein the substituted phenyl radical at least one substituent from Group contains halogen atoms, lower alkyl radicals, lower alkoxy radicals, cyano, nitro and amino;R 'is hydrogen, methyl or ethyl;R "is hydrogen or methyl, but in cases where Ar * is an α-tetralyl radical, n is zero, and their therapeutically effective acid addition salts, characterized in that compounds of the general formula R, -C - C = O I l R, te with compounds of the general formula H ^ CH ^ -Ar ', (III) 15 in a suitable solvent and in the presence of an acid to compounds of the general formula R (IV) N I R ^ CC ^ N ^ iCH Ar * Rz Ar reacts and the compounds (IV) reduced to compounds of general formula (XI) and the latter, if desired, converted into their therapeutically active acid addition salts, 20 2, Process according to claim 1, characterized in that one for the preparation of novel imidazole derivatives of the general formula (XI), wherein R "is hydrogen, Ar phenyl, halophenyl, dihalogenophenyl, lower-alkylphenyl, lower alkoxyphenyl, thienyl or Halogenthienyl with the The proviso means that the halogen atoms each have an atomic weight below 80, Ar * phenyl, halophenyl, dihalogenophenyl, lower-alkylphenyl, lower - alkoxyphenyl, nitrophenyl, dinitro16 No. 296289 phenyl, aminophenyl or α-tetralyl with the proviso symbolizes that the halogen atoms each have an atomic weight below 80 and R *, R, and n have the above meaning, corresponding compounds of the general formulas (I) and (II) wherein R, Ar and Ar 'are the above and R', R 1 , and n have the meaning given in claim 1. Pamphlets considered by the Patent Office to delineate the subject-matter of the prior art;GB-PS 1 099 787 OE-PS 260 235 Printed by Ing, E. Voytjech, Vienna

314 paragraphs in 15 sections, as filed

Beginning of the patent period: June 15, 1971.

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

R "_ | (4) (3) il

-N (5) (2> -R »\ (D / XNH (XI)

Rx-C -C -NH-iCHjh-Ar '

Rj Ar wherein Rxand R2 independently of one another hydrogen atoms or lower alkyl radicals; n zero, 1 or 2; Ar is phenyl, substituted phenyl, thienyl or halogenthienyl, wherein the substituted phenyl radical contains at least one substituent from the group of halogen atoms, lower alkyl radicals and lower alkoxy radicals; Ar 'is phenyl, substituted phenyl or α-tetralyl, where the substituted phenyl radical contains at least one substituent selected from the group consisting of halogen atoms, lower alkyl radicals, lower alkoxy radicals, cyano, nitro and amino; R 'is hydrogen, methyl or ethyl; R is hydrogen or methyl, but in cases where Ar * is an α-tetralyl radical, n is zero.

Me production of the therapeutically active acid addition salts of the aforementioned Verbin fertilize (XI) is also within the scope of the invention,

Me above mentioned lower alkyl radicals and lower alkoxy radicals may be straight or branched saturated hydrocarbon radicals having 1 to about 6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, similar, alkyl radicals, or, the corresponding alkoxy radicals, such as methoxy, ethoxy, propoxy, isopropoxy, etc. Preferred as lower alkyl radical and lower alkoxy radical are the methyl radical or the methoxy radical. Suitable halogen atoms are fluorine, iodine, bromine and chlorine. Substituted phenyl radicals in which Ar represents are mono-, m- and trihalogenophenyl radicals, lower alkylphenyl radicals and lower radicals Alkoxyphenyl radicals are preferred and substituted phenyl radicals in which Ar * is mono-, M- and trihalophenyl radicals, mono- and M- (lower alkyl) -phenyl radicals, 20 lower alkoxyphenyl radicals, Cyanophenylreste, mono- and Mnitrophenylreste and aminophenyl radicals preferred.

