KR790001254B1 - Process for preparing imizole - Google Patents

Abstract

Imidazole derivs. (I; R1,R2 = one is hydrogen or lower alkyl group, the other is nitro, R3 = lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl, lower alkylsulfonyl lower alkyl, amino lower alkyl, R4 = oxo, thioxo, X = carbonyl, thiocarbonyl, sulfinyl, sulfonyl, R5 = lower alkoxy, amino, lower alkylamino, loweralkyl, aryl, ALK = C1-2 lower alkylene) were prepd. Compd. II(R1',R2' = one is hydrogen, lower alkyl, the other is hydrogen, R3,R4,R5,X, ALK are given) was nitrogenated by acid treatment in dinitrogentetroxide solvent to give I.

Description

Method for preparing imidazole derivative

The present invention relates to a method for preparing an imidazole derivative of the following formula (I), which is effective as a chemotherapeutic agent.

In the above structural formula,

_One of R ₁ and R ₂ is hydrogen or lower alkyl, the other is a nitro group,

R ₃ is lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl, lower alkylsulfonyl lower alkyl or amino lower alkyl,

R ₄ is oxo or thioxo,

X is carbonyl, thiocarbonyl, sulfinyl or sulfonyl,

R5 is lower alkoxy, amino, lower alkylamino or dialkylalkylamino when X is carbonyl, and R5 is lower alkyl, aryl, amino, alkylamino or dialkylalkylamino when X is thiocarbonyl, sulfinyl, sulfonyl Indicates

Alk represents a lower alkylene group.

"Lower" herein means containing up to seven carbon atoms, with up to four carbon atoms being preferred.

Suitable examples of lower alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, iso- Hexyl or n-heptyl.

The hydroxy lower alkyl group contains up to 7 carbon atoms, in particular up to 4 carbon atoms, the lower alkyl moiety as described above, for example hydroxymethyl, 3-hydroxy-n-propyl Especially 2-hydroxyethyl.

Lower alcohol lower alkyl groups are groups having up to 7 carbon atoms, in particular up to 4 carbon atoms, for example methoxymethyl, ethoxymethyl, n-propoxymethyl, n-butoxymethyl, -(n-butoxy) -ethyl, 3- (n-propoxy) -propyl, especially 2-methoxyethyl.

Examples of lower alkyl sulfonyl lower alkyl include methylsulfonylmethyl, ethylsulfonylethyl, 2-methylsulfonylethyl, n-propylsulfonylmethyl, 2-n-propylsulfonylethyl, 3-n-propylsulfonyl lower alkyl groups having lower alkylsulfonyl groups such as -n-propyl and ethylsulfonylethyl (particularly 2-ethylsulfonylethyl).

Amino lower alkyl is the aforementioned lower alkyl having an amino group, in particular a tertiary amino group. As the tertiary amino group, a lower alkylamino such as dimethylamino, N-methyl-ethylamino, diethylamino, di-N-propylamino or di-N-butylamino, or a lower alkylene moiety is an oxa lower alkylene. Amino, thia lower alkylene amino or aza lower alkylene amino (pyrrolidino, piperidino, morpholino, thiomorpholino, 2, 6-dimethylthiomorpholino, piperazino, N'-methylpy) Ferrazino, lower alkyleneamino, which is N '-(β-hydroxyethyl) -piperazino). Examples of amino lower alkyl include dimethylaminomethyl, diethylaminomethyl, 2-dimethylaminoethyl, pyrrolidinomethyl, 2-pyrrolidinoethyl, 3-pyrrolidino-n-propyl, piperidinomethyl, mor Polyno-methyl, 2-morpholino-ethyl, 2-thiomorpholino-ethyl, piperazino-methyl, 2-piperazino-ethyl, N'-methyl-piperazino-methyl, 3- ( N-methylpiperazino) -n-propyl, N- (β-hydroxyethyl) -piperazino-methyl.

