KR790000980B1 - Process for preparing imidazole derivatives - Google Patents

Abstract

Imidazoles (I; R1, R2= one is H or low alkyl, the other is nitro, R3= low alkyl, hydroxy low alkyl, low alkoxy low alkyl, low alkyl sulfonyl, R4 = oxo or thioxo, X= carbonyl, thio carbonyl, sulfinyl, sulfonyl, ALK = C2-4 low alkylene), and some related compds., useful as bactericide, were prepd. by reaction of II (z = esterificated hydroxy group, free or esterificated mercapto group, ammonium group, sulfinyl, sulfonyl) and III.

Description

Method for preparing imidazole derivative

The present invention relates to a method for preparing an imidazole derivative of 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,

When X is carbonyl R ₅ is lower alkoxy, amino, lower alkylamino or dilower alkylamino,

When X is thiocarbonyl, sulfinyl, sulfonyl R ₅ represents lower alkyl, aryl, amino, alkylamino or lower alkylamino,

Alk represents a lower alkylene group having 2 to 4 carbons in alkylene.

Here, "lower" means containing up to seven carbon atoms, and up to four carbon atoms are 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 seven carbon atoms, in particular up to four carbon atoms, the lower alkyl moiety as described above, for example hydroxymethyl, 3-hydroxy-n-propyl Especially 2-hydroxyethyl.

Lower alkoxy lower alkyl groups are groups in which the lower moiety has up to 7 carbon atoms, in particular up to 4 carbon atoms, for example methoxymethyl, n-propoxymethyl, n-butoxymethyl, 2- (n-part Methoxy) -ethyl, 3- (n-propoxy) -propyl, especially 2-methoxy ethyl.

Examples of lower alkyl sulfonyl lower alkyl are methylsulfonylmethyl, ethylsulfonylmethyl, 2-methylsulfonylethyl, n-propylsulfonylmethyl, 2-n-propylsulfonylethyl, 3-n-propylsulfonyl lower alkyl groups having lower alkyl sulfonyl 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-N-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-dimethylthio morpholino, piperazino, N'- Lower alkyleneamino which is methyl piperazino, N '-(β-hydroxyethyl) -piperazino). Examples of aminolower alkyl include dimethylaminomethyl, diethylaminomethyl, 2-dimethylaminoethyl, pyrrolidinomethyl, 2-pyrrolidinoethyl, 3-pyrrolidino-n-propyl, piperidinomethyl, mole 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 R ₅ is an optionally substituted aryl group, for example a phenyl or naphthyl group optionally substituted with one or more substituents as well as an optionally substituted 5,6,7,8-tetrahydro-1- or 2-naphthyl group There is this. 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 a lower alkyl group, a lower alkoxy group, a chlorine fluorine, or a halogen atom such as bromine, or a 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, especially 1,2-ethylene desirable.

The imidazole derivatives of formula (I) prepared according to the invention have effective pharmaceutical properties. In particular against bacteria (especially Gram-negative bacteria), protozoa (e.g. trichomonas), amoeba, helmins (larvae such as skistosomes), for example hamsters infected with Entamoeba histolytica (e.g. hamsters) shows activity as shown in the oral administration of 10 to 100mg / 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 the 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 and R ₃ , R ₅ are as defined in 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), and Alk represents a lower alkylene group having 2 to 4 carbon atoms.

In particular among the compounds of formula (Ia), R ₁ , R ₃ , R ₄ , R ₅ and Alk are the same as in formula (Ia), 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 as in formula (Ib) and X is a carbonyl group.

In addition, R ₁ or R ₂ , R ₃ , R ₄ , R ₅ and Alk of the compounds of formulas (Ia) and (Ib) are the same as above, and compounds in which X is thiocarbonyl and acid addition salts thereof also attract special attention. to be.

In addition, in 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. Of special interest.

Of particular interest among the compounds according to the invention are those wherein R ₃ 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 compound in which Alk 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 sulfonyl group, R ₁ or R ₂ and R ₅ are the same as in (Ia) or (Ib), and R ₃ is methyl Or lower alkyl group such as ethyl or lower hydroxyalkyl such as β-hydroxyethyl or β-hydroxy propyl, Alk is 1,2-ethylene, R ₄ is oxo group and acid addition salts thereof Of interest as above.

Of these nitroimidazole compounds in particular 1- (methylsulfonyl) -2-oxo-3- [1-methyl-5-nitro-imidazolyl (2)]-tetra hydroimidazole, 1-N, N-di Ethylcarbamoyl-2-oxo-3- [1methyl-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-nitroimidazolyl-2] -tetrahydroimidazole is used for the treatment of hamsters infected with entameva histolytica. It is effective in treating liver tumors.

The imidazole derivative of formula (I) according to the present invention can be prepared by reacting a compound of formula (2) with a compound of formula (3).

In the above structural formula,

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , Alk and X are the same as in formula (1), Z is the active esterified hydroxy group, free or etherified mercapto group, ammonium group, sulfy Nyl group or sulfonyl group is represented.

The active esterified hydroxy group Z is in particular an inorganic or organic acid, in particular hydrochloric acid, such as hydrochloric acid, hydrofluoric acid, hydrofluoric acid, sulfuric acid or benzenesulfonic acid, aromatic sulfides such as P-bromo-benzenesulfonic acid or P-toluenesulfonic acid. And hydroxy groups esterified with organic sulfonic acids such as aliphatic sulfonic acids such as phenolic acid or methanesulfonic acid or ethanesulfonic acid.

Active esterified hydroxy groups refer to aromatic, aliphatic, in particular lower aliphatic alcohols, for example optionally substituted phenoxy groups, or alkoxy groups, in particular hydroxy groups etherified with lower alkoxy such as methoxy or ethoxy.

