YU46038B - PROCEDURE FOR THE PREPARATION OF AZONIASPIRONORTROPANOLESTRES - Google Patents

Abstract

POSTOPEK ZA PRIPRAVO AZONIASPIRONORTROPANOLESTROV, s splošno formulo I v kateri pomenijo R enega od naslednjih ostankov a) alkilenski ostanek s splošno formulo v kateri pomeni R3 atom vodika ali alkilno, benzilno, arilno, ali alkoksikarbonilno skupino in n stoji za celo število od 1 do 4, b) alkenilenski ostanek s splošno formulo v kateri pomenita R4 in R5, ki sta lahko enaka ali različna, atom vodika ali alkilni ali alkenilni ostanek, in n stoji za celo število od 1 do 4, c) azaalkilenski ostanek s splošno formulo v kateri pomeni R6 atom vodika, alkilno, alkoksikarbonilno ali acilno skupino in n stoji za celo število od 2 do 4, d) oksaalkilenski ostanek s splošno formulo -(CH2)n-O-(CH2)n- -v kateri stoji n za celo število od 2 do 4, e) epoksialkilenski ostanek s formulo f) o-fenilenski ostanek s splošno formulo g) peri-naftilenski ostanek s splošno formulo in h) 2,3-kinoksalinenski ostanek s splošno formulo pri čemer v formulah f) do h) ostanka X in Y neodvisno drug od drugega pomenita atom vodika ali alkilni ali alkoksi ostanek, R1 in R2, ki sta lahko enaka ali različna, atom vodika ali atom halogena ali alkilni, alkoksi, alkoilni, cikloheksilni, fenilni, alkilfenilni, alkoksifenilni, halogenofenilni, tienilni ali furilni ostanek, pri čemer vsebujejo alkilne skupine, ki se nahajajo v navedenih ostankih, 1 do 6 atomov ogljika in so lahko ravne ali razvejene, in A- anion 1- do 3- valentne mineralne kisline, z a) demetiliranjem tropina v nortropin, b) presnovo nortropina z dihalogenidi v ustrezne azonia spojine in c) zaestrenjem azonia spojin označen s tem, da A) izvedemo demetiliranje tropina s formulo II tako, da bodisi delamo s C1-C3-kloroalkanom, ki vsebuje najmanj eno skupino CCl3, v prisotnosti oksidacijskega sredstva v bazični vodni raztopini, bodisi presnovimo tropin z estrom klormravljinčne kisline v inertnem topilu v prisotnosti sredstva za vezanje kisline v 8-alkoksikarbonilnortropin in le-tega hidroliziramo v vodni raztopini z bazo, B) tako dobljeni nortropin s formulo III presnavljamo v dipolarnem aprotičnem topilu s spojino s splošno formulo A - R - A, v kateri imata A in R zgoraj navedene pomene, v prisotnosti sekundarnega ali terciarnega amina pri sobni temperaturi en do več dni, in C) tako dobljeno spojino s splošno formulo IV v kateri imata R in A- zgoraj navedene pomene, v brezvodnem, dipolarnem aprotičnem topilu zaestrimo z imidazolidom s splošno formulo V v kateri imata R1 in R2 zgoraj navedene pomene, v prisotnosti katalizatorja, D) in v primeru, da vsebuje ostanek R potem, ko je prešel skozi stopnji B in/ali C, eno ali več olefinskih dvojnih vezi v azonijevem obroču, te nenasičene spojine hidriramo v polarnem topilu s pomočjo katalizatorja iz žlahtne kovine v ustrezne nasičene spojine, pri čemer doA PROCEDURE FOR PREPARING AZONIASPIRONORTROPANOLESTERS OF GENERAL FORMULA I IN WHICH R RATES OF ONE OF THE FOLLOWING RESIDUES , b) an alkenylene radical of general formula in which R4 and R5, which may be the same or different, is a hydrogen atom or an alkyl or alkenyl radical, and n represents an integer from 1 to 4, c) an azaalkylene radical of general formula in which R6 represents a hydrogen atom, an alkyl, alkoxycarbonyl or acyl group and n represents an integer from 2 to 4, d) an oxaalkylene residue of the general formula - (CH2) nO- (CH2) n- in which n represents an integer from 2 to 4, e) an epoxyalkylene residue of formula f) an o-phenylene residue of general formula g) a peri-naphthylene residue of general formula and h) a 2,3-quinoxalinine residue of general formula wherein in formulas f) to h) residue X and Y independently of one another d other means a hydrogen atom or an alkyl or alkoxy residue, R 1 and R 2, which may be the same or different, a hydrogen atom or a halogen atom or an alkyl, alkoxy, alcohol, cyclohexyl, phenyl, alkylphenyl, alkoxyphenyl, halophenyl, thienyl or furyl residue, wherein contain alkyl groups present in said residues, 1 to 6 carbon atoms and may be straight or branched, and A- anion of 1- to 3-valent mineral acid, for) demethylation of tropine to nortropin, b) metabolism of nortropin with dihalides in the corresponding azonium compounds and c) esterification of the azonium compounds characterized in that A) demethylation of the tropine of formula II is carried out by either working with a C1-C3-chloroalkane containing at least one CCl3 group in the presence of an oxidizing agent in a basic aqueous solution, either metabolize the tropin with chloroformic acid ester in an inert solvent in the presence of an acid scavenger in 8-alkoxycarbonylnortropin and hydrolyze it in an aqueous solution with a base, B) the nortropin of formula III thus obtained is metabolised in a dipolar aprotic solvent with a compound of general formula A - R - A in which A and R have the meanings given above, in the presence of a secondary or tertiary amine at room temperature for one to several days, and C) thus the resulting compound of general formula IV in which R and A- have the meanings given above is esterified in an anhydrous, dipolar aprotic solvent with an imidazolid of general formula V in which R1 and R2 have the meanings given above, in the presence of a catalyst, D) and in the case of that the residue R, after passing through steps B and / or C, contains one or more olefinic double bonds in the azonium ring, these unsaturated compounds are hydrogenated in a polar solvent by means of a noble metal catalyst to the corresponding saturated compounds, up to