The aryl group R5 is an optionally substituted aryl group, for example, an optionally substituted 5, 6, 7, 8-tetrahydro-1- or 2-naphthyl group as well as a phenyl or naphthyl group optionally substituted with one or more substituents. have. Preferred are any mono- or di-substituted phenyl or naphthyl groups, in particular mono-substituted phenyl or naphthyl groups, with mono-substituted phenyl groups being most preferred.

The aryl group R ₅ may be substituted with the above-mentioned lower alkyl group, lower alkoxy group or halogen atom such as chlorine, fluorine or bromine, or may be substituted with trifluoromethyl group.

Examples of lower alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butyloxy or n-pentyloxy groups, and lower alkylamino groups include methylamino, ethylamino and lower alkyl Amino includes dimethylamino, diethylamino or ethylmethylamino.

Lower alkylenes are branched or straight chain lower alkylenes (preferably straight chains) of 1, 2-propylene, 1, 2-butylene, 1, 2-pentylene, 1, 2 having 2 to 4 carbon atoms in the alkylene group -Hexylene, 2-methyl, 1, 2-propylene, 2, 3-butylene, 1, 3-butylene, 1, 3-propylene, 1, 4-butylene, with 1, 2-ethylene being particularly preferred Do.

The imidazole derivatives of formula (I) prepared according to the invention have effective pharmaceutical properties. Especially for bacteria (especially Gram-negative bacteria) or protozoa (e.g. trichomonas), amoeba, helmins (larvae such as skistosomes), for example, hamsters infected with Entamoeba histolytica (e.g. hamsters) show activity as shown by oral administration of 10 to 100 mg / kg of liver. These compounds are also useful as starting materials or intermediates in the manufacture of other chemotherapeutic agents.

In particular, the compounds according to the invention relate to compounds of the formula (Ia) and their acid addition salts.

In the above structural formula

R ₁ is hydrogen or a lower alkyl group,

R ₄ is oxo group,

X, R ₃ and R ₅ are as defined in the formula (I), and Alk represents a lower alkylene group having 2 to 4 carbon atoms. The present invention further relates to compounds of the following structural formula (Ib) and acid addition salts thereof.

In the above structural formula

R ₂ is hydrogen or lower alkyl group,

R ₄ is oxo group,

X, R ₃ and R ₅ are as defined in the above formula (I),

Alk represents a lower alkylene group having 2 to 4 carbon atoms.

In particular, in the compound of formula (Ia), R ₁ , R ₃ , R ₄ , and R ₅ , Alk are the same as in formula (Ia), and X represents a carbonyl group and R ₂ , R _{3 in the} compound of formula (Ib). Of note are compounds in which R ₄ , R ₅ , and Alk are the same as in formula (Ib), wherein X is a carbonyl group.

Of the compounds of formula (Ia) and (Ib), R ₁ or R ₂ , R ₃ , R ₄ , R ₅ , and Alk are the same as above, and compounds in which X is thiocarbonyl and their acid addition salts also attract special attention. Compound.

Further, among the compounds of formulas (Ia) and (Ib), R ₁ or R ₂ , R ₃ , R ₄ , R ₅ , and Alk are the same as above, and X is a sulfinyl or sulfonyl group and acid addition salts thereof Is of particular interest.

Of particular interest among the compounds according to the invention are those wherein R ₁ or R ₂ and R ₅ in the compounds of formulas (Ia) and (Ib) are the same as in formulas (Ia) and (Ib) and R ₃ is methyl, ethyl or Lower alkyl such as hydroxy lower alkyl (β-hydroxymethyl or β-hydroxypropyl), A is 1, 2-ethylene, X is a carbonyl group, R ₄ is an oxo group and acid addition salts thereof .

In the compounds of formulas (Ia) and (Ib), X represents a thiocarbonyl, sulfinyl or sulfinyl group, R ₁ or R ₂ and R ₅ are the same as in (Ia), and R ₃ is the same as methyl or ethyl. Lower alkyl group or lower hydroxyalkyl such as β-hydroxyethyl or β-hydroxypropyl, A is 1, 2-ethylene, R4 is oxo group, and their acid addition salts are also of interest It is a target.

