DE1795342A1 - 1-lower-alkyl-2-hydroxymethyl-5-nitro-imidazoles and process for their preparation - Google Patents

Description

l-lower-alkyl-2-hydroxymethyl-5-uitrO'-imidazole and methods of making them

The present invention relates to l-low-alkyl-2-hydroxymethyl-5-nitroimidazole, which against infections by. Parasites are valuable. The invention also relates to the production of the new imidazoles.

Known verschiedenenNitroimidazolverbindungen 1st "that they are frichomoniasis useful against GeflUgelcrkrankung Histomoniasis and / or against the protozoa '. Examples of such substances include l- (2-hydroxyethyl) -5-

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nitroimidazole, l ^ a-pimethyl-S-nitroimidazole, l-methyl-5-nitroimidazole and 1- (2-hydroxyethyl) -2-raethyl-5-nitroimidazole.

Histomoniasis is a poultry disease caused by the protozoal parasite Kiatomonas meleagridis. This disease, which affects turkeys or turkeys, is also known as turkey blackhead or enterohepatitls. It is a significant economic problem in the turkey farming industry because it spreads rapidly among turkey flocks and mortality rates can be as high as 80%. The compounds currently available for the treatment of blackhead turkey have not yet proven to be completely satisfactory because they allow the development of residual sternia in the infecting organism or lead to undesirable side effects when fed to the poultry in the quantities required to treat the disease. So the search for new and improved compounds against histomoniasis has not stopped.

TTlchomoniaslß is another protozoal disease that caused by Trichomönaa vaginalis. T. vaglrialis mainly infects the vagina in humans and is the etiological cause of a very disturbing and widespread

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This form of vaginal inflammation known as T. vaginalis Vaginitis is known. The drugs available up to now for the treatment of this disease have certain Limitations and Disadvantages «so that also in this area improved medicaments for combating triohomoniasis are needed.

The invention relates to l-lower-alkyl-2-hydroxyraethyl-5-nitroimidazoles of the general Forasel

where R is a lower alkyl radical, such as methyl, Ethyl, propyl or butyl.

According to the invention, the new l-lower-alkyl-2-hydroxyethyl-5-nitroimidazoles are synthesized by the process shown in the following scheme. '' ν, '-,

N »p-— η-

^ J ₂₂ I ^ j ₂ glj ^

ι- t. ι

H H R

ir ί πι

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In the above formulas, K denotes a lower alkyl radical.

To prepare the starting compound II for the process according to the invention, 2-hydroxymethylimidazole is nitrated to form 2-hydroxyniethyl-5-nitroimidazole. This nitration step is carried out by contacting the hydroxyraethyl compound with a suitable nitrating agent. Nitric acid in the presence of boron trifluoride is preferably used as the nitrating agent. However, acetyl nitrate or sulfur trioxide nitric acid are also satisfactory. To achieve the best results, it is useful that the hydroxymethyl substituent by esterification. or etherification is protected from nitration. It is advisable to prepare a lower alkanoic acid ester, such as, for example, the acetic acid ester, by reacting the hydroxymethyl compound with acetic anhydride. Other esters can of course be used * the starting material being treated with the appropriate esterifying agents such as propionic anhydride and the like. The nitration is carried out by treating the ester of 2-hydroxymethylimidazole with the nitrating agent in an anhydrous reaction medium. The reactants can be mixed in the cold and then allowed to warm slowly to room temperature. The Nitrierungsreaktionsgemisöh is then at temperatures ranging from 60 to 100 ⁰ C.

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heated for a short period of time. Acetylnitra.t is used as a nitrating agent used, the reaction is usually practically complete in less than 1 hour, while reaction times of about 2 to 8 hours in the case of nitric acid-boron trifluoride are preferred. The reaction times and temperatures are not particularly critical and can be varied within reasonable limits. It can be seen »that the reaction comes to an end more quickly at higher temperatures. At the end of the nitration the reaction mixture is neutralized with a base and the nitrated imidazole in an organic solvent, such as chloroform, methyl ethyl ketone, butanol or Ethyl acetate, extracted. When an esterified hydroxymethyl group is present, it is hydrolyzed, and the 2-hydroxyethyl-5-nitroimidazole is extracted and purified.

