FI55434B

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

Abstract

This record has no abstract on file.

FI55434B, drawing sheet 1 — Sheet 1 of 20

Term

Term ended

Expired 25 June 1995, 31.2 years ago.

1 claim: 1 independent, 0 dependent

1
Patenttivaatimus:Säilöntäaineissa, desinfektioaineissa ja ei-lääketieteellisissä fungisideissa käytettävät 1-(/9 -aryyli)etyyli- imidatsoli johdannaiset, tunnetut kaavasta (I) jossa S, R^ ja Rg ον&ΐ vety tai alempi alkyyli, X on oksi tai RH, n on kokonaisluku 0, 1 tai 2, Ar on tienyyli tai halogeenitienyyli, tai fenyyli, joka voi olla substituoitu yhdellä tai useammalla halogeeni-, alempi-alkyyli- tai alempi-alkoksiryhmällä, Ar* on tx-tetralyyliryhmä tai fenyyli, joka voi olla substituoitu yhdellä tai useammalla halogeeni-, alempi-alkyyli-, alempi-alkoksi-, syano-, nitro- tai aminoryhmällä, R' on vety, metyyli tai etyyli, ja R on vety tai metyyli, edellytettynä, ettäs (1) kun X on RH, silloin R on vety, (2) kun Ar' on fenyyliryhmä, joka on substituoitu ainakin yhdellä nitrotai aminoryhmällä, silloin X on oksi ja n on 0, (3) kun Ar' on or-tetralyyli, silloin X on RH ja n on 0, ja (4) kun X on oksi ja Ar' on fenyyli, joka voi olla substituoitu ainakin yhdellä halogeeni-, alempi-alkyyli-, alempi-alkoksi- tai syanoryhmällä, silloin n on muu kuin 0.

486 paragraphs in 41 sections, as filed

This invention experiments with novel 1- (9-aryl) ethylimidazole derivatives of the formula: for use in preservatives, disinfectants and non-medical fungicides.

B - nN

H · (I) x - (CH2)of - Arjossa K, K1 and Bg <> ▼ ** hydrogen or lower alkyl, X is okay or NH, n is an integer 0, 1 or 2, Ar is thienyl or halothienyl, or phenyl which may be substituted by one or more halogen, lower alkyl or lower -alkoxy, Ar 'is a β-tetralyl group or phenyl which may be substituted by one or more halogen, lower alkyl, lower alkyl, eyano, nitro or amino groups, R * is hydrogen, methyl or ethyl, and R is hydrogen or methyl, provided that:

(1) when X is NH, then R is hydrogen, (2) when Ar · is a phenyl group substituted with at least one nitro or amino group, then X is oxy and n is 0, (?) When Ar 'is or-tetralyl, then X is NH and n is O, and (4) when X is oxy and Ar * is phenyl which may be substituted by at least one halogen, prime alkyl, lower alkoxy or cyano group, then n is other than 0 .

Also included within the scope of the invention are the fungidally acid addition salts of said compounds (i) which are not used in medicine.

By lower alkyl and lower alkoxy are meant straight or branched chain saturated hydrocarbons having 1 to 6 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, psentyl, hexyl and the like alkyl, and the corresponding alkoxy is, e.g., matoxy, ethoxy , propoxy, isopropoxy, etc.

Preferred lower alkyl and lower alkoxy are methyl and methoxy, respectively. By halogen is meant halogen having an atomic weight of less than 127. fluorine, iodine, bromine and chlorine. Preferred substituted phenyls for Ar are mono-, di- and trihalophenyl, lower alkylphenyl and lower alkoxyphenyl, and for Ar * are mono-, di- and tri-halophenyl, mono- and di- (lower alkyl) phenyl, lower alkoxyphenyl , cyanophenyl, mono- and di-nitrophenyl and aminophenyl.

Amines of formula (i) wherein X is -NH- are obtained by reductive amination of 1- (aroylmethyl) imidazoles of formula (II) wherein R 1, R 2 K ', and R and Ar are as defined above, e.g. by treating a ketone (II) with an amine of formula (IIi) wherein n and Ar * are as defined above, in a suitable solvent, e.g. an aromatic hydrocarbon such as benzene, toluene, in ksylesn and the like. The amination is preferably carried out under reflux conditions and in the presence of a small amount of an acid, e.g. p-toluenesulfonic acid. After the evolution of water has ceased, the aromatic hydrocarbon solvent is evaporated off and the residual product (IV) is taken up in a lower alkanol solvent and reduced to the corresponding amine (ia), e.g. by treatment with a suitable reducing agent such as a metal hydride complex, e.g. with potassium borohydride, sodium borohydride and the like, or by catalytic hydrogenation, e.g. by contact with hydrogen and palladium on carbon. The amine product is recovered from the reaction mixture in a known manner either as the free base or, if desired, as an acid addition salt by treating the base with a suitable acid. The reductive amination described above can be represented by the following reaction scheme:

R- —-CC = 0 «2 ΑΓ (II) (III)

OF

+ H2N- (CH2)of-Ar '

R.-C —C = N- (CH2) -Ar ' 1 II

R „Ar - c CH- NH- (CH2 ) of- Ar ·

R2 Ar (1-a)

Ethers of formula (i) wherein X is oxy are prepared by O-alkylation of a N- (Ar-imidazole-1-ethanol of formula (V) wherein R, R 1, R *, R and Ar are as defined above). e.g. by contacting an alcohol (v) whose hydroxyl has been previously converted to an alkali metal salt by treatment with an appropriate strong base such as an alkali metal amide or hydride with a halide of formula (Vi) wherein n is as defined above, Y is halogen, preferably chlorine or bromine, and Ar 'has the same meaning as above except for aminophenyl. Suitable solvents for O-alkylation include aromatic hydrocarbons, e.g. benzene, toluene, xylene and the like, dialkylformamides such as dimethylformamide and diethylformamide, ethers such as tetrahydrofuran, 1,2-dimethoxyethane and the like, and hexamethylphosphoric triamide. Elevated temperatures can be advantageously used to accelerate the reaction rate. Like the amines of formula (ia), the resulting ethers (ib) can be recovered as the free base or acid addition salt. This O-alkylation can be illustrated by the following reaction scheme:

(V)

NaHk

-->

Ethers of formula (i) wherein Ar 'is aminophenyl are obtained by reduction of the corresponding nitrophenyl ethers of formula (ib) in a known manner by reduction of the nitro group to an amino group, e.g. by catalytic hydrogenation such as contact with hydrogen and palladium on carbon in ethanol or contact with released hydrogen , first. by administering an appropriate metal and acid, e.g. zinc and acetic acid, iron and ammonium chloride, tin and hydrochloric acid interact.

The starting ketones (II) can be prepared in several different ways.

For example, ketones (II) are obtained by the following methods, in which the symbols R 1, R 8, Y, R ', R and Ar have the same meaning as above:

A. Known substance, N-acetylimidazole / W. Otting, Ber. 89, 1940 (1956) 7 is contacted with a compound of formula Y-CHg-CO-Ar in a suitable organic solvent, e.g. acetonitrile, and preferably under reflux conditions for a few hours. The solvent is then evaporated off and the residue is dissolved in water and filtered if necessary. The aqueous solution is treated with an appropriate base, e.g. sodium bicarbonate solution to a pH of about 9 to precipitate the corresponding ketone 1-aroylmethylimidazole. If desired, the resulting ketone can be dissolved in a suitable organic solvent and reprecipitated as an acid addition salt in the usual manner with an acid; or

B. 2-R '-4 (5) -R-imidazole and a halide of the formula Y-CR1-CO-Ar are contacted in a suitable solvent, e.g. dimethylformamide, a lower alkanol and the like, from which mixture the desired ketone is mixed by adding water. Alternatively, a ketone of the formula HCR ^ Rg-CO-Ar is first brominated with liquid bromine in a known manner to give the compound Br-CR ^ R ^ CO-Ar, which is then reacted with said 2-R'-4 (5) -R-imidazole. ;

