DE1770850A1 - 2-Cyano-2-nitroimidazoles and process for their preparation - Google Patents

Description

2-Cyano-2-nitroimidazoles and process for their preparation Subject matter of the invention are 2-cyano-5-nitroimidazoles of the formula in which R1 is lower alkyl or - (CH2) nOX, where n is 2, 3 or 4 and X is hydrogen or lower alkanoyl, and a process for the preparation of these compounds, which is characterized in that a compound of the formula in which R1 has the meaning given above and R is alkyl having 1 to 5 carbon atoms, phenyl or bensyl, is reacted with cyanide ions in a non-aqueous reaction medium.

The symbol R can, for example, for ethyl, ethyl, propyl or butyl or a cycloaliphatic radical, e.g. cyclopentyl. The symbol R1 means for example methyl, xethyl, propyl or butyl, X is for example acetyl or propionyl.

The inventive reaction is preferably carried out in a polar, organic solvents such as dimethylformamide, diethyl sulfoxide or a lower one Alkanol. For bed. The result is an approximately 5 to 15% molar excess If desired, however, cyanide can also be used in practically equimolar amounts of the reaction components. or even an even greater excess of cyanide is used Will.

The source of the cyanide ions is preferably an alkali metal cyanide, how Potassium or sodium cyanide, but other compounds that soluble in the reaction medium and under the reaction conditions used Cyanide ions can be used with a satisfactory result.

The reaction proceeds rapidly at temperatures from about 500 ° C to 1000 ° C completely. 1-lower alkyl or 1- (acyloxy-lower alkyl) -2-cyano-5-nitroimidazole obtained from the E is extracted from the reaction mixture according to methods known in the art. Appropriately the reaction mixture is diluted with water and the 2-cyanoimidazole with a Water-immiscible organic solvent from which the 2-cyanoimidazole easily recovered and purified by recrystallization, like ether, extracted.

A 1- (acyloxy-lower alkyl) -2-cyano-5-nitroimidasole is also used hydrolyzed with acid: u 1- (hydroxy-lower alkyl) -2-cyano-5-nitroimidarol. As a sura is preferably hydrohalic acid in an alkanol, e.g. ethanolic hydrochloric acid or hydrobromic acid is used; however, other mineral acids such as Sulfuric acid. The hydrolysis is based on brief heating causes increased temperatures. Reaction temperatures of about 50 up to 100 ° C and reaction times of 5 to 15 minutes are quite satisfactory. After the hydrolysis has ended, the 1- (hydroxy-lower alkyl) -2-cyano-5-nitroimidazole by extraction with an organic solvent which cannot be washed out with water and subsequent removal of the solvent can be obtained.

The ala starting materials used for the process according to the invention substit.-2-R-sulfonyl-5-nitroimidazoles can be used as follows from 1-lower alkyl or (hydroxy-lower alkyl) -2-R-thio-5-nitroimidazoles are prepared: For example is a correspondingly substituted 2-mercaptoimidazole with an alkyl iodide or Alkyl sulfate. treated with an aralkyl iodide or with diphenyl iodonium iodide. That Imidasol obtained is then reacted with nitric acid.

Finally, the 1-substit-2-R-thio-5-nitroimidazole obtained is obtained oxidized to the corresponding 2-sulfonyl-5-nitroimidazole.

The new compounds are for the treatment and prevention of the poultry disease known as turkey blackhead and the human trichomonas disease T. vaginalis vaginitie.

Example 1 1-methyl-2-cyano-5-nitroimidazole 0.5 g (2.44 millimoles) 1-methyl-2-methylaulfonyl-5-nitroimidazole and 175 mg (2.70 millimoles) potassium yyanide 2.5 ml of dimethylformamide are added on the same side. The sulfone dissolves immediately in the stirred solution. The solution becomes slightly warm for 1 minute, and they is then heated on a steam bath for an additional minute. The mixture is then cooled, diluted with 40 ml of water and extracted three times with 40 ml of ether each time. After drying and concentrating the combined ether extracts, a brown one forms Oil that soon crystallizes. This material is dissolved in 15 to 20 ml of ether and pass the solution through a 4 g column of Merck's acid washed alumina, produced in ether, piped The column is further eluted with 100 - 120 al ether, and the combined column effluent and the elute are evaporated in vacuo, whereby Pale brown, slightly sticky crystals of 1-methyl-2-cyano-5-nitroimidazole were obtained will. This substance can be converted into 1-methyl-5-nitroimidazole-2-carboxamide without further purification be transferred.

B e i s p i e l 2 A. 1- (ß-Acetoxyethyl) -2-cyano-5-nitroimidazole 0.99 B (3.54 millimoles) unpurified 1- (β-acetoxyethyl) -2-methylaulfonyl -5-nitroimidazole and 256 mg (3.9 millimoles) of potassium cyanide are added together for 5 minutes with stirring heated in a steam bath in 5 ml of dimethyl sulphide. The reaction milk is then cooled to room temperature and diluted with 50 ml of water. The solution obtained is extracted three times pit 50 ml of ether each time. The ether extracts are combined, Dried over sodium sulfate and evaporated in vacuo to an oil. The oily product is dissolved in ether and filtered through 6 g of A1203 (Merck) washed with acid. The eluate obtained is evaporated to dryness in vacuo, with 1- (ß-acetoxyethyl) -2-cyano-5-nitroimidazole is obtained in the form of an aileless oil which easily crystallizes on killing. By recrystallization from ether-hexane, practically pure 1- (β-acetoxyethyl) -2-cyano-5-nitroimidazole is obtained sol F = 55-57 ° C.

B. 1- (ß-Hydroxyethyl) -2-cyano-5-nitroimidazole Bin mixture of 350 ig (1.56 millimoles) 1- (ß-acetoxyethyl) -2-cayno-5-nitroimidazole, 2 ml of ethanol and 2 ml of 6N hydrochloric acid is heated at 1000 ° C. for 5 minutes. The reaction mixture is on Cooled to room temperature and diluted with 20 ml of water.

The solution is extracted three times with 20 ml of ethyl acetate each time.

The combined extracts are dried with sodium sulfate and Concentrated to dryness in vacuo. The solid 1- (β-hydroxyethyl) -2-cyano-5-nitroimidazole obtained in this way is recrystallized from benzene, practically pure material from F »99.5-101 ° C receives.

Claims (5)

P atent claims 1. 2-Cyano-5-nitroimidazoles of the formula in which R1 is lower alkyl or - (CH2) nOX, where n is 2, 3 or 4 and X is hydrogen or lower alkanoyl. 1 1- (β-hydroxyethyl) -2-cyano-5-nitroimidazole. 3. 1- (β-Autoxyethyl) -2-cyano-5-nitroimidazole. 4. Process for the preparation of the compounds according to claim 1, characterized in that a compound of the formula in which R1 has the meaning given in claim 1 and R is alkyl having 1 to 5 carbon atoms, phenyl or benzyl, is reacted with cyanide ions in a non-aqueous reaction medium. 5. Active pharmaceutical ingredient, characterized in that it is a compound fled claim 1 is.