Of these nitroimidazole compounds in particular 1- (methylsulfonyl) -2-oxo-3- [1-methyl-5-nitro-imidazolyl (2)]-tetrahydro imidazole, 1-N, N-di Ethylcarbamoyl-2-oxo-3- [1-methyl-5-nitro-imidazolyl (2)]-tetrahydroimidazole and 1-N, N-dimethylcarbamoyl-2-oxo-3- [1 -Methyl-5-nitro-imidazolyl- (2)]-tetrahydroimidazole, 1-N-ethylthiocarbamoyl-2-oxo-3- [1-methyl-5-nitro-imidazole-2] Tetrahydroimidazole, 1-N-methylthiocarbamoyl-2-oxo-3- [1-methyl-5-nitroimidazol-2] -tetrahydroimidazole is hamsters infected with entameva histolytica It is effective for the treatment of tumor of liver.

The imidazole derivatives of formula (I) according to the invention are prepared by nitrating the compounds of formula (II).

In the above structural formula

One of R ₁ ′ and R ₂ ′ is hydrogen and the other is hydrogen or lower alkyl group.

The nitration of the compound of formula II is heated with nitric acid or mixed acid or a mixture of nitric acid and carboxylic acid (acetic acid) or a mixed anhydride of nitric acid and carboxylic acid (acetic acid) and or the nitrate of formula II is dinitrogen tetroxide ( Acid treatment with N ₂ O ₄ ) (e.g. nitric oxide / BF ₃ ) (if necessary in a suitable solvent such as nitrohydrocarbons (e.g. nitroalkanes such as nitromethane)) or with nitrogen tetroxide in acetonitrile Treatment or acid treatment with N-nitroderivatives.

Examples of the N-nitro compound include nitroamides such as nitrourethane, nitroguanidine, and nitrobiurete, and nitroreas such as ethylenenitrourea.

The acid treatment reaction of nitrate of the compound of formula (II) can be carried out at 40 to 100 ° C (60 to 80 ° C).

Compounds of formula (I) can be converted to other compounds by known methods. For example, a compound wherein R ₃ is hydroxy lower alkyl can be converted to a compound that is lower alkoxy-lower alkyl by alkylating with a suitable alkylating agent.

For example, derivatives substituted with hydroxy lower alkyl may be reacted with an active ester such as an ester of a lower alkanol (preferably in the presence of a basic condensing agent such as an alkali metal hydroxide) or a dia such as diazomethane. It can be reacted with lower alkanes (preferably in the presence of brontrifluoride). However, the hydroxy-loweralkyl group R3 can also be converted to an amino-loweralkyl group. It is thus possible to convert the obtained hydroxy-lower alkyl compound into a compound having an active esterified hydroxy-lower alkyl group. The active esters here are particularly strong esters of inorganic or organic acids, in particular hydrochloric acid, hydrobromic acid, halogenated acids such as hydroiodic acid, or arylsulfonic acids or alkylsulfonic acids such as benzenesulfonic acid or toluenesulfonic acid or esters of sulfuric acid. For example, the hydroxy-lower alkyl compound can be converted to a halogeno-lower alkyl compound by treatment with a halogenating agent such as thionylchloride, forster oxychloride, phosphorus pentabromide. The active esterified hydroxyl groups thus obtained can be substituted with amino groups by conventional methods such as by treatment with the corresponding amines.

When R ₃ in the compound of formula (I) is an aminolower alkyl group having at least one substitutable hydrogen atom attached to nitrogen, it may be substituted. For example, when R ₃ represents a primary or secondary amino group in the compound of formula (I), this group can be substituted by reacting with an active alcohol ester corresponding to the substituent of the amino group of the aminolower alkyl group.

Furthermore, it is also possible to oxidize the compound of formula (I) with N-oxide.

This oxidation reaction can be carried out using, for example, an N-oxidizing agent, i.e. inorganic peracids such as hydrogen peroxide, ozone, persulfate (katosan) or especially organic peracids such as peracetic acid, pertrifluoroacetic acid, perbenzoic acid, monoperphthalic acid (This can also be substituted with halogen atoms such as chlorine. For example chloromonophthalic acid or m-chloroperbenzoic acid) or organic peroxy compounds such as tertiary hydroperoxide compounds such as tertiary butyl peroxide or cumin peroxide And optionally proceed in the presence of a catalyst such as vanadium, titanium or molybdenum compounds.