Me amines of general formula (XI) can be reduced by reducing amination of a entspre2

Nos. 296289 1 - (aroylmethyl) imidazoles of the formula (Π) in which Rj, Rj, R ', R and Ar have the abovementioned meaning, can easily be prepared by reacting this ketone (II) with a corresponding amine of the formula (II) III), in which n and Ar 'have the meanings given above, in a suitable solvent, for. B, in an aromatic hydrocarbon such as benzene, toluene and xylene. The amination is preferably carried out under reflux conditions and in the presence of a small amount of a suitable acid, eg, p-toluenesulfonic acid. When the evolution of water has ceased, the aromatic hydrocarbon used as the solvent is evaporated and the residual product (IV) is converted to a lower alkanol solvent and converted to the corresponding amine (XI) e.g. B. by treatment with a suitable reducing agent, for example a complex metal hydride, z, B, potassium borohydride and sodium borohydride, or by catalytic hydrogenation, for example by treatment with hydrogen and a catalyst consisting of palladium on activated carbon. The amino product can be easily isolated from the reaction mixture by conventional methods either as a free base or optionally in the form of an acid addition salt by treatment of the base with a suitable acid.

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

A. The known compound N-acetylimidazole (s, Otting, Ber, 89 [1956], p. 1940) is reacted with a compound of the formula Y-CHj-CO-Ar (Y = halogen atom) in a suitable organic solvent, e.g. As acetonitrile, preferably reacted under reflux for several hours. The solvent is then evaporated and the residue dissolved in water, optionally filtered. The aqueous solution is treated with a suitable base, eg, sodium carbonate solution, to about pn 9 to precipitate the corresponding ketone, namely 1-aroylmethylimidazole. Optionally, the formed ketone can be dissolved in a suitable organic solvent and reprecipitated by conventional treatment with an acid as an acid addition salt,

For example, 2-R * -4 (5) -R-imidazole and a halide of the formula Y-CRjRj-CO-Ar are reacted in a suitable solvent, e.g., dimethylformamide or a lower alkanol. From the mixture, the desired ketone is precipitated by the addition of water. It is also possible to brominate a ketone of the formula HCRjRj-CO-Ar first with liquid bromine by known methods to give the compound Br-CR ^ -CO-Ar, which is then reacted with the 2-R'-4 (5) - R - imidazole is reacted.

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

Br-C

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

EtO-C

N

No. 296289 is then extracted from the reaction mixture with a suitable solvent, eg, anus. By evaporation of the solvent, the ester is obtained. It is also possible to treat the ester by treating the extract with an acid, e.g. As nitric acid, precipitate. Conventional hydrolysis of the ester or ester salt obtained gives the corresponding 4-carboxylic acid derivative, which is then decarboxylated in a conventional manner, for. B. by heating (about 250 ° C) a mixture of the acid in paraffin oil until the formation of carbon dioxide ceases. The thus obtained 1- (2-ar-1,3-dioxolan-2-ylmethyl) ~ 5-methyl · imidazole

which can be obtained by extraction and precipitation similar to the abovementioned 4-carboxylate ester, is then hydrolyzed, preferably under acidic conditions, whereby the dioxolane function is converted into a carbonyl function and the desired 5-methyl ketone of the formula (II) is obtained:

Rj-C - C - Ar

Several of the halides used as reactants of the formula (VII) have been mentioned in the literature 15 (Cl Feugeas, Bull. Soc, Chim, Fr .; [1963], p. 2568 and AR Patei, J. Pharm. Sc. 52 (6) [1963], pages 588 to 593). The hitherto unknown halides can be readily prepared by first preparing a ketone of the formula CHs-CO-Ar, in which Ar has the abovementioned meaning, is brominated by customary bromination processes, and the resulting bromide is treated with ethylene glycol in a suitable organic solvent, for example an aromatic hydrocarbon, such as benzene, toluene and xylene, containing a small amount of Toluene sulfonic acid can be added is reacted. The above reactions can be further illustrated by the following scheme.

<td>II 0</td><td>dioxane</td><td>II 0</td><td>benzene</td>

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

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

Depending on the conditions under which the reactions are carried out, the new compounds are either in the form of the free bases or salts. The salts are converted in the usual way into the free bases, for. B, by reaction with alkali such as sodium or KaliumNr.296289

- 4 hydroxyd. The compounds in the base form can be prepared by reaction with suitable acids, for example, inorganic acids such as hydrohalic acids, hydrochloric, hydrobromic or hydroiodic acid, sulfuric acid, nitric acid or thiocyanic acid, a phosphoric acid, with organic acids such as acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid , Oxalic acid,

Malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, p-aminosalicylic acid, 2-phenoxybenzoic acid or 2-acetoxybenzoic acid are converted into their therapeutically valuable acid addition salts ,

