KR820001588B1 - Process for preparing 1,2 di-substituted-4-haloimidazole-5-acetic acid derivatives - Google Patents

Abstract

Title compds. (I; R1 = H, nitro, amino; R2 = substituted phenyl, furyl, thienyl; R3 = H, lower alkyl; X = halogen), useful as diuretic, were prepd. by hydrolysis of compd.(II) or by alcoholysis with R3OH. Thus, the mixt. of 1-benzyl-2-(p-methoxyphenyl)-4-chloro-5-cyanomethylimidazole 2.8 g, conc HCl 15 ml, water 15 ml and glacial acetic acid 15 ml was refluxed for 5 hr, diluted with water 1l and then ice cooled to give 1-benzyl-2-(p-methoxyphenyl)-4-chloroimidazole-5-acetic acid 4 g. (m.p. 170-180≰C).

Description

Preparation of 1,2-disubstituted-4-haloimidazole-5-vinegaric acid derivative

The present invention relates to a process for the preparation of novel imidazole derivatives having good pharmacological action. In more detail, the present invention has excellent diuretic action, blood pressure lowering action, for example, a general formula useful as a diuretic, blood pressure lowering agent.

Wherein R ¹ is a phenyl group, a furyl group or a thienyl group which may have a halogen, a lower alkyl group, a lower alkoxy group or a di lower alkyl amino group on a ring containing R ² , wherein R ³ is hydrogen or a lower alkyl group X represents a halogen), to provide a 1, 2-disubstituted-4-haloimidazole-5-vinegar acid derivative and a salt thereof. Furthermore, the present invention is also intended to provide an industrially advantageous method for producing the compound (1) and salts thereof. Although many imidazole derivatives are known, 4 (or 5) -halimidazole-5 (or 4) -vinegar derivatives have not been known at all, and of course, no knowledge regarding their physiological activity has been reported.

Regarding the general formula (1), the nitro group and the amino group as R ¹ may be at any position of the benzyl group, and particularly preferably at the p-position. The furyl group and thienyl group as R ² are preferably 2-furyl group and 2-thienyl group, respectively. The phenylfuryl group or thienyl group as R ^{2 may have} a halogen, a lower alkyl group, a lower alkoxy group or a di lower alkyl amino group on the ring. Halogen is preferably chlorine or cancellation as the substitution, and lower alkyl groups may be either straight chain or branched, for example methyl, ethyl, propyl, isopropyl, Isobutyl, tertiary butyl, etc. are mentioned, Especially the thing of C4 is preferable.

The lower alkoxy group may be either linear or branched, and examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and the like, and those having 4 or less carbon atoms are particularly preferable. As the di lower alkyl amino group, those having 4 or less carbon atoms in total, dimethylamino, diethylamino and the like are preferable. These substitutions may be in any position on the ring of a phenyl group, a furyl group, and a thienyl group, and in the case of a phenyl group, it is preferable to be located in the p-position especially. The lower alkyl group as R ³ is linear. Any branched one may be used, for example, methyl, ethyl, propyl, isobutyl or the like having 4 or less carbon atoms, and methyl and ethyl are particularly preferable. Examples of the halogen represented by X include chlorine, cancellation and the like.

The compound (1) described above may be, for example, a general formula

The compound represented by (wherein R ¹ , R ² and X have the same meanings as described above) can be produced in high yield by solvolysis of the compound. As solvolysis, either hydrolysis or alcoholic decomposition may be used. When hydrolysis is applied, compound (1) in which R ³ is hydrogen is produced, and compound (1) in which R ³ is lower alkyl group can be obtained by applying alcoholic decomposition. Hydrolysis is generally done with acids or alkalis. As the acid, a mineral acid such as sulfuric acid or hydrochloric acid is preferable. The concentration of sulfuric acid in the reaction system is preferably about 40 to 60%, and the concentration of hydrochloric acid is preferably about 10 to 20%, and when compound (II) is difficult to dissolve in them, coexisting about 30 to 50% vinegar acid is difficult. It is advantageous. As alkali, alkali metal hydroxides, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, are preferable, and it is advantageous to use hydrous methanol, hydrous ethanol, etc. as a solvent. Hydrolysis reaction advances by heating, and it is good to heat about 2 to 10 hours normally in the vicinity of boiling point of about 50-150 degreeC especially the solvent to be used.

