DE2221546A1 - Process for the production of new imidazole derivatives - Google Patents

Description

CIBa-GEIGYAG, BASEL (SWITZERLAND) 2221546

Case 4-7499 / 1 + 2

Process for the preparation of new Ijpidazoläerivaten.

The present invention relates to new indd. A2.0 derivatives with valuable pharmacological properties / Process for their manufacture, medicinal products which the contain new imidazole derivatives and their application; in particular imidazole derivatives of the general formula

^B l

~ ² ~ 2221548

in which R .. lower alkyl, cycloalkyl or an optionally phenyl substituted by halogen, lower alkyl or lower alkoxy, and one of the groups R1 and R2, if appropriate by halogen, lower alkyl ,. Hydroxy, lower alkoxy, lower alkylthio or lower alkylsulfonyl substituted phenyl and the other is a six-membered, heteroaromatic radical with 1 or 2 ring nitrogen atoms, as well as N-oxides thereof and salts of such compounds.

The compounds of the present invention have valuable pharmacological properties, in particular anti-inflammatory, antinociceptive and antipyretic efficacy with a favorable therapeutic index.

The anti-inflammatory effectiveness of the new imidazole derivatives in the case of oral administration, for example, in rats in the bolus alba edema test according to G. Wilhelmi, Yep J. Pharmacol. JL5, 187 (1965).

The analgesic effectiveness of the new imidazole derivatives is determined, for example, on the mouse according to the method described by E. Siegmund, R. Cadmus and G. Lu, Proc. Soc. Exp. Biol. Med. 95, method described 729 (1957) nachgewieseni wherein the amount of substance is determined, which is necessary to prevent the 4-benzoquinone by intraperitdneale injection of 2-phenyl-l _J, caused syndrome.

To determine the antipyretic effect, the new "compounds" are administered orally in suitable doses to groups of rats who have been given a suspension of 15% baker's yeast with 1% tragacanth and 1% sodium chloride in distilled water 16-18 hours beforehand Amount of 1 ml per 100 g of body weight had been injected intramuscularly. The fever temperatures generated by the yeast are measured rectally one hour and a half hour before administration of the test substances and for half an hour to 5 hours after administration of the test substances and the maximum Temperature depression and the arithmetic mean temperature decrease during the 5 hours after administration of the test substances compared to the average of the two measurements before administration were determined as a basis for comparison.

The new imidazole derivatives are suitable as active ingredients for drugs that can be used orally, rectally or parenterally for the relief and elimination of pain of various origins as well as for the treatment of rheumatic ,. arthral and other inflammatory diseases.

In the imidazole derivatives of the general formula I and the corresponding starting materials given below contains a lower alkyl radical R in particular up to 6 carbon atoms and is primarily a branched one Alkyl radical or a cycloalkyl radical, preferably with up to

2 0 9 8 A 7/1 1 9 8

6 carbon atoms, especially isopropyl or sec-butyl or preferably tert-butyl, also cyclopropyl. The substituent R ₁ as a phenyl radical which is optionally substituted by halogen, for example fluorine, chlorine or bromine, lower alkyl, for example methyl or ethyl, or lower alkoxy, for example methoxy or ethoxy, means in particular a phenyl radical which is correspondingly substituted in the p-position , a chlorine atom preferably being considered as the halogen substance.

A substituted phenyl radical R_ or R is preferred monosubstituted and can contain a substituent in the o-, m- or p-position. As substituents are especially chlorine, methyl, hydroxy, methoxy, ethoxy, methylthiO / Called ethylthio, methylsulfonyl or ethylsulfonyl.

A monoazacyclic radical R or R is pyridyl, like 2-, 3- or 4-pyridyl, while a diazacyclic radical R or R in particular represents pyrazinyl.

Particularly valuable are compounds of the formula I in which R. is preferably lower alkyl with up to 6 carbon atoms branched lower alkyl having 3 and in particular 4 carbon atoms, or optionally by methyl, methoxy or chlorine is monosubstituted phenyl, and one of the radicals R and R is optionally represented by methyl, methoxy or chlorine-substituted phenyl and the other pyridyl, such as 2-pyridyl or 4-pyridyl, but especially 3-pyridyl bcdeu-

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tet, as well as acid addition salts thereof.

Examples of pharmacologically valuable compounds of the above indicated indication are particularly called:

2-tert-butyl-4 (5) -phenyl-5 (4) - (3-pyridyl) -imidazole, as well as 2-tert-butyl-4 (5) - (p-methoxyphenyl) -5 (4) - (3-pyridyl) -imida-ZOl ₁ 2- (p-Chlorophenyl) -4 (5) - (p-methoxyphenyl) -5 (4) - (3- pyridyl) -imidazole, 2-tert-butyl -4 (5) - (m-methylphenyl) -5 (4) - (3-pyridyl) -imidazole and 2- (p-chlorophenyl) -4 (5) -phenyl-5 (4) - (β-pyridy 1) -imidazole , also 2- (p-chlorophenyl) -4 (5) - (p-methoxyphenyl) -5 (4) - (2-pyridyl) -imidazole, 2-tert.-butyl-4 (5) - (p-methoxyphenyl) -5 (4) - (4-pyridyl) -imidazole , 2-tert-butyl-4 (5) -phenyl-5 (4) - (4-pyridyl) -imdazole and 2- (p -Chlorophenyl) - \ (5) - (p-methoxyphenyl) -5 (4) - (4-pyridyl) - imidazole, and their salts, in particular the pharmaceutically usable acid addition salts.

The new compounds can be prepared in a manner known per se; for example a substituted piketon the general one! formula

e = ο

(H)

= ο

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a corresponding mono-oxime or N-oxide, with ammonia and an aldehyde of the general formula R-CHO (III), and, if desired, a compound obtained into an N-oxide, or convert a obtained N-oxide into the free compound and / or, if desired, a obtained compound convert into a salt or a obtained salt into the free compound.

In the above reaction, the ammonia (also in the form of an ammonia-releasing agent), preferably im Excess used, at least the two molar when using a diketone and when using the corresponding mono-oxime, which leads to the formation of an N-oxide a compound of formula I leads, at least the equimolar amount applies.

An ammonia-releasing agent is, for example, an ammonium salt of an organic carboxylic acid, such as an ammonium lower alkanoate, preferably ammonium acetate, and ammonium formate, and also a suitable carboxamide, in particular formic acid, such as formamide. An ammonium salt is usually in a larger excess and in the presence of an acid, such as a _{lower alkanecarboxylic acid, for example formic or acetic acid or another acid of the formula R 1} -C (= 0) -OH (IV), v / orin R, preferably a residue aliphatic character is used, wherein such an acid can be used as a solvent at the same time. Formamide, preferably in excess, such as a 5-25 fold

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Used in excess can also serve as a solvent at the same time. The reaction can be carried out in the presence of an additional Solvent, for example in the presence of dimethylformamide, preferably at elevated temperature, e.g. at the boiling point of the reaction mixture, when using formamide at about 180 C to about 200 C (at which Temperature, the formamide decomposes), and, if desired, in a closed vessel, if necessary below Pressure and / or in an inert gas, such as nitrogen atmosphere.

In the above process, the diketone of the formula II can also be converted into this in the form of a Use the compound, e.g. by performing the above reaction with an α-hydroxy ketone of the formula

R C = O

I (Ha)

R CH-OH

or a mono-oxime thereof and in the presence of one for its conversion in the diketone of the formula II common oxidizing agent, such as an oxidizing heavy metal salt, preferably an organic copper (II) salt, such as copper (II) acetate or citrate, the resulting Imidazole derivative of the general formula I is usually obtained as a copper salt. The reaction will usually be carried out as described above, i.e. one

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preferably the ammonia or ammonia releasing agent in greater excess; the oxidation and simultaneous Condensation is, for example, in a lower alkanol such as methanol or ethanol, preferably at elevated levels Temperature, for example at about 30 to about 100 ° C. The free can from an accumulating copper salt Imidazole derivative in the usual way, for example by reaction with hydrogen sulfide in a lower alkanol and in the warmth to be released.

The diketones of the formula II or α-hydroxyketones of the formula Ha used as starting materials are known or can be prepared in a manner known per se. For example, mono-oximes of compounds of Formula II can be obtained by, for example, an R carboxylic acid ester, in which R represents the heterocyclic radical R or R, such as a corresponding lower alkyl, e.g. ethyl ester, or optionally an N-oxide thereof with an R -acetic acid ester, such as lower alkyl, e.g. ethyl esters, in a known manner to give the corresponding ketone of the formula

^R 2 ^CH 2

(Hb)

R C = 0

and this reacts with nitrous acid in an alcoholic solvent.

