DE1203271B - Process for the preparation of new 2-mercapto-imidazole derivatives and their salts - Google Patents

Description

Process for the production of new 2-mercaptoimidazole derivatives and their salts The invention relates to a process for the production of new 2-mercaptoimidazole derivatives of the general formula I in which R1 is a hydrogen atom, a methyl, carboxy or carbalkoxy group and R2 is an alkyl radical with a maximum of 10 carbon atoms, an alkenyl radical with a maximum of 6 carbon atoms, a cycloalkyl radical with a maximum of 7 carbon atoms, a u), ci-dialkoxyalkylene radical with a maximum of 6 carbon atoms, a dialkylaminoalkyl group with a total of at most 10 carbon atoms, in which the two alkyl radicals together with the nitrogen atom can also be linked to form a 5- to 7-membered alkyleneimino radical, a phenyl or a phenylalkylene group with a maximum of 4 carbon atoms in the alkylene radical, the phenyl and phenylalkylene groups through Halogen atoms, the hydroxy, cyano, nitro, amino-trifluoromethyl, acetoxy, carboxy or carbethoxy group, a lower alkylthio or a lower alkanoyl radical with a maximum of 4 carbon atoms or 1 to 3 lower alkyl or alkoxy radicals with a maximum of 4 carbon atoms can be substituted, mean, and their salts, there s is characterized in that formaldehyde with primary amines of the general formula II R2 - NH2 (II) and with a-isonitrosoketones of the general formula III in which R1 'denotes a methyl or carbalkoxy radical, reacts in the presence of solvents, treats the resulting reaction mixture with hydrogen sulfide or ammonium, alkali or alkaline earth metal sulfides or hydrosulfides, optionally saponifying the resulting reaction products in a manner known per se, then decarboxylating and the bases obtained are reacted with acids. Sodium sulfide, potassium sulfide, calcium sulfide or ammonium sulfide are preferably used. To saponify the 4-carbalkoxyimidazoles, these are preferably suspended or dissolved in aqueous solutions of alkali metal hydroxides. The decarboxylation of the 4-carboxyimidazole derivatives obtained can be carried out by simply heating them to the melting temperature or using high-boiling tertiary amines such as quinoline as solvents and metal catalysts, e.g. B. copper powder.

For example, in the compounds of the general formula, R2 is an alkyl radical such as methyl, ethyl, n-propyl, isopropyl, n-butyl, a-ethylpropyl, oc-methyl-butyl, n-hexyl or n-octyl radical, an alkenyl radical, preferably the allyl radical, a cycloalkyl radical such as the cyclopentyl, cyclohexyl or cycloheptyl radical w, co-dialkoxyalkylene radical, such as dimethoxymethyl, ß, ß-dimethoxyethyl, ß, ß-diethoxyäthyl ory, y-dimethoxypropyl radical, a dialkylaminoalkyl radical, such as dimethylaminomethyl, Diethylaminomethyl, ß-dimethylaminoethyl, ß-diethylaminoethyl, y-dimethylaminopropyl or γ-diethylaminopropyl radical as well as an N-ß-pyrrolidinylethyl, , B-piperidinoethyl or ß-hexamethyleneiminoethyl radical, a phenylalkylene radical, such as the benzyl, ß-phenylethyl, ß-phenylisopropyl or γ-phenylpropyl radical or a Phenyl radical. These phenylalkylene or phenyl radicals can have one of the following ring substituents carry: halogen atoms, such as fluorine, chlorine or bromine, the hydroxy, cyano, nitro, Amino, trifluoromethyl, acetoxy, carboxy or the carbethoxy group, and also one lower alkylthio radical, preferably the methylthio radical or a lower alkanoyl radical, preferably the acetyl radical. Furthermore, the phenylalkylene or phenyl radicals 1 up to 3 lower alkyl groups, preferably the methyl group or lower alkoxy groups, preferably carry the methoxy or ethoxy group.

By treatment with inorganic or organic acids, such as Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, Ethane disulphonic acid, ß-hydroxyethane sulphonic acid, acetic acid, succinic acid, fumaric acid, Maleic acid, malic acid, tartaric acid, citric acid, benzoic acid, and salicylic acid Mandelic acid, the 2-mereaptoimidazole bases are converted into salts, some of which are water-soluble are convicted.

The products of the process have valuable pharmacological properties. They have analgesic, calming, sedative and muscle relaxing effects due to their dampening effect on the central nervous system.

They also have antipyretic and anti-inflammatory properties on.