C. A known substance, ethyl 5-methylimidazole-4-carboxylate, in the form of an alkali metal, preferably sodium metal salt, is contacted under reflux with the appropriate 2-bromomethyl-2-Ar-1,3-dioxolane of formula:

in a suitable solvent, e.g. dimethylformamide, and in the presence of potassium iodide. The product thus obtained, ethyl 1- (2-Ar-1,3-dioxolan-2-ylmethyl) -5-methylimidazole-4-carboxylate:

O

is then extracted from the reaction mixture as a suitable solvent, e.g. ether, and evaporation gives an ester, or alternatively the ester may be precipitated by treating the extract with an acid such as nitric acid. Hydrolysis of the resulting ester or ester salt results in the corresponding 4-carboxylic acid derivative, which is then decarboxylated in the usual manner, e.g. by heating the acid mixture in paraffin oil to about 25 ° C until the evolution of carbon dioxide ceases. The 1- (2-Ar-1,3-dioxolan-2-ylmethyl) -5-methylimidazole thus obtained:

OF

which can be recovered by extraction and precipitation in a manner similar to the above-mentioned 4-carboxylate ester, is then hydrolyzed, preferably under acidic conditions, to convert the dioxolane group to a carbonyl group to give the desired 5-methyl ketone of formula (II):

OF

The starting alcohols (V) are also obtained by several syntheses, such as the following methods, in which the symbols R, R 1, R 2, Y, R ', R and Ar have the same meaning as above:

A. The carbonyl group of ketones (II) is reduced to the carbinol group by contacting with a suitable reducing agent, e.g. sodium borohydride, lithium aluminum hydride and the like in a suitable solvent, e.g. lower alkanol; or

B. 2-R'-U (5) -R-imidazole in the form of an alkali metal salt obtained by treatment with sodium methoxide is contacted with a compound of formula Y-CR1Rg-CRiOHj-Ar in a suitable organic solvent, e.g. dimethylformamide. Subsequent addition of water to the reaction mixture precipitates the desired alcohol, which is then separated in the usual manner; or

C. 2-R '-4 (5) -R-imidazole is contacted with a compound of formula

-Ar in a suitable organic solvent, e.g. lower alkanol and an organic base, e.g. in the presence of a small amount of pyridine, whereby mixing with the addition of water gives the corresponding alcohol of formula (v) in which R, R 1 and R 2 all represent hydrogen.

Several different halide reaction components of formula (vii) have been described in Feugeas Cl., Bull. Soc. Chim. Fr., 1963 (il), 2568; and Patel AR, J. Pharm. Se., 52 (6), 588-593 (1963). and then reacting the resulting bromide with ethylene glycol in a suitable organic solvent, e.g. in an aromatic hydrocarbon such as benzene, toluene, xylene and the like to which a small amount of p-toluenesulfonic acid may be added. The following reaction scheme illustrates the above reactions:

CHO-C-Ar 3 I o

Br, dioxane

Br-CH 2 -C-Ar

HO-CH „CH„ OH

-—Fc- £ - benzene (VII)

Due to the asymmetric carbon atoms in the compounds of formula (i), it is clear that they exist as stereochemical isomers (enantiomorphs). If desired, any desired form can be isolated or prepared according to known methods. Said enantiomorphic forms are, of course, also within the scope of the invention. Depending on the conditions used during the reaction, the compounds obtained are either free bases or their salts. The salts are converted to the free bases in the usual manner, e.g. by reaction with an alkali hydroxide such as sodium or potassium hydroxide. The bases, on the other hand, can be made fungially useful by acid addition salts by reacting them with an acid such as e.g. with an inorganic acid such as hydrochloric acid, hydrobromic acid or hydroiodic acid, with sulfuric, nitric or thiocyanic acid, with phosphoric acid or with an organic acid such as acetic, propionic, glycolic, lactic, pyruvic, oxalic, malonic, succinic , maleic, fumaric, mallinic, wine, lemon, benzoic, cinnamine, almond, methananiphone, ethanesulfonyl, hydroxyethanesulfonic, p-toluenesulfonic, salicylic, p-amnosalicylic, With 2-phenoxy benzoic or 2-acetoxy-benzoic acid.

The compounds of formula (i) and their acid addition salts are useful antifungal agents as shown by their broad spectrum of antifungal activity. The data presented in the following tables illustrate such activity. The values shown in the tables have been obtained using the method described by Vanbreuseghem et al., Chemotherapia, 12, 107 (1967) ·

Experiments against fungi were performed using Saboraud's liquid medium (1 g neopeptone Difoo per 100 ml of distilled water) in 16 x 160 mm test tubes, each containing 4.5 ml of liquid medium treated in an autoclave at 120 ° C for 15 minutes. The test substance was dissolved in 50% ethanol at a concentration of 20 mg / ml and then diluted with sterile distilled water to obtain a concentration of 10 mg / ml. Successive decimal dilutions were performed with distilled water. To each tube containing 4.5 ml of Sabouraud liquid medium was added 0.5 ml dilutions of test substance to obtain concentrations of 1000 Y, 50 Ϋ, 10010 F, and 1 / ml per medium (symbol means micrograms). A control tube was prepared by adding 0.5 ml of distilled water to 4 * 5 ml of medium. The ethanol concentration in the control tubes was the same as in those tubes containing 1000 Z and 5θθ / Vei of the test substance. In Säijemäl, mushrooms were grown at 25 ° C for 2-5 weeks. A square body with a side of 2 mm was cut and inoculated into the liquid medium. For yeasts, a 5-day-old culture in Saboraud's liquid medium was used. The inoculum was 0.05 ml per tube. Cultures were performed twice and cultured at 25 ° C for 14 days. The first readings were taken after 7 days and the last readings after 14 days (the values in Tables I and II correspond to the final values after 14 days for each compound at a concentration of 100 micrograms per ml of culture).

The largest increase was considered to be in a control tube given growth 4. A complete absence of growth after 14 days was considered 0, while growth corresponding to 1/4, 1/2, and 3/4 of the control growth was rated 1, 2, and 3, respectively.

The compounds shown in the following tables are given as examples to illustrate the useful properties of all compounds of the invention.

Table I Amine derivatives

CH2-CH-NH- (CH2)of-Ar '

Ar fungistatic effect (at a final reading of 1 ml pg / ml)

<td rowspan="2">Ar</td><td rowspan="2">of</td><td rowspan="2">Ar '</td><td rowspan="2">salt</td><td colspan="9">fungistic effect line reading at 100</td><td colspan="2">(finally / μg / ml</td>

χ) 1 = Microsporum canis «Trichophyton mentagrophytes = Trichophyton rubrum = Phialophora verrucosa = Cryptococcus neoformans xx) - or-tetralyl xxx) C ^ H ^ S - 2-thienyl * Candida tropicalis Candida albicans = Mucor

- Aspergillus fumigatus = Sporotrichum schenckii

- Saprolegnia

Table II-a

• Ether derivatives

R

I

CO- (CH9) -Ar 'ι u Π

Ar fungistatic effect (final reading at 100 μg / ml)

fungistal effect (final reading at 100 ug / ml) Ar R n Ar 'salt--

1- (p-chloro [H 2,6-dichlorobenzyloxy] - ΟΟΟΟΟ444 4Ο1 phenethyl) -2-ethylimidazoline nitrate 1- (p-chloro - / - (2,4-dichlorobenzylcyclo) cis) 000004 44 301 phenethyl-2-ethyl -imidazoline nitrate 1- [p-chloro- [3- (2,4-dichlorobenzyloxy) - 0000043 2,000 phenethyl] -2-methylimidazoline nitrate 1- [p-chloro [3- (2,6-dichlorobenzyloxy) - 00000332 3 θ θ phenethyl7 “2-diethylinidazoline nitrate

1 - // J- (p-chlorobenzyloxy) -ck, cA-dimethyl-θ 000 0000000 phenethyl7 “imidateol

Table Iira (continued)

For entries 1, 2, 3 and 11, see the table below for the corresponding amine derivatives C 1 H 9 Cl 2 = 5-chloro-2-thienyl for

Table Il-b. Ether derivatives, t

CR1R2 - CRAr - 0 - (CH2)of- Ar '