The compound of formula (I) having an N-oxidized N-heterocyclic group can be converted to the compound of formula (I) having a phase having an N-heterocyclic group.

Compounds of formula (I) wherein X is a sulfinyl group can be oxidized to S-dioxide (sulfone).

Oxidation to sulfones is peracids such as hydrogen peroxide, peracetic acid, perbenzoic acid, monoperphthalic acid (also may be substituted with halogen atoms), 1-chlorobenzotriazole, chromic acid, potassium permanganate, hypohalite, nitric acid And an S-oxidant such as nitrous acid gas or the like, or by electrolysis. Sulfone is obtained by heating and / or by proceeding these reactions with at least 2 molar equivalents of oxidant.

The S-dioxide obtained can be reduced to the corresponding S-oxide of formula (I). Reducing agents include di-light metal hydrides (sodium boron hydride) or light metal hydrides (diborane) or boron hydride-etherates (BH ₃ -tetrahydrofuran), in particular dichloroborane or acetylchloride, sulfite, urethurization Hydrochloric acid or triphenylphosphine.

Care must be taken not to damage other groups that may be reduced in the reduction reaction. In other words, particular care should be taken to ensure that the halogen atoms bonded to the aromatic rings are not replaced by hydrogen.

In particular, the nitro group (R ₁ or R ₂ ) should not be reduced. Sulfur-insensitive catalysts are preferably used and, if necessary, the hydrogenation should be stopped after the calculated amount of hydrogen has been absorbed.

R ₂ can be converted to nitrolognitroimidazole. That is, R ₁ can be converted to a compound of formula (I) wherein the nitro group. This dislocation reaction is caused by the action of excess alkali metal iodide, especially potassium iodide, in an inert solvent (preferably polar active groups such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile or hexamethylphosphoric acid triamide). Solvent with).

This dislocation reaction can also proceed with the action of an iodine corresponding to R ₃ , ie, R ₃ J (formula (I) compound wherein R ₃ is methyl methyl iodide), in which the unsubstituted nitrogen source of imidazoling The sleeping becomes level 4, after which the quaternary salt becomes pyrrole. This dislocation reaction may also occur in the presence of an inert solvent (preferably the solvent mentioned above). Subsequent conversion reactions can then proceed individually or in combination, requiring care not to attack other functional groups.

The reaction according to the invention is carried out according to the usual methods at room temperature or under high pressure, cooling or heating, if necessary, in an inert atmosphere such as diluents, catalysts and condensing agents and / or nitrogen.

Depending on the reaction conditions and starting materials, the final product is obtained in free or acid addition salt form. Basic, neutral or mixed salts can also be obtained, for example, hemihydrates, monohydrates, sesquihydrates or polyhydrates. This acid addition salt can be converted to the free compound using a basic substance such as alkali or ion exchange resin. Free bases, on the other hand, may react with organic or inorganic acids to form salts. Particularly, the acids used to prepare acid addition salts that can be used as chemotherapeutic agents include Hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid: formic acid, acetic acid, propionic acid, linear acid, glycolic acid, lactic acid, malic acid, tartaric acid, ascorbic acid, maleic acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, P Aliphatic, substituted, aromatic, or heterocyclic carboxylic acids such as aminobenzoic acid, anthranilic acid, P-hydroxybenzoic acid, salicylic acid, P-aminosalicylic acid, emboic acid: methanesulfonic acid, ethanesulfonic acid, hydroxy ethanesulfonic acid, ethylene Sulphonic acids such as sulfonic acid, halogenobenzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, sulfanilinic acid: methionine, tryptophan, lysine, arginine are used.

These or other salts such as picrate are also used for the purpose of purifying the obtained base. That is, the free base is converted into salts and separated, and then the base is separated and purified from these salts again.