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

The experiments with fungi were carried out using liquid Sabouraud medium (1 g Neopepton 15 and 2 g glucose per 100 ml distilled water) in 16 x 160 mm test tubes containing 4.5 ml each of the liquid medium at 120 min for 15 min ° C was autoclaved. The product to be tested is first dissolved in 50% ethanol to a concentration of 20 mg / ml. The solution is diluted to a concentration of 10 mg / ml with sterile distilled water. Successive dilutions to 1/10 each-of the previous concentration were made with distilled

Water made. In each test tube, containing 4.5 ml of the liquid Sabouraud medium, is added 0, 5 ml of a dilution of the preparation to obtain 1000 y, 500 g, 100 y, 10 y and 1 y per ml of medium (y "). = Microgram). A comparative glass was prepared by adding 0.5 ml of distilled water to 4.5 ml of medium. The ethanol concentration in the comparative test tubes was the same as in the test tubes containing 1000 y of the compound per ml. The filamentous fungi were incubated for 2 to 3 weeks at 25 ° C. A square block of 2 mm edge length was cut and seeded in the liquid medium. A three day old culture on liquid Sabouraud medium was used for yeasts. The amount of inoculum was 0.05 ml / reagent glass. All cultures were duplicated and incubated for 14 days at 25 ° C. The first test was made after 7 days and the last test after 14 days (the values in Tables I and II are the final scores for each compound at the concentration of 100 y / ml of culture determined after 14 days). The weighting was determined assuming maximum growth for the control glass to which rating 4 was assigned. Full absence of growth after 14 days, the score 0, while a growth of 1/4, 1/2 and 3/4 of the control samples was rated 1, 2 and 3 respectively,

The experiments with bacteria were carried out on phenol red dextron broth and on tryptone broth by the same decimal dilution method as in the experiments with fungi (100 y / ml and 10 y / ml). The amount of inoculum was 0.1 ml from a 24-hour culture diluted 10-fold with distilled water for Streptococcus pyogenes and 0.05 ml for the other microorganisms. The results after 72 h were rated + or 0 according to the presence or Ab40 essence of growth. The results given in Table ΙΠ illustrate the antibacterial activity,

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

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No. 296289

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

As solid carriers are suitable for the preparation of preparations in powder form a variety of inert, porous and powdery distribution agents of inorganic or organic nature, z, B. tricalcium phosphate, calcium carbonate, in the form of chalk or limestone, kaolin, bolus, bentonite,

Talc, kieselguhr and boric acid. Cork flour, sawdust and other finely powdered materials of plant origin are also suitable as carrier materials.

The active ingredient is mixed with these carriers, for example by grinding them with them. The inert carrier can also be impregnated with a solution of the active ingredient in a volatile solvent and the solvent then by heating or suction filtration under reduced

Pressure to be removed. By adding wetting agents and / or dispersants these powdered preparations can also be made slightly wettable with water, so that suspensions are obtained.

The inert solvents used for the preparation of liquid preparations should preferably not be easily flammable, as odorless as possible and as non-toxic as possible to warm-blooded animals or plants in the environments in question. Suitable solvents for this purpose are high-boiling oils, for example of vegetable origin, and lower-boiling solvents having a flash point of at least 30 ° C., eg Isopropanol, dimethylsulfoxide, hydrogenated naphthalenes and alkylated naphthalenes. Of course, solvent mixtures can also be used. Solutions may optionally be prepared using solubilizers where appropriate. Other candidate liquid forms consist of emulsions or suspensions of the active ingredient in water or suitable inert solvents or concentrates for the preparation of these emulsions, which can be adjusted directly to the required concentration. For this purpose, the active ingredient is mixed, for example, with a dispersant or emulsifier. The active ingredient may also be dissolved or dispersed in a suitable inert solvent and mixed simultaneously or subsequently with a dispersant or emulsifier.

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

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

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

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

When the compounds obtainable according to the invention in combination with suitable excipients, for. B, in solution, suspension, as dusts, powders, ointments, emulsions and similar forms, a very high activity is observed over a very wide range of dilutions. In the example, concentrations of the active ingredient were from 0.1 to 10% by weight. %, based on the

No. 296289

Weight of the preparation used, effective for the control of fungi or bacteria. Of course, higher concentrations may be used which are justified in the particular situation.

