NO890803L - Fremgangsmaate for fremstilling av trisubstituerte aminer. - Google Patents

Fremgangsmaate for fremstilling av trisubstituerte aminer.

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Publication number
NO890803L
NO890803L NO89890803A NO890803A NO890803L NO 890803 L NO890803 L NO 890803L NO 89890803 A NO89890803 A NO 89890803A NO 890803 A NO890803 A NO 890803A NO 890803 L NO890803 L NO 890803L
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Norway
Prior art keywords
radical
denotes
branched
unsubstituted
residue
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NO89890803A
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English (en)
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NO890803D0 (no
Inventor
Christos Tsaklakidis
Herbert Leinert
Peter Freund
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Boehringer Mannheim Gmbh
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Application filed by Boehringer Mannheim Gmbh filed Critical Boehringer Mannheim Gmbh
Publication of NO890803D0 publication Critical patent/NO890803D0/no
Publication of NO890803L publication Critical patent/NO890803L/no

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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/092—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings with aromatic radicals attached to the chain
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
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  • Cephalosporin Compounds (AREA)
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  • Furan Compounds (AREA)
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Description

Foreliggende oppfinnelse angår fremstilling av nye trisubstituerte aminer, deres farmakologisk forenlige salter, såvel som legemidler som inneholder disse forbindelser.
Oppfinnelsen omfatter nye amino-forbindelser med generell formel I
hvori
R^angir hydrogen, en rettlinjet eller forgrenet ci~C]_2~
alkylrest, en C^-C^-cycloalkylrest, en rettlinjet eller forgrenet C2-C^2-alkenylrest eller en usubstituert eller substituert C^-C^-mono- eller bicycloalkenylrest, en usubstituert eller en én- eller flersubstituert mono-cykliskaromatisk eller heteroaromatisk rest,
1*2 og R- kan være like eller forskjellige, angi en rett eller forgrenet, mettet eller umettet C1 ,-CD, alifatisk rest, eller danne en mettet eller umettet ring sammen med N-atomet, som kan inneholde ytterligere heteroatomer og eventuelt være substituert gjennom en liten alkylgruppe, en liten alkoxygruppe eller et oxygenatom,
R4angir en usubstituert eller en én- eller flersubstituert monocyklisk aromatisk rest, en usubstituert eller substituert fem- eller 6-leddet heteroaromatisk rest,
R,, angir hydrogen,
en usubstituert, en én- eller flersubstituert monocyklisk aromatisk rest eller en usubstituert eller substituert fem- eller seks- leddet heteroaromatisk rest,
R 7 angir hydrogen, en C^-C-^-alkylrest eller en N-dialkylamino-C,-C,-alkylrest,
8 J-b
R og Rg kan være like eller forskjellige og betegne hydrogen, en rettlinjet, forgrenet, mettet eller umettet alifatisk C^-C12-rest, eller de kan danne en mettet eller
umettet ring med 2-6 C-atomer sammen med nitrogen,
R1Qangir hydrogen, en rettlinjet eller forgrenet C^-Cg-alkyl- eller C^-Cg-alkenylrest, en aralkylrest eller en
acylrest,
X angir en valensstrek eller methylengruppen,
Y angir en valensstrek eller en rettlinjet, forgrenet,
mettet eller umettet hydrocarbonrest med 1-6 carbonatomer, og
Z angir en valensstrek, et oxygenatom eller carbonylgruppen.
Oppfinnelsen omfatter også disse forbindelsers uskade-lige salter og optiske isomerer. C-^-C^-alkylresten fra R^ angir fortrinnsvis methyl, ethyl, propyl, isopropyl, isobutyl, isoamyl, isohexyl, n-hexyl, n-octyl, n-dodecyl, spesielt isobutyl, isoamyl eller isohexyl. C^-C^-cycloalkylresten angir vanligvis cyclopentyl eller cyclohexyl. C2-C12-alkenylresten er fortrinnsvis allyl, methallyl, isopentenyl eller geranyl. C3-C7mono- eller bi-cycloalkenylresten angir vanligvis cyclopentenyl, cyclo-hexenyl eller myrtenyl.
R2 og R^angir fortrinnsvis methyl, ethyl, propyl, allyl eller methallyl. Ringer som kan dannes av R2og R^ sammen med N-atomet de er bundet til, er fortrinnsvis en pyrrolidin- eller piperidinring, spesielt en pyrrolidinring.