Etherylated mercapto groups include optionally substituted phenyl mercapto or benzyl mercapto groups or especially lower alkyl mercapto groups such as ethyl or methyl mercapto.

Ammonium groups are in particular quaternary ammonium groups, of which trimethyl, but triethylammonium groups, or cations of aromatic nitrogen bases such as pyridium or quinolinium groups.

Sulfonyl groups are in particular organic sulfonyl groups, among which are aromatic sulfonic acid residues, and Z is benzenesulfonyl, P-bromobenzenesulfonyl, P-toluenesulfonyl, in particular methylsulfonyl group.

This reaction can be carried out in the presence of a basic condensation agent or by reaction with a N-alkali metal derivative obtained by reacting a compound of formula III with an amide, hydride, hydroxide or alcoholate of an alkali metal such as lithium, sodium or potassium. Proceed (if necessary, proceed immediately without separating intermediates). Basic condensing agents include alkali earth metal hydroxides such as sodium hydroxide, potassium hydroxide and calcium hydroxide or organic tertiary bases such as trialkylamines such as trimethylamine and triethylamine or pyridine. This reaction proceeds at high temperatures or in the presence of an inert solvent, if necessary. Inert solvents include solvents with polar active groups, for example dimethylformamide, dimethylacetamide, dimethyl- sulfoxide, acetonitrile or cycloaliphatic ethers such as dioxane or tetrahydrofuran.

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 may be reacted with crude alkanes (preferably in the presence of borontrifluoride). However, the hydroxy-loweralkyl group R ₃ 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 hydrogen acids such as iodide hydrochloric acid, or arylsulfonic acids such as benzenesulfonic acid or toluenesulfonic acid, or esters of alkylsulfonic acids or sulfuric acid. . For example, hydroxy-lower alkyl compounds can be converted to halogeno-lower alkyl compounds by treatment with halogenating agents such as thionylchloride, phosphorus 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 amino lower 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 amino group in the compound of formula (I), the group can be substituted by reacting with an active alcohol ester corresponding to the substituent of the amino group of the amino lower alkyl radical.

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

This oxidation reaction is carried out using, for example, N-oxidants, i.e. inorganic acids such as peroxide, ozone, persulfate (caroic acid) 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 and cumin peroxide And optionally proceed in the presence of a catalyst such as vanadium, titanium or molybdenum compounds.

Compounds of formula (I) having N-oxidized N-heterocyclic groups can be converted into the corresponding compounds of formula (I) having N-heterocyclic groups.

The reduction reaction is carried out in accordance with conventional methods by the action of phosphorus halides.

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, It may be reacted with an S-oxidant such as nitrous acid gas or the like or by electrolysis. Sulfones are 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 born hydride-etherates (BH ₃ -tetrahydrofuran), in particular dichloroborane or acetyl chloride, sulfite, hydroiodic 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. Catalysts which are not susceptible to sulfur are preferably used and, if necessary, the hydrogenation should be stopped after the calculated amount of hydrogen has been absorbed.

Compounds of formula (I) having nitro groups in R ₂ can be converted to the corresponding 4-nitro imidazoles by translocation. 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, in particular potassium iodide, in an inert solvent (preferably with diethylformamide, dimethylacetamide, dimethylsulfoxide, acetnitrile or hexamethylphosphoric acid triamide). Solvent with the same polar activator).

This dislocation reaction can also proceed with the action of an iodine corresponding to R ₃ , that is, R ₃ I (a compound of formula (I) 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 a conventional method at room temperature or under cooling or heating, under normal pressure or high pressure and, if necessary, in an inert atmosphere such as diluents, catalysts and condensing agents and / or nitrogen.

The compound of formula (III) according to the present invention is obtained by reacting a compound of formula (VII) with R ₅ -XZ.

In the above structural formula,

Alk, R ₄ , R ₅ , X and Z are as defined above.

The novel nitro-imidazoles described here as intermediates and starting materials show useful pharmacological properties. They are effective by oral administration of 10 to 100 mg / kg of bacteria, in particular against Gram-negative bacteria, protozoa and protozoa (eg trichomonas, skistosome, coccidia, especially amoeba).

Depending on the reaction conditions and starting materials, the final product is obtained in free or acid addition salt form. As basic, neutral or mixed salts, for example, hemihydrates, monohydrates, sesquihydrates or polyhydrates can also be obtained. 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, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascolic acid, maleic acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, Aliphatic, cycloaliphatic, aromatic or heterocyclic carboxylic acids such as benzoic acid, P-aminobenzoic acid, anthranilic acid, P-hydroxybenzoic acid, salicylic acid, P-aminosalicylic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxy ethane Sulphonic acids such as sulfonic acid, ethylene sulfonic acid, halogeno benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, sulfanilinic acid, methionine, tryptophan, lysine, arginine are used. These or other salts such as picrates are used for the purpose of purifying the resulting base. That is, the organic base is converted to a salt, separated, and purified by separating the base from these salts again.

Since the free forms of these novel compounds and their salts are very similar, the free base is considered herein 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, depending on differences in the physicochemical properties of the components.

Pure racemates are recrystallized from the optically active solvent by microorganisms to decompose 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. Particularly optically active acids include D and L type tartaric acid, di-O-toltuyl-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.

Compounds of formula (I), their 5-N-oxides and salts, in high amounts of about 5% of high molecular weight hydrogen-based substances and 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, where an effective compound can be added in the range of 5 to 500 ppm.