The compound (1) thus obtained, wherein R ³ is hydrogen, can also be induced into compound (I) having a lower alkyl group as R ^{3 by} esterifying it. This esterification is, for example, an acid catalyst in a compound (I) wherein R 3 is hydrogen in a solvent containing an alcohol corresponding to a desired alkyl group (alcohol design or a mixture of benzene, 1, 2-dimethoxy ethane and the like). It can be easily achieved by heating in the presence of (hydrogen chloride, sulfuric acid, methane sulfonic acid, etc.) and removing the water produced as necessary out of the reaction system.

Gaal alcohol decomposition is generally carried out by adding compound (II) to an alcohol corresponding to a lower alkyl group as R ³ by adding an acid and heating. As the acid, photoacids such as sulfuric acid, hydrochloric acid and the like are preferable, and these are preferably used about 1 to 10 times molar (Mol) of the compound (II). It is preferable to heat this reaction to about 50-100 degreeC generally, and it is especially preferable to heat about 1 to 10 hours near the boiling point of the alcohol to be used. Thus, compound (I) in which R ³ is a lower alkyl group can be derived to compound (I) in which R ³ is hydrogen by hydrolysis.

Hydrolysis is performed with alkali or an acid, for example, and alkali is especially preferable. As an alkali, alkali metal hydroxides, such as sodium hydroxide and potassium hydroxide, are preferable. As a solvent, it proceeds by making it react for 5 to 20 hours at about 20-100 degreeC, using hydrous ethanol and a hydrous ethanol.

In addition, in the compound (I) to be produced, when R ¹ is a nitro group, the compound (I) having an amino group can be induced as R ^{1 while} reducing this. As this reduction treatment, a commonly used method, for example, tin-hydrochloric acid, iron-hydrochloric acid, zinc-vinegar acetic acid, catalytic reduction, and the like can be cited. As the contact reduction, 5 to 10% palladium-carbon raninickel, platinum, etc. desirable.

The compound (1) thus produced can be easily isolated from the reaction solution by conventional separation and purification means such as extraction, concentration, neutralization, filtration, recrystallization, column chromatography and the like. Compound (I) can also be obtained as a salt with a base or an acid addition salt according to the kind of R <^1> , R <^2> , R <^3> . That is, compound (I) in which R ³ is hydrogen is a salt with a physiologically acceptable base, for example, a salt with an alkali metal (titanium salt, potassium salt, etc.) by an ordinary method, or of It can be derived from the amount of calcium. Moreover, the compound (I) which has an amino group as R <^1> or a di lower alkylamino group on a R <^2> ring is an acid addition salt which can be physiologically acceptable by a conventional method, for example, a mineral acid salt (hydrochloride, sulfate, etc.). Or the like.

Compound (I) and salts thereof thus produced exhibit excellent diuretic and blood pressure-lowering effects, particularly for mammals (e.g., humans, dogs, rabbits, rats, etc.), for example edema and hypertension due to various causes. It is useful as a therapeutic agent for such diseases. When used as such a medicament, Compound (I) and salts thereof may be mixed with themselves or with suitable pharmacologically acceptable carriers, excipients, diluents, and administered in the form of powders, granules, tablets, capsules, injections, and the like. There is a number. The dosage varies depending on the disease, symptom, administration target, administration method, etc., but when administered as a treatment for essential hypertension in adults, 10 to 100 mg daily for oral administration and 5 to 50 mg daily for intravenous injection 2-3 times It is recommended to administer in divided doses.

Raw material compound (II) used by this invention can be manufactured easily by the combination of well-known reaction as shown below. Each process is briefly described below.