Heteroatomet som kan inneholdes i ringen, er nitrogen, svovel eller oxygen. Med dette menes ringer som f.eks. piper-azin, morfolin og thiomorfolin. Substituenter til de ovenfor beskrevne ringer er spesielt C^-C^-alkyl- eller C-^-C^-alkoxy-grupper, som f.eks. methyl, ethyl eller propyl eller methoxy, ethoxy eller propoxy. Oxygenet danner vanligvis en carbonylgruppe sammen med C-atomet det er bundet til. Tilsvarende ringer er f.eks. pyrrolidon- eller piperidon-ringen.
Den usubstituerte eller substituerte aromatiske rest til , R^og R,, angir fenyl eller én- eller f lersubstituert fenyl,
hvori aktuelle substituenter er spesielt,
C1-Cg-alkyl-, C^-Cg-alkenyl-, C^-Cg-alkoxy-, C^-Cg-alkeny1-oxy-, hydroxyalkyl-, C^-Cg-alkylendioxy-, hydroxy-alkoxy-, alkoxy-alkoxy-, alkylamino-, dialkylamino-, alkoxy-carbonyl-alkoxy-, fenylmercapto-, alkylsulfinyl-, alkylsulfonyl-, alkylsulfonyloxy-carboxy-, alkoxy-carbonyl-, amino-carbonyl-, mono- eller dialkylamino-carbonyl-, halogenalkyl- eller cyano-grupper såvel som halogenatom, som klor, brom eller fluor.
Heteroaromatiske rester for substituentene R^, R^og
R,, er fortrinnsvis pyridyl, pyrimidyl, pyrazinyl, thienyl, oxazolyl, pyrazolyl, imidazolyl, tetrazolyl, thiazolyl, isoxa-zolyl, spesielt pyridyl, furanyl, thienyl. C-^-C-^2-alkylresten til R^, Rg og Rg angir fortrinnsvis methyl, ethyl, propyl, isopropyl, isobutyl, isoamyl, isohexyl, n-hexyl, n-octyl, n-dodecyl. N-dialkylamino-(C-^-Cg)-alkylresten angir vanligvis en methyl-, ethyl-, propyl- eller hexylrest, som er substituert via en dimethylamino- eller diethylamino-gruppe, fortrinnsvis en dimethylaminoethyl-rest.
Ringer som kan dannes av R0 og Rn sammen med N-atomet de er bundet til, er fortrinnsvis pyrrolidin- eller piperidin-ringen.
C^-Cg-alkylresten til substituent R^q angir fortrinnsvis methyl, propyl, isobutyl. C^-Cg-alkylenresten angir fortrinnsvis allyl, methallyl eller isobutenyl. Aralkylresten angir vanligvis benzyl eller picolyl. Foretrukne acylrester er rester av alifatiske C^-Cg-carbonsyrer,som formyl,
acetyl, pivaloyl eller arylcarbonsyre, som benzoyl.
Foretrukne forbindelser ifølge den foreliggende oppfinnelse er forbindelser med formel I,
hvori
R1angir isobutyl, methallyl, isopentenyl, furyl, thienyl,
pyridyl, fenyl eller fenyl som er substituert med methyl,
methoxy eller halogen,
R~og R^angir i blant ethyl eller de danner en pyrrolidin-,
piperidin- eller morfolin-ring sammen med nitrogen-atomet de er bundet til,
R^angir furyl, thienyl, pyridyl, fenyl eller fenyl som er
substituert via methyl, methoxy eller halogen,
R,, angir hydrogen, nitril, ethoxycarbony1, furyl, thienyl,
pyridyl, fenyl eller fenyl som er substituert via methyl,
methylendioxy, methoxy eller halogen,
Rg angir hydrogen, nitril, methoxycarbonyl, ethoxycarbonyl,
n-propoxycarbonyl, isopropoxycarbonyl, aminocarbonyl, di-ethylaminocarbonyl, dimethylaminoethoxycarbonyl eller
piperidincarbonyl eller hydroxymethyl,
X angir en valensstrek eller methylengruppen,
Y angir en valensstrek, en methylen- eller ethylengruppe og
Z angir en valensstrek, et oxygenatom eller carbonylgruppen.
Oppfinnelsen omfatter også disse forbindelsers uskade-lige salter og optiske isomerer.