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. External preparations include ointments, powders, and linking agents for the purpose of disinfecting healthy skin, disinfecting wounds, dermatitis, infection of mucous membranes caused by bacteria and fungi, and treatment of skin diseases. The ointment is dehydrated and is a mixture of lanolin with soft paraffin, but there is an aqueous emulsion in which the active substance is suspended. Suitable carriers for the breakers are rice starch and other starches. The weight of these carriers may be lightened by addition of very fine powdery silicic acid, if desired, or by weighting 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, 45-75% ethanol, 10-20% glycerol is added. Liquids containing polyethylene glycol or other solubilizing agents are especially 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 orbital vesicles, are effective for disinfecting the oral cavity or throat. Throat disinfectants are alcoholic liquids containing 1 to 5% of the active substance and added glycerol or flavoring agents. As a solid preparation, troche is relatively high in sugar and similar substances, and contains little active substance, and 0.2 to 20% of its weight is the active substance by adding conventional additives such as binders and flavoring agents.

In particular, the solid preparations are used as place poisons such as tablets, dragees and capsules. 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, powdered carriers, magnesium stearate and calcium stearate. It is produced by combining with a suspending agent such as a rate and a 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. A pigment may be added to this film in order to distinguish a thing with a different capacity. Soft gelatin capsules and other capsules are a mixture of gelatin and glycerol and contain polyethylene glycol in a mixture of the compound of formula (I), 5-N-oxide and salt thereof. Hard gelatin capsules are mixed with the active substance and powder carriers such as lactose, sucrose, sorbitol, mannitol, starch (potato, corn, amylopectin) cellulose derivatives, magnesium stearate or stearic acid to fill and fill the granules.

The compound of formula (I), 5-N-oxide, or a salt thereof may be prepared by itself, or may be prepared by adding other pharmacologically active antibacterial 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, chlorangphenicol, tetracycline, other antibiotics , 3,4 ', 5-tribromosalinine anilide or other halogenated salicylic anilide, halogenated carvinide, halogenated benzoxazolone, polychloro-hydroxy-diphenyl-methane, halogen-dihydroxy -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 an ointment may also be used as a carrier.

In addition, when the material is treated with the compound of formula (I), 5-N-oxide or acid addition salt according to 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, 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) Granulate 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 to compress the core tablets 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 gum 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 (cacao butter). It is molded into 2.0 g of 1,000 suppositories (active ingredient content 25 mg).

(d) Lightly heat 1.5 l of glycerin, 42 g of P-hydroxy benzoic acid-methyl ester and 18 g of P-hydroxy benzoic acid-n-propyl ester to prepare a syrup containing 0.25% of active ingredient in 3 liter 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 Sobule Fluid") or 5 g of "half" Half and half "-equences are added and the solution is filtered and distilled water is added to make 10 liters.

The following example is a specific example of the manufacturing method according to the present invention all parts and percentages are expressed in weight unless otherwise indicated, the temperature means degrees Celsius.

Example 1

In a solution of 7.95 g of 1- (methylthiocarbamoyl) -2-oxo-2,3,4,5-terahydroimidazole in 100 ml of dimethylformamide, 2.4 g of a 50% sodium hydride slurry in mineral oil was added. Add. The mixture is heated and stirred at 50 ° C. for 30 minutes. 10.25 g of 1-methyl-2-methanesulfonyl-5-nitroimidazole is added and the mixture is stirred at 100 ° C. for 4 hours. The solution is concentrated in vacuo to a small volume and water is added. The crystal precipitate was filtered off, washed with water and ether and recrystallized with alcohol, then 1- (methylthiocarbamoyl) -2-oxo-3 [1-methyl-5-nitroimidazolyl- (2)] Obtain tetrahydroimidazole.

Melting Point: 185 to 187 ° C

The starting material 1- (methylthiocarbamoyl) -2-oxo-2,3,4,5-terahydroimidazole is prepared as follows. 86 g of ethylene urea and 73 g of methyl isothiocyanate mixture are stirred at 100 ° C. for 4 hours. Ether and water are added to the crystal obtained by cooling, filtered, washed with an alcohol-ether mixture, and recrystallized with methanol.

Melting Point: 168 to 171 ° C

Example 2

0.95 g of a 50% sodium hydride slurry in mineral oil was added to a solution of 4.7 g of 1- (benzenethiocarbamoyl) -2-oxo-2,3,4,5-tetrahydroimidazole in 50 ml of dimethyl formamide. do. The mixture is heated and stirred at 50 ° C. for 30 minutes. 4.1 g of 1-methyl-2-methanesulfonyl-5-nitroimidazole is added and stirred at 100 ° C. for 4 hours. The solution is concentrated in vacuo to a small volume, then water is added and the mixture is extracted with chloroform. The chloroform solution is washed with water, dehydrated over sodium sulfate and evaporated in vacuo. The residue obtained by diluting the residue with ether was crystallized with chloroform-alcohol to give 1- (benzylthiocarbamoyl) -2-oxo-3- [1-methyl-5-nitroimazolyl- () having a melting point of 178 to 180 ° C. 2)]-tetrahydroimidazole is obtained.

The starting material thiocarbamoylimidazole is prepared as follows. 86 g of ethylene urea and 149 g of benzylisothiocyanate are stirred at 150 ° C. for 6 hours. The solid obtained after cooling is diluted with ether and then diluted with hot alcohol and filtered. Recrystallization with chloroform-methanol affords 1- (benzylthiocarbamoyl) -2-oxo-tetrahydroimidazole.

Example 3

1.7 g of a 50% sodium hydride slurry in mineral oil is added to a solution of 5 g of 1- (methylcarbamoyl) -2-oxo-2,3,4,5-tetrahydroimidazole in 50 ml of dimethylformamide. The mixture is stirred at 50 ° C. for 1 hour. To this was added a solution of 7.2 g of 1-methyl-2-methanesulfonyl-5-nitroimidazole dissolved in 30 ml of dimethylformamide, and then the mixture was stirred at 100 ° C for 3 hours. The solvent is evaporated off in vacuo and then water is added to the residue. The resulting red solution was extracted with chloroform to give an oil, washed with methanol, and the obtained solid was recrystallized three times with methanol to obtain 1- (methylcarbamoyl) -2-oxo-3- [1-methyl-5-nitroimazolyl -(2) [-tetrahydroimidazole is obtained.