Compound x

A

B

C

D

E

F

G

X

I

J

K

L

M

OF

P

Q

R

S

T u

V w X

Y z

AA

BB

CC

DD fungistic

2 3 4

0 0 1

0 0-3

0 0 0

0 0 4 .1 0 12 θ 'Ό' o

0 0 1

0003 0 0 0 0

0 0 I

0 0 2 ooo 3

0 0 0

0 0 1

0003 0 0 0 °

0 0 2

0 0 1 oo · - oo

0 0 2

0 0 3

0003 0 0 0 2

0 0 1

0 0 2

0 0 1

O 0 0 1 effect (final at 100 yug> 6 7 8 q io o 3 0 0 4 4 o 3 o · ooo 14 2 142 0 4 1 14 4 3 4 3 12 2 0 3 1 1.4 2 3 4 4 030 o 4 0 130

4 1

4 2

4 3 0 2 0 030 0 3 1 O 3 1

4 4 2 4 4 0 4 1 2 M 2 O 2 UO 2 0 0 2 0

2 0

3 1

3 0'

0 0

432 430 · 400 400 440 10 0 2 10 '2 3 O

0 0

OC

OO

0 3

3 1 o 10 0 '2 OO

0 0

3 1

0 0

0 1

0 0

111 ) ϊΪΓ * o

O

1 'o

oo 1 oo 1 1 3 1 x Name of the compound

A 1- [p-chloro- (2,4-dichlorobenzyloxy) phenethyl] -5-methyl-imidazole nitrate

B 1- [p-Chloro-4- (2,4-dichlorobenzyloxy) phenethyl] -4-dimethylimidazole nitrate

C (+) - 1- [2,4-Dichloro-N- (2,4-dichlorobenzyloxy) phenethyl] imidazole nitrate

D (-) - 1- (2,4-Dichloro-N- (2,4-dichlorobenzyloxy) phenethyl) imidazole nitrate

E 1- [B, 4,6-trichloro-N- (2,4-dichlorobenzyloxy) phenethyl] imidazole nitrate

F 1- [2,4,6-trichloro- [3- (2,6-dichlorobenzyloxy) phenethyl] limidazole nitrate

G 1- [2,4-Dichloro-N- (3,4-dimethylbenzyloxy) phenethyl] imidazole nitrate

H 1- / 2,4-Dichloro - / <5- (p-iodobenzyl) phenethylimidazoline nitrate

I 1- [2,4-Dichloro-N- (2-methoxy-4-nitrobenzyloxy) phenyl] imidazole nitrate

J4- [1- (2,4-dichlorophenyl) -2- (1-imidazole) ethoxy] -p-toluene triilide nitrate

K 1- (3,4-Dichloro- [3- (2,4-dichlorobenzyloxy) phenethyl] imidazole nitrate

L 1- [3,4-dichloro- [3- (2,6-dichlorobenzyloxy) phenethyl] -imidazole nitrate

M 1- [3,4-dichloro- [3- (3,4-dichlorobenzyloxy) phenyl]? - imide zol nitrate

N 1 - [2,4-dichloro-N- (3,4-dichlorobenzyloxy) phenethyl] -imidazole nitrate 1- [o-chloro] -3- (3,4-dichlorobenzyloxy) Phenyl] -imidazole ni traa tti

P 1 - [3- (3,4-Dichlorobenzyloxy) -p-fluorophenethyl] imidazole nitrate

Q '4-Dichloro-γ- (p-chloro-benzyloxy) -phenyl] -'-imidazole nitrate

R 1- [2,6-dichloro- [9- (2,4-dichlorobenzyloxy) Phenyl] -imidazole nitrate

S 1- / 2, $ * - Dichloro / O- (2,6-dichlorobenzyloxy) Phenyl / imidazole Nitrate Name of the compound

T 1 - [2,6-dichloro-η 2 - (p-chlorobenzyloxy) phenyl] -imidazole nitrate

U 1- [2'5-dichloro-N- (p-chlorobenzyloxy) -phenethylimidazoline nitrate

V 1- (2,5-Dichloro-yl) - (2,6-dichlorobenzyloxy) Phenyl-4-imidazole nitrate

N, 5-Dichloro-N- (2,4-dichlorobenzyloxy) phenethyl] imidazole initiator

X 1- [2,5-Dichloro-β- (2,5-dichlorobenzyloxy) phenyl] β-imidazole nitrate

V 1 - [3- (p-tert-butylbenzyloxy) -2,4-dichlorophenethyl] imidazole nitrate

Z 1- [2,4-Dichloro- [3- (p-cumenylmethoxy] phenethyl] imidazole nitrate

AA 1- [2,6-Dichloro - [? - (p-methoxybenzyloxy) phenethyl] -imidazole nitrate

BB 1- [p-Chloro- (2,6-dichloro-benzyloxy) -] [((dimethylphenethyl) -imidazole nitrate

CC 1 - / p-chloro-η 3 - (p-fluorobenzyloxy) - ε, ε-dimethylphenethyl-β-imidazole nitrate

DD 1- [p-chloro] - (2,4-dichlorobenzyloxy) -c/,oN-dimethylphenethyl N-imidazole nitrate.

The present invention provides valuable mixtures containing amines or ethers of formula I or their acid addition salts as active ingredient in a solvent or solid, semi-solid or liquid diluent or carrier, which can be roped to control fungal growth. The compounds may be used in suitable solvents or diluents in the form of emulsions, suspensions, dispersions or ointments, in suitable solid or semi-solid carriers, in conventional or synthetic soaps, in detergents or in dispersion media.

Solid carriers suitable for the preparation of mixtures in powder form include various inert, porous or powdered substances having an inorganic or organic nature, such as, for example, tricalcium phosphate, calcium carbonate in the form of lime or quicklime, kaolin, talc, basalt, bentonite, bentalt ; ground cork, sawdust and other fine powdered substances of vegetable origin are also suitable carriers.

The active ingredients are mixed with these carriers, e.g. by co-milling; alternatively, the inert carrier is impregnated with a solution of the active component in a volatile solvent and the solvent is then removed by heating or suction filtration under reduced pressure. When wetting and / or dispersing agents are added, such powdered preparations can also be easily made wettable with water so as to obtain suspensions.

Inert solvents used for the preparation of liquid preparations must not be highly flammable and, where possible, must be odorless and possibly non-toxic. Suitable solvents for this purpose include high-boiling oils, e.g. vegetable oils, and low-boiling solvents having a flash point of at least 30 ° C, such as, for example, isopropanol, dimethyl sulfoxide, hydrogenated naphthalenes and alkylated naphthalenes.

It is also possible to use mixtures of solvents. Solutions can be prepared in the usual manner using, if necessary, solution formation accelerators. Other liquid forms which may be used are emulsions or suspensions of the active compound in water or a suitable inert solvent, or also concentrates for the preparation of emulsions which can be directly adjusted to the desired concentration. For this purpose, the active ingredient is mixed with a dispersing or emulsifying agent. The active ingredient may also be dissolved or dispersed in a suitable inert solvent and mixed simultaneously or subsequently with the dispersing or emulsifying agent.

It is also possible to use a semi-solid carrier which has the character of a cream, paste or wax and to which the active ingredient is added, if necessary with solution media and / or emulsifiers. Vaseline and other ointment bases are examples of semi-solid carriers.

In addition, it is possible to use the active ingredient in the form of aerosols. For this purpose, the active ingredient is dissolved or diepersed, if necessary with suitable inert solvents, such as difluorodichloromethane, which boils at atmospheric pressure below room temperature, or is dissolved in other volatile solvents. In this way, pressurized solutions are obtained which, when sprayed, give aerosols which are particularly suitable for controlling fungi, e.g. in enclosed rooms, and storage rooms, and for preventing fungal infections in vegetation.

The compounds according to the invention and mixtures containing them can thus be used in known ways. In protecting the substances to be treated against fungi, they may be treated with the compounds and mixtures thereof by dusting, spraying, brushing, dipping, lubricating, impregnating or other suitable means.

When the compounds of the invention are used in combination with suitable carriers, e.g. as a solution, suspension, dust, powder, cream, emulsion and the like, a very strong effect is observed over a very wide dilution range. For example, concentrations of the active ingredient in the range of 0.1 to 10% by weight based on the weight of the mixture used are effective in controlling fungi. Naturally, higher concentrations can be used for special cases.