Forbindelsene ifølge den foreliggende oppfinnelse med generell formel I kan fremstilles ved kjente fremgangsmåter,
a) ved at en forbindelse med generell formel II,
hvori Y, Z, R^, og med de ovenfor beskrevne betydninger, reageres med en forbindelse med generell formel III
hvori X, R^, R^og Rg har de ovenfor beskrevne betydninger, eller
b) en forbindelse med generell formel IV,
hvori Y, Z, R^, L og R^har de ovenfor beskrevne betydninger,
omsettes med en forbindelse med generell formel III,
i overensstemmelse med dette kan, hvis ønskelig, de erholdte forbindelser omdannes til andre forbindelser med formel I.
Omsetningen av forbindelser med generell formel II og IV med en forbindelse med generell formel III til forbindelser ifølge oppfinnelsen med generell formel I, foregår ved kjent fremgangsmåte i et inert løsningsmiddel som toluen, xylen, dimethylformamid eller tetrahydrofuran, ved tempera-turer mellom 20°C og løsningsmidlets tilbakestrømmingstem-peratur under tilstedeværelse av et alkalisk kondensasjons-middel som f.eks. natriumhydrid eller lithiumdiisopropylamid.
Forbindelser med generell formel II kan fremstilles ved at man omsetter en forbindelse med generell formel V
hvori Y, Z og R^har de ovenfor beskrevne betydninger, med epiklorhydrin under tilstedeværelse av natronlut og en fase-overføringskatalysator, f.eks. tetrabutylammoniumbromid, de således erholdte forbindelser med generell formel VI omsettes med et amin med generell formel VII hvori R«og R^har den ovenfor beskrevne betydning, i en alkohol med generelle formel VIII, og til slutt omsettes alkoholen med generell formel VIII
med thionylklorid i et inert løsningsmiddel.
Forbindelser med generell formel IV kan fremstilles
ved at man på kjent måte reduserer en forbindelse med generell formel IX
hvori Y, Z, R^, R. og R, har de ovenfor beskrevne betydninger og R betyr en alkylrest, med et komplekst hydrid, f.eks. lithiumaluminiumhydrid, i et inert løsningsmiddel, til en forbindelse med generell formel X
og denne forbindelse kloreres i et inert løsningsmiddel med thionylklorid.
Den etterfølgende omdannelse av forbindelser med formel I til andre forbindelser angår f.eks. omdannelsen av substituenten . Heri kan den vanligvis anvendte ester for-såpes til en fri carbonsyre, eller reduseres til den beskrevne alkohol.
Utgangsforbindelsene med generell formel IX kan fremstilles ved hjelp av fremgangsmåten beskrevet i DE-B-2802864.
Forbindelsene ifølge oppfinnelsen med generell formel
I inneholder én til to asymmetriske carbonatomer.
Oppfinnelsen angår også derfor diastereomerer, race-mater og de optisk aktive forbindelsesformer ifølge oppfinnelsen med generell formel I. Gir syntesen av forbindelsene ifølge oppfinnelsen diastereomerer, så kan disse adskilles ved hjelp av søylekromatografi i de beskrevne race-mater.
De optisk aktive forbindelser kan fremstilles ved hjelp av kjente fremgangsmåter, fra deres racemiske blandinger over diastereomere salter. Til racematspaltning kan f.eks. vinsyre, eplesyre, kamfersyre, kamfersulfonsyre eller di-benzoylvinsyre anvendes.
For å overføre forbindelsene med generell formel I
til deres farmakologisk akseptable salter, omsetter man disse, fortrinnsvis i et organisk løsningsmiddel, med den ekvivalente mengde av en uorganisk eller organisk syre, f.eks. saltsyre, hydrogenbromid, fosforsyre, svovelsyre, eddiksyre, salicylsyre, sitronsyre, benzosyre, nafthosyre, o-acetoxybenzosyre, adipinsyre, maleinsyre eller oxalsyre. Forbindelsene ifølge oppfinnelsen med generell formel I har verdifulle farmakologiske egenskaper. De utmerker seg spesielt ved en blodkarberoligende virkning, og kan derfor anvendes til terapi av hjerte-/kretsløpssykdommer.