Melting Point: 176 to 177 ° C

The starting material methyl carbamolimimidazole is obtained by heating a mixture of 8.6 g ethylurea and 5.7 g methyl isocyanate at 130 ° C. in a sealed tube for 3 hours and then crystallizing the obtained solid with water first and then recrystallization with chloroform-methanol. .

Melting Point: 198 to 200 ° C

Example 4

4.8 g of 50% sodium hydride slurry in mineral oil was added to a solution of 16.4 g of 1- (methylsulfonyl) -2-oxo-2,3,4,5-tetra hydroimidazole in 120 ml of dimethylformamide. The mixture is stirred at 50 ° C. for 30 minutes. To this was added a solution of 20.5 g of 1-methyl-2-methanesulfonyl-5-nitroimidazole dissolved in 70 ml of dimethylformamide, and the mixture was heated at 100 ° C for 1 hour. The solvent is evaporated off in vacuo and the residue is dissolved in water. After cooling, the precipitate was filtered off and recrystallized from acetone-methanol to give 1- (methylsulfonyl) -2-oxo-3- [1-methyl-5-nitroimidazolyl- (2)]-tetrahydroimidazole. Obtained.

Melting Point: 202-204 ℃

The starting material 1- (methylsulfonyl) -2-oxo-2,3,4,5-tetra hydroimidazole is prepared as follows. 86 g of ethyleneurea and 115 g of methanesulfonyl chloride mixture are heated at 120 ° C. for 6 hours with stirring. At this time, sodium chloride is removed through nitrogen gas. After cooling, water is added and the mixture is heated until a crystal powder is formed in a steam bath. It is filtered off, washed with alcohol-ether and recrystallized with methanol.

Melting Point: 192 ~ 195 ℃

Example 5

In a suspension in which 1.5 g of 50% sodium hydride was suspended in 10 ml of anhydrous dimethylformamide, a solution of 5.3 g of 1-N-ethylthiocarbamoyl-2-oxo-tetrahydroimidazole in 20 ml of anhydrous dimethylformamide was dissolved. Add with stirring for 15 minutes. The reaction mixture was stirred for 30 minutes at 50 ° C. under a nitrogen gas, and a solution of 4.5 g of 1-methyl-2-methylsulfonyl-5-nitroimidazole dissolved in 10 ml of anhydrous dimethyl formamide was added over 5 minutes, followed by 100 Heat at 4 ° C. The solvent is evaporated off in vacuo and the residue is diluted with 50 ml of water and extracted with ethylene dichloride. The ethylene dichloride extract is dried over anhydrous sodium sulfate and evaporated to dryness. The residue was chromatographed on silica gel and the eluate was eluted with 20% methanol (in chloroform) and then recrystallized from a methylene chloride-hexane mixture to give 1-N-ethylthio carbamoyl-2-oxo-3- [. 1-methyl-5-nitroimidazole- (2)]-tetrahydroimidazole is obtained.

Starting materials are prepared as follows. After heating 8.6 g of ethylene urea and 8.7 g of ethyl isothiocyanate mixture at 100 ° C. for 4 hours and cooling, the obtained crystal product was recrystallized from an ethanol and ether mixture to obtain 1-N-ethyl-thiocarbamoyl-2-oxo. Obtain tetrahydroimidazole.

Melting Point: 135-136 ° C

Example 6

8.7 g of 1- (N, N-dimethylsulfamoyl) -2-oxo-tetrahydroimidazole was mixed with 10 ml of anhydrous dimethylformamide containing 2.2 g of 50% sodium hydride for 15 minutes with 20 ml of anhydrous dimethylform. The solution dissolved in amide is added. The reaction mixture was stirred at 50 ° C. under nitrogen for 1 hour, and a solution of 9.25 g of 1-methyl-2-methylsulfonyl-5-nitroimidazole in 20 ml of anhydrous dimethylformamide was added all at once. The reaction mixture is heated to 95 ° C. under nitrogen for 3 hours with stirring. The solvent is evaporated off in vacuo and the residue obtained by dilution with 45 ml of water is extracted with ethylene dichloride, dried and evaporated to dryness. The residue is washed with hexane and diluted with acetone to give crystalline solid. It was recrystallized from a mixture of methylene chloride and ether to give 1-N, N (dimethyl-sulfamoyl) -2-oxo-3- [1-methyl-5-nitroimidazolyl- (2)]-tetrahydro at a melting point of 217 ° C. Get imidazole

Starting materials are prepared as follows. 17.2 g of ethylene urea and 28.7 g of N, N-dimethylsulfamoylchloride mixture are heated to 110 ° C. for 3 hours, then cooled and diluted with 100 ml methanol. The separated solid is decanted and the filtrate is evaporated to dryness and the residue is dissolved in 5% methanol chloroform solution and chromatographed on 150 ml silica gel column. The fraction eluted with 2% methanol chloroform solution is recrystallized from methylene chloride and hexane to give 1- (N, N-dimethylsulfamoyl) -2-oxo-tetrahydro imidazole.

Melting Point: 129 ℃

Example 7

34.4 g of ethylene urea and 54.2 g of N, N-diethylcarbamyl chloride mixture are heated to 110 ° C. under nitrogen for 3 hours, then cooled and diluted with 200 ml of acetone. The oily product obtained by filtration and evaporation and drying of the filtrate is chromatographed on 450 g silica gel column. From the fraction eluted with a 3% chloroform solution of methanol, 1- (N, N-dimethylcarbamoyl) -2-oxo-tetrahydroimidazole as colorless oil is obtained.