Since the free forms of these new compounds and their salts are very similar, the organic bases in the present specification are considered to include the corresponding salts.

The compound of formula (I) may be obtained in the form of racemate mixtures, racemates or optically cognates depending on the number of subatomic carbon atoms, starting materials and preparation methods.

Racemate mixtures can be separated into pure racemates by methods such as chromatography, fractional crystallization, etc., depending on differences in the physicochemical properties of the components.

Pure racemates are recrystallized from the optically active solvent by microorganisms to separate them into diastereomers or reacted with optically active acids to form salts, which are separated according to solubility to decompose into diastereomers and then suitable for Reagent is added to separate the colon. Especially common optically active acids are D and L type tartaric acid, di-0-toluyl-tartaric acid, malic acid, mandelic acid, campo-10-sulfone or quinic acid. The salt thus obtained can be converted to other salts or to free or optically active bases, and the optically active bases can be converted to acid addition salts according to the above methods.

The compounds of formula (I), their 5-N-oxides and salts, in an amount of about 5% in high molecular weight hydrophobic or other organic substances susceptible to decay by bacteria or other microorganisms due to their antimicrobial activity Treatment can be used to protect these materials. It can also be used as a growth-promoting additive in animal feed, with the addition of 5 to 500 ppm of the active compound.

Therefore, a therapeutic composition containing an effective amount of a pharmaceutically acceptable solid carrier or liquid diluent is prepared by using the compound of formula (I) prepared according to the present invention or 5-N-oxide or a pharmaceutically acceptable salt thereof as an active ingredient. Can be. The carrier actually used depends on the method of administration. Medical materials include ointments, powders, and linking agents for the purpose of disinfecting healthy skin, disinfecting wounds, dermatitis, infection of mucous membranes by bacteria and fungi, and treatment of skin diseases. The ointment base is dehydrated, and a soft paraffin is mixed with lanolin, but there is an aqueous emulsion in which an active substance is suspended. Suitable carriers for powders are rice starch and other starches. The weight of these carriers can be lightened by adding very fine silicic acid, if necessary, or by adding talc. The linking agent contains at least one active ingredient of formula (I) or contains 5-N-oxide or a salt thereof in an aqueous alcohol solution. If necessary, add 45 to 75% ethanol and 10 to 20% glycerol. Liquids containing polyethylene glycol or other solubilizers are particularly effective for disinfecting healthy skin. The active substance content of the external preparation is suitably 0.1 to 5%.

Throat disinfectants (gargles), or concentrates of the preparations or umbilical cords, are effective for disinfecting the oral cavity or throat. Throat disinfectants are alcoholic liquids containing 1 to 5% of the active substance and to which glycerol or a flavourant is added. As a solid preparation, troche is relatively high in sugar and similar substances, contains little active substance, and 0.2 to 20% of its weight is the active substance by adding common additives such as binders and flavoring agents.

In particular, as a solid preparation, tablets, dragees, and capsules are used as place poisons. These preparations contain 10 to 90% of the compound of formula (I) or a 5-N-oxide, salt thereof, with a daily adult dose of 0.1 to 2.5 g, and moderately reduced by children. Tablets and dragees are formulated with compounds of formula (I), 5-N-oxides, salts thereof, lactose, sucrose, sorbitol, corn starch, potato starch or amylopectin, cellulose derivatives and powdered carriers such as magnesium stearate and calcium stearate. It is prepared by combining with a suspending agent, such as a rate, polyethylene glycol of a suitable molecular weight. Dragees are then coated with sugary sugar, which may also contain gum arabic, talc and / or titanium dioxide, and may be avoided by dissolving lacquer in a volatile solvent. The coating may be added with a pigment to distinguish between different doses. Soft gelatin capsules and other capsules are a mixture of gelatin and glycerol, and the compound of formula (I) and its 5-N-oxide, and its salts contain polyethylene glycol in the mixture. Hard gelatin capsules are made by mixing the active substance with powdered carriers such as lactose, sucrose, sorbitol, mannitol, starch (potato, corn, amylopectin) cellulose derivatives and powdered carriers such as magnesium stearate or stearic acid to form granules. .