The compounds of the invention are used in forms commonly used to control fungi, e.g. suspensions, poly powders, solutions, ointments and the like. The following are examples of products containing the compounds of the invention.

(1) Suspension:

kg 1 - [- (u-chlorobenzylcoloyl) phenethyl] stripnanol

1 technical xylene

350 ml Atlox 4055 (surfactant trademark

Atlas Povdor Co., ViJmington, Del) water to dilute the active ingredient to the desired concentration

- (p-chlorobenzyl): jl) i,ene.styl7imidat The bol forms a stable aqueous suspension dissolved in keyylene and emulsified with a surfactant.

(2) Dust powder = 20 parts of 1- [2,4-dichloro-, O- (p-chlorobenzyloxy) phenethyl] imidazole are ground with 360 parts of talc in a ball mill, then Ö part of olein is added and grinding is continued, finally the mixture is mixed with 4 parts of quenched lime. The formed powder can be sprayed satisfactorily and has a good adhesion force. It can be used for pollination or for plant protection.

(3) Solution: 5 parts of 1- [p-chloro- [7- (2,10-dichlorobenzyloxy) phenethyl] imidazole is dissolved in 95 parts of alkylated naphthalene and used as an injection to treat fungal infections or on walls, floors or other sites of fungal infections. to prevent infection.

The following examples illustrate the preparation of the starting materials used. Parts are by weight unless otherwise indicated.

Example I

A mixture of 11 parts of H-aoethylimidazole and 19 parts of phenoyl bromide in 40 parts of acetonitrile is stirred and heated under reflux for 2 hours. The solvent is evaporated in vacuo. The residue is taken up in hot water and the solution is cooled and filtered. A solution of sodium carbonate in water is added to the water filtrate to a pI of 9; the product precipitates immediately. It is filtered and recrystallized twice, first from hot water and then from a mixture of diisopropyl ether and 2-propanol to give 1- (benzoylmethyl) imidazole, m.p. 11-14 ° C.

In the same manner as in Example I, and substituting an equivalent amount of acetone for phenacyl bromide, the following compounds are obtained? 1- (7β-methylbenzoyl) methyl / imidazole, m.p. 133-134 ° C.

1- (4-methylbenzoylmethyl) imidazole hydrochloride; sp. 210.52-16 ° C.

1- (4-chlorobenzoylmethyl) imidazole hydrochloride; sp. 228-229 ° C Example II

To a solution of 20.4 parts of imidazole in 40 parts of methanol is added 23.3 parts of o-chlorophenacyl bromide and stirred for 2 hours at 0 ° C. The solvent is evaporated in vacuo. The residue is poured into water. The product 2'-chloro-2- (1-imidazolyl) acetophenone is extracted with chloroform. From the remaining free base, the hydrochloride salt is prepared in the usual manner to give, after two crystallizations, first 2'-chloro-2- (1-imidazolyl) -acetophenone hydrochloride, a mixture of 2-propanol and diisopropyl ether and then a mixture of methanol and diisopropyl ether. . 186.5-189 ° C.

Example III

To a solution of 276 parts of p-fluoroacetophenone in 400 parts of dioxane and 640 parts of dry ether are added dropwise 320 parts of bromine on ice while cooling and stirring. The mixture is then brought to room temperature and the solvent is removed in vacuo until a temperature of 110 ° C is reached. The residue is cooled in an ice-salt bath and 640 parts of acetone are added. At 0 ° C, a solution of 528 parts of imidazole in 640 parts of methanol is added while stirring. The mixture is stirred for a further 3 hours while cooling. The solvent is removed at atmospheric pressure up to 125 ° C. After cooling, 750 parts of chloroform and 5θθ parts of water are added to the residue. The chloroform layer is separated, stirred for 30 minutes, washed with water, dried, filtered and evaporated. From the residue containing 1- (p-fluorophenyl) imidat20 Sol, the hydrochloride salt 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 re-liberated by treatment with an equivalent amount of sodium hydroxide and after crystallization from a mixture of 2-propanol and diisopropyl ether, about 176 parts of 1- (p-fluorophenyl) imidazole are obtained, m.p. 149-155 ° C.

According to Example III, and replacing p-fluoroacetophenone with an equivalent amount of methyl aryl ketone or 2-methylpropiophenone, the following compounds are obtained:

3'-chloro-2- (1-imidazolyl) acetophenone nitrate, m.p. 179-7 ° C.

4'-bromo-2- (1-imidazolyl) acetophenone; sp. 164 ° C.

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

2- (1-imidazolyl) -2'-methylacetophenone nitrate; sp. 165.5-167 ° C 2- (1-imidazolyl) -2'-methoxyacetophenone hydrochloride; sp. 208 ° C.

(1-imidazolylmethyl) -2-thienyl ketone nitrate 5 m.p. 136 ° C.

2- (1-imidazolyl) -2-methylpropiophenone nitrate; sp. 16715 ° C.

Example IV

To a cooled (5-15 ° C) slurry of 120 parts imidazole in 125 parts of dimethylformamide is added portionwise 82 parts of 2- (5-chloro-2-thienyl) acetyl bromide in 125 parts of dimethylformamide. After the addition is complete, the mixture is stirred on ice for 2 hours. The reaction mixture is poured into water, whereupon the product (5-chloro-2-thienyl) - (1-imidazolylmethyl) ketone precipitates. It is filtered and taken up in 75θ parts of chloroform, washed with water and the chloroform is evaporated. The residue is taken up in ether and filtered again to give the free base, m.p. 10-4-1O6 ° C. 4.4 parts of this fraction are converted into the nitrate salt, whereby, after crystallization, 3.7 parts of (5-chloro-2-thienyl) - (1-imidazolylmethyl) ketone nitrate are obtained from ethanol, m.p. lll, 5 ° C ·

According to Example IV, and replacing imidazole with an equivalent amount of the appropriate imidazole if necessary and 2- (S-chloro-2-thienyl) acetyl bromide with an equivalent amount of the appropriate acetophenone or propiophenone, the following compounds are obtained:

M'-chloro-2- (1-imidazolyl) isobutyrophenone nitrate; m.p. 178.2 ° C.

k'-chloro-2- (2-methyl-1-imidazolyl) acetophenone; sp. 209.5 ° C.

U'-chloro-2- (2-ethyl-1-imidazolyl) acetophenone; sp. L60 ° C

4'-chloro-2- (2,4-dimethyl-1-imidazolyl) acetophenone; sp. 185.8 ° C.

Example V

To a stirred and hot (60-80 ° C) solution of 155 parts of p-chloroacetophenone in 250 parts of propylene glycol is added dropwise 160 parts of bromine and the mixture is stirred overnight. The reaction mixture is poured into dilute sodium hydroxide solution and the product is extracted with benzene. The extract is dried and evaporated in vacuo.

The resulting oily residue is distilled to give 220 parts of oily 2- (bromomethyl) -2- (p-chlorophenyl) -4-methyl-1,3-dioxolane, b.p. 131-133 ° C at a pressure of 1.25 mm. When the distillate is mixed with 400 parts of 2-propanol while cooling, the oil solidifies. It is filtered and crystallized from 2-propanol to give 2- (bromomethyl) -2- (p-chlorophenyl) -4-ethyl-1,3-dioxolane, m.p. 71 ° C.

According to Example V, substituting an equivalent amount of the appropriate ketone and glycol for an azeophenone and glycol gives the following compounds:

2- (bromomethyl) -2-O-tolyl-1,3-dioxolane; kp. 113r.15 ° C

0.8 mm.

2- (bromomethyl) -2-p-tolyl-1,3-dioxolane; kp. 135-137 ° C

2.5 mm.

2- (bromomethyl) -2 - (, 5-dichlorophenyl) -1,3-dioxolane and m.p. 6.1 ° C.

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

2- (bromomethyl) -2- (o-methoxyphenyl) -1,3-dioxolane; sp. 99-100 ° C. 2- (bromomethyl) -2- (p-fluorophenyl) -1,3-dioxolane; sp. 50 ° C.