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

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

Parts of acetonitrile are refluxed for 2 hours with stirring. The solvent is evaporated under reduced pressure, the residue is taken up in hot water and the solution is cooled and filtered. To the aqueous filtrate is added a solution of sodium carbonate in water until pH 9. The product is precipitated immediately. It is filtered off and recrystallized twice, first from hot water and then from a mixture of diisopropyl ether and 2-propanol. Hiebei l- (benzoylmethyl) imidazole of melting point 114 to 117 C is obtained.

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

l - [(4-methylbenzoyl) methyl] imidazole, m.p. 133-134 ° C;

l - [(4-methylbenzoyl) methyl] imidazole hydrochloride, m.p .: 210.5 to 216 ° C;

1- [(4-chlorobenzoyl) methyl] imidazole hydrochloride, m.p. 228-229 ° C.

Example 2; To a solution of 20.4 parts of imidazole in 40 parts of methanol are added 23.3 parts of o-chlorophenacyl bromide. The mixture is stirred for 2 h at 0 ° C. The solvent is evaporated under reduced pressure and the residue is poured into water. The product, 2 * -chloro-2- (1-imidazolyl) acetophenone, is extracted with chloroform. From the free base remaining as the residue, the hydrochloride is prepared in the usual manner, after which, upon recrystallization, first from a mixture of 2-propanol and diisopropyl ether and then from a mixture of methanol and diisopropyl ether 2'-chloro-2- (1-imidazolyl) acetophenori hydrochloride of the melting point 186.5 to 189 ° C is obtained.

Example 3: To a solution of 276 parts of p-fluoroacetophenone in 400 parts of dioxane and 640 parts of dry ether is added dropwise 320 parts of bromine while cooling on ice and stirring. The mixture is then brought to room temperature and the solvent removed under reduced pressure until an internal temperature of 110 ° G has been established. The residue 30 is cooled on an ice-salt bath, whereupon 640 parts of acetone are added. At a temperature of 0 ° C, a solution of 528 parts of imidazole in 640 parts of methanol is added with stirring. The mixture is stirred for a further 3 days with cooling. The solvent is removed at normal pressure up to an internal temperature of 125 ° C. To the residue, after cooling, 750 parts of chloroform and 500 parts of water are added. The chloroform layer is separated, stirred for 30 min, washed with water, dried, filtered and evaporated. From the residue containing 1- (p-fluorophenacyl) imidazole, the hydrochloride is prepared in the usual manner. The crude salt is recrystallized twice from a mixture of 2-propanol, methanol and diisopropyl ether. The free base is liberated again by treatment with an equivalent amount of sodium hydroxide. After recrystallization from a mixture of 2-propanol and diisopropyl ether, about 178 parts of 1- (p-fluorophenacyl) 40-imidazole of melting point 149.degree.-155.degree. C. are obtained.

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

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

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

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

2- (1-imidazolyl) -2'-methylacetophenone nitrate, m.p. 165, 5-167 ° C;

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

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

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

No. 296289

in 125 parts of dimethylformamide. After complete addition, the mixture is stirred for 2 h on ice. The reaction mixture is poured into water to precipitate the product (5-chloro-2-thienyl) - (1-imidazolylmethyl) ketone. The product is filtered off and taken up in 750 parts of chloroform and washed with water. The chloroform is evaporated. The residue is triturated in ether and filtered again to give the free base of melting point 104-106 ° C. From this fraction, 4.4 parts are converted into the nitrate. Hiebei be obtained after recrystallization of the crude solid salt from ethanol 3.7 parts of (5-chloro-2-thienyl) - (l-imidazolylmethyl) ketonnitrat the melting point of 161.5 ° C.

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

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

4'-chloro-2- (2-methyl-1-imidazolyl) acetophenone, mp 209.5 ° C;

4'-Chloro-2- (2-ethyl-1-imidazolyl) acetophenone, m.p. 160 ° C, 4'-chloro-2- (2,4-dimethyl-1-imidazolyl) acetophenone, m.p. 185.8 ° C.

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

It is filtered off and recrystallized from 2-propanol to give 2- (bromoethyl) -2- (p-chlorophenyl) -4-methyl-1,3-dioxolane of melting point 71 ° C.