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The new compounds of the general formula I. and. their salts can be used, for example. also manufacture by © in amid of the general formula

GH- M

treated with ammonia and, if desired _t a compound obtained into a N-oxide transferred _t and / or if ,, ER

a received compound into a. Salt or a salt converted into the free compound. The ammonia can also be used as ammonia-releasing agent, in which case, for example, the ammonium salts of carboxylic acids of the formula IV / in particular ammonium as a lower alkanecarboxylic acid, ammonium acetate, and also formamide; _t usually üiederalkancarbonsäure in Geeiner, such as acetic or used mei & ^ _t, pie reaction is preferably carried out at er · ^ temperature durchgeführt-.

The starting materials of the general formula V can?, B, by acylating 2-AmXnQ ^ l-OXQ-IR ₂ -ZR -athane with

, such as chlorides _t of carboxylic acids of the formula IV / j. with appropriate anhydrides.

One can also use the new Imidazolderiyate n. Formula I and its salts are obtained by a yeaivable: ester of a -Pifdrgxyketons der; Alles-

common formula Ua with an amidine of the general formula

J ₁ (VI)

or a salt thereof, and, if desired, one compound obtained converted into an N ^ oxide, and / or, if desired, a compound obtained is converted into a salt or a salt obtained is converted into the free compound.

A reactive ester is, for example, a corresponding ester with a hydrohalic acid, in particular the corresponding chloride or bromide, also with a strong organic sulfanic acid, such as a lower alkane or Arenesulfonic acid, e.g. methane or p-toluenesulfonic acid. the Condensation can usually be achieved by heating the reaction components in an inert solvent such as a halogenated aliphatic hydrocarbon, e.g. chloroform, at moderately elevated temperatures, if necessary, in the presence of a suitable condensing agent such as one Base.

Salts of amidines of the formula VI are, for example, their more stable hydrochlorides, which can be used before use preferably converted into the free amidines, e.g. by carrying out the reaction advantageously in a two-phase system, consisting of a solution of a reactive

201141 / 1VSI

- 31 -.

Esters of an α-hydroxyketohs of the general formula Ha in an inert organic solvent, such as, for example, chloroform, and an aqueous solution of the salt , for example hydrochloride, of the amidine of the general formula VI. While warming and stirring vigorously, a dilute, aqueous solution of an alkali metal hydroxide, e.g. potassium hydroxide or sodium hydroxide, is added dropwise in a total of twice the molar amount in order to release the amidine on the one hand and to bind the acid released during ring closure on the other. - ■ -

The compounds of general formula I can also be obtained by adding an oxazole to the general formula

(VII)

reacts with ammonia, and, if desired, converts a compound obtained into an oxide, and / or, if desired, converting a compound obtained into a salt or a salt obtained into the free compound.

The ammonia can be used in the form of an ammonia-releasing agent, e.g. formamide, optionally used together with ammonia.

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For example, an oxazole of the formula VII can be mixed with a mixture of liquid ammonia and formamide in an autoclave to temperatures of about 180 to about 220 C, or a mixture of said oxazole with formamide to the Siedebzw. Heat the decomposition temperature of the formamide.

The new oxazoles of the general formula VII used as starting materials can be prepared, for example, by one ct-hydroxyketones of the general formula Ha with halides, e.g. chlorides, of carboxylic acids of the formula IV or corresponding anhydrides with the formation of the corresponding Ester converts. The latter is allowed to react with an ammonium salt of a lower alkanoic acid in the heat; for example boil them with excess ammonium acetate in glacial acetic acid under reflux, producing the desired oxazole arises.

According to a further process, the oxazoles of the general formula VII are obtained by adding an amide of the general formula Formula V, e.g., "by boiling with thionyl chloride in the presence or absence of an inert solvent such as e.g. Benzene, under reflux until the evolution of hydrogen chloride ceases, or by treatment with conc. sulfuric acid at temperatures from about 0 C to room temperature, dehydrated.

The above oxazoles of the general formula VII can also be obtained if a nitrile of the formula

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Kiel R-CN (VIII) with a compound of the general for-; mel Ha, in the presence of a mineral acid. For example allowed to concentrate on an equimolar mixture of the starting materials mentioned. Sulfuric acid at temperatures between 0 to 30 C, or polyphosphoric acid at about 80 ° to 120 C act.

The oxazoles of the general formula VII can also be obtained by condensation of reactive esters, especially with hydrohalic acids, of compounds of the general formula Ha with amides of the formula R-C (= O) -NH_ (IX), preferably when heated to temperatures between about 130 and about 170 C, or by reacting with Tin (IV) chloride complexes of carboxylic acid nitriles of the formula VIII can be obtained at room temperature to about 100.degree.

A compound obtained can in a manner known per se, for example by treatment with an N-oxidizing agent Agents such as hydrogen peroxide or a suitable peracid, such as a lower alkane percarboxylic acid such as peracetic acid, a benzene percarboxylic acid such as perbenzoic acid, 3-chloro-perbenzoic acid or monoperphthalic acid, or an organic persulfonic acid, can be converted into an N-oxide.

An N-oxide obtained can be reductively, e.g. by Treatment with hydrogen in the presence of a catalyst,

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like Raney nickel, whereby one e.g. a lower alkanol, in particular methanol or ethanol, used as a solvent, or with one, for the reduction, of N-oxides common chemical reducing agents such as lithium aluminum hydride, phosphorus trichloride or sodium dithionite (sodium hyposulfite) , the latter can also be converted into a compound of the formula I in the form of a hydrate, such as dihydrate.

The method also includes those embodiments after which compounds obtained as intermediates are used as starting materials and the rest Process steps are carried out with these, or the process is terminated at any stage; further Starting materials can be used in the form of derivatives or formed during the reaction.

Such starting materials are preferably used and the reaction conditions are chosen so that one to the compounds listed at the beginning as being particularly preferred got.

The compounds of the general formula I obtainable according to the process, and also N-oxides thereof, can, if desired in the usual way in their salts, e.g. in addition salts with inorganic and organic acids, be transferred. Suitable acids are primarily those that are pharmaceutically acceptable with the free compounds, Form non-toxic salts such as hydrogen chloride acid, hydrobromic acid, sulfuric acid, phos-

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phosphoric acid, methanesulfonic acid, ethanesulfonic acid, 0-hydroxyethanesulfonic acid, Acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, Maleic acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid or emboxylic acid. The acid addition salts can in a manner known per se, e.g. by treatment with an acid in the presence of a suitable solvent, can be obtained.

The new imidazole compounds of the general formula I and their N-oxides, as well as the pharmacologically acceptable ones Salts such as acid addition salts thereof can be in the form of pharmaceutical preparations, preferably enterally, e.g. perorally or administered rectally. The daily dose of the active substance ranges between about 1 mg / kg and about 100 mg / kg. Suitable unit dosage forms, such as dragees, tablets, Suppositories or ampoules contain the active substance preferably in an amount of 0.25-5 mg / kg body weight the species to be treated.

Unit dosage forms' for oral use preferably contain between 10-90% of the active ingredient. For their production, the active ingredient can be used, for example, with solid, powdery carriers such as carbohydrates, e.g. lactose, sucrose, sorbitol or mannitol; Starches, such as potato starch, Corn starch or amylopectin, also laminaria powder or citrus pulp powder; Cellulose derivatives or

2 0 9 8 /. 7/1 19 8

Combine gelatine, optionally with the addition of lubricants such as magnesium or calcium stearate or polyethylene glycols, to produce tablets or dragee cores. The latter can, for example, be coated with concentrated sugar solutions, which may also contain gum arabic, talc and / or titanium dioxide, or with a varnish that is dissolved in volatile organic solvents or solvent mixtures. Dyes can be added to these coatings, for example to indicate different doses of active ingredient. Push-fit capsules made of gelatin, as well as soft, closed capsules made of gelatin and a plasticizer such as glycerine, are suitable as further oral unit forms. The former contain the active ingredient preferably as granules mixed with lubricants, such as talc or magnesium stearate, and optionally stabilizers, such as sodium disulfite (Na SO ₁ ) or ascorbic acid. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as liquid polyethylene glycols, it also being possible for stabilizers to be added.

As unit dose forms for rectal use, suppositories, for example, come into consideration, which consist of a combination an active ingredient with a suppository base based on natural or synthetic triglycerides (e.g. cocoa butter), polyethylene glycols or suitable higher

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Fatty alcohols exist, and gelatin rectal capsules, which a combination of the active ingredient with polyethylene glycols' contain.