De nye forbindelser ifølge oppfinnelsen med generell formel I og deres salter kan anvendes i flytende eller fast form, enteralt eller parenteralt. Som injeksjonsmedium anvendes fortrinnsvis vann, som inneholder de vanlige til-setningsstoffer for injeksjonsløsninger som stabiliserings- middel, oppløsningsmiddel eller buffer. Slike tilsetnings-stoffer er f.eks. tartrat- og citratbuffer, ethanol, kompleks-dannere (som ethylendiamintetraeddiksyre og deres ikke-toksiske salter), høymolekylære polymerer (som flytende poly-ethylenoxyd) til viskositetsregulering. Faste bærerstoffer er f.eks. stivelse, laktose, mannitol, methylcellulose, talkum, høydispergert kiselsyre, høymolekylære fettsyrer (som stearinsyre), gelatin, agar-agar, kalsiumfosfat, magne-siumstearat, dyrefett og plantefett eller faste høymolekylære polymerer (som polyethylenglycol). Egnede preparater for oral anvendelse kan om ønskelig inneholde smaks- og søtnings-stoffer.
Den anvendte dosering avhenger som kjent fra tidligere av helsen og vekten av mottakeren, sykdomsomfanget, fremgangsmåten for eventuelle samtidige gjennomførte videre be-handlinger, behandlingshyppigheten og denønskede virkning.
En egnet daglig dose av den aktive forbindelse ligger mellom 0,01 og 50 mg/kg kroppsvekt, hvorved denne dose kan leveres i egnede doseenheter én eller flere ganger pr. dag.
Ved siden av de etterfølgende beskrevne eksempler er spesielt de følgende forbindelser foretrukket innenfor opp-finnelsens område:
Eksempel 1
2,2-Bis-(4-methoxyfenyl)-4-(1-pyrrolidino)-5-isobutoxy-valeriansyreethylester
Til den isavkjølte suspensjon av 5,9 g (0,15 mol) lithiumaluminiumhydrid i 250 ml absolutt tetrahydrofuran, tildryppes under omrøring løsningen av 27,1 g (0,1 mol) 2-(1-pyrrolidino)-3-isobutoxy-propionsyreisobutylester (se DE-B 2802864) i 100 ml absolutt tetrahydrofuran, på en slik måte at reaksjonstemperaturen ikke overstiger 10°C. Etter tilsetningens slutt omrøres reaksjonsblandingen ytterligere i 30 minutter ved romtemperatur, blandingen tilsettes 40
ml vann, avsuges, bunnfallet vaskes tre ganger med 50 ml tetrahydrofuran, og tetrahydrofuranet fjernes fra de sammenslåtte filtrater i vakuum. Deretter vakuumdestilleres den tilbakeblevne gule olj. Det erholdes derved som hovedfrak-sjon (KpQ 05:90°C) 17,5 g (87%) l-isobutoxy-2-(1-pyrroli-dino) -3-hydroxy-propan.
Den ved 0°C avkjølte oppløsning av 16,1 g (0,08 mol) l-isobutoxy-2-(1-pyrrolidino)-3-hydroxy-propan i 100 ml 1,2-diklorethan tildryppes 7,6 ml (12,4 g = 0,1 mol) thionylklorid i 50 ml 1,2-diklorethan. Etter tilsetningen omrøres reaksjonsblandingen ytterligere i 3 timer ved romtemperatur, det overskytende thionylklorid fjernes og løsningsmidlet fjernes ved rotasjonsfordampning og bunnfallet oppløses i 100 ml methylenklorid. Methylenkloridløsningen mettes to ganger med 50 ml natriumhydrogencarbonatløsning og vaskes en gang med vann, tørkes over natriumsulfat og inndampes i vakuum. Vakuumdestillasjonen av råproduktet (KPq Qg:78°C) gir 12,5 g (71,2%) l-isobutoxy-2-(1-pyrrolidino)-3-klor-propan.
Til suspensjonen av 0,27 g NaH (0,011 mol) natriumhydrid i 50 ml tørket toluen og 5 ml tørket dimethylformamid, tildryppes under omrøring løsningen av 3,3 g (0,011 mol) 4,4<1->dimethoxy-difenyleddiksyreethylester (se<*>) i 10 ml tørket toluen, og omrøres deretter ytterligere 30 minutter ved romtemperatur.
<*>) A. Bistrz-ycki, I. Paulus, R. Perrin Chem.Ber. 4_4 , 2606)
Deretter tilsettes en løsning av 2 g (0,09 m) l-iso-butoxy-2- (1-pyrrolidino)-3-klorpropan i 10 ml tørket toluen, og reaksjonsblandingen oppvarmes i 2 timer ved 100°C. Etter avkjøling fjernes toluenet i vakuum, det resterende tilsettes 10 ml mettet ammoniumkloridløsning og den vandige blanding rystes tre 'ganger med 20 ml methylenklorid. Etter tørking av de blandede organiske faser over natriumsulfat, avsuges methylenkloridet ved rotasjonsfordampning og den gule oljeaktige rest renses ved søylekromatografi. Utbytte 2,3 g (53%) (fargeløs olje) 2,2-bis-(4-methoxyfenyl)-4-(1-pyrrolidino)-5-isobutoxy-valeriansyreethylester.