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

2- (bromomethyl) -2-o-tolyl-1,3-dioxolane, b.p. 113-115 ° C / 0.8 mm Hgj

2- (bromomethyl) -2-p-tolyl-1,3-dioxolane, b.p. 135-137 ° C / 2.5 mm Hg;

2- (bromomethyl) -2- (2,5-dichlorophenyl) -1,3-dioxolane, mp 61.5 ° C;

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

2- (bromomethyl) -2- (o-meihoxyphenyl) -1,3-dioxolane, m.p. 99-100 ° C;

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

Example 6; 37.8 parts of methyl 2-thienyl ketone are brominated with 48 parts of bromine in 48 parts of dioxane and 96% dry ether while being cooled and stirred. The solvent is removed under reduced pressure. To the residue are added 60 parts of ethylene glycol in 160 parts of toluene and a few crystals of p-toluenesulfonic acid. The mixture is refluxed for 15 hours with stirring in a 40-water trap device. The reaction mixture is cooled and the toluene layer separated, washed once with potassium carbonate solution and once with water, dried, filtered and evaporated under reduced pressure. The oily residue is distilled under reduced pressure from potassium carbonate to give 2- (bromomethyl) -2- (2-thienyl) -1,3-dioxolane of boiling point 95 ° C / 0.6 mm Hg.

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

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

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

2- (bromomethyl) -2- (2,3,4-trichlorophenyl) -1,3-dioxolane, m.p. 59.5 ° C; 2-bromomethyl-2- (m-chlorophenyl) -1,3-dioxolane, b.p. 149 ° C / 0.2 mm Hg,

No. 296289

Example 7: 154 parts of ethyl 5-methylimidazole-4-carboxylate are added to a solution of 23 parts of sodium in 600 parts of ethanol. Then 440 parts of ethanol are evaporated. To the warm residue, 1600 parts of 2-diisopropyl ether are added. After cooling, the sodium salt separates from ethyl-5-methylimidazole-4-carboxylate, which is filtered off,

A mixture of 17.7 parts of the sodium salt of ethyl 5-methylimidazole-4-carboxylate, 35 parts of 2-bromomethyl-2- (p-chlorophenyl) -1,3-dioxolane (described by AR Patei in J. Pharm. Sci , -, 52 (6) [1963], pages 588 to 592), 22.5 parts of potassium iodide, 30 parts of dimethylformamide and 4 parts of toluene is heated at reflux for 12 h with stirring. The reaction mixture is cooled and treated with 400 parts of ether. The organic phase is washed three times with water, dried and treated with concentrated nitric acid in excess. The precipitated nitrate salt is filtered off and recrystallized from a mixture of 40 parts of absolute ethanol and 400 parts of diisopropyl ether to give ethyl 1 - [2- (p-chlorophenyl) -1,3-dioxolan-2-ylmethyl] -5-methylimidazole-4 -Carboxylatni occurred from the melting point 130.3 ° C is obtained.

A mixture of 2 parts of this compound and 7.5 parts of a 10N sodium hydroxide solution is added

15 heated under stirring with stirring at reflux. Then 20 parts of water and then 4.5 parts of acetic acid are added, whereby the product is precipitated. It is filtered off and recrystallized from 80 parts of ethanol to give 1- [2- (p-chlorophenyl) -1,3-dioxolan-2-ylmethyl] -5-methylimidazole-4-carboxylic acid of melting point 258.3 ° C ,

To 40 parts of paraffin oil is added portionwise 25 parts of 1- [2- (p-chlorophenyl) -1,3-dioxolan-2-yl20-methyl] -5-methyldiimidazole-4-carboxylic acid at 250 ° C. The mixture is heated to 270 ° C until no more carbon dioxide is formed. The reaction mixture is cooled and treated with 240 parts of ether. The solution is filtered and the filtrate is treated with concentrated nitric acid solution in excess. The precipitated nitrate is filtered off and recrystallized from a mixture of 120 parts of ethanol and 340 parts of diisopropyl ether to give 1 - [2 - (p-chlorophenyl) -1,3-dioxolane. 2-ylmethyl] -5-methylimidazole nitrate of melting point 153.6 ° C.