Example VI

37 parts of methyl 2-tlenyl ketone are brominated with 48 parts of bromine in 48 parts of dioxane and 96 parts of dry ether while cooling and stirring. The solvent is removed in vacuo. 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 stirred and refluxed in a water-equipped apparatus for 15 hours. The reaction mixture is cooled and the toluene layer is separated, washed once with potassium carbonate solution, once with water, dried, filtered and evaporated in vacuo. The oily residue is distilled in vacuo and crystallized from potassium carbonate to give 2- (bromomethyl) -2- (2-tlenyl) -1,3-dioxolane, b.p. 95 ° C / O> 6 mm.

Following the procedure of Example VI and substituting an equivalent amount of the appropriate ketone and glycol for acetophenone and glycol, the following dioxolanes are obtained:

2-bromomethyl-2- (o-chlorophenyl) -1,3-dioxolane, b.p. 13 ° C / 0.8 mm 2- (bromomethyl) -2- (m-methoxyphenyl) -1,3-dioxolane; sp. 61 ° C.

2- (bromomethyl) -2- (2,3,4-trichlorophenyl) -1,3-dioxolane; sp. 59.5 ° C.

2-bromomethyl-2- (m-chlorophenyl) -1,3-dioxolane, b.p. 149 ° C / 0.2 mm Example VII

To a solution of 23 parts of sodium in 600 parts of ethanol is added 154 parts of ethyl 5-methylimidazole-4-carboxylate.

440 parts of ethanol are then evaporated off and 1600 parts of 2-diisopropyl ether are added to the warm residue. Upon cooling, the sodium salt precipitates. It is filtered to give ethyl23

Sodium salt of 5-methylimidazole-4-carboxylate.

A mixture of 17.7 parts of ethyl 5-methylimidazole-4-carboxylate sodium thiol, 35 parts of 2-bromomethyl-2- (p-chlorophenyl) -1,3-dioxolane / Patel AR, J. Pharm. Sci., 52 (6),

588-592 (1963) ?, 22.5 parts of potassium iodide, 30 parts of dimethylformamide and 4 parts of toluene are stirred and refluxed for 12 hours. The reaction mixture is cooled and 400 parts of ether are added. The organic phase is washed three times with water, dried and an excess of concentrated nitric acid is added. The precipitated nitrate salt is filtered and crystallized from a mixture of hO 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-carboxylate nitrate, m.p. 130.3 ° C.

A mixture of 2 parts of ethyl 1- [2- (p-chlorophenyl) -1,3-dioxolan-2-ylmethyl] -5-methylimidazole-4-carboxylate titrate and 7 to 5 parts of sodium hydroxide 10-n solution, stir and heat at reflux for 15 minutes. Then 20 parts of water and then 4.5 parts of acetic acid are added, whereupon the product precipitates. It is filtered and crystallized from 80 parts of ethanol to give 1- [2- (p-chlorophenyl) -1,3-dioxolan-2-ylmethyl] -5-methylimidazole-4-carboxylic acid, m.p. 258.3 ° C.

To a portion of paraffin oil is added portionwise 25 parts of 1- [2- (p-chlorophenyl) -1,3-dioxan-2-ylmethyl] -5-methylimidazole-4-carboxylic acid at 25 ° C. The mixture is heated to 27 ° C until no more carbon dioxide is evolved. The reaction mixture is cooled and 240 parts of ether are added. The solution is filtered and an excess of concentrated nitric acid solution is added to the filtrate. The precipitated nitrate salt is filtered and crystallized from a mixture of 120 parts of ethanol and 340 parts of diisopropyl ether to give 1- [2- (p-chlorophenyl) -1,3-dioxano-2-ylmethyl] -5-methylimidazoline nitrate, sp. 153-6 ° C.

A mixture of 13 parts of 1- [N- (p-chlorophenyl) -1,3-dioxolan-2-ylmethyl>The p-5-methylimidazole, 100 parts of acetic acid and 5 parts of dilute hydrochloric acid are stirred and refluxed for 18 hours. The solvents are evaporated off and 100 parts of water and an excess of sodium hydroxide are successively added to the residue, whereupon the product 4'-chloro-2- (5-methyl-1-imidazolyl) acetophenone precipitates. It is filtered and recrystallized from dimethylformamide (50 parts; 10%) to give 6.5 parts of 4'-chloro-2- (5-methyl-1-imidazolyl) acetophenone, m.p. 123 ° C. The process of this example thus describes the preparation of a 5-methylimidazolyl ketone of formula (II).

Example VIII

To a stirred and cooled (5 ° C) suspension of 6 parts

2-bromo-2 ', 4', 6'-trichloroacetophenone in 24 'part of methanol, added

0.3 parts of sodium borohydride. At the end of the addition, the mixture is stirred for one hour in an ice bath and then for 2 hours at room temperature.

The mixture is cooled to 5 ° C and a second portion of 0.3 parts of sodium borohydride is added portionwise. At the end of the addition, stirring is continued first for 1 hour in an ice bath and then for 1 hour at room temperature. Finally, a third portion of 0.3 parts of sodium borohydride is added at 5 ° C and the mixture is stirred for 30 minutes in an ice bath and for 30 minutes at room temperature. Hydrochloric acid is then added to pH 3 and the mixture is evaporated. The residue is taken up in 200 parts of boiling water and, after cooling, the solution is extracted with carbon tetrachloride. The organic phase is washed with water, dried over magnesium sulphate and evaporated to give <?<- (bromomethyl) -2,4,6-trichlorobenzyl alcohol.

Example IX

To a suspension of 40 parts of 1- (p-chlorobenzoylmethyl) imidates in 120 parts of methanol is added portionwise 4 parts of sodium borohydride while cooling with ice and stirring. After 30 minutes, the reaction mixture is stirred and refluxed for 1 hour and 100 parts * of water are added. Methanol is removed at atmospheric pressure. 16 parts of concentrated hydrochloric acid solution are then added and the mixture is stirred and refluxed for 5 minutes. After cooling in an ice bath, an excess of ammonium hydroxide solution is added, whereupon the alcohol product precipitates. It is filtered, washed with water and crystallized from a mixture of dimethylformamide and water to give E- (p-chlorophenyl) imidazole-1-ethanol, m.p. 180 ° C.

The procedure of Example XI is repeated, but using the appropriate ketones as starting materials to give the following alcohols, some of which are converted to the acid addition salts by treatment with an acid in the usual manner:

ot- (o-chlorophenyl) imidazole-1-ethanol nitrate; sp. 143 ° C.

oC- (p-fluorophenyl) imidazole-1-ethanol; sp. 146.5 ° C. - (2,4-dichlorophenyl) imidazole-1-ethanol; sp. 136.5 ° C.

(p-o-tolylimidazole-1-ethanol nitrate ·, mp 131 ° C. c * -p-tolylimidazole-1-ethanol; mp 155 ° C.

phenyl) imidazole-1-ethanol;

(m-chlorophenyl) imidazole-1-ethanol; sp. 109.8 ° C. (p-bromophenyl) imidazole-1-ethanol; sp. 188.5 ° C.

<N- (o-methoxyphenyl) imidazole-1-ethanol hydrochloride; sp. 171.5JC. σ * - (5-chloro-2-thienyl) imidazole-1-ethanol; sp. 131.5 ° C.

N- (2-thienyl) -imidazole-1-ethanol N, N-dimethyl-N-phenylimidazole-1-ethanol, m.p. 139 ° C.

<N- (p-chlorophenyl) -3-dimethylimidazole-1-ethanol, mp 187.5 ° C.

oL- (p-chlorophenyl) -2-methyl-1-imidazoleethanol; sp. 165.5 ° C. oC- (p-chlorophenyl) -5-methylimidazole-1-ethanol; sp. 194 ° C. o- (p-chlorophenyl) -2,4-dimethylimidazol-1-ethanol; sp. 128.8 ° C kX- (p-chlorophenyl) -2-ethyl-1-imidazollethanol; sp. 151.5 ° C ·

Example X

To a sodium methoxide solution prepared from 9.2 parts of sodium in 140 parts of methanol are added successively 27.2 parts of imidazole and 100 parts of dimethylformamide. The solvent is removed at atmospheric pressure with stirring. At 130 [deg.] C. (all methanol has been removed), 47 parts of .beta.-chloromethyl-.alpha.-methylbenzyl alcohol are added. The mixture is stirred at 130 ° C for 1 hour. Add 5θθ parts of water, whereupon the alcohol product crystallizes.