Eksempel 2
2-Fenyl-2-(2-pyridyl)-4-(1-pyrrolidino)-5-isobutoxyvalero-nitril
Til suspensjonen av 0,15 g (5,2 mmol) 100% natriumhydrid i 20 ml tørket toluen, tilsettes under omrøring 1,1 g (5,7 mmol) 2-pyridyl-fenyl-acetonitril [Lit.: Klosa, Arch.Pharm. 286/58, 435 (1953)] i 5 ml tørket toluen, og blandingen oppvarmes 10 minutter ved 100°C. Deretter tildryppes løsningen av 1,1 g (5 mmol) l-isobutoxy-2-(1-pyrro-lidino) -3-klorpropan i 5 ml tørket toluen, og reaksjonsblandingen oppvarmes 2 timer under tilbakestrømming. Etter avkjøling avsuges toluenet ved rotasjonsfordampning, resten tilsettes 10 ml mettet ammoniumkloridoppløsning, den vandige oppløsning rystes tre ganger med 20 ml methylenklorid, og de sammenslåtte organiske faser tørkes over natriumsulfat. Etter fjerning av oppløsningsmidlet og søyle-kromatograf isk rensning av råproduktet erholdes 1,2 g (64%)
(fargeløs olje) 2-fenyl-2-(2-pyridyl)-4-(1-pyrrolidino)-5-isobutoxy-valeronitril.
Eksempel 3
2,2-Difenyl-4-(N,N-diethyl)amino-5-isobutoxy-valeriansyre-ethylester
Til blandingen av 64 ml isobutanol, 155 ml konsentrert natronlut og 2 g tetrabutylammoniumbromid tildryppes under kraftig omrøring 217 ml epiklorhydrin på en slik måte at reaksjonstemperaturen ikke overstiger 40°C. Etter tildryppin-gens slutt lar man reaksjonsblandingen omrøres ytterligere i 2 timer ved romtemperatur, deretter tilsettes 500 ml isvann, den organiske fase adskilles, den vandige fase ut-rystes ytterligere to ganger med 50 ml methylenklorid og de sammenblandede organiske faser tørkes over natriumsulfat. Etter fjerning av methylenklorid ved rotasjonsfordampning, vakuumdestilleres resten. Det erholdes ved 40 torr og 66 - 70°C 66 g (72%) isobutylglycidether.
Løsningen av 5,2 g (0,04 mol) isobutylglycidether og 5,2 ml (0,05 mol) diethylamin i 60 ml absolutt ethanol, kokes i 20 timer med tilbakeløpsstrømming under nitrogen-atmosfære. Deretter avsuges ethanol og overskuddet av diethylamin ved rotasjonsfordampning, og resten renses ved søylekromatografi. Det erholdes 6,9 g (85%) l-isobutoxy-2-hydroxy-3-(N,N-diethyl)-amino-propan som fargeløs olje.
Løsningen av 3 g (1,6 mmol) l-isobutoxy-2-hydroxy-3-(N,N-diethyl)amino-propan i 30 ml 1,2-diklorethan tildryppes ved romtemperatur 1,2 ml (16,4 mmol) thionylklorid i 10 ml 1,2-diklorethan. Deretter oppvarmes denne reaksjonsblanding i 2 timer under tilbakeløpsstrømming, omrystes to ganger med 50 ml mettet natriumhydrogencarbonatoppløsning og den organiske fase tørkes over natriumsulfat. Etter fjerning av oppløsningsmidlet kromatograferes resten på kiselgel. Det erholdes 2 g (62,5%) l-isobutoxy-2-klor-3-(N,N-diethyl)amino-propan som gul olje.
