AT220153B - Process for the preparation of new iminodibenzyl derivatives and their salts - Google Patents

Description

  

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  Process for the preparation of new iminodibenzyl derivatives and their salts
The present invention relates to a process for the preparation of new N-heterocyclic compounds with valuable pharmacological properties and the associated intermediates.



   It has been found that compounds with valuable pharmacological properties which correspond to the general formula I
 EMI1.1
 wherein X is a straight-chain or branched alkylene radical with 2-6 carbon atoms and Am is a dialkylamino group, where one of the two alkyl radicals of a dialkylamino group Am is directly (1) with the alkylene radical X or both alkyl radicals directly (2) or via an oxygen atom (3) , a lower alkylimino (4), hydroxyalkylimino (5) or alkanoyloxyalkylimino group (6) can be linked, or

   their salts can be prepared with inorganic or organic acids by adding a compound of the general formula II
 EMI1.2
 where X and Am have the meaning given above, with oxygen or hydrogen peroxide in a neutral to weakly acidic aqueous solution in the presence of a compound with the atomic grouping - CO-C (OH) = C (OH) - or-CO-CO-CO- such as B. ascorbic acid or dehydroascorbic acid, ions of a heavy metal from the group iron, nickel, cobalt and manganese and optionally a complexing agent, e.g. B. ethylenediamine tetraacetic acid, citric acid or o-phenanthroline, oxidized.



   The following formulas are specific examples to illustrate the above-mentioned six bonding possibilities in the grouping X-Am:
 EMI1.3
 

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 EMI2.1
 
 EMI2.2
 
2-propylene, 1, 3-zinyl (1) or 4-hydroxyethyl-piperazinyl (1) radical and X-Am together also z. B. embodied by 1-methyl-piperidyl- (3) -methyl, l-methyl-piperidyl- (2) -ethyl- or 1-methyl-pyrrolidyl- (2) -ethyl radical.



   Starting materials of the general formula II are obtained by reacting iminodibenzyl in the presence of an alkaline condensing agent with a reactive ester of an alcohol of the general formula
HO-X-Am ', (III) where Am' denotes a radical corresponding to the definition for Am with the exception of a monoalkylamino group or a lower N-arylmethy1alky1amino group or N-acyl-alkylamino group and X has the meaning given above. If necessary, the condensation product of the general formula IV is then converted, which already includes some of the compounds of the general formula II:
 EMI2.3
 depending on the meaning of Am ', by preferably acid hydrolysis or by hydrogenolysis into a compound of the general formula I defined above, in which Am is represented by a lower alkylamino group.



   Sodium amide, lithium amide, potassium amide, sodium, potassium, butyllithium, phenyllithium, sodium hydride or lithium hydride are particularly suitable as alkaline condensing agents for the reaction of iminodibenzyl with reactive esters of basic alcohols of the general formula III. The reaction can be carried out in the presence or absence of an inert organic solvent, examples of which are benzene, toluene and xylenes.



   According to a further process, compounds of the general formula 11 are obtained by adding a halide of a compound of the general formula
 EMI2.4
 wherein X has the meaning given above, with a compound of the general formula
Am "-H, (VI)

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 in which Am "has the meaning given above, but of course there can be no bond between an alkyl radical of Am" and X, in the presence of an acid-binding agent, preferably an excess of amine of the general formula VI to be converted.



   The compounds which can be prepared according to the invention have, in particular, antiallergic, sedative, serotonin-antagonistic, antipyretic and thymoleptic activity with only minor vegetative side effects. They are suitable, for example, for the treatment of certain forms of mental illness, in particular mood depression, and they can also be used orally or parenterally in the form of aqueous solutions of non-toxic salts. Some of them are also suitable as intermediate products for the manufacture of other substances with similar properties.



   With inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulphonic acid, ethane disulphonic acid, acetic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, citric acid, benzoic acid and phthalic acid, the compounds of the general formula I which can be prepared according to the invention form salts, which for the Partly are water soluble.



   The following example is intended to explain the preparation according to the invention of compounds of the general formula I in more detail, but in no way represents the only possible way of carrying out the same.



  In the example, parts mean parts by weight, unless otherwise noted; these are related to parts of volume as g to cm3. The temperatures are given in degrees Celsius.



   Example: 10.5 parts of ferrous sulfate, 76.2 parts of the disodium salt of ethylenediaminetetraacetic acid, 75 parts of ascorbic acid and finally 75 parts of 5- (γ-dimethylaminopropyl) -iminodibenzyl with vigorous stirring
 EMI3.1
 



  The solution is then cooled, adjusted to pH 10 with concentrated ammonia and the solution, which is now deep blue, is extracted three times with ethyl acetate. The combined extracts are washed at least six times with water in order to remove any dissolved iron salts. The clear ethyl acetate solution is then shaken three times with 50 parts by volume of 2-n. Hydrochloric acid, makes the clear acidic extracts alkaline with concentrated ammonia and takes up the precipitated basic substances in ethyl acetate. The ethyl acetate solution is dried over sodium sulfate and freed from the solvent by evaporation in vacuo, an almost black oil remaining behind.

   This is dissolved in 420 parts by volume of 70% methanol and the solution is shaken out four times with 420 parts by volume of pentane each time, a black resin which can be neglected settles on the walls of the separating funnel. The methanolic solution is then concentrated in vacuo, the residue is taken up in ethyl acetate, the solution is washed with water, dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on an acid prepared in ether from 450 parts of silica gel. When eluting with mixtures of equal parts of ether and acetone, fractions of the crude product with melting temperature ranges between 120 and 1260 are eluted.

   These are combined and recrystallized first from very little acetone and then from a lot of ether, 2-hydroxy-5- (γ-dimethylamino-propyl) -iminodibenzyl having a melting point of 134-1350. Further pure substance can be obtained from the following ether-acetone eluates and acetone eluates, the residue of which has a melting point range of 100 to 1140, by repeated analogous recrystallization.

 

Claims (1)

PATENT CLAIM: Process for the preparation of new iminodibenzyl derivatives of the general formula: EMI3.2 wherein X is a straight-chain or branched alkylene radical with 2-6 carbon atoms and Am is a dialkylamino group, where one of the two alkyl radicals of a dialkylamino group Am directly with the alkylene radical X or both alkyl radicals directly or via an oxygen atom, a lower alkylimino, hydroxyalkylimino or Alkanoyloxyalkylimino group can be connected, or their salts with inorganic or organic acids, characterized in that a compound of the general formula <Desc / Clms Page number 4> EMI4.1 wherein X and Am have the meaning given above, with oxygen or hydrogen peroxide in a neutral to weakly acidic aqueous solution in the presence of a compound with the atomic grouping - CO-C (OH) == C (OH) - or -CO-CO-CO , of ions of a heavy metal from the iron, nickel, cobalt and manganese group and optionally a complexing agent to form a compound of the general formula I, and the bases obtained are optionally converted into salts with inorganic or organic acids.