22 g of 1- (N, N-diethylcarbamoyl) -2-oxo-tetrahydroimidazole was dissolved in 40 ml of anhydrous dimethyl formamide in a 5.8 g 50% sodium hydride suspension dispersed in 20 ml of anhydrous dimethyl formamide. The solution is added with stirring for 15 minutes. The reaction mixture was stirred for 1 hour at 50 ° C. under nitrogen gas, and a solution of 24.6 g of 1-methyl-2-methylsulfonyl-5-nitroimidazole dissolved in 40 ml of anhydrous dimethylformamide was added all at once.

The reaction mixture was subjected to a reaction according to Example 5 to obtain a black oily residue (36 g) which was chromatographed on a 360 g silica gel column. Crystalline material obtained from the fraction eluted with a 2.5% chloroform solution of methanol was recrystallized from a mixture of methylene chloride and hexane to give 1-N, N-diethylcarbamoyl-2-oxo-3- [1-methyl-5-nitro Imidazolyl- (2)]-tetrahydroimidazole is obtained.

Melting Point: 133 ℃

Example 8

150 ml of 78.5 g of 1- (N, N) -dimethylcarbamoyl) -2-oxo-tetrahydroimidazole was stirred for 15 minutes with a suspension of 24.5 g of 50% sodium hydride suspended in 100 ml of anhydrous dimethyl formamide. A solution dissolved in anhydrous dimethyl formamide is added. The reaction mixture was stirred at 50 ° C. under nitrogen gas for 1 hour, and a solution of 102.5 g of 1-methyl-2-methylsulfonyl-5-nitroimidazole in 100 ml of anhydrous dimethylformamide was added for 10 minutes, followed by stirring. Under heating at 100 ° C. for 3 hours. The residue obtained by carrying out the reaction according to Example 5 was recrystallized from a mixture of methylene chloride and hexane to give 1-N, N-dimethyl-carbamoyl-2-oxo-3- [1-methyl-5 at a melting point of 190 to 191 ° C. -Nitroimidazolyl- (2)]-tetrahydroimidazole.

Starting materials are prepared as follows. 86 g of ethylene urea and 118 g of N, N-dimethylcarbamoyl chloride mixture are refluxed under nitrogen gas in 200 ml of ethylene dichloride for 3 hours. The solution is evaporated to dryness and the residue is dissolved in chloroform and chromatographed on a 1.5 kg silica gel column. The fractions eluted with a 5% chloroform solution of methanol are combined and recrystallized from a mixture of methylene chloride and hexane to give 1-N, N-dimethylcarbamoyl-2-oxo-tetrahydroimidazole having a melting point of 134 to 136 ° C.

Example 9

a) A solution of 16 g of 1-ethyl-sulfonyl-2-oxo-tetrahydroimidazole in 4.5 g of 50% sodium hydride suspension dispersed in 10 ml of anhydrous dimethyl formamide in 30 ml of anhydrous dimethyl formamide in solution Add with stirring for 15 minutes. The reaction solution was stirred at 50 ° C. under nitrogen gas for 45 minutes, and a solution of 18.5 g of 1-methyl-2-methylsulfonyl-5-nitroimidazole dissolved in 30 ml of anhydrous dimethyl formamide was added at once and the reaction mixture was added. Heat at 100 ° C. for 3 hours.

The residue obtained by carrying out the reaction according to Example 5 was recrystallized from a mixture of methylene chloride and hexane to form 1-N-ethyl-sulfonyl-2-oxo-3- [1-methyl- having a melting point of 176 to 177 ° C. 5-nitro-imidazolyl- (2)]-tetrahydroimidazole is obtained.

b) Starting materials are prepared as follows. 29.2 g of ethylene urea and 43.7 g of ethanesulfonyl chloride mixture are heated to 110 ° C. under nitrogen gas for 3 hours, and the reaction mixture is diluted with 30 ml of methanol and filtered. The residue obtained by evaporation of the filtrate is dissolved in chloroform and chromatographed on 750 g of silica gel column. The fraction eluted with a 5% chloroform solution of methanol is recrystallized from a mixture of methylene chloride and hexane to give 1-ethylsulfonyl-2-oxo-tetrahydroimidazole having a melting point of 114 to 116 ° C.

Example 10

5.8 g of 1- (4-fluorophenylsulfonyl) -2-oxo-tetrahydroimidazole according to Example 9 a) were mixed with 5.0 g of 1-methyl-2-methylsulfonyl-5-nitroimidazole. 1-N- (4-fluorophenylsulfonyl) -2-oxo-3- [1-methyl-5-nitroimidazolyl- (2)]-tetra of the following structural formula having a melting point of 198 to 200 캜. Obtain hydroimidazole.

Starting materials are prepared as follows. A mixture of 17 g of ethylene urea and 19.5 g of P-fluorobenzenesulfonylchloride was heated at 110 ° C. for 3 and a half hours, and the residue was recrystallized from a mixture of methanol and water to obtain 1- (4-fluoro at a melting point of 183 to 185 ° C. Phenylsulfonyl) -2-oxo-tetrahydroimidazole is obtained.

Example 11

A solution of 1-piperidino carbonyl-2-oxo-tetrahydroimidazole dissolved in 15 ml of dimethylformamide in 1.3 g of 50% sodium hydride stirred suspension suspended in mineral oil in 20 ml of anhydrous dimethyl formamide at an appropriate temperature Add it down. Raise the reaction temperature to 50 ° C. and stir for 30 minutes. A solution of 5.12 g of 1-methyl-2-methylsulfonyl-5-nitro-imidazole in 20 ml of dimethyl formamide is added in 20 minutes, the temperature is raised to 95 ° C. and maintained at this temperature for 1 hour. The solvent is removed under reduced pressure and the residue is washed with ether and treated with water containing ice cubes. After removal of the liquid layer, the residue was treated with isopropane with ether (5: 1) to recrystallize the precipitate of colorless granules with ethyl acetate-hexane to yield 1-piperidino-2-oxo-3- [1-methyl-5 -Nitro-imidazolyl- (2)]-tetrahydro imidazole.