(Wherein R ¹ , R ² and X have the same meanings as above, and Y represents halogen)

According to the method described in 2-amino-3, 3-dichloroacrylonitrile (III) and the aldehyde represented by general formula (IV), according to the method described in Chemical and Pharmaceutical Burlesine, Vol. 24, 9,96 (1976). The 5-formylimidazole derivative represented by general formula (VI) is synthesized via a Schiff base represented by formula (V).

The reaction between the compound (VI) and the benzyl halide represented by the general formula (VII) is generally carried out in a solvent under the WHS of the deoxidizer. As the deoxidizer, alkali metal carbonates such as potassium carbonate and sodium carbonate are preferable. Dimethyl formamide, dimethyl sulfooxide, etc. are preferable as a solvent. It is common to heat reaction at about 100-150 degreeC for 1-2 hours. In this reaction, although 1-benzyl-5-formylimidazole represented by the general formula (VII) is the main product, it is usually a by-product of the isomers represented by the general formula (VII ') and (VII'). ) Is a conventional chemical means.

For example, it is performed by recrystallization or clomatographie. By reduction of (i), 1-benzyl-5-hydrooxy methylimidazole represented by general formula (i) is obtained. As a reduction method, it is advantageous to make it react with 0.5-1 time molar sodium borohydride for 1-2 hours at a room temperature, using alcohol as a solvent.

Chlorination of (i) gives 1-benzyl-5-chloromethylimidazole represented by general formula (X). As a method of chlorination, it is advantageous to react with thionyl chloride for 1 to 2 hours at room temperature in an inert solvent such as chloroform and benzene. (X) generally does not need to be purified, and after distilling off the solvent and excess thionyl chloride, it is reacted with sodium cyanide to obtain an electrical raw material compound represented by the general formula (II). This reaction proceeds in dimethyl sulfooxide with agitation at room temperature or 50 ° C. for 2 to 3 hours. In order to isolate (II), conventional chemical means, for example, after removing the inorganic substance, can be performed by recrystallization or clomatographie.

Hereinafter, the present invention will be described in more detail with reference to Examples, Reference Examples, and Experimental Examples, but it goes without saying that these are not limitations of the present invention.

Example 1

20 g of 1-benzyl-2-phenyl-4-chloro-5-cyanomethylimidazole was stirred overnight at 145 ° C. in 120 ml of 60% sulfuric acid. The reaction solution was neutralized in an aqueous sodium hydroxide solution with ice cooling. The precipitated precipitate was recrystallized from acetonitrile to obtain 18.9 g of colorless acicular crystal of 1-benzyl-2-phenyl-4-chloroimidazole-5-vinegar acid.

Fusion 161 ~ 163 ℃

Elemental Analysis Value: C ₁₉ H ₁₇ N ₂ O ₃ C11 / 2H ₂ O

Calculated Value: C 62.40% H 4.97% N 7.66% CI 9.71%

Found: 62.01 4.88 7.67 9.33

Example 2

2.8 g of 1-benzyl-2- (p-methoxyphenyl) -4-chloro-5-cyanomethylimidazole was mixed in 15 ml of concentrated hydrochloric acid, 15 ml of water, and 15 ml of glacial vinegar for 15 hours. It was refluxed. When the reaction solution was diluted with 1 L of water and ice-cooled, 2.5 g of colorless plism-like crystals of 1-benzyl-2- (p-methoxyphenyl) -4-chloroimidazole-5-vinegar acid precipitated. Melting Point 192 ~ 194 ℃

Elemental analysis value: C ₁ H ₉₁₇ N ₂ O ₃ C1 · 1 / 2H ₂ O

Calculated Value: C 62.40% H 4.97% N 7.66% CI 9.71%

Found: 62.01 4.88 7.67 9.33

Example 3

5 g of 1-benzyl-2- (p-dimethylaminophenyl) -4-chloro-5-cyanomethyl imidazole was refluxed for 3 hours in a mixed solution of 25 ml of concentrated hydrochloric acid, 25 ml of water, 25 ml of glacial acetic acid. The reaction solution was evaporated to dryness under reduced pressure, the residue was dissolved in 50 ml of water, and sodium hydrogencarbonate was added to adjust pH to 3. The precipitate which precipitated was collected by filtration and recrystallized in hydrated ethanol to obtain 4 g of pale yellow acicular crystal of 1-benzyl-2- (p-dimethylaminophenyl) -4-chloroimidazole-5-vinegar acid. Melting Point 170 ~ 180 ℃