Den omrørte suspensjon av 200 mg (8,3 mmol) natriumhydrid i 30 ml tørket toluen og 1 ml dimethylformamid, tilsettes 2 g (8,3 mmol) difenyleddiksyreethylester i 10 ml tørket toluen ved romtemperatur, og deretter oppvarmes blandingen i 20 minutter ved 80°C. Deretter tildryppes ved 80°C løsningen av 1,6 g (7,2 mmol) l-isobutoxy-2-klor-3-(N,N-diethyl)amino-propan i 5 ml tørket toluen, og blandingen oppvarmes ytterligere i 2 timer ved tilbakeløpsstrømming. Etter avkjøling tilsettes reaksjonsblandingen 20 ml mettet ammoniumkloridløsning, den organiske fase adskilles og tørkes over -natriumsulfat. Etter fjerning av oppløsnings-midlet renses råproduktet ved søylekromatografi. Det er holdes 1,4 g (46%) 2,2-difenyl-4-(N,N-diethy1)amino-5-iso-butoxy-valeriansyreethylester som fargeløs olje.
Eksempel 4
2,2-Difenyl-4-(1-pyrrolidino)-5-benzyloxy-valeriansyre-ethylester
Blandingen av 7,6 g (70,4 mmol) benzylalkohol og 0,2 g tetrabutylammoniumbromid i 16 ml konsentrert natronlut tildryppes under kraftig omrøring ved 15 - 20°C 21,7 ml (277 mmol) epiklorhydrin i løpet av 20 minutter. Deretter om-røres reaksjonsblandingen i ytterligere 3 timer ved 40°C. Etter avkjøling tilsettes deretter reaksjonsblandingen 50 ml isvann, den organiske fase adskilles og den vandige fase omrystes to ganger med 20 ml methylenklorid. Etter tørking av de sammenblandede organiske faser over natriumsulfat og fjerning av oppløsningsmidlet ved rotasjonsfordampning, erholdes 11,5 g rå benzyl-glycidether. 11,5 g rå benzyl-glycidether oppløses i 300 ml absolutt ethanol og tilsettes 25 ml.pyrrolidin. Deretter oppvarmes reaksjonsblandingen i
3 timer under tilbakeløpsstrømming, oppløsningsmidlet fjernes og overskuddet av pyrrolidin fjernes ved rotasjonsfordampning, resten tilsettes 100 ml vann, den vandige oppløsning omrystes tre ganger med 50 ml methylenklorid og de sammenblandede organiske faser tørkes over natriumsulfat. Etter fjerning av methylenklorid ved rotasjonsfordampning, destil-leres resten i vakuum. Det erholdes ved 0,05 torr og 114 - 118°C, 15,2 g (92%) l-benzyloxy-2-hydroxy-3-(1-pyrrolidino)-propan som et fargeløst fluidum. Løsningen av 3,4 g (14,5 mmol) l-benzyloxy-2-hydroxy-3-(1-pyrrolidino)-propan i 30
ml 1,2-diklorethan, tildryppes ved romtemperatur 1,2 ml
(16,4 mmol) thionylklorid i 10 ml 1,2-diklorethan. Deretter oppvarmes reaksjonsblandingen i 2 timer under tilbakeløps-strømming, avkjøles, omrystes to ganger med 50 ml mettet natriumhydrogencarbonatoppløsning, og den organiske fase tørkes over natriumsulfat. Etter fjerning av oppløsnings-midlet kromatograferes resten på kiselgel. Det erholdes 2,5 g (68%) l-benzyloxy-2-klor-3-(1-pyrrolidino)-propan.
Den omrørte suspensjon av 200 mg (8,3 mmol) natrium hydrid i 30 ml tørket toluen og 1 ml dimethylformamid til-føres ved romtemperatur 2 g (8,3 mmol) difenyleddiksyreethylester i 10 ml tørket toluen, og deretter oppvarmes blandingen i 20 minutter ved 80°C. Deretter tildryppes -ved 80°C oppløsningen av 2 g (7,9 mmol) l-benzyloxy-2-klor-3-(1-pyrrolidino)-propan i 5 ml tørket toluen, og blandingen oppvarmes ytterligere i 2 timer under tilbakeløpsstrømming. Etter avkjøling tilsettes reaksjonsblandingen 20 ml ammonium-kloridoppløsning, den organiske fase adskilles og tørkes over natriumsulfat. Etter fjerning av oppløsningsmidlet renses råproduktet ved søylekromatografi. Det erholdes 1,7 g (47%) 2,2-difenyl-4-(1-pyrrolidino)-5-benzyloxy-valeriansyreethyl-ester som fargeløs olje.