Further application forms are, for example ^ " wisely called lotions, tinctures and ointments for percutaneous use prepared with the scanned auxiliary materials.

The following rules are intended to manufacture explain a number of typical application farms in more detail:

a) 1000 g of 2 "tert." Butyl-4 (5) "phenyl-5 {4) - '(3-'pyriäyl} -iraldaüol are mixed with 550 g of lactose and 292 g of potato starch, the mixture with an alcoholic solution of moistened 8 f gelatin and granulated through © in sieve * After $ em drying, are mixed. 60 g of potato starch, 60 g of talc and 10 f Kagnesiumstearat and 20 g of highly dispersed silieiuirtdioxyd and the mixture is compressed ^ u 10 * 000 tablets each of 200 mg

and 100 mg active ingredient content, if desired provided with partial notches for fine adjustment of the dosage

h) 100 g of 2 "(p" ehlorphenyl} '- 4 (5) -' (p- "methoxyphenyl) -5 C4i" (2 "pyridyl)" imidazQl are mixed well with 16 g of corn starch and 6 g of h © ehdispersera _; silicon dioxide . Ώίβί mixture is granulated with a solution of 2 g g gg stearinsäy _rei Aethylcellylose stearin and 6 * ca. in, IQ ml isopropyialkohol moistened, and by © in sieve III (Ph. Helv. V). The granulate is ca, 14 stood dried and then beaten through sieve Ill-Illa. Then it is mixed with 16 g corn starch * 16 g talc and 2 g Magne'-eiuiiistearat and pressed to 1000. dragee cores,

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2221

These are with a concentrated syrup of 2 g Lacca, 7.5 g Arabic Gummit, O _f 15 g of dye, 2 g of finely divided silica, 25 g of talc and 53.35 sugar-coated and dried. The coated tablets each weigh 260 mg and each contain 100 mg of active ingredient.

c) 50 g of 2-tert-butyl-4 (5) -p-methoxyphenyl} -5 {4) - (4-pyridyl) -iraidazole and 1950 g of finely grated suppository base (e.g. cocoa butter) are mixed thoroughly and then melted »1000 suppositories of 2 g are poured from the melt, which has been kept homogeneous by stirring. They each contain 50 mg of active ingredient.

d) 60 g of pQlyoxyethylene anhydrosorbitol monostearate, 30g Anhydrosorbitol monostearate, 150 g paraffin oil and 120 g steary alcohol are melted together, 50 g 2 * -tert, -Butyl ~ 4 (5) -phenyl * -5 (4) - (3-pyridyl) - * imidazole (finely powdered) are added and 590 ml emulsified in 40 preheated water. The emulsion will sit on until it cools down Stirred at room temperature and filled into tubes.

: The following examples explain the production of the new imidazole derivatives of the general formula I, but are not intended to encompass the scope of the invention in any way restrict. The temperatures are given in degrees Celsius.

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example 1

2-tert-butyl-4 (5) - (p-methoxyphenyl) -5 (4) - (3-pyridyl) -imidazole

a) p-Methoxybenzyl (3-pyridyl) ketone

The mixture of 56.6 g (0.375 mol) of ethyl nicotinate and 75.6 g (0.39 mol) of ethyl p-methoxyphenylacetate is added in portions under nitrogen with 31.6 g (0.585 mol) Sodium methylate is added at 20-25 °. The reaction mixture is stirred for 20 hours at 60-70 °, the alcohol formed being blown off with a gentle stream of nitrogen. Afterward 118 ml of conc. Hydrochloric acid was added dropwise to the solid mass and refluxed for three hours. After this After cooling, the acidic solution is washed with ether. The acidic, aqueous phase is then diluted with ammonia and ice Set pH 5 and made alkaline with sodium bicarbonate solution. The suspension is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and evaporated, whereby the p-methoxybenzyl- (3-pyridyl) -ketone as yellow crystals remains behind. M.p. 86-87 °.

b) 1- (p-Methoxyphenyl) 2- (3-pyridyl) -glyoxal

The mixture of 6.8 g (0.03 mol) of p-methoxybenzyl (3-pyridyl) ketone, 3.32 g (0.03 mol) of selenium dioxide and 80 ml of glacial acetic acid are refluxed for 6 hours and then filtered while hot. The filtrate is evaporated in vacuo in ethyl acetate

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and charged through a with 240 g of silica gel Column filtered. The filtrate is evaporated and the residue thus obtained is recrystallized from cyclohexane. You get 1- (p-Methoxyphenyl -) - '2- (3-pyridyl) -glyoxal of m.p. 70-72 °.

c) 2-tert-butyl-4 (5) - (p-methoxyphenyl) -5 (4) - (3-pyridyl) -imidazo! The mixture of 10.0 g (0.0415 mol) 1- (p-methoxyphenyl) 2- (3-pyridyl) -glyoxal, 3.58 g (0.0415 mol) pivalaldehyde, 20 g ammonium acetate and 100 ml glacial acetic acid becomes Boiled under reflux for 22 hours and then poured into a mixture of 350 g of ice and 250 ml of conc. poured aqueous ammonia solution. The crystal slurry is extracted with ethyl acetate and the organic phase washed neutral with saturated sodium chloride solution, dried with sodium sulfa and evaporated. The residue is recrystallized from toluene and dried in a high vacuum at 120 °. The 2-tert-butyl-4- (5) - (p-methoxyphenyl) -5 (4) - (3-pyridyl) -imidazole is obtained as white crystals with a melting point of 202-204 °.

The following are produced in the same way:

2-isopropyl-4 (5) - (p-methoxyphenyl) -5 (4) - (3-pyridyl) imidazole, M.p. 160-162 °, starting from 10.0 g of the above diketone and 3.7 g of isobutyraldehyde;

2- (p-Chlorophenyl) -4 (5) - (p-methoxyphenyl) -5 (4) - (3-pyridyl) -imidazole, . M.p. 200-203 °, starting from 10.0 g of 1- (p-methoxyphenyl) 2- (3-pyridy-glyoxal and 6.5 g of p-chlorobenzaldehyde; 2- (p-Chlorophenyl) -4 (5) -phenyl-5 (4) - (3-pyridyl) -imidazole, m.p. 206 - 208 °, starting from 10.0 g of l-phenyl-2- (3-pyridyl) -glyoxal and 6.7 g of p-chlorobenzaldehyde.

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Example 2 ^Λ _

2-tert-butyl-4 (5) - (o-chlorophenyl) -5 (4) - (3-pyridyl) -imidazole

a) o-chlorobenzyl (3-pyridyl) ketone .

The mixture of 25.0 g (0.126 mol) of ethyl o-chlorophenylacetate and .19.0 g (0.126 mol) of ethyl nicotinate is added in portions under nitrogen with 10.2 g (0.196 mol) Sodium methylate is added at 20-25 °. The reaction mixture is stirred for 20 hours at 60-70 °, the alcohol formed being blown off with a weak stream of nitrogen. To the dropwise addition of 40 ml of conc. Hydrochloric acid is refluxed for 18 hours, then cooled and washed with ether extracted. The aqueous acidic phase is adjusted to pH 5 with dilute ammonia solution and ice and with sodium hydrogen carbonate solution made alkaline. The suspension thus obtained is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and evaporated, whereby yellow crystals of o-chlorobenzyl (3-pyridyl) ketone with a melting point of 64 ° -67 ° are obtained.

The following are produced in the same way:

o-Xylyl (3-pyridyl) ketone (oil), starting from 21.0 g of ethyl o-tolylacetate and 17.8 g of ethyl nicotinate; m-Xylyl- (3-pyridyl) «ketone (oil), starting from 21.0 g of ethyl m-tolylacetate and 17.8 g of ethyl nicotinic acid;

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p-xylyl (3-pyridyl) ketone, m.p. 90-91 ° (from ether), starting from 21.0 g of ethyl p-tolylacetate and 17.8 g of ethyl nicotinate;

m-chlorobenzyl (3-pyridyl) ketone, m.p. 65-67 °, starting from 25.0 g of ethyl m-chlorophenylacetate and 19.0 g of ethyl nicotinate;

p-chlorobenzyl (3-pyridyl) ketone (oil), starting from 25.0 g ethyl p-chlorophenylacetate and 19.0 g ethyl nicotinate;

p-Methoxybenzyl (4-pyridyl) ketone, m.p. 130-132 °, starting of 25 ', 2 g of ethyl p-methoxyphenylacetate and 18.9 g Ethyl nicotinate;

m-methoxybenzyl (3-pyridyl) ketone, b.p. 160 - 165 ° / O, O5 Torr, starting from 25.2 g of ethyl m-methoxyphenylacetate and 19.0 g of nicotine ethyl ester.

b) 1- (o-Chlorophenyl) 2- (3-pyridyl) -glyoxal The mixture of 13.2 g (0.057 mol) o-chlorobenzyl- (3-pyridyl) -ketone, 6.65 g (0.06 mol Selenium dioxide and 50 ml of glacial acetic acid are refluxed for 12 hours and then filtered hot. The filtrate is evaporated in vacuo, taken up in ethyl acetate and filtered through a column filled with 450 g of silica gel. The filtrate is evaporated, with yellow crystals of melting point 50 ° -52 ° remaining, which are used further directly.