Elemental Analysis Value: C ₂₀ H ₂₀ N ₃ O ₂ C1

Calculated Value: C 64.95% H 5.45% N 11.34% C1 9.58%

Found: 64.83 5.53 11.26 9.22

[Examples 4 to 12]

According to Examples 1-3, the following compounds were obtained.

TABLE 1

Example 13

2 g of 1- (p-nitrobenzyl) -2-phenyl-4-chloroimidazole-5-vinegar acid was dissolved in 100 ml of ethanol, 300 mg of 10% palladium-carbon was added, and the mixture was shaken in a hydrogen stream for 2 hours. The catalyst was filtered off, the filtrate was dried under reduced pressure, and then recrystallized from ethanol nucleic acid to obtain 1.4 g of colorless acicular crystal of 1- (p-aminobenzyl) -2-phenyl-4-chloroimidazole-5-vinegar acid. Melting point: 141-145 캜 (decomposition).

Elemental Analysis: C ₁₈ H ₁₆ N ₃ O ₂ Cl

Calculated Value: C 63.25% H 4.72% N 12.29% C1 10.37

Found: 62.66 4.70 11.91 9.96

Example 14

6.53 of 1-benzyl-2-phenyl-4-chloroimidazole-5-vinegar was dissolved in 100 ml of ethanol, the hydrogen chloride was saturated under ice cooling, and stirred at room temperature overnight. The reaction solution was evaporated to dryness under reduced pressure, followed by a column of 200 g of silica gel, eluted with benzene chloroform (1: 1), and crystallization of 1-benzyl-2-phenyl-4-chloro-5-ethoxycarbonylmethylimidazole 2.28 g was obtained. Colorless needle crystal recrystallized from diethyl ether-hexane, melting point 72-73 degreeC

Elemental Analysis Value: C ₂₀ H ₁₉ N ₂ O ₂ Cl

Calculated Value: C 67.70% H 5.40% N 7.89%

Found: 67.55 5.23 7.84

Example 15

3.08 g of 1-benzyl-2-phenyl-4-chloro-5-cyanomethylimidazole was dissolved in 20 ml of ethanol containing 0.3 g of hydrogen chloride and heated to 80 ° C. in a sealed tube for 10 hours. The reaction solution was dried under a reduced pressure, and then treated in the same manner as in Example 14 to obtain 0.9 g of 1-benzyl-2phenyl-4-chloro-5-ethoxycarbonylmethylimidazole. Melting Point 72 ~ 77 ℃

1 g of the product was dissolved in 20 ml of ethanol, 5 ml of 2-N-sodium hydroxide aqueous solution was added, and the mixture was self-suspended for 5 hours. When 5 ml of 2N hydrochloric acid was added to the reaction solution and ethanol was distilled off under reduced pressure, 0.5 g of colorless needles of 1-benzyl-2-phenyl-4-chloroimidazole-5-vinegar acid precipitated. Melting Point 161 ~ 163 ℃

Example 16

3.27 g of 1-benzyl-2-phenyl-4-chloroimidazole-5-vinegar acid is dissolved in 20 ml of ethanol, and 0.4 g of sodium hydroxide is dissolved in 2 ml of water. When 20 m of acetone and then 20 ml of ether were added and allowed to cool, 3.5 g of white crystalline powder of 1-benzyl-2-phenyl-4-chloroimidazole-5-sodium acetate salt was precipitated.

Melting Point 288 ~ 292 ℃

Example 17

When using compound (I) of this invention as a hypertensive therapeutic agent, it can be used, for example by the following prescription.

2/3 of (1), (2), (3) and (4) and 1/2 of (5) are granulated after mixing. The remainder (4) and (5) are put into these granules and press-molded with tablets.