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

100 Parts of acetic acid and 50 parts of dilute hydrochloric acid are refluxed for 18 hours with stirring. The solvents are evaporated and to the residue are added successively 100 parts of water and excess sodium hydroxide, precipitating the product, 4'-chloro-2- (5-methyl-1-imidazolyl) aceto-30-phenone. The product is filtered off and recrystallized from 10% dimethylformamide (50 parts) to give 6.5 parts of 4 '-chloro-2- (5-methyl) -1-imidazolyl) acetophenone of melting point 123 ° C.

Example 8: A solution of 8.16 parts of 1- (benzoylmethyl) imidazole and 14.5 parts of β-phenethylamine in 160 parts of dry benzene containing a small amount of p-toluenesulfonic acid becomes 35 in a device provided with a water trap , heated to reflux while stirring. After 24 h, the theoretical amount of water is deposited. The solvent is removed under reduced pressure and the residue is dissolved in 120 parts of ethanol. This solution is at an initial pressure of 4.5 kg / cm2 hydrogenated at room temperature in the presence of 3 parts of oily palladium carbon. After the calculated amount of hydrogen has been absorbed, the hydrogenation is stopped. The solution 40 is filtered and the solvent removed under reduced pressure. The residue is dissolved in acetone and the solution is treated with nitric acid solution (concentrated) in diisopropyl ether in excess. The nitrate salt separates out as oil. The solvent is decanted. It is filtered off, washed with acetone and recrystallized from a mixture of methanol, acetone 45 and diisopropyl ether to give l- (β-phenylethylaminophenylethyl) imidazole dinitrate of the

formula

CH2-CH-NH-CH2-CH2-. 2ΗΝΟ,

No. 296289 from F, = 164.5 to 168 ° C.

By repeating the experiment described in Example 8, but using an equivalent amount of a corresponding amine in place of 0-phenylethylamine, the following imidazolamines are obtained.

l- (β-anilinophenethyl) imidazole dihydrochloride, m.p. 217.5 to 230 C (dec.)

1-Γ0 - (- tetralinylamino) phenethyl] imidazole dinitrate, mp 139-143 ° C.

Example 9: A solution of 18.6 parts of 1- (benzoylmethyl) -imidazole and 12.9 parts of benzylamine in 80 parts of benzene containing a small amount (about 0.5 part) of p-toluenesulfonic acid is stirred for 4 hours with stirring Reflux heated. (The reaction vessel is fitted with a reflux condenser and water separator.) The solvent is removed under reduced pressure and the residue is dissolved in 120 parts of ethanol. At room temperature, a first portion of 3.8 parts of sodium borohydride is added and the mixture is refluxed for 30 minutes with stirring. Then a second portion of 3.8 parts of sodium borohydride is added, followed by another 1 hour while stirring under reflux. The solvent is removed under reduced pressure. To the residue are added successively 100 parts of water and 70 parts of concentrated hydrochloric acid solution (pjj 2 to 3). This solution is stirred for 1 h and heated to reflux. After cooling on ice, the solution is filtered and the filtrate made strongly alkaline with a 10N sodium hydroxide solution. The free base is extracted with methylene chloride. The extract is washed with water, dried, filtered and evaporated under reduced pressure. The residual free base is dissolved in acetone. To this solution is added 2-propanol, which has previously been saturated with gaseous hydrogen chloride, in excess. Upon further addition of diisopropyl ether, the hydrochloride is precipitated. It is filtered off and recrystallized twice, namely once from a mixture of diisopropyl ether and then from a mixture of ethanol and diisopropyl ether to give 1- (β-benzylaminophenylethyl) imidazole hydrochloride of melting point 263.5 to 266.5 ° C.

The reducing amination process described in Example 9 is repeated with the difference that an equivalent amount of corresponding ketones and a corresponding amount of corresponding amines are used as starting materials, the following imidazolamines being obtained:

-N

Rj-C - CH-NH- (CH2)n - Ar '«2

No, 296289

- 14 No. 296289

Table II (continued):