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The following are produced in the same way:.

1- (ρ-Chlorophenyl) -2- (3-pyridyl) -glyoxal, m.p. 80-82 °, starting of 13.2 g of p-chlorobenzyl (3-pyridyl) ketone and 6.65 g of selenium dioxide; 1- (m-Chlorophenyl) -2- (3-pyridyl) -glyoxal, m.p. 55-57 °, starting of 13.2 g of m-chlorobenzyl (3-pyridyl) ketone and 6.65 g of selenium dioxide; l- (o-Tolyl) -2- (3-pyridyl) -glyoxal, boiling point 150 ° / 0.01 Torr, starting from 42.0 g of o-xylyl (3-pyridyl) ketone and 24.0 g of selenium dioxide; 1- (m-ToIyI) * 2- (3-pyridyl) -glyoxal, b.p. 160 ° / O, 0.5 Torr, starting from 28.0 g of m-xylyl (3-pyridyl) ketone and 16.0 g of selenium dioxide; 1- (p-Tolyl) -2- (3-pyridyl) -glyoxal, m.p. 38-40 °, starting from 42.0 g of p-xyIyI- (3-pyridyl) ketone and 24.0 g of selenium dioxide; 1- (m-Methoxyphenyl) -2- (3-pyridyl) -glyoxal, m.p. 48-50 °, starting from 4.9 g of m-methoxybenzyl (3-pyridyl) ketone and 2.6 g of selenium dioxide; 1- (p-Methoxyphenyl) -2- (4-pyridyl) -glyoxal, m.p. 64-65 °, starting of 4.9 g of p-methoxybenzyl- (4-pyridyl) ketone and 2.5 g of selenium dioxide.

c) 2-tert-butyl-4 (5) - (o-chlorophenyl) -5 (4) - (3-pyridyl) -imidazo!

The mixture of 9.83 g (0.04 mol) 1- (o-chlorophenyl) -2- (3-pyridyl) -glyoxal, 3.79 g (0.044 mol) of pivalaldehyde, 20 g of ammonium acetate and 100 ml of glacial acetic acid is refluxed for 24 hours and then poured into a mixture of 350 g of ice with vigorous stirring and poured 250 ml of concentrated aqueous ammonia solution. The crystal slurry is extracted with ethyl acetate, and the organic Phase washed neutral with saturated sodium chloride solution, dried with sodium sulfate and evaporated. The residue will be off Recrystallized toluene and dried in a high vacuum at 120 °. Man receives 2-tert-butyl-4- (5) - (o-chlorophenyl) -5- (4) - (3-pyridyl) -imidazole from m.p. 205-206 °.

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The following are produced in the same way:

2-tert-butyl-4 (5) - (p-chlorophenyl) -5 (4) - (3-pyridyl) -imidazole, Melting point 241-244 °, starting from 9.83 g of 1- (p-chlorophenyl) -2- (3-pyridyl) -glyoxal and 3.79 g of pivalaldehyde; 2-tert-butyl-4 (5) - (m-chlorophenyl) -5 (4) - (3-pyridyl) -imidazole, Mp. 170-174 °, starting from 9.83 g of 1- (m-chlorophenyl) -2- (3-pyridyl) -glyoxal and 3.79 g of pivalaldehyde; 2-'tert. Butyl-4 (5) - (o-tolyl) -5 (4) - (3-pyridyl) - imidazole, m.p.

215-217 °, starting from 9.0 g of 1- (o-tolyl) -2- (3-pyridyl) -glyoxal and 3.79 g of pivalaldehyde;

2-tert-butyl-4 (5) - (m-tolyl) -5 (4) - (3-pyridyl) -imidazole, m.p.

170 - 171 °, starting from 9.0 g of 1- (m-tolyl) -2- (3-pyridyl) -glyoxal and 3.79 g of pivalaldehyde;

2-tert-butyl-4 (5) - (p-tolyl) -5 (4) - (3-pyridyl) imidazole, m.p. 228 229 °, starting from 9.0 g of 1- (p-tolyl) -2- (3-pyridyl) -glyoxal and 3.79 g of pivalaldehyde;

2- (p-Chlorophenyl) -4 (5) - (m-tolyl) -5 (4) - (3-pyridyl) -imidazole, M.p. 182-183 °, starting from 10.1 g of 1- (m-tolyl) -2- (3-pyridyl) -glyoxal and 6.4 g of p-chlorobenzaldehyde; 2-tert-butyl-4 (5) - (m-methoxyphenyl) -5 (4) - (3-pyridyl) -imidazole, Mp. 151-152 °, starting from 10.0 g of 1- (m-methoxyphenyl) -2- (3-pyridyl) -glyoxal and 3.6 g pivalaldehyde; 2-tert-butyl-4 (5) - (p-methylthio-phenyl) -5 (4) - (3-pyridyl) -imidazole, Melting point 199-200 °, starting from 11.0 g of 1- (p-methylthiophenyl) -2- (3-pyridyl) -glyoxal and 3.64 g of pivalnaldehyde.

209847/1198

Example 3

2-tert-butyl-4 (5) -phenyl-5 (4) - (3-pyridyl) -imidazole The mixture of 14.0 g (0.0664 mol) l-phenyl-2- (3-pyridyl) - glyoxal, 5.76 g (0.067 mol) of pivalaldehyde, 42 g of ammonium acetate and 110 ml of glacial acetic acid are refluxed for 18 hours and then poured into a mixture of 350 g of ice with vigorous stirring. and poured 270 ml of concentrated aqueous ammonia solution. The crystal pulp is extracted with ethyl acetate and the organic phase washed neutral with saturated sodium chloride solution, dried with sodium sulfate and evaporated on a rotary evaporator. The residue is recrystallized from toluene and dried in a high vacuum at 120 °. 2-tert-Butyl-4 (5) -phenyl-5 (4) - (3-pyridyl) -imidazole is obtained as white crystals from Spm. 188-189 °.

The starting material is obtained as follows: a) Benzyl (3-pyridyl) ketone

The mixture of 27.4 g (0.2 mol) of methyl nicotinate and 30 g (0.2 mol) of methyl phenylacetate is mixed in portions with 16.2 g (0.3 mol) of sodium methylate at 20-25 ° under nitrogen. The reaction mixture is stirred for 20 hours at 60-70 °, the disfiguring alcohol being blown off with a weak nitrogen atom. Then 60 ml of kdnz. Hydrochloric acid was added dropwise to the solid mass and refluxed for 3 hours. The still hot yellow solution is mixed with 30 ml of water and cooled to 50 °. 60 ml of chloroform are then added and the reaction mixture is cooled to 5 °. The white crystals that form are filtered off with suction and washed with chloroform, m.p. 225 · <«..« th.no «. _47/119 g

b) l-phenyl-2- (3-pyridyl) glyoxal

23.4 g (0.1 mol) of benzyl (3-pyridyl) ketone hydrochloride. taken up in 180 ml of dimethyl sulfoxide and mixed with 20 ml of 487 _o iger
Hydrobromic acid crosslinked. The reaction mixture is stirred for 18 hours at 80-85 ° and then poured onto a mixture of 800 g of ice and 1000 ml of water. The yellow emulsion is extracted twice with 200 ml of ethyl acetate each time. The two organic
Phases are combined ^ washed with water and dried over sodium sulfate. The red solution is concentrated on a rotary evaporator until an oil remains, which is distilled in a bulb tube at 140-150 ° / 0.1 Torr. M.p. 56-57 °.