After half of (1), (2), (3) and (4) are mixed, they are granulated. Thereafter, the remaining (4) is added to the granules, and the whole is enclosed in a gelatin capsule.

(1), (2), and (3) are dissolved in distilled water for injection so as to have a total amount of 2 ml, and are filled in ampoules. The previous step is carried out in a sterile state.

Reference Example 1

15 g of 2-amino-3-, 3-dichloroacrylonitrile and 17.8 g of p-butoxybenzaldehyde were refluxed for 9 hours using a water separator in 200 ml of toluene. The reaction solution was dried under reduced pressure, and 100 ml of metarol was added to the residue to cool, and 25 g of yellow needles of 2- (p-butoxybenzylidene) amino-3,3-dichloroacrylonitrile were precipitated. Melting | fusing point 74 degreeC This product was melt | dissolved in 500 ml of ether, saturated hydrogen chloride under ice cooling, and was left to stand at room temperature for 3 days. Precipitated crystals were filtered off, and 300 ml of water was added thereto and heated at 90 to 100 ° C for 1 hour. After cooling, the precipitate was recovered by filtration and recrystallized with hydrous ethanol to obtain 20 g of brown needles of 2- (p-butoxyphenyl) -4-chloro-5-formylimidazole. Melting point 185-187 ℃

Reference Example 2

40 g of 2-amino-3,3-dichloroacrylonitrile and 40 g of dimethylaminobenzaldehyde were refluxed for 13 hours using a water separator in 400 ml of toluene. When the reaction solution was concentrated to about 50 ml and allowed to cool, 60 g of yellow needles of 2- (p-dimethylaminobenzylidene) amino-3,3-dichloroacrylonitrile was precipitated. Melting | fusing point 134-135 degreeC This product was melt | dissolved in 800 ml of dioxanes, and the hydrogen chloride was saturated at room temperature, and it stirred at 50-60 degreeC for 2 days. The precipitate which precipitated after cooling was collected by filtration, suspended in 600 ml of water, and stirred at 90 ° C. for 1 hour while neutralizing with sodium hydrogencarbonate.

Reference Example 3

The following compound was obtained based on the said reference example 1,2.

TABLE 2

Reference Example 4

206.5 g of 2-menyl-4-chloro-5-formylimidazole, 133 g of benzyl chloride and 103.5 g of anhydrous potassium carbonate were stirred in 150 ml of dimethylformolaldehyde at 110-120 ° C for 1 hour. The reaction solution was poured into an ice-water solution, and the precipitated precipitate was collected by filtration, recrystallized twice from acetonitrile to obtain 143 g of colorless acicular crystal of 1-benzyl-2-phenyl-4-chloro-5-formylimidazole. Melting Point 117 ~ 118 ℃

Reference Example 5

10.3 g of 2-phenyl-4-chloro-5-formylimidazole, 1.3 g of p-nitrobenzyl bromide and 5.2 g of anhydrous potassium carbonate were stirred at 50 to dimethylformamide at 110 to 120 ° C. for 2 hours. The reaction solution was poured into ice water, and the precipitated precipitate was placed on a column of 100 g of silica gel and eluted with chloroform. The first fraction was concentrated to dryness and then recrystallized from ethanol to give 13.6 g of colorless needles of 1- (p-nitrobenzyl) -2-phenyl-4-chloro-5-formylimidazole. Melting Point 150 ~ 152 ℃

Reference Example 6

The following compounds were obtained in accordance with the above Reference Examples 4 and 5.

