CS268487B1 - Process for preparing a 4,5-dihydrcimidazole derivative and its maleate - Google Patents

Abstract

The invention falls into the field of synthesis of substances. Its subject is a method for preparing 2-(3-/2-biphenylyloxy/propyl/-4,5-dihydroimidazole /1/ and its maleate. Substance I is an intermediate in the synthesis of pharmacodynamically active substances and its maleate exhibits a moderate centrally depressant activity, slightly potentiates the toxicity of yohimbine and has a moderate antimicrobial activity. The method for preparing substance I according to the invention consists in a two-step synthesis from 4-(2-biphenylyloxy/butyronitrile, which is converted by reaction with ethanol and hydrogen chloride into hydrochloride (ethyl) 4-(2-biphenylyloxy/butyrimidate, which by reaction with ethylenediamine provides the desired substance I. Its neutralization with maleic acid yields crystalline hydrogen maleate.

Description

The invention relates to a process for preparing 4,5-dihydroimidazolového derivative of the formula I O / CH _2/3

H / 1 / and its maleate.

The compound of formula I, i.e. 2- [3- (2-biphenyloxy) propyl] -4,5-dihydro-1-billionazole, is an intermediate in the synthesis of pharmacodynamically active substances. In the form of its maleate, it itself has some useful biological effects. Its acute oral toxicity in mice is 187 mg / kg. In the rotating rod test in mice, it has an ataxic effect apparently based on its mild central damping effect; ΕΡ ^ θ i * 50 mg / kg p.o. Slightly potentiates the toxicity of yohimbine in mice; an oral dose of 50 mg / kg is effective in 20% of animals. It has mild anti-microbial activity in in vitro tests against cocci. Pseudomonas aeruginosa, Escherichia coli and Proteus vulgaris.

The compound of formula I is prepared according to the invention in a two-step process from 4- (2-biphenylyloxy) butyronitrile. This nitrile is converted in the first step by reaction with hydrogen chloride and ethanol in ether and chloroform to the hydrochloride of (ethyl) 4- (2-biphenylyloxy) -butyrimidate, which in the second step in reaction with ethylenediamine in ethanol gives the desired compound of formula I. This is obtained as a crystalline base which, upon neutralization with maleic acid, gives a crystalline hydrogen maleate. The starting 4- (2-biphenylyloxy) butyronitrile is a blue substance and its preparation is described in the example. All substances described here are new and their identity has been ensured by analytical and spectral methods. The example is only an illustration of the possibilities of the invention and is not intended to list all possibilities.

Example

To a solution of 4.7 g of 4- (2-biphenylyloxy) butyronitrile in a mixture of 30 ml of ether and 20 ml of chloroform was added 1.5 ml of ethanol, and the mixture was saturated with hydrogen chloride (weight 2.3 g). It is left to stand overnight at 0 DEG C., diluted with ether and the precipitated crystalline hydrochloride (ethyl) 4- (2-biphenylyloxy) butyrimidate (5.9 g, 94%) is isolated by filtration.

A mixture of 14.3 g of the preceding hydrochloride, 4.5 g of ethylenediamine and 15 ml of ethanol is fed for 30 hours at 65-70 ° C. The solvent was then evaporated in vacuo, the residue quenched with aqueous ammonia and the base isolated by extraction with a mixture of ether and benzene. Work-up of the extract gave 10.1 g (98%) of the desired 2- (3- (2-biphenylyloxy) propyl) -4,5-dihydroimidazole (1). This base crystallizes from acetone and melts at 99-101 ° C. Neutralization with maleic acid in a mixture of acetone and ether gives crystalline hydrogen maleate melting at 81-84 ° C.

The starting 4- (2-biphenylyloxy) butyronitrile used is prepared as follows: To a stirred solution of 2.2 g of sodium cyanide in 20 ml of dimethyl sulfoxide at 55-60 ° C is added 11.6 g of 2- (3-bromopropoxy) biphenyl over 10 minutes. / Wilbur JM, Jr., J. Med. Chem. 21, 1168 (1978) 7. The mixture is stirred at 75 DEG-80 DEG C. for 45 minutes,, after cooling, diluted with 100 ml of water and extracted with benzene. The extract was washed with 6M HCl and water, dried over magnesium sulfate and evaporated under reduced pressure. The residue is distilled in vacuo. 7.8 g (83%) of the desired nitrile boiling at 210 DEG-212 DEG C. (2.1 kPa) are obtained. Completely pure material is obtained by chroniatography of the sample on silica gel and distillation; t.v. 174 ° C / 1.9 kpa.

Claims (1)

EXCELLENT OF THE INVENTION Process for the preparation of a 4,5-dihydroimidazole derivative of formula I (1) and its maleate, characterized in that 4- (2-biphenylyloxy) butyronitrile is converted in the first step by reaction with ethanol and hydrogen chloride in a mixture of ether and chloroform to hydrochloride (ethyl) of 4- (2-biphenylyloxy) butyrimidate, which is subjected in a second step to ethylenediamine in ethanol, after which the base of formula I obtained is converted into crystalline hydrogen maleate by neutralization with maleic acid.