209 847/1 198

Example 4

2-tert-butyl-4 (5) - (p-methoxyphenyl) - 5 (4) - (4-pyridyl) - imidazo! The mixture of 3.7 g (0.015 mol) 1- (p-methoxyphenyl) ~ 2- (4-pyridyl) -glyoxal, 1.32 g (0.015 mol) pivalaldehyde, 12 g ammonium acetate and 40 ml glacial acetic acid is under for 13 hours Boiled under reflux and then poured into a mixture of 120 g of ice and 100 ml of concentrated aqueous ammonia solution with vigorous stirring. The crystal pulp is extracted with ethyl acetate and the organic phase washed neutral with saturated sodium chloride solution, dried with sodium sulfate and evaporated on a rotary evaporator. The residue is recrystallized from toluene and dried in a high vacuum at 120 °. 2-tert-Butyl-4 (5) - (p-methoxyphenyl) 5 (4) - (4_pyridyl) -imidazole is obtained as white crystals with a melting point of 258 ° -260 °

Analog is produced:

2-tert-butyl-4 (5) -phenyl-5 (4) - (4-pyridyl) -imidazole, m.p. 266-268 ° starting from 3.2 g of l-phenyl-2- (4-pyridyl) -glyoxal and 1.3 g of pivalaldehyde;

2- (p-Chlorophenyl) -4 (5) - (p-methoxyphenyl) -5 (4) - (4-pyridyl) - imid'azole Mp. 286-288 °, starting from 7.0 g of 1- (p-methoxyphenyl) -2- (4-pyridyl-glyoxal and 4.2 g of p-chlorobenzaldehyde.

209847/1 1 98

Example 5

2-tert. Rutyl-4 (5) - (p-methoxyphenyl) -5 (4) - (2-pyridyl) -imidazole

a) 1- (p-Methoxypheriyl) -2- (2-pyridyl) -glyoxal

30 g (0.142 mol) 2- (4'-methoxystyryl) pyridine are inert 34.5 g (0.31 mol) of selenium dioxide were added in portions for 30 minutes at 200 °. The reaction mixture is a further 30 Maintained for minutes at approx. 200 ° and then cooled to 50 °. The warm residue is dissolved in 250 ml of methylene chloride taken up and filtered through a chromatography column with 1000 g of silica gel. Yellow crystals, m.p. 97-98 °.

b) 2-tert-butyl-4 (5) - (p-methoxyphenyl) -5 (4) - (2-pyridyl) -imidazo l 7.2 g (0.03 mol) 1- (p-methoxyphenyl) - 2- (2-pyridyl) -glyoxal are refluxed for 18 hours together with 2.6 g (0.03 mol) of pivalaldehyde, 16 g of ammonium acetate and 70 ml of glacial acetic acid and then, with vigorous stirring, in a mixture of 220 g of ice and 190 Poured ml of concentrated ammonia solution. The crystal pulp is extracted with ethyl acetate and the organic phase washed neutral with saturated sodium chloride solution, dried with sodium sulfate and evaporated on a rotary evaporator. The residue is recrystallized from cyclohexane and dried in a high vacuum at 110 °. The 2-tert-butyl-4 (5) - (p-methoxyphenyl) -5 (4) - (2-pyridyl) imidazole is obtained as white crystals with a melting point of 139-140 °.

209847/1198

_ OQ _

Analog is produced:

2-Phenyl-4 (5) - (p-methoxyphenyl) -5 (4) - (2-pyridyl) -imidazo !, Mp. 207-208 °, starting from 2.5 g of the above diketone and 1.1 g of benzaldehyde;

2- (p-Chlorophenyl) -4 (5) - (p-methoxyphenyl) -5 (4) - (2-pyridyl) -imidazole, M.p. 219-220 °, starting from 6.0 g of the above diketone and 3.5 g of p-chlorobenzaldehyde;

2-tert-butyl-4 (5) -phenyl-5 (4) - (2-pyridyl) -imidazole, m.p. 162-164 °, starting from 12.0 g of l-phenyl-2 * (2-pyridyl) -glyoxal and 4.9 g Pivalaldehyde.

209847/1198

Example 6

2-tert. Butyl-4 (5) -phenyl-5 (4) - (3-pyridyl) -imidazo!

38.4 g (0.18 mol) of α-hydroxybenzyl-3-pyridyl ketone (prepared according to J. Chem. Soc. 1956 , 2913) are dissolved in 750 ml of methanol while warming. At 30 to 35 °, 36.6 g (0.18 mol) of copper (II) acetate monohydrate are added, followed by 17.2 g (0.20 mol) of pivalaldehyde. 375 ml conc. Aqueous ammonia solution are then added dropwise over the course of 10 minutes, then the solution is refluxed for 3 hours and filtered while hot. The copper salt of the desired imidazole obtained als'Nutschgut is washed twice with 50 ml of hot methanol each time and then suspended in 1000 ml of 80% ethanol. The ethanol suspension is saturated with hydrogen sulfide at 80 °. After 3 hours of stirring at 80 °, the hot suspension is suction filtered to remove the copper sulfide. The filtrate is evaporated, the residue is recrystallized from toluene and dried in a high vacuum at 120 °. The 2-tert-butyl-4 (5) -phenyl-5 (4) - (3-pyridyl) -imidazole obtained melts at 188-189 °.

209847/1198

Example 7

5.6 g (0.020 mol) of N- [α- (3-pyridyl-carbonyl) -benzyl] -pivalamide are refluxed for 14 hours with 13.1 g (0.17 mol) of ammonium acetate in 60 ml of glacial acetic acid. Then the brown one Solution to 120 ml conc. Poured ammonia and 120 g of ice and extracted with ethyl acetate. The organic phase is separated washed neutral with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue is crystallized from ethyl acetate, 2-tert-butyl-4 (5) -phenyl-5 (4) - (3-pyridyl) -imidazole of m.p. 188-189 °

209847/1198

Example 8

2-tert-butyl-4 (5) -phenyl-5 (4) - (2-pyridyl) -imidazole

To a solution of 6.90 g (0.025 mol) 2- (α-bromo-phenacyl) -pyridine (prepared according to B. Eistert and E. Endres, Ann 734 , 56-69 (1970) in 40 ml of chloroform are 10 g (0.03 mol) of pivalamidine hydrochloride in 15 ml of water. With vigorous stirring and introduction of nitrogen, the emulsion is at 15 -

20.degree. With the solution of 2.9 g (0.06 mol) of potassium hydroxide in 15 ml of water, added dropwise, and the mixture was refluxed for 4.5 hours and poured into a separating funnel while still hot. The lower organic phase is separated off with 2N sodium carbonate solution and saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue will recrystallized from toluene and dried in a high vacuum at 120 °, the 2-tert-butyl-4 (5) -phenyl-5 (4) - (2-pyridyl) -imidazole of m.p. 162-164 ° is obtained.

Analogously one obtains:

2-tert-butyl-4 (5) -phenyl-5 (4) - (3-pyridyl) -imidazole, m.p. 188-189 °, starting from 6.9 g of 3- (α-bromo-phenacyl) -pyridine and 4.1 g of pivalamidine hydrochloride.

209847/1 198

Example 9

a) (α-Hydroximino-benzyl) - (3-pyridyl) -ketone

9.8 g (0.05 mol) of benzyl (3-pyridyl) ketone are dissolved in 250 ml of ethanol and 88 ml of 2n. Dissolved hydrochloric acid. At 20 25 ° a solution of 7.0 g of sodium nitrite in 100 ml of water is added dropwise within 20 minutes. The reaction mixture is stirred for 15 hours at 20-25 ° and then Made alkaline with 2N sodium hydrogen carbonate solution. After adding 1000 ml of water, it is suction filtered. The suction product is recrystallized from alcohol. 169-172 °.

Analogously one obtains:

(a-Hydroximino-p-methoxybenzyl) - (3-pyridyl) -ketone, Mp. 183-186 °, starting from 11.3 g of p-methoxybenzyl) - (3-pyridyl) ketone.

b) 2-tert-Butyl-A-phenyl-S- (3-pyridyl) -imidazole-3-oxide The mixture of 11.3 g (0.05 mol) (α-hydroximino-benzyl) - (3-pyridyl ) ketone, m.p. 169-172 °, 5.3 g (0.05 mol) of pivalaldehyde, 10 g of ammonium acetate and 50 ml of glacial acetic acid is refluxed for 3 hours. The still hot solution is poured onto ice and made with conc. aqueous ammonia solution made alkaline. The crystal pulp is extracted with ethyl acetate. After washing until neutral and drying over sodium sulfate, the organic phase is evaporated. The residue is recrystallized from ethyl acetate and dried in a high vacuum at 150 °. M.p. 247-248 °.

