Patent HU-201930-B (HU)
Title: Process for producing azoniaspiro(notropanol) esters and pharmaceutical compositions comprising same
Inventor: GRIMMINGER WOLF
IPC: C07D471/22
Filed: 1986-12-27
Abstract: The present invention provides a process for the preparation of azoniaspironortropanol esters of the general formula: <IMG> (I) wherein R signifies one of the following radicals: a) an alkylene radical of the general formula: R3 -(CH2)n-CH-(CH2)n-in which R3 is a hydrogen atom or an alkyl, benzyl, aryl or alkoxy radical and n is a whole number of from 1 to 4, b) an alkenylene radical of the general formula: <IMG> in which R4 and R5, which can be the same or different, are hydrogen atoms or alkyl or alkenyl radicals and n is a whole number of from 1 to 4, c) an azaalkylene radical of the general formula: R6 -(CH2)n-N-(CH2)n-in which R6 is a hydrogen atom or an alkyl, alkoxycarbonyl or acyl radical and n is a whole number of from 2 to 4, d) an oxaalkylene radical of the general formula: -(CH2)n-O-(CH2)n-in which n is a whole number of from 2 to 4, e) an epoxyalkylene radical of the formula: <IMG> f) an o-phenylene radical of the general formula: <IMG> g) a peri-naphthylene radical of the general formula: <IMG> h) a 2,3-quinoxalinene radical of the general formula: <IMG> in which in formulae f) to h), the symbols X and Y, which can be the same or different, are hydrogen atoms or alkyl or alkoxy radicals; and wherein R1 and R2, which can be the same or different, are hydrogen or halogen atoms or alkyl, alkoxy, alkoyl, cyclohexyl, phenyl, alkylphenyl, alkoxyphenyl, halophenyl, thienyl or furyl radicals, the alkyl moieties in the said radicals containing up to 6 carbon atoms and being straight-chained or branched, and A ? is the anion of a mono- to tribasic mineral acid, by a) demethylation of tropine to give nortropine, b) reaction of nortropine with a dihalide to give a corresponding azonia compound, and c) esterification of the azonia compound, wherein A) the demethylation of tropine of the formula: <IMG> (II) is carried out either by working in a C1-C3-chloro-alkane which contains at least one trichloromethyl radical in the presence of an oxidation agent in basic aqueous solution or the tropine is reacted with a chloroformic acid ester in an inert solvent in the presence of an acid-binding agent to give an 8-alkoxy-carbonylnortropine and this is hydrolysed with a base in aqueous solution, B) the nortropine thus obtained of the formula: <IMG> (III) is reacted at ambient temperature for 1 or more days in a dipolar aprotic solvent with a compound of the general formula: A - R - A in which A and R have the above-given meanings, in the presence of a secondary or tertiary amine and C) the compound thus obtained of the general formula: <IMG> (IV) in which R and A ? have the above-given meanings, is esterified in an anhydrous, dipolar, aprotic solvent with an imidazolide of the general formula: <IMG> (V) in which R1 and R2 have the above-given meanings, in the presence of a catalyst, and D) when the radical R contains one or more olefinic double bonds in the azonium ring after passing through steps B and/or C, this unsaturated compound is optionally hydrogenated in a polar solvent with the help of a noble metal catalyst to give the corresponding saturated compound of general formula (I) in which R is a radical a) as defined hereinbefore.