Melting Point: 152 ℃

Example 12

In a suspension in which 1.92 g of 50% sodium hydroxide dispersed in mineral oil was suspended in 25 ml of anhydrous dimethyl formamide, 7.96 g of 1-morpholinocarbonyl-2-oxo-tetrahydroimidazole was dissolved in 15 ml of anhydrous dimethylformamide. The solution is added at a suitable temperature. The suspension is stirred at 50 ° C. for 30 minutes. A solution of 8.2 g of 1-methyl-2-methylsulfonyl-5-nitro-imidazole in 15 ml of dimethylformamide was added over 5 minutes, and the reaction temperature was raised to 95 ° C. and stirring continued for 2 hours. The solvent is removed under reduced pressure and the residue is washed with ether and then iced. The solid thus obtained was filtered and recrystallized with ether to give 1-morpholino carbonyl-2-oxo-3- [1-methyl-5-nitro-imidazolyl- (2)]-at a melting point of 180 ° C. according to the following structural formula. Obtain tetrahydroimidazole.

The starting material 1-molpolycarbonyl-2-oxo-tetrahydroimidazole is prepared as follows. To a stirred solution in which 22.27 g of 1-chloro-carbonyl-2-oxo-tetrahydroimidazole was dissolved in 80 ml of anhydrous benzene, a solution of 26.1 g of morpholine dissolved in 20 ml of benzene was added dropwise. The mixture is refluxed for 4 hours and the resulting product is filtered, treated with saturated NaHCO ₃ solution and filtered. Recrystallization with isopropanol affords 1-morpholinocarbonyl-2-oxo-tetrahydroimidazole having a melting point of 158 ° C.

Example 13

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 off, 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-nitroimida having the structure Obtain the zoleofluoroborate.

Melting Point: 265-267 ℃

Example 14

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)]-tetra The solution in which the hydroimidazole is dissolved is heated under reflux for 16 hours. The solvent is removed under reduced pressure, water is added to the evaporated residue, and the residue is 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 off and recrystallized twice with acetone-methanol to give 1- (methylsulfonyl-2-oxo-3- [1-methyl-4-nitroimidazolyl) at a melting point of 180 to 181 ° C. -(2)]-tetrahydroimidazole is obtained.

Example 15

To 25 ml of dimethylformamide containing 3.0 g of potassium iodide, 3.0 g of 1- (methylthio carbamoyl) -2-oxo-3- [1-methyl-5-nitroimidazolyl- (2)]- Tetrahydrazole added solution 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 16

a) 0.49 g of 1- (methylsulfonyl) -2-oxo-tetrahydroimidazole was added to 5 ml of dimethylformamide with 0.15 g of a 50% suspension of sodium hydroxide added to an inorganic acid for 1 hour at 50 ° C. Stir it. 0.57 g of 1-methyl-2- (methylsulfinyl) -5-nitroimidazole is then added and the solution is heated to 100 ° C. and stirred for 3 hours. The solvent is evaporated off under reduced pressure and water is added to the residue. The crystalline precipitate was filtered off and recrystallized from acetone-methanol to give 1- (methylsulfonyl) -2-oxo-3- [1-methyl-5-nitroimidazolyl- (2)]-tetra having a melting point of 202 to 204 캜. Hydroimidazole is obtained, which is the same as that prepared in Example 4 above.

b) 1-methyl-2- (methylsulfinyl) -5-nitroimidazole used as starting material in the reaction is prepared as follows. A solution containing 5 g of 30% hydrogen peroxide and 3.4 g of 1-methyl-2- (methylmercapto) -5-nitroimidazole in 20 ml of methoxyethanol with titanium dioxide just prepared for 6 hours at 100 ° C Heat it. Then, diluted with water and filtered, the filtrate is extracted with chloroform. Evaporation of the chloroform layer yields 2.5 g of oil which solidifies slowly upon standing. This solidified material was recrystallized once each as ethanol and chloroform-ether to give 1-methyl-2- (methylsulfinyl) -5-nitroimidazole.

Example 17

a) 30 ml of 1- (N, N-diethylsulfamoyl) -2-oxo-tetra in 50 ml of anhydrous dimethylformamide while stirring the suspension in which 6.1 g of 50% sodium hydride was added to 20 ml of anhydrous dimethylformamide; Hydroimidazole added solution is added over 15 minutes. The reaction mixture was stirred for 1 hour at 50 ° C. under nitrogen gas, and 40 ml of anhydrous dimethylformamide was added to a solution of 25.6 g of 1-methyl-2-methylsulfonyl-5-nitro-imidazole at once. give. The reaction mixture is heated to 95 ° C. for 3 hours with stirring under nitrogen gas.

The solvent is distilled off under reduced pressure, and 100 ml of water is added to the residue, and the obtained suspension is extracted with ethylene dichloride, dehydrated and evaporated to dryness. The residue is chromatographed on a silica gel column and the fraction is eluted as 1% methanol in chloroform to give crystalline material. When recrystallized with methylene chloride and ether, 1-N, N-diethyl sulfamoyl-2-oxo-3- [1-methyl-5-nitroimidazolyl- (2)]-tetrahydro has a melting point of 146 to 147 ° C. Imidazole is obtained.

b) The starting material in the reaction is prepared as follows.

A mixture of 51.6 g of ethylene urea and 90 g of N, N-diethyl-sulfamoyl-chloride is heated at 110 ° C. for 3 hours. The reaction mixture is cooled, treated with 300 ml of methanol, filtered and the filtrate is evaporated to dryness, the residue is dissolved in 5% methanol in chloroform and chromatographed on a silica gel column. Elution of the fractions with 5% methanol in chloroform and recrystallization as a mixture of methylene chloride and hexanes yields 1- (N, N-diethylsulfamoyl) -2-oxo-tetrahydroimidazole having a melting point of 80 to 82 ° C. .