The compound of formula (I), 5-N-oxide, or salt thereof may be prepared by itself, or may be prepared by adding other pharmacologically active antimicrobial agents and / or antifungal agents to broaden the application. It may be prepared. Examples include 5, 7-dichloro-2-methyl-8-quinolinol or other derivatives of 8-quinolinol, sulfamerazine or sulfaprazole, other sulfa agents, chloramphenicol, tetracycline, other antibiotics, 3, 4, 5-tribromosalicylate, or other halogenated salicylates, halogenated caranilides, halogenated benzoxazoles, zenoxazolones, polychloro-hydroxy-diphenyl-methanes, halogen-dihydroxys -Diphenylsulfide-4, 4'-dichloro-2-hydroxy-diphenyl ether 2, 4, 4'-trichloro-2-hydroxy-diphenyl ether or other polyhalogen hydroxydiphenyl ethers, Bactericidal quaternary compounds, dithiocarbamic acid derivatives such as tetramethyl thiuram disulfide, other nitrofuran and the like. In addition, sulfur as a powder base and zinc stearate as a broth may also be used as a carrier.

In addition, by treating the compound with the compound of formula (I), 5-N-oxide, or acid addition salt of the present invention, it is possible to prevent the decay of organic substances susceptible to invasion of bacteria or microorganisms. The organic materials may be natural materials, synthetic polymers, proteinaceous materials, carbohydrates, natural or synthetic fibers.

Examples a) to d) below are methods for preparing dosage forms.

a) 250.0 g of active ingredient is mixed with 550.0 g of lactose and 292.0 g of potato starch, and the mixture is soaked with 5 g of alcoholic solution of gelatin. After mixing with 60.0 g of potato starch and 60.0 g of talc, 10.0 g of magnesium stearate and 20.0 g of colloidal silicon dioxide, it is compressed into 10,000 tablets. One tablet has 25 mg of active ingredient and weighs 125 mg.

b) Granules are made with an alcoholic solution of 100.0 g of active ingredient, 379.0 g of lactose and 6.0 g of gelatin, 10.0 g of colloidal silicon dioxide, 40.0 g of talc, 60.0 g of potato starch and 5.0 g of magnesium stearate. Mix with rate to tablet the nuclei of 10,000 sugars. It is filmed and dried with a syrup made of 533.5 g of sucrose, 20.0 g of shellac, 75.0 g of arabic gum, 250.0 g of talc, 20.0 g of colloidal silicon dioxide, and 1.5 g of dye. This dragee has a weight of 150 mg and contains 10 mg of active ingredient.

c) Mix and dissolve 25.0 g of active ingredient and 1,975 g of suppository base (coverover). Molded with 2.0 g of these 1,000 suppositories (active ingredient content 25 mg).

d) 1.5 L of glycerin, 42 g of P-hydroxybenzoic acid-methyl ester and 18 g of P-hydroxybenzoic acid-n-propyl ester are lightly heated to prepare a syrup containing 0.25% of active ingredient in 3 L of distilled water. 25.0 g of active compound are dissolved in 3 L of distilled water and 4 L of 70% sorbitol solution, 1,000 g of sucrose crystals, 350 g of glucose and aromatics (e.g. 250 g of "Orange Peel Soluble Fluid") or 5 g of "Half and half-equence is added and the solution is filtered and distilled water is added to make 10 liters.

The following example is a specific example of the preparation method according to the present invention in which all parts and percentages are indicated by weight unless otherwise indicated. Temperature means Celsius.

Example 1

To 0.4 ml of concentrated nitric acid and 4 drops of sulfuric acid, 68 mg of 1- (methylsulfonyl) -2-oxo-3 [1-methylimidazolyl- (2)]-tetrahydroimidazole was added to the reaction mixture. It is left to stand at 115 degreeC for 2 hours. The reaction mixture is poured onto ice, neutralized with sodium bicarbonate and extracted with ethyl acetate. The extract is dried over Na ₂ S0 ₄ and evaporated. Silica gel chromatography of the evaporated residue gave 1- (methyl-sulfonyl) -2-oxo-3- [1-methyl-5-nitroimidazolyl (2)]-tetrahydroimidazole. Melting point: 202 to 204 ℃, starting material is prepared as follows.