It is filtered and crystallized from toluene to give (N-methyl- o(.-phenylimidazole-1-ethanol, mp 119.5 ° C).

The procedure of Example XII is repeated and o (chloromethyl) methylbenzyl alcohol is replaced with an equivalent amount of o4-chloromethyl - (c-chlorobenzyl) alcohol to give the following compound: (p-chlorophenyl) - -methyl-imidazole-1-ethanol, mp 140 ° C.

Example XI

To a suspension of 4.5 parts of sodium methoxide solution (30%) in 15 parts of dimethylformamide and 16 parts of benzene is added 2 parts of imidazole. The solvent is distilled off up to 130 ° C. A solution of 5.4 parts of οό- (bromomethyl) -3,4-dichlorobenzyl alcohol in 5.5 parts of benzene (temperature 13θ-115 ° θ) is then added and the solvent is distilled off. The temperature is brought to 130 ° C and then slowly cooled to 40 ° C. Add diisopropyl ether (32 parts) followed by 5θ parts of water and cool to crystallize the product. It is filtered, washed with ether and boiled for a few minutes in a mixture of 25 parts of dimethylformamide and 5 parts of water. The product is recrystallized at room temperature and separated to give oZr (3,4-dichlorophenyl) imidazo-1-ethanol, m.p. ΐ48.7 ° θ ·

Following the procedure of Example XIII and replacing the cyclo (bromomethyl) -3,4-dichlorobenzyl alcohol with an equivalent amount of the appropriate starting alcohol, the following compounds are obtained:

οΔ- (2,5-dichlorophenyl) imidazole-1-ethanol; sp. 145.3 ° C.

Λ- (2,6-dichlorophenyl) imidazole-1-ethanol; sp. 131.6 ° C.

ot- (2,4,6-trichlorophenyl) imidazole-1-ethanol; sp. 151.8 ° C.

Example XII

This example illustrates the resolution of a compound of formula (v) into optical isomers.

154.8 parts of «(, - (2,4-dichlorophenyl) imidazole-1-ethanol (obtained according to Example XI) are suspended in 960 parts of acetone at 50 [deg.] C. Add 10 [mu] l of dibenzoyl-D-tartaric acid dissolved

120 to a portion of acetone to give a 1-phase system. This solution is filtered at 50 ° C. The temperature is allowed to lower to 20 ° C (over 2 hours) and the product is removed by filtration (filtrate A).

It is washed with 400 parts of acetone. The product consists of the diastereoisomeric salt of (+) - N- (2,4-dichlorophenyl) imidazole-1-ethanol with dibenzoyl-D-tartaric acid. The compound is a 1-1 adduct because the analytical values correspond to the following structure:

COOH o HCOl- ~~

-OF

(-)

O "c·0·

CH

COOH

The yield of dibenzoyl-D-tartaric acid with (+) - N- (2,4-dichlorophenyl) -imidazole-1-ethanol (1: 1) is 101 parts (54.3%)!

o = -20 ° (c = 1, methanol). Liberation of the corresponding free base by treatment of the salt with a strong alkali gives 33 to 5 parts of (+) - (2,4-dichlorophenyl) imidazole-leanol, m.p. 112-115 »2 ° C.

This is a dextrorotatory enantiomer with a rotation capacity of ο ^ ρθ = + 100 ° (c = 1, methanol).

The initial mother liquor (filtrate A) contains 34.8 parts of (+) - 5 - (- (2,4-dichlorophenyl) imidazole-leanol, 77-4 parts of (_) _θ / _ (2,4-dichlorophenyl) imidazole-1-ethanol and 49 parts of dibenzoyl-D-tartaric acid. hydrochloride salts of imidazole-1-ethanol. The yield is 84 parts and the specific rotation of the substance = -18 ° (c = 1, methanol); thus, an excess of the (-) form is obtained compared to the (+) form.

A portion of (+) - o - (2,4-dichlorophenyl) imidazole-1-ethanol remains in solution because after filtration of the hydrochloride it is possible to separate 14 parts of (+) - & {? (2,4-dichlorophenyl) imidazole-1-ethanol. The latter is filtered and the filtrate is evaporated and the residue is dissolved in water. The aqueous solution is made alkaline and extracted with chloroform. The solvent is evaporated and the residue is crystallized from acetone to give 14 parts of (+) - N- (2,4-dichlorophenyl) imidazole-1-ethanol. The specific rotation of the latter = -80 (c = 1, methanol). This means that the fraction comprises 10% (-) - ε (2,4-dichlorophenyl) imidazole-1-ethanol and 9% (-) - (2,4-dichlorophenyl) imidazole-1-ethanol (assuming that the specific rotation of the pure enantiomer is -100 °).

The purification of this (-) - enriched fraction is described below. Addition of 3 parts of dibenzoyl-D-tartaric acid to a solution of 11 parts (taken from the above 14 parts) in 80 parts of acetone precipitates a crystalline salt of (-) - o4 (2,4-dichlorophenyl) imidazole-1-ethanols dibenzoyl-D2O o tartaric acid salt (1: 2). Specific rotation = -100 (c = 1, methanol). This salt corresponds to the following structure by analysis;

COOH (-)

A sample comprising 7 parts of this diastereoisomeric salt after release of the free base gives 3 parts of (-) - o- (2,4-dichlorophenyl) imidazole-1-ethanol; sp. 111.4-113 ° C;

o own! rotation o4. mp = -99 ° (o = 1, methanol).

The following examples illustrate the preparation of the final products of formula (i).

Example 1

A solution of 18.6 parts of 1- (benzoylmethyl) imidataol and 14.5 parts of N-phenylethylamine in 160 parts of dry benzene containing a small amount of p-toluenesulfonic acid is stirred and heated under reflux equipped with a water lacquer. After 24 hours, a theoretical amount of water has formed. The solvent is removed in vacuo. The residue is dissolved in 120 parts of ethanol and this solution is hydrogenated at an initial pressure of 4.5 kg / cm 3 at room temperature in the presence of 3 parts of palladium on carbon (5%). After the calculated amount of hydrogen has been absorbed, the hydrogenation is stopped.

The solution is filtered and the solvent is removed in vacuo. The residue is dissolved in acetone and to this solution is added an excess of concentrated nitric acid in diisopropyl ether; the nitrate salt separates as an oil. The solvent is decanted off and a new volume of acetone is added to the residue together with a small amount of diisopropyl ether to crystallize the solid salt. It is filtered, washed with acetone and crystallized from a mixture of methanol, acetone and diisopropyl ether to give 1- (p-phenethylamino-phenethyl) imidazole dinitrate, m.p. 164.5-168 ° C.

Following the procedure of Example 1 and substituting an equivalent amount of the appropriate amine for p-phenethylamine, the following imidazole amines are obtained:

1- (phenanilinophenethyl) imide zole dihydrochloride; sp. 217.5-23 ° C (dec.).

1- [3- (1-tetrainylamino) phenyl] thymidazole dinitrate;

sp. 139-143 ° C.

Example 2

A solution of 18.6 parts of 1- (benzoylmethyl) imidateo and 12.9 parts of benzylamine in 80 parts of benzene containing a small amount (about 0.5 parts) of p-toluenesulfonic acid is stirred and refluxed for 4 hours, (reaction vessel is equipped with a reflux condenser and a water separator). The solvent is removed in vacuo and the residue is dissolved in 120 parts of ethanol. At room temperature, a first portion of 3 · 8 parts of sodium chlorohydride is added and the mixture is stirred and heated using

55424 reflux condenser for 30 minutes. A second portion of 3 to 8 parts of sodium borohydride is then added and mixed again and heated for 1 hour. The solvent is removed in vacuo. To the residue are added successively 100 parts of water and 7θ parts of concentrated hydrochloric acid solution (pH = 2-3). The solution is stirred and heated for 1 hour. After cooling with ice, it is filtered and made alkaline (vigorously) with 10N sodium hydroxide solution and the acidic base is extracted with methylene chloride. The extract is washed with water, dried, filtered and evaporated in vacuo. The remaining free base is dissolved in acetone and to this solution is added an excess of 2-propanol pre-saturated with gaseous hydrogen chloride. Upon addition of diisopropyl ether, the hydrochloride salt precipitates. It is filtered and crystallized twice first from a mixture of methanol and diisopropyl ether and then from a mixture of ethanol and diisopropyl ether to give 1- (N, N-benzoylaminophenethyl) imidazole dihydrochloride, m.p. 263> 5-266.5 ° C.

