KR800001418B1 - 1-methyl-2-(phenyl-oxymethyl)-5-nitro-imidazoles - Google Patents

Abstract

Title compds.(I; A = S, sulfoxide group, R1 = methyl, or ethyl; R2 = methyl, halogen), useful as protozoacides, were prepd. by reaction of nitroimidazole(II; X = halogen, acyloxy group, arylsulfonyloxy group) with phenol or its alkaline metal salt or ammonium salt(III; Y = H, alkaline metal, ammonium) followed by oxidation of intermediate sulfide compd. Thus, K2CO3 13.8 g and 1-methyl-2-chloromethyl-5-nitroimidazole 17.6 g were added in the 3-methyl-4-methylmercaptophenol 15.4 g in dimethylformamide 30ml soln. and stirred for1hr at 25≰C to give 1-methyl-2-(3-methyl-4-methylthiophenyl-oxymethyl)-5-nitroimidazole 21.7g.

Description

Method for preparing 1-methyl-2- (phenyl-oxymethyl) -5-nitro-imidazole

The present invention relates to a process for preparing 1-methyl-2- (phenyl-oxymethyl) -5-nitro-imidazole of the following structural formula (I), which is useful as a therapeutic agent for protozoa.

In the above structural formula

A is sulfur or a sulfoxide group (-so-)

R ₁ is methyl or ethyl

R ₂ is methyl or halogen.

German patent application P 2 531 303.5 describes the preparation of 1-methyl-2- (phenyl-oxymethyl) -5-nitro-imidazoles of the following structural formula and the use of pharmaceutical compositions.

In the above structural formula

A is sulfur or a sulfoxide group (-so-)

R is a C 1 to C 3 straight or branched chain alkyl group such as methyl, ethyl, propyl or isopropyl. 1-Methyl-2- (phenyl-oxymethyl) -5-nitroimidazole of the structural formula (I) according to the present invention is prepared as follows. That is, the nitro imidazole of the following structural formula (II) is reacted with the phenol of the following structural formula (III), or an alkali metal salt or an ammonium salt thereof to prepare a compound of the structural formula (I), and optionally, the resulting sulfide compound is oxidized to form sulfoxide. .

In the above structural formula

X is halogen such as fluorine, chlorine, bromine or iodine; Acyloxy groups such as acetoxy, propionyloxy, butyryloxy, benzoyloxy, toloyloxy or nitrobenzoyloxy; Or an arylsulfonyloxy group, such as a benzene-sulfonyloxy, toluene-sulfonyloxy or nitrobenzene-sulfonyloxy group;

Y is hydrogen, alkali metal (particularly sodium, potassium) or ammonium and A, R ¹ and R ² are as described above.

The compounds of the formula (II) as starting materials include 1-methyl-2-chloro-, 2-bromo-, 2-urodo-methyl-5-nitro-imidazole, 1-methyl-2-acetyloxy, -2-benzoyloxy, -2- (4-nitrobenzoyloxy)-, -2- (4-toluenesulfonyloxy) -methyl-5-nitro- imidazole, etc. are mentioned.

The starting material of formula (II) was prepared by reacting 1-methyl-2 hydroxymethyl-5-nitro-imidazole (DOS 1 470 102) with thionyl halide according to the method described in German Publication 1 595 929. Or by reacting with acetyl, benzoyl, 4-nitrobenzoyl or 4-toluene sulfonyl halide or anhydride.

Compounds of the structural formula (III) as starting materials include 3-methyl-, 3-fluoro-, 3-chloro-, 3-bromo-, 3-urodo-4-methyl- and 4-ethyl-mercaptophenol , 3-methyl-, 3-fluoro-, 3-chloro-, 3-bromo-, 3-yodo-4-methyl-, 4-ethyl-sulfinyl-phenol and the like.

Instead of the free phenols, these alkali metal salts or ammonium salts may be used.

The starting material of formula (III) can be prepared by reacting a 4-mercaptophenol substituted in 3-position with 1 molar equivalent of dialkyl-sulfate in the presence of 1 molar equivalent of alkali.

Di-methyl- or di-ethyl-sulfate is used as the dialkyl-sulfate.

Alkyl-sulfinyl-phenols are prepared by the reaction of alkyl-mercapto-phenols with one molar equivalent of an oxidizing agent such that hydrogen peroxide or peracid (e.g. peracetic acid, perbenzoic acid, m-chloro-perbenzoic acid), nitric acid Or chromic acid.

The reaction of the present invention is carried out with the same amount of starting material in the presence of a solvent or a dispersion medium.

In the reaction of the present invention, it is preferable to use a polar solvent, and alcohols such as methanol, ethanol, propanol, isopropanol, butanol, 2-methoxy and 2-ethoxy-ethanol; Ketones such as acetone, diethyl ketone, methyl-ethyl ketone and methyl isobutyl ketone; Amides such as dimethylformamide, diethylacetamide, N-methylpyrrolidone, tetramethyl-urea, hexamethylphosphoric acid triamide and dimethyl sulfoxide; Heterocyclic bases such as pyridine, picoline or quinoline.

When using the free phenol of formula III, an acid-binder is also used. Acid binders include bases such as triethyl amine or pyridine, alkali or alkaline earth metal carbonates and bicarbonates, hydroxides and alkoxides such as methoxide, ethoxide and butoxide.

The reaction temperature of the present invention is advantageously performed at 0 ° C to 80 ° C but at room temperature and the reaction time is several minutes to several minutes.