209847/1198

You get analog

2-tert. Butyl-4- {p-methoxyphenyl} -5- (3-pyridyl) -imidazole-3-oxide, M.p. 245-247 °, starting from 12.8 g (a-hydroximino-p-methoxybenzyl) - (3-pyridyl) ketone.

c) 2-tert-Butyl-A- (5) -phenyl-5 (4) - (3-pyridyl) -imeaazole A solution of 5.0 g of 2-tert-butyl-A-phenyl-S- (3- pyridyl) imidazole-3-oxide in 30 ml of chloroform is added dropwise with 6.5 ml of phosphorus trichloride while cooling with ice and then stirred for 2 hours at 100 °. After cooling, the reaction mixture is mixed with 20 ml of water and diluted with. Ammonia adjusted to pH 7.5. The mixture is extracted with ethyl acetate. The ethyl acetate solution is washed in saturated sodium chloride solution, dried over sodium sulfate and evaporated under 11 torr. The residue is crystallized from toluene. The 2-tert-butyl-4 (5) -phenyl-5 (4) - (3-pyridyl) - imidazoI melts at 188-189 ° after drying in a high vacuum at 120 °.

Analogously one obtains

2-tert-butyl-4- (p-methoxyphenyl) -5- (3-pyridyl) -imidazole, Mp. 202-204 °, starting from 2-tert-butyl-4- (p-methoxyphenyl) -5- (3-pyridyl) -imidazole-3-oxide.

209847/1198

Example 10

a) Benzyl-ί3- (pyridyl-1-oxide)) ketone

A mixture of 31.2 g of ethyl nicotinate N-oxide (0.19 mol) ₁ UHd of 31 ml of phenylacetic acid ethyl ester (0.195 mol) is added in portions under nitrogen with 15.8 g of sodium methylate (0.291 mol). The mixture is stirred for 1 hour at 20 ° and then for 20 hours at 60-70 °, the alcohol formed being removed by the nitrogen introduced. The mixture is cooled to room temperature, with 60 ml of conc. Hydrochloric acid was added and the mixture was refluxed for 3 hours. It is then cooled to room temperature, 40 ml of water are added, the dark solution is extracted twice with 50 ml of chloroform each time and adjusted to pH 5 with dilute ammonia and ice. Add sodium carbonate solution to an alkaline reaction and extract the aqueous solution with ethyl acetate. The ethyl acetate solution is washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated under 11 torr at 40 °. The benzyl-13- (pyridyl-1-oxide)] - ketone melts at 123 - 125 °.

b) l-phenyl-2-f3- (pyridyl-l-oxide)] - glyoxal

A mixture of 8.2 g of benzyl [3- (pyridyl-1-oxide)] ketone (0.0385 mol) 5.0 g of selenium dioxide and 50 ml of glacial acetic acid is refluxed for 6 hours, filtered hot and mixed with 500 ml of water. The mixture is made with ethyl acetate extracted, the iithylacetatlösung with saturated

209847/1198

Washed sodium chloride solution, dried over sodium sulfate and evaporated under 11 torr at 40 °. The l-benzyl-2- [3- (pyridyl-1-oxide)! - glyoxal is available as OeI.

c) 2-tert-butyl-4 (5) -phenyl-5 (4) - [3- (pyridyl-l-oxide)] - imidazole A mixture of 9.5 g of l-phenyl-2- [3- ( pyridyl-1-oxide)] - glyoxal (0.042 mol), 4.6 ml of pivalaldehyde, 20.0 g of ammonium acetate and 150 ml of glacial acetic acid is refluxed for 5 hours, then cooled and concentrated in a mixture of 300 g of ice and ml. poured aqueous ammonia solution. The mixture is extracted with ethyl acetate and the ethyl acetate solution is washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated under 11 torr, the 2-tert-butyl-4 (5) -phenyl-5 (4) - [3-pyridyl -1-oxide)] - imidazole.

d) 2-tert-Butyl-4 (5) -phenyl-5 (4) - (3-pyridyl) -imidazole Analogously to Example 9c, 2-tert-butyl-4 (5) -phenyl-5 (4) is obtained - (3-pyridyl) -imidazole, m.p. 188-189 °, starting from 2-tert-butyl-4 (5) -phenyl-5 (4) - [3- (pyridyl-1-oxide)) - imidazole.

2 0 9 8 4 7/1198

Example .11

A solution of 27.8 g (0.10 mol) of 2-tert-butyl-4 (5) -phenyl-5 (4) - (3-pyridyl) -imidazole in 900 ml of acetone is at'20 τ 25 ^ό with 9.61 g (6.5 ml, 0.10 mol) of methanesulfonic acid crosslinked and then stirred for about 15 hours. The white crystals are sucked off. After crystallization from ethariol-ether, the 3-tert-butyl-4 (5) -phenyl-5 (4) - (3-pyridyl) -imidazole methanesulfonate obtained melts at 238-240 °.

■ 209 847/1 198

Example 12

a) Phenyl- (pyraztnyl-2-methyl) ketone "

To one of 9.2 g sodium (0.4 MpI), 0.1 g ferric chloride and 300 ml of liquid ammonia produced sodium amide solution are 37.6 g of .2-methylpyrazine (0.4 mol) for 20 minutes -40 ° added dropwise. The red solution is stirred for 2 hours at -40 °. A solution of 27.2 g of methyl benzoate is then added (0.2 mol) in 30 ml of abs. Ether within 20 minutes at τ40 ° added dropwise. The mixture is stirred for one hour at -40 ° and then in portions with 25.0 g of ammonium chloride and 250 ml abs. Ether is added, the ammonia is evaporated at -20 °, after 2 hours another 150 ml of abs. ether can be added. After stirring for 1 hour at room temperature The phenyl (pyrazinyl-2-methyl) ketone crystallizes out of the ethereal solution. Recrystallized from ethanol makes dirt the ketone at 97-100 °.

The following is obtained analogously:

p-Methoxyphenyl (pyrazinyl-2-methyl) ketone, m.p. 77-85 °, starting from 27.6 g of 2-methylpyrazine and 34.2 g of methyl anisate.

b) 1-phenyl-2- (2-pyrazinyl) glyoxal

A mixture of 7.2 g of phenyl (pyrazinyl-2-methyl) ketone, 6 * 1 g Selenium dioxide and 80 ml abs. Dioxane is refluxed for 6 hours and then filtered. The suction product is washed well with dioxane and the combined filtrates under

209847/1198 '

Evaporated 11 torr. The residue, an oil, is dissolved in 100 ml of chloroform. The chloroform solution is shaken with Florosil and filtered off. The filtrate is concentrated below 11 torr. The residue is distilled in a bulb tube. The l-phenyl-2 ~ (2-pyrazinyl) -glyoxal boils at 170-180 ⁰ ZO ₅ OS Torr,

The following is obtained analogously:

1- (p-Methoxyphenyl) -2- (2-pyrazinyl) -glyoxal, b.p. 190-210 ° / 0.001 Torr starting from 10.0 g of p-methoxyphenyl (pyrazinyl-2-methyl) ketone. . ■ -.

c) 2-tert ♦ Butyl-4 (5) - (2-pyrazinyl) -5 (4) -phenyl-imidazole A mixture of 4.7 g of l-phenyl-2- (2-pyrazinyl) -glyoxal, 2, 9 ml of pivalaldehyde, 15.0 g of ammonium acetate and 50 ml of glacial acetic acid are heated to boiling under reflux for 2 hours and then poured into a mixture of 170 g of ice and 120 ml of conc. poured aqueous ammonia solution. The precipitated crystal slurry is extracted with ethyl acetate. The ethyl acetate extract is washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated under 11 torr at 40 °. The residue is crystallized from toluene. That. 2-tert-Butyl-4 (5) - (2-pyrazinyl) -5 (4) -phenyl-imidazole melts at 153-156 °.

The following is obtained analogously:

2-tert-butyl-4 (5) - (2-pyrazinyl) -5 (4) - (p-methoxyphenyl) imidazole, Mp. 161-163 °, starting from 6.5 g of 1- (p-methoxyphenyl) -2- (2-pyrazinyl) -glyoxal.