The reductive amination procedure is repeated except that an equivalent amount of the appropriate ketone and an equivalent amount of the appropriate amine are used as the starting material to give the following imidazole amines:

R.-C- CH-NH- (CHO) -Ar 'XI, dn

Rg Ar

<td>B</td><td>B</td><td>B</td><td>B</td><td>p-Cl-Ph</td><td> . 0</td><td>1-tetralinyl</td><td>2HC1 .3B20</td><td> 193-198</td>

<td>B</td><td>B</td><td>B</td><td>B</td><td>p- F-Ph</td><td> 1</td><td>μ -MeO-Ph</td><td>2HN0j</td><td>164.5-183 (dckomy.)</td>

<td>B</td><td>B</td><td>ri</td><td>B</td><td>pF-Ph</td><td> 0</td><td>1-tetralinyl</td><td>2HN0j</td><td> 122 - 136</td>

<td>B</td><td>B</td><td>B</td><td>B</td><td>2-thienyl</td><td> 1</td><td>p-Cl-Ph</td><td>2 HCl</td><td> 263.5</td>

Example 3

A solution of 140 parts of imidazole, 240 parts of 2-phenylethylene oxide, 400 parts of denatured absolute ethanol and 8 parts of pyridine is heated under reflux (an exothermic reaction takes place, followed by cooling in an ice bath). After completion of the exothermic reaction (about 15-3θ minutes), the mixture is allowed to cool to 50 ° C. 240 parts of diisopropyl ether are added and the mixture is poured into 1000 parts of water. After cooling, the crude product is filtered, mixed with ice-cold acetone, filtered again, washed with ice-cold acetone and then with ether to give 1- (β-hydroxyphenethyl) -imidazole, m.p. 149-15 ° C.

one part of 1- (γ2-hydroxyphenethyl) imidazole is dissolved in 250 parts of dry hexamethylphosphoric triamide at about 40 ° C while adding an antifoam. This solution is added over 1 hour to 22 parts of a dispersion of sodium hydride in 100 parts of dry hexamethylphosphoric triamide while cooling to 5-15 ° C. At the end of the addition, the mixture is allowed to reach room temperature (takes about 3θ minutes). After stirring for 1 hour at 45-5 ° C, the mixture is cooled to 5 ° C and 80 parts of p-chlorobenzyl chloride are added portionwise while keeping the temperature below 25 ° C. The mixture is stirred for 3 minutes at room temperature, heated to 45 ° C and then allowed to cool to room temperature (over about an hour). After the addition of 1500 parts of water, the ether product 1- [γ- (p-chlorobenzyloxy) phenethyl] imidazole is extracted three times with ether. The combined extracts are washed with water and excess nitric acid is added. After cooling, the precipitated nitrate salt is filtered off, stirred twice with acetone / ether (1: 1) and dried in vacuo to give 1- [4- (p-chlorobenzyloxy) phenethyl] imidazoline nitrate, m.p. 132-134 ° C.

Example 4

To a stirred and refluxing solution of 40 parts of benzene and 35 parts of dimethylformamide (both solvents pre-azeotroped) are added successively 1.6 parts of sodium hydride and 7.7 parts of S- (2,4-dichlorophenyl) imidazole -1-ethanol (cooled on ice if necessary). After the addition is complete, stirring and refluxing are continued for 30 minutes. It is then added

7.8 parts of 2,6-dichlorobenzyl chloride and the mixture are stirred while refluxing for a further 3 hours. The reaction mixture is then poured into water and the product 1- [2,4-dichloro- [3- (2,6-dichlorobenzyloxy) phenethyl] imidazole is extracted with benzene. The extract is washed twice with water, dried, filtered and evaporated in vacuo. The base residue is dissolved in a mixture of acetone and diisopropyl ether, and an excess of concentrated nitric acid solution is added to this solution. The precipitated nitrate salt is filtered and crystallized from a mixture of methanol and diisopropyl ether to give 1-Z * 2,4-dichloro-N- (2, ύ-dichlorobenzyloxy) phenethyl] imidazole nitrate, m.p. 179 ° C.

By repeating the procedure of Example 4 and replacing Λ- (2,4-dichlorophenyl) imidazole-1-ethanol with an equivalent amount of the appropriate imidazole alcohol and substituting an equivalent amount of the appropriate benzyl halide for 2,6-dichlorobenzyl alcohol, the following compounds are obtained:

1- (β-benzyloxyphenethyl) imidazole nitrate; sp. 93 ° C.

1- [2,4-dichloro- [3- (m-methoxybenzyloxy) phenethyl? imidazoline nitrate; sp. 115.5 ° C.

1 “Z2,4-Dichloro- [3- (of fluorobenzyloxy) phenethyl.? imidazoline nitrate; sp. 146.5 ° C.

1- [2,4-dichloro- [3- (p-fluorobenzyloxy) phenethyl] imidazoline nitrate; sp. 141 ° C.

l- £ 2,4-dichloro- [? » - (p-methoxybenzyloxy) phenylx.7 imidates solinitrate m.p. 148 ° C.

Example 5

A suspension of 5 parts of β- (p-chlorophenyl) imidazole-letanol and 1.1 parts of sodium hydride in 27 parts of dry tetrahydrofuran is stirred and refluxed for 2 hours, after which the evolution of hydrogen ceases. 30 parts of dimethylformamide and 4.8 parts of p-chlorobenzyl chloride are added and the mixture is stirred and refluxed for 2 hours. The tetra hydrofuran is evaporated at atmospheric pressure and the dimethylformamide55434 solution is poured into water. The product is extracted with benzene. The extract is washed with water, dried, filtered and evaporated in vacuo. The residue is washed with petroleum ether. The latter is decanted and the nitrate salt is prepared from the remaining oily free base from 1- [p-chloro-N- (p-chlorobenzyloxy) -phenethyl] imidazole in the usual manner using nitric acid in 2-propanol. The crude solid salt is filtered and crystallized from a mixture of 2-propanol and diisopropyl ether to give 1- [p-chloro- [3- (p-chlorobenzyloxy) -phenethyl] imidazole nitrate, m.p. 155 ° C.

The O-alkylation procedure of Example 5 is repeated, but using an equivalent amount of the appropriate alcohol and an equivalent amount of the appropriate halide as the starting material to give the following imidazole ethers:

. θ ',

II

R. - C · »C - 0 - (CH_> - Ar ',, 2 n

B2. Ar

<td>B</td><td>B</td><td>B</td><td>5-Cl-2-thienyl</td><td> 1</td><td>o-Cl-Ph</td><td> 125</td><td>HNOj</td>

<td>B</td><td>B</td><td>B</td><td>o, p-di-Cl-Ph</td><td> 1</td><td>p-isoPr-Ph</td><td> 135.7</td><td>hno3</td>

<td>K</td><td>B</td><td>B</td><td>o, p-di-Cl-Ph</td><td> 1</td><td>o, m, p-fcruCl-Ph</td><td> 180.5</td><td>HNOj</td>

<td>k '</td><td>K</td><td>B</td><td>o, p-di-Cl-Ph</td><td> 1</td><td>2,4,6-triCl-Ph</td><td> 180,1</td><td>HNOj</td>

<td>K</td><td>B</td><td>B</td><td>2,4,6-triCl-Ph</td><td> 1</td><td>o, p-di-Cl-Ph</td><td> 162.9</td><td>HHOj</td>

<td>B</td><td>B</td><td>K</td><td>2,4,6-triCl-Ph</td><td> 1</td><td>2,6-di-Cl-Ph</td><td> 180.3</td><td>ΗΝΟ?</td>

Example 6

To a stirred and warm mixture of 1.66 parts of sodium hydride (50%) in 45 parts of tetrahydrofuran is added portionwise 7.9 parts of 3- (p-chlorophenyl) -5-methylimidazoleethanol at 50 ° C. After the addition is complete, stirring is continued for 3 hours at reflux temperature. Then 73 parts are added

2,4-Dichlorobenzyl chloride and stirring and heating are continued using a reflux condenser for 5 hours. The reaction mixture is cooled and 240 parts of ether are added. The ether phase is washed four times with water, dried and, after addition of excess concentrated nitric acid, the nitrate salt precipitates. It is filtered, mixed with ether acetate and crystallized from a mixture of 2-propanol and diisopropyl ether (1: 9 by volume) to give 1- [p-chloro- [3- (2,4-dichlorobenzyloxy) phenethyl] -5-methyl- imidazole nitrate, m.p. 150 ° C.