Example 18

a) 30 ml of anhydrous dimethylformamide suspension containing 1.6 g of 50% sodium hydride in mineral oil is stirred, and 5.9 g of 1-pyrrolidinocarbonyl-2-oxo-tetrahydro in 15 ml of anhydrous dimethylformamide. The imidazole added solution is added over 15 minutes. The reaction mixture was stirred for 1 hour at 50 ° C. under a nitrogen gas, followed by addition of 6.6 g of 1-methyl-2-methyl-sulfonyl-5-nitroimidazole in 20 ml of anhydrous dimethylformamide. give. The reaction mixture is heated to 95 ° C. for 1 hour with stirring under nitrogen gas. The solvent is removed by distillation under reduced pressure, the residue is dissolved in water, extracted with methylene chloride, dehydrated and evaporated to dryness. The residue is chromatographed on silica gel and the fractions are eluted as 3% methanol in chloroform to give crystalline material. It was recrystallized from a mixture of methylene chloride and hexane to give 1-pyrrolidino-carbonyl-2-oxo-3- [1-methyl-5-nitro-imidazolyl- (2)]-having a melting point of 155 to 156 占 폚. Tetrahydroimidazole is obtained.

b) The starting material used in the reaction is prepared as follows.

A mixture of 40 g of ethylene urea and 72 g of 1-pyrrolidinocarbonyl chloride (boiling point: 100-104 ° C./4.5 mmHg) is heated at 110 ° C. for 3 hours. The reaction mixture is cooled, 200 ml of chloroform is added thereto, the insoluble substance is filtered off, and the filtrate is evaporated to dryness. The residue was chromatographed on a silica gel column and recrystallized from ethyl acetate eluted with 4% ethanol in chloroform to give 1-pyrrolidino-carbonyl-2-oxo-tetrahydroimidazole having a melting point of 153 to 154 ° C. .

Example 19

a) 20 ml of dimethylformamide was added to a suspension of 3.5 g of 50% sodium hydride while stirring with 40 ml of anhydrous dimethyl formamide, 15.6 g of 1-pyrrolidino-sulfonyl-2-oxo-tetrahydroimidazole The added solution is added over 15 minutes. The reaction mixture was stirred for 1 hour at 50 ° C. under nitrogen gas and a solution of 14.4 g of 1-methyl-2-methyl-sulfonyl-5-nitroimidazole was added to 30 ml of anhydrous dimethylformamide at once. The reaction mixture is heated at 95 ° C. for 3 hours with stirring under nitrogen gas. The solvent is distilled off under reduced pressure and the residue is treated with 50 ml of water to form a crystalline precipitate. It was filtered and recrystallized from a mixture of methylene chloride and ether to give 1-pyrrolidino-sulfonyl-2-oxo-3- [1-methyl-5-nitroimidazolyl- (2)]-tetrahydro at a melting point of 226 ° C. Imidazole is obtained.

b) Starting materials used in the reaction are prepared as follows.

A mixture of 30 g of ethylene urea and 64.5 g of pyrrolidino-1-sulfonylchloride (boiling point: 120 ° C./11 mmHg) is heated at 110 ° C. for 3 hours. The reaction mixture is cooled and dissolved in 300 ml of chloroform, filtered and the filtrate is evaporated off and the residue is redissolved in 2.5% methanol in chloroform and chromatographed on a silica gel column. The fraction was eluted with 2.5% methanol in chloroform and recrystallized with ethyl acetate to give 1-pyrrolidino-sulfonyl-2-oxo-tetrahydroimidazole having a melting point of 150 ° C.

Example 20

a) 1.92 g of 50% sodium hydride in mineral oil was added to 20 ml of anhydrous dimethylformamide, and 9.3 g of 1-piperidino-sulfonyl-2-oxo-tetrahydroimidazole was added to 15 ml of dimethylformamide. The solution is added dropwise at room temperature. The reaction temperature is raised to 50 ° C. and stirred at that temperature for 30 minutes. To this was added a solution of 8.2 g of 1-methyl-2-methylsulfonyl-5-nitroimidazole added to 25 ml of dimethylformamide at once, followed by maintaining the reaction temperature at 100 ° C. for 2 hours. After removal of the solvent under reduced pressure, water containing freezing is added to the residue. The residue obtained by removing the aqueous layer was treated with isopropanol-ether (5: 1) to recrystallize the yellow precipitate with ethyl acetate, thereby obtaining 1-piperidino-sulfonyl-2-oxo-3- [1-methyl-5-nitroimida. Zolyl- (2)]-tetrahydroimidazole is obtained.

Melting Point: 192 ℃

b) Starting material in the reaction is prepared as follows.

36 g of piperidino sulfonyl chloride (boiling point: 130 ° C./11 mmHg) was added to 17.4 g of ethylene urea, and the reaction mixture was heated to a temperature of 100 ° C. under nitrogen gas for 3 hours, followed by cooling. Is treated with methanol-isopropanol (1: 1). Recrystallization with methanol gives a granular 1-piperidinosulfonyl-2-oxo-tetrahydroimidazole having a melting point of 201 占 폚.