In 165 ml of acetonitrile solution containing 16 g of 2-amino-1-methylimidazole, 80 ml of acetonitrile solution containing 31 g of chloroethyl isocyanate was added dropwise for 30 minutes with stirring at room temperature, followed by heating under reflux for 10 hours. . Cooling and crystallization of this solution yields the free base 1- [methyl-imidazolyl (2)]-imidazolidinone, which is removed with potassium carbonate and crystallized with chloroform ether. Melting point: 136-137 degreeC.

5 ml of dimethylformamide and 300 ml of dioxane solution containing 500 mg of 1- [methyl-imidazolyl- (2)]-imidazolidin-2-one were cooled to 10 ° C. and then 0.16 g of sodium hydride (50% dispersion in oil) is added and stirred for 30 minutes.

Methane sunfonyl chloride (0.6 g) is added dropwise and the solution is cooled in an ice bath for 1 hour and then left at room temperature for 3 hours. Filtration and evaporation gave 0.6 g of oily residue, which was subjected to silica gel chromatography. Elution with chloroform gives crystallization from isopropanol ether to give 1- (methylsulfonyl) -2-oxo-3- [1-methylimazolyl (2)]-tetrahydro imidazole. Melting point: 171 to 172 캜.

Example 2

200 ml of 2.9 g of 1- (methylsulfonyl) -2-oxo-3- [1-methyl-5-nitroimidazolyl- (2)]-tetrahydroimidazole and 1.9 g of ethyloxonium fluoroborate The solution dissolved in anhydrous chloroform was left at room temperature for 72 hours. The thick oil layer is separated, treated with alcohol to crystallize, filtered, boiled with acetone and filtered. The residue was crystallized from an alcohol solution to give 1-methyl-2- [3- (methylsulfonyl) -2-oxo-tetrahydroimidazolyl- (1)]-3-ethyl-5-nitroimidazolium of the formula Obtain fluoroborate.

Melting Point 265-267 ℃

Example 3

To 30 ml of dimethylformamide containing 3.0 g of potassium iodide 3.0 g of 1- (methylsulfonyl) -2-oxo-3- [1-methyl-5-nitroimidazolyl (2)]-tetrahydroimi The solution in which the dazol is dissolved is heated under reflux for 16 hours. The solvent is removed under reduced pressure, water is added to the evaporation residue and filtered. 2N hydrochloric acid is added to the filtrate, acidified, cooled and filtered to remove unreacted starting material. The filtrate was further cooled and the separated crystals were filtered and recrystallized twice as acetone-methanol. (2)]-tetrahydro imidazole is obtained.

Example 4

To 25 ml of dimethylformamide containing 3.0 g of potassium iodide, 3.0 g of 1- (methylthiocarbamoyl) -2-oxo-3- [1-methyl-5-nitroimidazolyl (2)]-tetra The solution to which hydrazole was added is heated under reflux for 16 hours. The solvent was removed under reduced pressure, water was added to the residue, the residue was filtered, the precipitate was washed with hot ethanol and methanol and recrystallized with acetone-methanol to give 1- (methylthio carbamoyl) -2-oxo- at a melting point of 239 to 241 ° C. 3- [1-methyl-4-nitroimidazolyl (2)]-tetrahydroimidazole is obtained.