209847/1198

Example 13

a) (p-Methylthiobenzyl) - (3-pyridyl) ketone

A mixture of 14.6 g of ethyl nicotinate and 19.5 g p-Methylthiophenylacetic acid ethyl ester is introduced with introduction 9 Ag sodium methylate were added in portions of nitrogen. The mixture is stirred for one hour at 20 ° and then for four hours at 65 °. 40 ml are then added conc. Hydrochloric acid is added and the suspension is heated to boiling under reflux for 7 hours, cools, 40 ml of water are added and extracted with ethyl acetate. The ethyl acetate solution is extracted with 2N hydrochloric acid, the hydrochloric acid extract with 2N sodium carbonate solution made alkaline, the suspension extracted with ethyl acetate and the ethyl acetate solution with saturated Washed sodium chloride solution, dried over sodium sulfate and evaporated under 11 torr. The residue crystallizes one from ethyl acetate-petroleum ether. The (p-methylthiobenzyl) - (3-pyridyl) ketone melts at 125 - 127 °.

b) (p-Methylsulfonylbenzyl) - (3-pyridyl) ketone

A mixture of 5.0 g of (p-methylthiobenzyl) - (3-pyridyl) ketone, 10 ml of 30% hydrogen peroxide and 100 ml of glacial acetic acid is used

Stirred for 10 hours at room temperature and then poured onto 4000 ml of ice. The mixture is extracted with ethyl acetate, the ethyl acetate solution with saturated sodium chloride solution washed, dried over sodium sulfate and under

Evaporated 11 torr at 40 °. The residue is crystallized from ethanol. The (p-methylsulfonylbenzyl) - (3-pyridyl) ketone melts at 146-148 °. . ". ,. ,. q «

^c ) 1- (p-Methylsulfonyjphenyl) -2- (3-pyridyl) -glyoxal

The mixture of 27.0 g (p-methylsulfonyl-benzyl) -3-pyridyl) ketone, 11.1 g of selenium dioxide and 500 ml of glacial acetic acid are refluxed for 8 hours and filtered through Hyflo. The filtrate is diluted with 3000 ml of water and adjusted to pH 6-7 with ammonia, then extracted with ethyl acetate, washes the ethyl acetate solution with saturated sodium chloride solution, dry them over sodium sulfate and concentrate them below 11 torr at 40 °. The yellow crystalline residue is crystallized from toluene. 1- (p-Methylsulfonylphenyl) -2- (3-pyridyl) -glyoxal melts at 160 - 170 °.

d) 2- tert. Butyl-4 (5) - (p-methylsulfonylphenyl) -5 (4) - (3-pyridyl) imidazole

A mixture of 9.0 g of 1- (p-methylsulfonyi-phenyl) -2- (3-pyridyl) glyoxal, 3.5 ml of pivalaldehyde, 20.0 g of ammonium acetate and 200 liters of glacial acetic acid is refluxed for 5 hours heated and then concentrated in a mixture of 300 ml ice and 200 ml. poured aqueous ammonia solution. The suspension is extracted with ethyl acetate. The ethyl acetate solution is then washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated under 11 torr. The residue is chromatographed on 200 g of silica gel. Fractions 5 and 6, each eluted with 250 ml of ethyl acetate, contain 2-tert-butyl-4 (5) - (p-methylsulfonylphenyl) -5 (4) - (3-pyridyl) -imidazole. Snip. 120 - 125 ° (from toluene).

2098A7 / 1198

Claims (2)