The procedure of Example 6 is repeated and β- (p-chlorophenyl) -5-methylimidazole-1-ethanol is replaced with an equivalent amount of β- (p-chlorophenyl) -2,4-dimethylimidazole-1-ethanol or an equivalent amount. with 2-ethyl-4 (5) -methylimidazole-1-ethanol / Uindaus et al., Ber. 5513, 3706 (1922) ./ to give the following compounds:

1- [p-chloro-3- (2,4-dichlorobenzyloxy) phenethyl] -2,4-dimethylimidazole nitrate, m.p. 145.1 ° C;

Example 7

A mixture of 8.7 parts of N- [3- (2,4-dichlorophenyl) imidazole-1-ethanol hydrochloride and 3.4 parts of sodium hydride in 40 parts of benzene and 35 parts of dimethylformamide is stirred while cooling in an ice bath (the solvents have been azeotropically dried). ). First, 3 parts of manganese dioxide are added, followed by 8 parts of p-nitrophenylbenzene and stirred for 3 hours at room temperature. The reaction mixture is filtered through hyflon and water is added. The product is extracted with benzene. The extract is dried, filtered and evaporated in vacuo. From the remaining free base, the nitrate salt is prepared in the usual manner in acetone. The precipitated solid salt is filtered off and crystallized from a mixture of methanol and diisopropyl ether to give 1- [2,4-dichloro- [3- (p-nitrophenoxy) phenethyl] imidazole nitrate, m.p. 167 ° C.

By repeating the procedure of Example 7 and replacing p-nitrofluorobenzene with an equivalent amount of 2,4-dinitrochlorobenzene, 1- {2,4-dichloro- [3- (2,4-dinitrophenoxy) phenethyl] imidazoline nitrate is obtained, m.p. 167.5 ° C.

Example 8

To a stirred and refluxable mixture of 13.5 parts of iron, 10 parts of ammonium chloride and 150 parts of water are added portionwise 20 parts of 1- [2,4-dichloro- [3- (p-nitrophenoxy) -phenethyl] imidazole nitrate and the mixture is stirred. and heated under reflux for 6 hours. The reaction mixture is cooled in an ice bath and methylene chloride is added. The mixture is filtered through hyflon. The methylene chloride layer is separated from the filtrate, dried, filtered and evaporated in vacuo. The residue is crystallized from diisopropyl ether to give 1- [η 3 - (p-aminophenoxy) 2,4-dichlorophenyl] imidazole. sp. 94 ° C.

Example 9

To a stirred mixture of 10.32 parts of (+) - (4- (2,4-dichlorophenyl) imidazole-1-ethanol in 75 parts of tetrahydrofuran is added portionwise 2.1 parts of sodium hydride (50%) and the mixture is stirred and refluxed. 1 hour 44 parts of dimethylformamide are added, followed by 8.7 parts of 2,4-dichlorobenzyl chloride in 22 parts of dimethylformamide, and at the end of the addition, stirring is continued at reflux for 2 hours. Tetrahydrofuraar.i is distilled off in vacuo and the residue is poured into 200 parts of water. The product is extracted several times with xylene (160, 80 and 40 parts). The combined extracts are dried over magnesium sulfate, filtered and evaporated. The residue is dissolved in 36 parts of tetrahydrofuran and the solution is acidified with concentrated nitric acid solution. The nitrate salt crystallizes at room temperature. It is filtered and dried to give (+) - 1 / 2,4-dichloro- [3- (2,4-dichlorobenzyloxy) phenethyl] imidazoline nitrate, m.p. 135.3 ° C; e / + 59 ° (c = 1, methanol).

Example 10

To the mixed mixture; containing 10.32 parts of (-) - </ - (2,4-dichlorophenyl) imidazole-1-ethanol in 75 parts of tetrahydrofuran, 2.1 parts of sodium hydride (50%) are added portionwise and the mixture is stirred and refluxed for 1 hour. . To this is added 44 parts of dimethylformamide followed by 8.7 parts of 2,4-dichlorobenzyl chloride 2 in 2 parts of c'methylformamide. After the addition is complete, stirring is continued at reflux for 2 hours. Tetrahydrofuran is distilled off in vacuo and the residue is poured into 200 parts of water. The product is extracted several times with xylene (160, 80 and 40 parts). The combined extracts are dried over magnesium sulfate, filtered and evaporated. The residue is dissolved in 36 parts of tetrahydrofuran and the solution is acidified with concentrated nitric acid solution. The nitrate salt crystallizes at room temperature after the addition of 32 parts of diisopropyl ether. The salt is filtered off and dried to give (-) - 1- [2,4-dichloro- [3- (2,4-dichlorobenzyloxy) phenethyl] imidazole nitrate, m.p. 135 ° C;s -58 ° (c = 1, methanol).

Example 11

A. 188 parts of 1-phenyl-1-imidazoleethanol are dissolved

600 part of 2-propanol. To this solution is added a solution of 118 parts of (+) - camphor-10-sulfonic acid monohydrate in 200 parts of 2-propanol. The precipitate formed is filtered to give a crude product

(c = 1, methanol). '(The filtrate contains (+) - 4-phenyl-1-imidazoleethanol - (+) - camphor sulfonate). 163 parts raw (-) -oPhenyl-1-imidazolethanol - (+) - camphorsulfonate is crystallized from 1000 parts of water to give pure (-) -? 4> phenyl-1-imidazolethanol-

The pure camphorsulfonate olole is dissolved in water and, after being made alkaline with ammonium hydroxide, the precipitated free base is filtered off to give (-) - o4-phenylimidazole.

hexamethylene phosphoramide (pre-dried with sodium hydride) is cooled to 10 ° C. While keeping the temperature below 15 ° C, a solution of 20 parts of (-) - o-phenyl-1-imidazoliethanol in 65 parts of hexamethylphosphoramide is added. After the addition is complete, the mixture is stirred first for 30 minutes at room temperature and then for 1 hour at 45-5 ° C. The mixture is re-cooled to 50 ° C and 20 parts of p-chlorobenzyl chloride are added. After stirring for 3 minutes at room temperature, the mixture is warmed to 50 ° C and allowed to cool again to room temperature with stirring. 5θθ parts of water are then added and the product is extracted with a third portion of toluene (240, 160 and 80 parts). The combined extracts are washed with 25Ο of water, dried over magnesium sulfate and evaporated. The residue is taken up in 40 parts of toluene and concentrated nitric acid is added. The precipitated hydrate salt is filtered off with suction and washed with di-isopropyl ether to give (-) - 1- [4- (p-chlorobenzyloxy) -phenene].

(c = 1, methanol).

part of the sample is recrystallized from benzene and diisopropyl ether to give 9 parts of (-) (p-chloro).

ribentayloxy

Contents41

77 members in 28 offices

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

Priority claims3

Priority claims
Document	Office	Kind	Date
75372968	United States of America	A	1968-08-19
84876769	United States of America	A	1969-07-23
240169	Finland	A	1969-08-18

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
AT296289B	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
FI55434BThis record	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

Abstract

Term

OF

(V)

O

OF

OF

R

I

A

B

C

D

E

F

G

X

I

J

K

L

M

OF

P

Q

R

S

AA

BB

CC

0 0 I

4 3 0 2 0 030 0 3 1 O 3 1

4 4 2 4 4 0 4 1 2 M 2 O 2 UO 2 0 0 2 0

OC

OO

O

O

O

-OF

CH

COOH

COOH (-)

II

Priority claims3

Members77

Events

Numbers

Titles2

Classification