Example 5

According to Example 1, the following compounds are prepared.

a) 1- (methyl-thiocarbamoyl) -2-oxo-3- [1-methyl-5-nitroimidazolyl (2)]-tetrahydroimidazole, melting point 185 to 187 ° C;

b) 1- (benzyl-thiocarbamoyl) -2-oxo-3- [1-methyl-5-nitroimidazolyl (2)]-tetrahydroimidazole, melting point 178-180 ° C .;

c) 1-N, N-diethylsulfamoyl-2-oxo-3- [1-methyl-5-nitroimidazolyl (2)]-yltetrahydroimidazole, melting point 146-147 ° C .;

d) 1- (methylsulfonyl) -2-oxo-3- [1-methyl-5-nitroimidazolyl- (2)]-tetrahydroimidazole, melting point 202-204 캜;

e) 1-N-ethyl-thiocarbamoyl-2-oxo-3- [1-methyl-5-nitroimidazolyl- (2)]-tetrahydroimidazole, melting point 213 ° C .;

f) 1-N, N-dimethyl-sulfamoyl-2-oxo-3- [1-methyl-5-nitroimidazolyl- (2)]-tetrahydroimidazole, melting point 217 ° C .;

g) 1- (N, N-diethylcarbamoyl) -2-oxo-3- (1-methyl-5-nitroimidazolyl- (2) -tetrahydroimidazole, melting point 133 ° C .;

h) 1-N, N-dimethyl-carbamoyl-2-oxo-3- [1-methyl-5-nitroimidazolyl- (2)]-tetrahydroimidazole, melting point 190-191 ° C .;

i) 1-N-ethylsulfonyl-2-oxo-3- [1-methyl-5-nitroimidazolyl- (2)]-tetrahydroimidazole, melting point 176 to 177 ° C;

j) 1-N- (4-Fluoro-phenyl-sulfonyl) -2-oxo-3- [1-methyl-5-nitroimidazolyl- (2)]-tetrahydroimidazole, melting point 198 to 200 ° C ;

k) 1-piperidino-carbonyl-2-oxo-3- (1-methyl-5-nitroimidazolyl-2-) (-tetrahydroimidazole, melting point 152 ° C .;

l) 1-morpholino-carbonyl-2-oxo- (1-methyl-5-nitroimidazolyl-2) -tetrahydroimidazole, melting point 180 ° C .;

m) 1- (methylsulfonyl-2-oxo-3- [1-methyl-4-nitroimidazolyl- (2)]-tetrahydro imidazole, melting point 180 to 181 ° C .;

n) 1- (methyl-thiocarbamoyl) -2-oxo-3- [1-methyl-4-nitroimidazolyl- (2)]-tetrahydro imidazole, melting point 239 to 241 ° C .;

o) 1-pyrrolidino-carbonyl-2-oxo-3- [1-methyl-5-nitroimidazolyl- (2)]-tetrahydro imidazole, melting point 155-156 ° C .;

p) 1-pyrrolidino-sulfonyl-2-oxo-3- [1-methyl-5-nitroimidazolyl- (2)]-tetrahydro imidazole, melting point 226 ° C .;

q) 1-piperidino-sulfonyl-2-oxo-3- [1-methyl-5-nitroimidazolyl- (2)]-tetrahydro imidazole, melting point 192 ° C .;

r) 1- (methylsulfonyl) -2-oxo-3- [1-methyl-5-nitroimidazolyl- (2)]-4-methyl-tetrahydroimidazole, melting point 199 to 200 ° C;

s) 1- (methylsulfonyl) -2-oxo-3- [1-N-methoxyethyl-5-nitroimidazolyl- (2)]-tetrahydro imidazole, melting point 126-127 degreeC;

Claims (1)

A method of preparing a compound of the following formula (I) and acid addition salts thereof by nitrating the compound of the following formula (II).

In the above structural formula One of R ₁ and R ₂ is hydrogen or lower alkyl, the other is nitro, One of R ₁ ′ and R ₂ ′ is hydrogen, lower alkyl and the other is hydrogen, R ₃ is lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, lower alkylsulfonyl lower alkyl or amino lower alkyl, R ₄ is oxo or thioxo group, X is a carboxy, thiocarbonyl, sulfinyl or sulfinyl group, when X is a carbonyl group R ₅ is a lower alkoxy, amino, lower alkylamino, dilower alkylamino group, and X is thiocarbonyl, sulfinyl , When sulfonyl, R ₅ is lower alkyl, aryl, amino, alkylamino or diloweralkylamino, Alk is a lower alkylene having 2 to 4 carbon atoms in the alkylene group.