Patent claims: I ^ Process for the preparation of new imidazole derivatives the general formula ^ ⁵ LJLJi ^x (D in which R is Nxederalkyl , cycloalkyl or a phenyl optionally substituted by halogen, Nxederalkyl or lower alkoxy, and one of the groups R and R optionally substituted by halogen, Nxederalkyl, hydroxy, lower alkoxy, lower alkylthio or Nxederalkylsulfonyl and the other a six-membered, heteroaromatic radical with 1 or represents 2 ring nitrogen atoms, so / ie N-oxides thereof and salts of such compounds, characterized in that one a) a substituted diketone of the general formula R ₂ -C = 0 R "C = 0 (II), a corresponding mono-oxime or N-oxide, with ammonia and an aldehyde of the general formula R ₁ -CHO (III), or 209847/1 198 b) an amide of the general formula ₀ - CO CO IL 2 ι ι 1 (V) , CH IiH treated with Ämmonailc, or c) a reactive ester of a-Hydroxyke.tons der general formula R ₂ -CO R "CHOH with an amidine of the general formula ₁ (VI) HW or a salt thereof, or d) an oxazole of the general formula R, (VII) 209847/1198 Reacts with ammonia, and, if desired, a obtained Compound into an N-oxide or a obtained N-oxide into the free. Compound converted, and / or, if desired, a compound obtained into a salt or a salt obtained converts into the free connection. 2. A process for the preparation of new imidazole derivatives of the general formula I given in claim 1, wherein R _{1 is} an alkyl or cycloalkyl group having a maximum of 6 carbon atoms or a phenyl radical optionally monosubstituted by fluorine, chlorine or bromine, methyl, ethyl, methoxy or ethoxy, a of the groups R- and R is a phenyl radical which is optionally monosubstituted by chlorine, methyl, hydroxy, methoxy, ethoxy, methylthio, ethylthio, methylsulfonyl, or ethylsulfonyl and the other is pyridyl or pyrazinyl, and acid addition salts of these compounds, characterized in that one a) a substituted diketone of the general formula II according to Claim 1, wherein R and R are as defined above have, with ammonia and an aldehyde of the general formula R-CHO (III), where R. has the meaning given above has implemented, or. ν 0 8 P / * 7/1 1 9 ~ ⁴⁵ ~ 222 VU B ί>) an amide of the general formula V according to claim I, ' ¹ W rin R., R _? and R has the meaning given above -has treated with ammonia, or c) a reactive ester of a-hydroxy-hydroxyke t'Qris # 6ir general formula Iia according to claim h, where R ^ uW <l R ^ have the meaning given above, with elima AiiiÜiti fet general formula VI according to claim ■!.> itfötift Ri has the meaning given, odet ei * iein or an Öxääöi of the general formula VlI ggmäsfe Äiisprueh R ^, R ₂ and R ^ converts the Ö'e'deütuhg given above with ammonia, or e) an iJ-ÖJi ^ d of a connection iöir f © fmil f> Μ & έΙή ilnöi R ^ the meanings given above. have> jeeäuäi and, if desired, »an erjiaitenö verbiiidurig in a Sau 3e # ädditiöhsöälä2 . A method according to claim 1, characterized one egg "öubstituiertäs DiKetön the form of oil it, AIN ent-speaking HONO oxime barren N-oxide with Aitimöniälc UNAE an Al dehyde of the formula R-Choe (iii) reacting, wherein ifiäh the" Ärrcnemiä as Ämmoniumsaiz a organic carboxylic acid or as eär bonsäureamid is used. 2 ο s s A 7/1 iit 2221548 4. The method according to claim 1, characterized in that there is a substituted diketone of the formula II in the form
an α-hydroxy ketone of the formula j (Ha) _E CH-OH or a mono-oxime thereof in the presence of an oxidizing agent customary for its conversion into the diketone of the formula II: begins. 5. The method according to claim 1, characterized in that an amide of the general formula V is treated with ammonia, the wan as the ammonium salt of an organic carboxylic acid or used as a carboxamide. 6. * The method according to claim 1, characterized in that the reactive ester of an α-hydroxyketone
of the formula Ha uses an ester with a hydrochloric acid or with an organic sulfonic acid. 7. The method according to claim 1, characterized in that a gxazole of the formula VII is reacted with ammonia, deri is used in the form of formamide. 209847/1198 - 47 - 22215A6 8 .. ... '■ "■ method according to claim 1, characterized in that that one can obtain an N-oxide by treating a compound obtained of formula I with hydrogen peroxide or a peracid manufactures. 9- method according to claim 1, characterized in, that one obtained N-oxide by treating with catalytic activated hydrogen or with a chemical reducing agent treated. ,. 10. The method according to claim 2, characterized in that a substituted diketone of the formula II, wherein R " and R have the meaning given there, with ammonia and an aldehyde of the formula R CHO (III), where R is there given meaning has converted, whereby the ammonia is used as the ammonium salt of an organic carboxylic acid or as a carboxamide begins. 11. The method according to claim 2, characterized in that that you have a substituted diketone of the formula II in the form of an oc-hydroxy ketone of the formula C = O (Ha) CH-OII 209847/1198 wherein R and R have the meaning given there, and an oxidizing agent commonly used to convert it into the diketone of the formula II. 12. The method according to claim 2, characterized in that an amide of the general formula V, wherein R ₁ , R and R "have the meaning given there, treated with ammonia, which is used as the ammonium salt of an organic carboxylic acid or as a carboxamide. 13. The method according to claim 2, characterized in that that one as a reactive ester of a ct-hydroxyketone of the formula Ha uses an ester with a hydrohalic acid or with an organic sulfonic acid. 14. The method according to claim 2, characterized in that an oxazole of the formula VII with ammonia in the form of Formamide uses. 15. The method according to claim 2, characterized in that the N-oxide of a compound of formula I, wherein R ,, R and R have the meaning given there, with hydrogen, Lithium aluminum hydride, phosphorus trichloride or sodium dithionite. 16. The method according to any one of claims 1 and 3-9, characterized in that a 'on' some level as (., fr Compound formed intermediate as starting material 209 847/1 1.9.8, is used and the remaining stage (s) with this is carried out (be), or the procedure on any Level is interrupted * 17. The method according to any one of claims 1, 3-B and 16 , characterized in that starting materials are formed under the reaction conditions or used in the form of salts or reactive derivatives * 18. The method according to any one of claims 1, 2 * »9 _t 16 and 17, characterized in that compounds of the formula I or acid addition salts thereof are prepared where ^ · rin R-isopropyl, sec-butyl, tert-butyl, Cyelopropyl, phenyl or pr-chlorophenyl and one of the groups iu and SL is a pheny group optionally substituted by chlorine, methoxy or methyl and the other is a « 19 * Method according to one of claims 2 and characterized in that 2 ~ (p-chlorophenyl) -4 (5) - (p-methoxyphenyl) -5 (4) - (2-pyridyl) imidaz oil, or making acid addition salts thereof " 20. The method according to one of claims 2 vtüa, characterized in that 2-tert * ~ butyl-4 £ 5) -phenyl-5 (4) - (3-pytidyli-imidazöl or acid addition salts thereof are prepared * 2098-47 / 119 » 2221548 21. The method according to any one of claims 2 and 10-15, characterized in that 2-tert-butyl-4 (5) - (p ~ methoxyphenyl) -5 (4) - (3-pyridyl) -imidazole or acid addition salts manufactures from it. 22. The method according to any one of claims 2 and 10-15, characterized in that 2-tert-butyl-4 (5) - (pmethoxyphenyl) -5 (4) - (4-pyridyl) imidazole or an acid addition salt thereof. 23. A method according _t one of claims 2 and 10-15, characterized in that 2-tert-butyl-4 (5) -phenyl-5 (4) - produces (4-pyridyl) -imidazole or an acid addition salt thereof. 24. The method according to any one of claims 2 and 10-15, characterized in that 2- (p-chlorophenyl) -4 (5) - (p-methoxyphenyl) -5 (4) - (3-pyridyl) -imidazole or an acid addition salt thereof * 25. The method according to any one of claims 2 and 10-15, characterized in that 2- (p-chlorophenyl) -4 (5) - (pmethoxyphenyl-5 (4) ~ (4-pyridyl) imidazole or makes an acid addition salt thereof * 26. The method according to any one of claims 2 and 10-15, characterized in that 2 ~ tört.-ButyI-4 209847/1138 methylphenyl) -5 (4) - (3-pyridyl) -imidazo! or an acid addition salt manufactures from it. 27. The method according to any one of claims 2 and 10-15, characterized in that 2- (p-chlorophenyl) -4 (5) -phenyl-5 (4) - (3-pyridyl) -imidazole or an acid addition salt thereof. 28. The procedure described in Examples 1-13, 29. The one of claims 1> 3—9 and 16-18 available connections. . - '· 30. The compounds obtainable according to one of claims 2, 10-15 and 19 ^ 28 ^v. 31. Compounds of the general formula ■ (D, in which R is lower alkyl, cycloalkyl or, optionally, one substituted by halogen, lower alkyl or lower alkoxy 2 0 9 8 4 7/1198 tuted phenyl, and one of the groups R and R optionally phenyl substituted by halogen, lower alkyl, hydroxy, lower alkoxy, lower alkylthio or lower alkylsulfonyl and the other is a six-membered, heteroaromatic radical having 1 or 2 ring nitrogen atoms, as well as N-oxides thereof and salts of such compounds. 32. Compounds of the general formula I given in claim 31, wherein R is an alkyl or cycloalkyl group with a maximum of 6 carbon atoms or optionally with fluorine, chlorine or bromine, methyl, ethyl, methoxy or ethoxy monosubstituted phenyl radical, one of the groups R and R is optionally substituted by chlorine, methyl, hydroxy, Methoxy, ethoxy, methylthio, ethylthio, methylsulfonyl or ethylsulfonyl monosubstituted phenyl radical and the other is pyridyl or pyrazinyl, as well as acid addition salts of these connections. 33. Compounds of the formula I according to claim 31, wherein R _{1 is} isopropyl, sec-butyl, tert-butyl, cyclopropyl, phenyl or p-chlorophenyl, one of the groups R ₂ and R is a phenyl group optionally monosubstituted by chlorine, methyl or methoxy , the other is a pyridyl group, and acid addition salts of these compounds. 34. 2-I.sopropyl-4 (5) - (p-methoxyphenyl) -5 (4) -3-pyridylimidazole. 209847/1198 35. 2-tert -Butyl-4 (5) - (o -chlorophenyl) -5 (4) - (3-pyridyl) -imidazole. 36. 2- (p-chloropheny 1) -4 (5) - (p-methoxyphenyl) -5 (4); - (3-pyridyl) -imidazole. 37. 2-tert-butyl-4 (5) - (p-chlorophenyl) -5 (4) - (3-pyridyl) -imidazole. 38. 2- (p-Chlorophenyl) -4 (5) -phenyl-5 (4> - (3-pyridyl) imidazole. 39.. 2-tert-butyl-4 (5) - (m-chlorophenyl) -5 (4) - t3 dyl) -iini 40. 2-tert-Butyl-4 (5) - (o-tolyl) -5 (4) - (3-pyridyl) imidazole. 41. 2-tert -Butyl-4 (5) - (m-tolyl) -5 (4) - (3-pyridyl) -imidazole. 42. 2-tert -Butyl-4 (5) - (p-tolyl) -5 (4) - (3-pyridyl) imidazole. 43. 2- (p-Chlorophenyl) -4 (5) - (m-tolyl) -5 (4) - (3-pyridyl) imidazole. 20 9847/119 44. 2-tert -Butyl-4 (5) - (m-methoxyphenyl) -5 (4) - (3-pyridyl) -imidazole. 45. 2-tert-Buty 1-4 (5) - (p-methylthio-phenyl) -5 (4) - (3-pyridyl) -imidazole. 46. 2-tert-butyl-4 (5) -phenyl-5 (4) - (3-pyridyl) -imidazole, 47. 2-tert i-Buty 1-4 (5) - (p-methoxyphenyl) -5 (4) - (4-pyridyl) imidazole. 48. 2-tert-Butyl-4 (5} -phenyl-5 (4) - (4-pyridyl) -imidazole. 49. 2- (p-Chlorophenyl) -4 (5) - (p-methoxyphenyl) -5 (4) - (4-pyrIdyl) -imidazole. 50. 2-tert -Butyl-4 (5) - (p-methoxyphenyl) -5 (4) - (2-pyridyl) -imidazole. 51. 2-Phenyl-4 (5) - (p-methoxyphenyl) -5 (4) - (2-pyridyl) -imidazole. 52. 2- (p-Chlorophenyl) -4 (5) - (p-methoxyphenyl) -5 (4) - (2-pyridyl) -imidazole. 209847/1198 2221548 53.. 2-tert-butyl-4. (5) -phenyl-5 (4) - (2-pyridyl) -imida 54 »2-tert-Butyl-4 (5) - (2-pyrazinyl) -5 (4) -phenyl-imidazole. 55 ..., 2-tert-butyl-4 (5) - (2-pyrazinyl) -5 (4) - (p-methoxyphenyl) imidazole. 56. 2-tert -Butyl-4 (5) - (p-iaethylsulfonylphenyl) -5 (4) - (3-pyridyl) iridazole. 57. 2-tert-butyl ~ 4-pheny1-5- (3-pyridyl) -imidazole-3-oxide. 58. 2-tert-Butyl-4- (p-methoxyphenyl) -5- (3-pyridyl) -imidazole-3-oxide. 59. 2-tert-Butyl-4 (5) -phenyl-5 (4) - [3- (pyridyl-1-oxide] -imidazole. 60. Acid addition salts of compounds of the claims 34-56. 61. Pharmaceutically acceptable acid addition salts of Compounds of claims 31 and 33. 209847/1198 62. Pharmaceutically usable acid addition salts of the compounds of claims 32 and 34-59. 63. Pharmaceutical preparations, characterized by a content of one of the claims 31, 33 and 61 connections shown. 64. Pharmaceutical preparations, characterized by a content of one of the claims 32, 34-59 and 62 connections shown. FO 3.34 / JZEyWlO ^. 1972 2 0 9 8 A 7/1 1 9 8