C - Chemistry – Metallurgy – 07 – D
Patent
C - Chemistry, Metallurgy
07
D
167/211, 260/246
C07D 451/00 (2006.01) A61K 31/46 (2006.01) C07D 471/20 (2006.01) C07D 471/22 (2006.01) C07D 498/20 (2006.01)
Patent
CA 1304369
ABSTRACT The present invention provides a process for the preparation of azoniaspironortropanol esters of the general formula:- Image (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:- Image 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, alkoxy- carbonyl 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:- Image f) an o-phenylene radical of the general formula:- Image g) a peri-naphthylene radical of the general formula:- Image h) a 2,3-quinoxalinene radical of the general formula:- Image 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, halo- phenyl, 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: Image (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:- Image (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:- Image (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:- Image (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 option- ally 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.
526376
Gorler Klaus
Grimminger Wolf
Odenthal Karl Peter
Madaus Aktiengesellschaft
Ogilvy Renault Llp/s.e.n.c.r.l.,s.r.l.
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