No. 296289

Contents15

77 members in 28 offices

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

Priority claims2

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

Members77

Family members, oldest first
Document	Office	Kind
LU59301A1	Luxembourg	A1	1970-01-06
BE737575A	Belgium	A	1970-02-18
IE33297L	Ireland	L	1970-02-19
NL6912331A	Netherlands (Kingdom of the)	A	1970-02-23
DE1940388A1	Germany	A1	1970-02-26
FR2015913A1	France	A1	1970-04-30
ZA695965B	South Africa	B	1971-03-31
ZM13669A1	Zambia	A1	1971-05-21
ES370593A1	Spain	A1	1971-07-01
AT291249B	Austria	B	1971-07-12
BE761412R	Belgium	R	1971-07-12
NL7100072A	Netherlands (Kingdom of the)	A	1971-07-15
DE2063857A1	Germany	A1	1971-07-22
CH511238A	Switzerland	A	1971-08-15
GB1244530A	United Kingdom	A	1971-09-02
FR2081427A2	France	A2	1971-12-03
AT296289BThis record	Austria	B	1972-02-10
US3658813A	United States of America	A	1972-04-25
AT299194B	Austria	B	1972-06-12
US3674667A	United States of America	A	1972-07-04
CH526553A	Switzerland	A	1972-08-15
ZA71174B	South Africa	B	1972-08-30
IL32840A	Israel	A	1972-09-28
NO126180B	Norway	B	1973-01-02
CH532585A	Switzerland	A	1973-01-15
US3717655A	United States of America	A	1973-02-20
BR6911658D0	Brazil	D0	1973-04-19
GB1318590A	United Kingdom	A	1973-05-31
US3740256A	United States of America	A	1973-06-19
US3740325A	United States of America	A	1973-06-19
SU408476A3	Soviet Union (until 1991)	A3	1973-12-10
SE363330B	Sweden	B	1974-01-14
ES390807A1	Spain	A1	1974-03-16
US3808115A	United States of America	A	1974-04-30
IE33297B1	Ireland	B1	1974-05-15
IT974527B	Italy	B	1974-07-10
FR2081427B2	France	B2	1974-08-23
US3839574A	United States of America	A	1974-10-01
RO56625A	Romania	A	1974-11-11
FI751886A	Finland	A	1975-06-25
FI751886A7	Finland	A7	1975-06-25
OA03898A	African Intellectual Property Organization (OAPI)	A	1975-08-14
JPS5039664B1	Japan	B1	1975-12-18
JPS5039665B1	Japan	B1	1975-12-18
DK579675A	Denmark	A	1975-12-19
JPS51115B1	Japan	B1	1976-01-05
IN139930B	India	B	1976-08-21
SU557755A3	Soviet Union (until 1991)	A3	1977-05-05
DK135769B	Denmark	B	1977-06-20
SE394432B	Sweden	B	1977-06-27
SE395690B	Sweden	B	1977-08-22
FI52858B	Finland	B	1977-08-31
DE1940388B2	Germany	B2	1977-09-15
DK135769C	Denmark	C	1977-11-21
FI52858C	Finland	C	1977-12-12
ES393167A2	Spain	A2	1977-12-16
DE1940388C3	Germany	C3	1978-05-11
DK137947B	Denmark	B	1978-06-12
SU617011A3	Soviet Union (until 1991)	A3	1978-07-25
CS184753B2	Czechoslovakia (until 1993)	B2	1978-09-15
CS184771B2	Czechoslovakia (until 1993)	B2	1978-09-15
CS184772B2	Czechoslovakia (until 1993)	B2	1978-09-15
YU212669A	Yugoslavia, later Serbia and Montenegro (until 2006)	A	1978-09-18
DK137947C	Denmark	C	1978-11-06
DK139255B	Denmark	B	1979-01-22
DE2063857B2	Germany	B2	1979-02-22
YU34194B	Yugoslavia, later Serbia and Montenegro (until 2006)	B	1979-02-28
NL159662B	Netherlands (Kingdom of the)	B	1979-03-15
FI55434B	Finland	B	1979-04-30
DK139255C	Denmark	C	1979-06-18
DK140213B	Denmark	B	1979-07-09
FI55434C	Finland	C	1979-08-10
CS194656B2	Czechoslovakia (until 1993)	B2	1979-12-31
DK140213C	Denmark	C	1980-01-14
MX3611E	Mexico	E	1981-03-31
NL169071B	Netherlands (Kingdom of the)	B	1982-01-04
NL169071C	Netherlands (Kingdom of the)	C	1982-06-01

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

Abstract

Term

N

S

N

TO

X

I

CO

EZI

HM HM HM HM HM

CH

I

OEO

WQ

II II W CO

-N

Priority claims2

Members77

Numbers

Titles2

Classification