TABLE 3

Reference Example 7

29.65 g of 1-benzyl-2-phenyl-4-chloro-5-formylimidazole is dissolved in 300 ml of methanol, and 1.23 g of sodium borohydride is added little by little while stirring at room temperature to react at exotherm. After 1 hour, the solvent was distilled off, cold water was added to the residue, and colorless crystals of insoluble 1-benzyl-2-phenyl-4-chloro-5-hydroxymethylimidazole were collected by filtration. 30.36 g, Melting point 175-177 ° C

Reference Example 8

4 g of 1-benzene-2- (p-methoxyphenyl) -4-chloro-5-formylimidazole was dissolved in 45 ml of methanol, 0.18 g of sodium borohydride was added, and the mixture was stirred at room temperature for 2 hours. 10 ml of water and 0.3 ml of glacial acetic acid were added to the reaction solution, and the mixture was left to cool, and 3 g of colorless needles of 1-benzyl-2- (p-methoxyphenyl) -4-chloro-5-hydroxymethylimidazole was precipitated. Melting Point 148 ~ 149 ℃

Reference Example 9

The following compound was obtained based on the said reference example 7,8.

TABLE 4

Reference Example 10

29.88 g of 1-benzyl-2-phenyl-4-chloro-5-hydroxymethylimidazole is suspended in 150 ml of chloroform, and 23.8 g of thionyl chloride is added dropwise at room temperature while stirring to exothermicly react. The reaction solution was dried under reduced pressure, and washed with benzene to obtain 35.4 g of a pale yellow powder of 1-benzyl-2-phenyl-4-chloro-5-chloromethylimidazole. 25.2 g of finely ground sodium cyanide is added to 85 ml of dimethylsulfooxide little by little to form a suspension. While stirring this, 85 ml of the dimethylsulfooxide solution as the chloromethyl compound is added dropwise. After dropping, the mixture was stirred at room temperature for 2 hours, and then the reaction solution was poured into ice water. 500 ml of ethyl vinegar is extracted, and the extract is washed with water and dried. The solvent was distilled off from this solution, the residue was suspended in a column of 200 g of silica gel, eluted with benzene-ethyl acetate (19: 1), and 1-benzyl-2-phenyl-4-chloro-5-cyanomethyl 1.2 g of a yellow powder of midazole were obtained. Some were recrystallized from diethyl ether. Melting Point 121 ~ 122 ℃

Reference Example 11

7.5 g of 1-benzyl-2- (p-methylaminophenyl) -4-chloro-5-hydroxymethylimidazole is suspended in 31 ml of chlorom, and 3.1 ml of thionyl chloride is added dropwise. After stirring at room temperature for 2 hours, the reaction solution was dried under reduced pressure, 30 ml of toluene was added to the residue, and dried under reduced pressure. This product is melt | dissolved in 25 ml of dimethyl sulfooxides, and it is dripped at 40-50 degreeC in the suspension of 6.2 g of dimethyl sulfooxides of sodium cyanide. After stirring for 2 hours at the same temperature, 300 ml of chloroform was added and washed twice with 400 ml of water. The chloroform layer was dried under reduced pressure, and the residue was suspended in a column of 80 g of silica gel, and eluted with chloroform. The main fractions were collected and dried under reduced pressure to obtain 5 g of pale yellow crystals of 1-benzyl-2- (p-dimethylaminophenyl) -4-chloro-5-cyanomethylimidazole. A part was recrystallized in methanol to obtain light yellow needles. Melting Point 147 ~ 149 ℃

Reference Example 12

The following compound was obtained according to the Reference Examples 10 and 11.

TABLE 5

Experimental Example

Representative diuretic action of the compound (1) of the present invention is shown in Table 6. The test method was performed in accordance with WLLipschitz's method (Journal. Of. Pharmacologic. & Experimental. Therapodex (J. harmacol. Exp. Ther), Vol. 79, P97, 1943). I did it by writing. The numerical value in a table | surface shows the value of the drug administration group when control is set to 100. In other words

TABLE 6

^* : p <0.05, ^** : p <0.01, ^*** : p <0.001

Claims (1)

A process for producing an association or salt thereof, wherein the compound represented by the following formula (II) is hydrolyzed or alcohol-decomposed with an alcohol of the general formula R ³ OH.

In the above formula R ¹ represents a toil, nitro group or amino group, R ² represents a phenyl group, a furyl group or a dienyl group even if a halogen, a lower alkyl group, a lower alkoxy group or a dilower alkyl amino group is present on the ring, and R ³ represents hydrogen or Lower alkyl group, and X represents halogen.