The following examples illustrate the invention. The temperatures are given in degrees Celsius. Example 11 a) 10.0 ml of an aqueous formaldehyde solution (37%) and 12.32 g of p-anisidine are added to 30 ml of ethanol. After 3 minutes a heavy precipitate has formed, 15.9 g of isonitrosoacetoacetic ester are then added, the mixture is heated to reflux and a vigorous stream of hydrogen sulfide is passed through it for one hour. The reaction is then terminated and the mixture is cooled to 5 °. After recrystallization of the precipitate formed from ethanol and then from chloroform-pentane, 13 g (45%) 1- (p-methoxyphenyl) -2-mercapto-4-carbethoxy-5-methylimidazole are obtained, melting point 203-205 °.

b) 27.8 g of 1- (methoxyphenyl) -2-mercapto-4-carbethoxy-5-methyl-imidazole are refluxed with 500 ml of 3N NaOH for 1 hour. After cooling down and Filtration, the filtrate is acidified and the precipitate on a Buchner funnel collected. After recrystallization from dioxane, the 1- (p-methoxyphenyl) -2-mercapto-4-carboxy-5-methylimidazole is obtained obtained in 97% yield; Mp. 265 ° (decomposition).

c) 10.70 g of 1- (p-methoxyphenyl) -2-mercapto-4-carboxy-5-methyl-imidazole are heated to 277 'in a metal bath for 7 minutes. A strong COZ development sets in and quickly subsides again. The product is cooled and immediately crystallizes. The cooled residue is recrystallized from ethanol-ether and the 1- (p-methoxyphenyl) -2-mercapto-5-methyl-imidazole is obtained in 63% yield; M.p. 226 to 230 °. Example 12 a) 10 ml of aqueous formaldehyde solution (37%) are added to the solution of 11.1 g of p-fluoroaniline in 50 ml of ethanol. The mixture is refluxed for 30 minutes and then cooled. A solution of 16.0 g of isonitrosoacetoacetic ester in 25 ml of ethanol and a solution of 75 g of sodium hydrosulfide in the smallest possible amount of water are added at the same time. The reaction mixture is refluxed for 4 hours, then another concentrated aqueous solution of 20 g of sodium hydrosulfide is added and refluxed for a further 10 hours. The reaction mixture is cooled and the precipitate is filtered off. 200 ml of water are added to the filtrate and the organic solvent is distilled off in vacuo.

b) The remaining aqueous phase is by adding 50 ml of 3 Make n-NaOH alkaline and heat it on the steam bath until everything has gone into solution is.

c) After cooling, the reaction mixture is acidified with $ n-HCl and heated. After the evolution of hydrogen sulfide and carbon dioxide has ceased, the reaction mixture is cooled and extracted with butanol and chloroform. The combined organic phases are dried over magnesium sulfate and filtered. The solvents are distilled off in vacuo and the residue is recrystallized from methanol-ethanol. The 1- (p-fluorophenyl) -2-mereapto-5-methylimidazole obtained melts at 265 to 268 '. Example 3 The hydrochloride is prepared as follows from the 1- (o) -diethylaminoethyl) -2-mercapto-5-methylimidazole prepared according to Examples 1 and 2: To a solution of 3.0 g of 1- (co-diethylaminoethyl) - The stoichiometric amount of 2N ethanolic hydrochloric acid is added to 2-mercapto-5-methyl-imidazole. The mixture is left at room temperature for 20 minutes. Then the solvent is distilled off at 12 torr and 50 °. The residue is dissolved in 15 ml of hot isopropanol; the crystalline hydrochloride separates out on cooling; 186 to 188 °.

Claims (1)

Claim: Process for the preparation of new 2-mercaptoimidazole derivatives of the general formula in which R1 is a hydrogen atom, a methyl, carboxy or carbalkoxy group and R2 is an alkyl radical with a maximum of 10 carbon atoms, an alkenyl radical with a maximum of 6 carbon atoms, a cycloalkyl radical with a maximum of 7 carbon atoms, a co, co-dialkoxyalkylene radical with a maximum of 6 carbon atoms, a Dialkylaminoalkyl group with a total of at most 10 carbon atoms, in which the two alkyl radicals together with the nitrogen atom can also be linked to form a 5- to 7-membered alkyleneimino radical, a phenyl or a phenylalkylene group with a maximum of 4 carbon atoms in the alkylene radical, the phenyl and phenylalkylene groups through Halogen atoms, the hydroxy, cyano, nitro, amino, trifluoromethyl, acetoxy, carboxy or carbethoxy group, a lower alkylthio or a lower alkanoyl radical with at most 4 carbon atoms, or 1 to 3 lower alkyl or lower alkoxy radicals with at most 4 carbon atoms can be substituted, mean, and you en salts, characterized in that formaldehyde is used with primary amines of the general formula Ra - NIIs and a-isonitrosoketones of the general formula in which RI 'denotes a methyl or carbalkoxy radical, reacted in the presence of solvents, treated the reaction mixture obtained with hydrogen sulfide or ammonium alkali or alkaline earth sulfides or hydrosulfides, optionally saponified the reaction products obtained in a manner known per se, then decarboxylated and the the bases obtained are reacted with acids.