The sulfides of formula (I) (A = -s-) obtained according to the process of the present invention are converted to the corresponding sulfoxides (A = -so-) by oxidation. The oxidation reaction is effective to use the first molar equivalent of oxidizing agent, and the oxidizing agent includes hydrogen peroxide or peracid (e.g. peracetic acid, perbenzoic acid, m-chloro- and benzoic acid) and nitric acid or chromic acid. It is carried out at ℃.

Separation of the product of the present invention is effective to distill, remove the solvent or dilute the reaction solution with water. If necessary, it is purified by recrystallization with a suitable solvent or mixture of solvents.

The 1-methyl-2- (phenyl-oxymethyl) -5-nitro-imidazole of formula (I) according to the invention is suitable for the treatment of diseases caused by protozoa in humans and animals, for example Trichomonas berg It is effective in treating diseases caused by the infection of Trichomonas Vaginalis and Entamoeba histolytica.

Moreover, they are very active against bacteria and fungi. The product of the present invention can be orally or topically administered.

When administered orally, the product is formulated in the form of a tablet or capsule containing 10 to 750 mg (daily dose) of the active substance and a pharmaceutically compatible carrier and / or adjuvant and in the form of a gel, cream, ointment or suppository upon topical administration.

The following examples illustrate the invention.

Example 1

1.1 1-Methyl-2- (3-phenyl-4-methylthiophenyl) -oxymethyl) -5-nitroimidazole

13.8 g (0.1 mole) of potassium carbonate powder was added to a solution of 15,4 g (0.1 mole) of 3-methyl-4-methyl-mercaptophenol in 30 ml of dimethylformamide, followed by 17.6 g (0.1 mole) of A solution of 1-methyl-2-chloromethyl-5-nitro-imidazole dissolved in 40 ml of dimethylamide was added dropwise while stirring at 25 ° C.

Cooling with ice water makes the temperature rise by mild exothermic reaction below 35 ℃. The mixture was stirred at 25 ° C. for 1 hour, poured into ice water, and the precipitate was suction filtered, washed with water and charcoal was added and recrystallized from methanol to give 1-methyl-2- (3-methyl-4) as a yellow crystal having a melting point of 108 ° C. 21.7 g (74% of theory) of -methylthiophenyl-oxymethyl) 5-nitro-imidazole are obtained.

The following compounds can be prepared according to the method described in Example (I).

1.2 1-methyl-2- (3-methyl-4-ethylthiophenyl) having a melting point of 80 ° C. from 1-methyl-2-chloro-5-nitroimidazole (MCNI) and 3-methyl-4-ethylmercaptophenol -Oxymethyl) -5-nitro-imidazole is obtained.

1.3-Methyl-2- (3-chloro-4-methylthiophenyl-oxymethyl) -5-nitro-imidazole having a melting point of 114 ° C. is obtained from MCNI and 3-chloro-4-methylmercaptophenol.

1.4-Methyl-2- (3-chloro-4-ethylthiophenyl-oxymethyl) -5-nitro-imidazole having a melting point of 86 ° C. is obtained from 1.4 MCNI and 3-chloro-4-ethylmercapto phenol.

Example 2 (Oxidation)

2.1 1-Methyl-2- (3-methyl-4-methylsulfinyl-phenyl-oxymethyl) -5-nitro-imidazole

17.25 g of a solution of 29.3 g (0.1 mol) of 1-methyl-2- (3-methyl-4-methylthiophenyl-oxymethyl) -5-nitro-imidazole in 200 ml of chloroform was stirred at 25 ° C. (0.1 mol) of 3-chloroperbenzoic acid is added dropwise to a solution dissolved in 70 ml of chloroform. The reaction mixture is stirred at 25 ° C. for 1 hour, shaken with sodium carbonate solution, the chloroform phase is separated, dehydrated over sodium sulfate, concentrated and evaporated. The residue was recrystallized from ethanol with charcoal added to give 21.0 g of 1-methyl-2- (3-methyl-4-methylsulfinyl phenyl-oxymethyl) -5-nitro-imidazole as a yellow crystal having a melting point of 121 ° C. (68% of theory).

The following compounds can be prepared according to the methods described in Example 2:

2.2 1-Methyl-2- (3-methyl-4-ethylthiophenyl-oxymethyl) -5-nitro-imidazole 1-methyl-2- (3-methyl-4-ethylsulfinylphenyl-oxymethyl ) -5-nitro-imidazole is obtained.

2.3 1-Methyl-2- (3-chloro-4-methyl-sulfinylphenyl-oxy from 1-methyl-2- (3-chloro-4-methylthiophenyl-oxymethyl) -5-nitro-imidazole Methyl) -5-nitro-imidazole is obtained.

2.4 1-Methyl-2- (3-chloro-4-ethylthiophenyl-oxymethyl) -5-nitro-imidazole 1-methyl-2- (3-chloro-4-ethylsulfinylphenyl-oxymethyl ) -5-nitro-imidazole is obtained.

Claims (1)

The nitro-imidazole of the following formula (II) is reacted with a phenol of the following formula (III) or an alkali metal or ammonium salt thereof and optionally, the resulting sulfide compound is oxidized to obtain a sulfoxide compound. A method for producing 1-methyl-2- (phenyl-oxymethyl) -5-nitro-imidazole of a compound.

Wherein A is sulfur, or sulfoxide group (-so-), R ¹ is methyl or ethyl, R ² is methyl or halogen, X is halogen, acyloxy group or arylsulfonyloxy group and Y is hydrogen, alkali Metal or ammonium.