Eksempel 5
2,2-Difenyl-4-(1-pyrrolidino)-5-(2-picolyl)oxy-valeriansyre-ethylester
Blandingen av 50 ml (0,52 mol) pyridin-2-carbinol og
8 g (0,025 mol) tetrabutylammoniumbromid i 200 ml konsentrert natronlut tildryppes under kraftig omrøring ved 15 - 20°C 190 ml (2,4 mol) epiklorhydrin. Deretter omrøres reaksjonsblandingen over natten ved romtemperatur, reaksjonsblandingen tilsettes 500 ml isvann, den organiske fase adskilles, vannfasen ekstraheres tre ganger med ether og de sammenblandede organiske faser tørkes over natriumsulfat. Etter fjerning av oppløsningsmidlet og overskudd av epiklorhydrin ved rotasjonsfordampning, erholdes 57,8 g rå 2-picolylglycidether. 57,8 g rå 2-picolylglycidether oppløses i 100 ml ethanol og tilsettes 58 ml pyrrolidin. Deretter oppvarmes reaksjonsblandingen i 1 time ved 50°C, oppløsnings-midlet og overskuddet av pyrrolidin fjernes og resten des-tilleres i vakuum. Det erholdes 57 g (69%) 1-(2-picolyl)oxy-2- hydroxy-3-(1-pyrrolidino)-propan. KpQ q1 = 133°C.
Løsningen av 48 g (0,2 mol) 1-(2-picolyl)oxy-2-hydroxy-3- (1-pyrrolidino)-propan i 600 ml 1,2-diklorethan tildryppes ved romtemperatur 18 ml thionylklorid i 100 ml 1,2-diklorethan. Deretter oppvarmes reaksjonsblandingen i 4 timer under tilbakeløpsstrømming, blandingen avkjøles og det tilføres 500 ml isvann. Deretter fjernes den organiske fase, og denne ekstraheres to ganger med 50 ml ln saltsyre. De sammenblandede vandige faser ble gjort svakt alkaliske med ln natronlut (pH 8-9). Deretter omrystes den alkaliske løsning tre ganger med 100 ml methylenklorid, de sammenblandede organiske faser tørkes over natriumsulfat og oppløsningsmidlet fjernes ved rotasjonsfordampning. Det erholdes 50 g (96,6%) rå l-(2-picolyl)oxy-2-klor-3-(1-pyrrolidino)-propan. 10 g (0,04 mol) 1-(2-picolyl)oxy-2-klor-3-(1-pyrrolidino)-propan og 12 g (0,05 mol) difenyleddiksyreethylester oppløses i 100 ml tørket dimethylformamid, oppløsningen tilsettes 1,2 g (0,05 mol) natriumhydrid og reaksjonsblandingen oppvarmes deretter i 1 time ved 80°C. Den avkjølte reaksjonsblanding tilsettes der-'etter 200 ml mettet ammoniumkloridoppløsning, og omrystes deretter med 50 ml methylenklorid. Etter tørking av de sammenblandede organiske faser over natriumsulfat og fjerning av oppløsningsmidlet, kromatograferes resten på kiselgel. Det erholdes 9,2 g (50,3%) av forbindelsen ifølge oppfinnelsen som lys gul olje, som krystalliserer ved gnidning. Smeltepunkt 68°C.
De følgende forbindelser ble fremstilt analogt:

Claims (5)

1. Forbindelser med formel I
karakterisert vedat angir hydrogen, en rettlinjet eller forgrenet ^ 2.~^ 12~ alkylrest, en C^-C^-cycloalkylrest, en rettlinjet eller forgrenet C^-C^-slkenylrest eller en usubstituert eller substituert C^-C^-mono- eller bicycloalkenylrest, en usubstituert eller en én- eller flersubstituert raono-cykliskaromatisk eller heteroaromatisk rest, R^ og R^kan være like eller forskjellige, og angi en rett, forgrenet, mettet eller umettet C^-C^-alifatisk rest, eller danne en mettet eller umettet ring sammen med N-atomet, denne ring kan inneholde ytterligere heteroatomer og eventuelt være substituert gjennom en liten alkylgruppe, en liten alkoxygruppe eller et O-atom, R^angir en usubstituert eller en én- eller flersubstituert monocyklisk aromatisk rest, en usubstituert eller substituert fem- eller seks-leddet heteroaromatisk rest, R5angir hydrogen,
en usubstituert, en én- eller flersubstituert monocyklisk aromatisk rest eller en usubstituert eller substituert fem- eller seks- leddet heteroaromatisk rest,
R 7 angir hydrogen, en C^-C-^-alkylrest eller en N-dialkyl amino-C-^-Cg-alkylrest, Rg og Rg kan være like eller forskjellige og betegne hydro gen, en rettlinjet, forgrenet, mettet eller umettet alifatisk C^-C-^2-rest, eller de kan danne en mettet eller umettet ring med 2-6 C-atomer sammen med nitrogen, R-^q angir hydrogen, en rettlinjet eller forgrenet C-^-Cg-alkyl- eller C^-Cg-alkenylrest, en aralkylrest eller en acylrest, X angir en valensstrek eller methylengruppen, Y angir en valensstrek eller en rettlinjet, forgrenet, mettet eller umettet hydrocarbonrest med 1-6 carbonatomer, og Z angir en valensstrek, et oxygenatom eller carbonylgruppe, såvel som disse forbindelsers farmakologisk akseptable salter og optiske isomerer.