In the process according to the invention, 2 <-hyroxymethyl-5-nitroimidazole is used alkylated in the 1-position by reaction with a low alkylating agent. Suitable alkylating agents are the di-lower alkyl sulfates, such as dimethyl sulfoE ^ diethyl sulfate and the like, or sulfonates such as methylbenzenesulfonate, ethyl p-toluenesulfonate or propylbenzenesulfonate. ".

It is a critical feature of the inventive method

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rens that anionization of the Iraidazola to a minimum is reduced and preferably practically completely suppressed. Otherwise, other undesirable will be alkylated Imidazoles formed. In order to achieve the desired purpose, the alkylation is preferably carried out in the absence carried out a solvent. When a solvent

Satisfactory results are "is considered for some reason to be necessary or appropriate, inert solvents such as Diphenyloxyd, tetramethylene, hexachlorobenzene, naphthalene or diphenyl ether used *. Are connecting using approximately equimolar amounts of the imidazo! And get the alkylating agent. It can however, an excess of up to about 50 % of the alkylating agent will be used without adversely affecting the reaction.

A 1st action substantially completed to 175 ⁰ C in 5 minutes to 1 hour at temperatures ranging from about 75 to 225 ⁰ C and preferably lOO. After this period of time, any remaining alkylating agent is neutralized with a base such as sodium hydroxide and the 1-lower alkyl-2-hydroxymethyl-5-nitroimidazole compound is recovered by extraction with an organic solvent. In this way, using the appropriate alkylating agents, l-methyl-2-hydroxy, netihyl-5- = nitroimidazole and the

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corresponding 1-ethyl-, 1-propyl- and 1-butylimidazoles can be obtained.

The following examples illustrate the invention; without her to restrict.

example 1

A, 8j5 ₅ O g (0.864 mol) of 2-hydroxymethylimidazole are dissolved in ml of acetic anhydride. The solution is left to stand overnight at room temperature. The acetate of 2-acetoxymethylimidazole crystallizes out. This crystalline solid is well suspended with ether and filtered, and the crystals are washed with ether until the odor of acetic acid can no longer be detected. The 2-acetoxymethylimidazole-acetic acid salt melts at 8o ⁰ C. The 2-Acetoxyraethylimidazol acetic acid salt is dissolved in lO ^ sodium bicarbonate, and the 2-acetoxymethylimidazole is extracted with Äthylacetät. Evaporation of the ethyl acetate extracts in vacuo and recrystallizing the residue from ethyl acetate obtained from 2-acetoxymethylimidazole Pp. "82 to 85 ⁰ C,

B. 176.6 g (0.882 mol) of 2-acetoxymethylimldazole-acetic acid

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Salt become in small amounts to 165 ml of cold smokers 90 # nitric acid added. This solution will slowly smoke while stirring and cooling to ISO ml colder ^ · of 90? aiger nitric acid with a content of 90.1 g of gaseous EF added. The reaction mixture is heated on a steam bath for 5 hours.

After cooling to room temperature, the reaction mixture is poured onto ice and neutralized with sodium hydroxide. The solution obtained is then extracted with ethyl acetate and the ethyl acetate is evaporated to dryness in vacuo. The residue is refluxed for 1 hour in a solution of 100 ml of 2, Sn sodium hydroxide and 100 ml of methanol. The solution is then neutralized with hydrochloric acid and extracted with ethyl acetate. The extracts are evaporated to dryness and the residue is dissolved in methanol and chromatographed over activated charcoal. The elution of the activated charcoal with 50 $ ether-acetone first removes a small amount of imidazole-2-carboxaldehyde. The subsequently eluted substance is 2-hydroxy-4 (5) -nitrolmidazole. After recrystallization from acetone, the product melts at 156 to 158 ^° C.