Example 21

a) 50% sodium hydride in mineral oil in a solution of 8 g of 1- (methylsulfonyl) -2-oxo-4-methyl-2,3,4,5-tetrahydroimidazole in 30 ml of anhydrous dimethylformamide 2.2 g of slurry is added. The mixture is stirred at room temperature for 1 hour and a solution of 9.2 g of 1-methyl-2-methanesulfonyl-5-nitroimidazole dissolved in 20 ml of anhydrous dimethylformamide is added. The mixture was stirred at room temperature for 3 hours, then the solvent was removed in vacuo, the residue was dissolved in water and cooled, and then the obtained crystalline precipitate was recrystallized from a mixture of methylene chloride and ether under filtration to give a melting point of 199 to 200 캜. (Methylsulfonyl) -2-oxo-3- [1-methyl-5-nitro-imidazolyl- (2)]-4-methyl-tetrahydroimidazole is obtained.

b) The starting material 1- (methylsulfonyl) -2-oxo-4-methyl-2,3,4,5-tetrahydroimidazole is prepared as follows. A mixture of 10 g of 4-methyl-2-imidazolidinone and 11.5 g of methanesulfonyl chloride is stirred at 120 ° C. for 3 hours with stirring. At this time, nitrogen chloride is continuously supplied to remove hydrogen chloride. After cooling, water is added and the mixture is heated in a steam bath until crystalline powder is formed. It is filtered and chromatographed on a silica gel column using chloroform as eluent. The fraction eluted with a chloroform-methanol (97: 3) mixture is determined with a mixture of methylene chloride and hexanes to give the title compound at a melting point of 129 to 130 ° C.

Example 22

2.4 g of 50% sodium hydride mineral oil suspension is added to 60 ml of dimethylformamide solution containing 8.2 g of 1- (methylsulfonyl) -2-oxo-2,3,4,5-tetrahydroimidazole. The mixture was allowed to stand at room temperature for 1 hour, and 20 ml of dimethylformamide containing 12.45 g of 1- (β-methoxyethyl) -2-methylsulfonyl-5-nitroimidazole was added thereto, followed by reaction mixture. The mixture is allowed to stand at room temperature for 4.5 hours. Dimethylformamide is evaporated off in vacuo and crystallized by adding 30 g of ice. Filtration of the crystalline residue and recrystallization from acetone / methanol and ether gave 1- (methylsulfonyl) -2-oxo-3- [1-β-methoxyethyl-5-nitro-imidazolyl- ( 2)]-tetrahydroimidazole.

Melting Point: 126 ~ 127 ℃

Starting materials are prepared as follows.

a) β-methoxy-ethylamino-acetaldehyde-diethylacetyl

A mixture of 170 ml 65% aqueous solution of β-methoxyethylamine and 90 g bromine acetaldehyde-diethyl acetal is heated at 120 ° C. for 10 hours. The reaction mixture was treated with 75 g of potassium hydroxide while cooling, filtered and the filtrate was dried over anhydrous potassium carbonate and distilled at 115-120 ° C./12 mmHg to give β-methoxy-ethylamino-acetaldehyde-diethylacetal. Lose.

b) 1- (β-methoxyethyl) -2-mercapto imidazole

50 ml of anhydrous ethanol solution containing 9.55 g of β-methoxyethylamino-acetaldehydediethylacetal are treated sequentially with 6 g of potassium thiocyanate and 27.5 ml of 2N hydrochloric acid. The solvent is removed by evaporation in vacuo and the residue is extracted with acetone. This extract is added in small amounts and treated with ether. The resulting residue is crystallized from a mixture of acetone / ether to give 1- (β-methoxyethyl) -2-mercaptoimidazole.

Melting Point: 92-95 ℃

c) 1- (β-methoxyethyl) -2-methylmercapto-5-nitro-imidazole

110 ml of 10N sodium hydroxide is added in one portion while stirring and cooling in 90 ml of methanol solution containing 15.8 g of 1- (β-methoxyethyl) -2-mercapto imidazole. 6.6 ml of methyl iodide was added dropwise to the reaction mixture over 1 hour, further stirred at 10 ° C. for 2 hours, methanol was removed under vacuum at 50 ° C., the residue was dissolved in water, extracted with methylene chloride, and evaporated. To dry.

82 ml of nitrous acid was added dropwise to the compound (15.3 g) obtained above under nitrogen atmosphere, and the reaction mixture was slowly heated while stirring and left at 100 ° C. for 40 minutes. After cooling to room temperature the residue is treated with 50 g of ice cubes, neutralized with 50% sodium hydroxide solution, extracted with methylene chloride and evaporated to dryness. Crystallization of the residue from hexanes affords the title compound.

Melting Point: 44-45 ℃

d) 1- (β-methoxyethyl) -2-methylsulfonyl-5-nitroimidazole

To 80 ml of methylene chloride solution containing 26 g of 1- (β-methoxyethyl) -2-methylmercapto-5-nitroimidazole is added dropwise 550 ml of 0.48 g monoperphthalic acid solution at 10 to 15 ° C. The reaction mixture is stirred at room temperature for 20 hours and then heated to reflux for 1 hour, then cooled to room temperature and filtered. The filtrate is washed sequentially with sodium carbonate solution and water and evaporated to dryness. Crystallization of the residue from methylene chloride and hexanes yields 1- (β-methoxyethyl) -2-methylsulfonyl-5-nitro-imidazole.

Melting Point: 92-93 ℃

Claims (1)

A method for preparing the compound of formula (I) and acid addition salts thereof by reacting a compound of formula (II) with a compound of formula (III).

In the above structural formula _One of R ₁ and R ₂ is hydrogen or lower alkyl and the other is nitro, R ₃ is lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, lower alkyl sulfonyl lower alkyl or amino lower alkyl, R ₄ is oxo or thioxo group, X is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl group, When X is a carbonyl group R ₅ is a lower alkoxy, amino, lower alkylamino, dilower alkylamino group, When X is thiocarbonyl sulfinyl, sulfonyl, R ₅ is lower alkyl, aryl, amino, alkylamino or diloweralkylamino, Alk is a lower alkylene having 2 to 4 carbons in the alkylene group, Z represents an active esterified hydroxy group, a free or etherified mercapto group, an ammonium group, a sulfinyl group or a sulfonyl group.