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C. For the preparation of 1-methyl ^ -hydroxymethyl-S-nitroimidazole 12.6 g of dimethyl sulfate 2U 11.1 g of 2-hydroxymethyl-4 (5) -nitroimidazole added, and the mass is mixed thoroughly. Then the mass is on a steam bath Heated for 2 hours and cooled to room temperature.

A small amount of bis is added and the remaining dimethyl sulfate and methyl hydrogen sulfate are neutralized by the slow addition of concentrated ammonium hydroxide. The resulting solution is extracted with chloroform. The chloroform extracts are separated off and evaporated to dryness, a residue consisting of 1-methyl-2-hydroxymethyl-5-nitroimidazole being obtained. By recrystallization from acetone, practically pure l-methyl-2-hydroxymethyl-5-nitroimidazole ~ Pp * from '117 to 119 ⁰ C.

If the above reaction is carried out using diethyl sulfate or dipropyl sulfate instead of dimethyl sulfate iso 'you get 1-ethyl- or »l-propyl-2-hydroxyrae- * 5-tftroimidazole.

Example 2

A. 1.56 g (0.0159 mol) of 2-hydroxymethylimidazole are in

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a solution of 1 ml of concentrated nitric acid dissolved in 10 ml of acetic anhydride. The mixture is warmed on a steam bath for 5 minutes and then poured onto ice. When the decomposition of the acetic anhydride has ended, the mixture is neutralized with 5% sodium bicarbonate solution and then extracted with an equal volume of ethyl acetate. The ethyl acetate extracts are washed with water and concentrated to a residue which is hydrolyzed by dissolving it in a mixture of 20 ml of methanol and 10 ml of aqueous sodium hydroxide and refluxing the resulting solution for 30 minutes. The hydrolysis mixture is cooled, neutralized with dilute hydrochloric acid and extracted with an equal volume of ethyl acetate. The solvent extracts are washed with water and concentrated to dryness in vacuo. The residue obtained in this way is dissolved in 10 ml of acetone and the solution is applied to a gelite prepared from 18 g of activated charcoal and 21 g. Column applied. The column is eluted with acetone-ether (ITI) and the eluates are evaporated to dryness to give praktisoh pure 2-hydroxymethyl-4- {5 or - j) ^ nitroimidazole obtained from Pp "■ 154-157 ⁰ C.

V,

V,

B. For the preparation of l-ethyl ^ -hydroxymethyl-S-nitroimidazole 1.43 g (10 mmol) of 2-hydroxymethyl-4 (5) -nitro-

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irridazol and 1.54 g (10 mmol) Äthylsuifat heated together for about 5 minutes at about 150 ⁰ C. The mixture is then cooled and dissolved in a mixture of chloroform and an excess of dilute aqueous sodium hydroxide. The chloroforaphase is separated off and dried over sodium sulfate. It is then evaporated to dryness in vacuo, leaving a viscous oil. This oil is dissolved in Xther / CHgClg (3: 1) and filtered through: 15 g of alkaline aluminum oxide (Merck). The eluate is evaporated in vacuo to give an almost colorless oily product. When this oil is cooled in an ice bath, crystals of 1-ethyl-S-hydroxymethyl-S-nitroimidazole form.

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Claims (1)

^ΐυ Τ79Β342 516 September 16, 19ββ Patent application ρ r tt eh e 1. i-lower-alkyl-S-hydroxymetiisrl-S-nitroimictazole of the general formula where R is a lower alkyl radical. 2. 1-methyl-S-hydroxyrtiethyl-S-nitroimidazole. j5. Process for the preparation of compounds according to claims 1 and 3, characterized in that 2-hydroxymethyl-5-nitroimidazole with a lower alkylating agent treated in a reaction medium in which a Anionization of the imidazole reaction component is practical it is completely suppressed. 4. Areneimittelwiricstoff, consisting of a compound naoh Claims 1 to 2. 109882/1816 - 12 -