2. Forbindelser med formel I ifølge krav 1,karakterisert vedat R^angir isobutyl, methallyl, isopentenyl, furyl, thienyl, pyridyl, fenyl eller fenyl som er substituert med methyl, methoxy eller halogen,
B>2 og R^angir i blant ethyl eller de danner en pyrrolidin-, piperidin- eller morfolin-ring sammen med nitrogen-atomet de er bundet til, R^angir furyl, thienyl, pyridyl, fenyl eller fenyl som er substituert via methyl, methoxy eller halogen, R,. angir hydrogen, nitril, ethoxycarbonyl, furyl, thienyl, pyridyl, fenyl eller fenyl som er substituert via methyl, methylendioxy, methoxy eller halogen, Rg angir hydrogen, nitril, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, aminocarbonyl, di-ethylaminocarbonyl, dimethylaminoethoxycarbonyl, piperidincarbonyl eller hydroxymethyl, X angir en valensstrek eller methylengruppen, Y angir en valensstrek, en methylen- eller ethylengruppe og Z angir en valensstrek, et oxygenatom eller carbonylgruppen, såvel som deres farmakologisk akseptabele salter av optiske isomerer.
3. Fremgangsmåte for fremstilling av forbindelser med formel I
hvori angir hydrogen, en rettlinjet eller forgrenet (^ i~(~' 12~ alkylrest, en C^-C^-cycloalkylrest, en rettlinjet eller forgrenet C2_Cg-alkenylrest eller en C^-C^-bicycloalkenylrest, en usubstituert eller en én- eller flersubstituert mono-cykliskaromatisk eller heteroaromatisk rest, R^og R^kan være like eller forskjellige, og angi en rett-kjedet, forgrenet, mettet eller umettet C^-C^ alifatisk rest, eller danne en mettet eller umettet ring sammen med N-atomet, som kan inneholde ytterligere heteroatomer og eventuelt være substituert gjennom en liten alkylgruppe, en liten alkoxygruppe eller et oxygenatom, R^angir en usubstituert eller en én- eller flersubstituert monocyklisk aromatisk rest, en usubstituert eller substituert fem- eller seks-leddet heteroaromatisk rest, R,, angir hydrogen,
en usubstituert, en én- eller flersubstituert monocyklisk aromatisk rest eller en usubstituert eller substituert fem- eller seks-leddet heteroaromatisk rest, R? angir hydrogen, en C^-C^-alkylrest eller en N-dialkyl- amino-C,-C,-alkylrest, 1 D Rg og Rg kan være like eller forskjellige og betegne hydro gen, en rettlinjet, forgrenet, mettet eller umettet alifatisk C^-C^2-res't:/ eller de kan danne en ring med 2-6 C-atomer sammen med nitrogen, R angir hydrogen, en rettlinjet eller forgrenet c^"cg~ alkyl- eller C^-Cg-alkenylrest, en aralkylrest eller en acylrest, X angir en valensstrek eller methylengruppen, Y angir en valensstrek eller en rettlinjet, forgrenet, mettet eller umettet hydrocarbonrest med 1-6 carbonatomer, og Z angir en valensstrek, et oxygenatom eller carbonylgruppen, såvel som disse forbindelsers akseptable salter og optiske isomerer, karakterisert vedat a) en forbindelse med generell formel II
hvori Y, Z, R^, og har de ovenfor angitte betydninger, omsettes på vanlig måte med en forbindelse med generell formel III
hvori X, R^, R^og R^har de ovenfor angitte betydninger, eller b) en forbindelse med generell formel IV
hvori Y, Z, R^, L og R, har de ovenfor angitte betydninger, omsettes med en forbindelse med generell formel III, og de erholdte forbindelser kan i tilslutning til dette over-føres til andre forbindelser av formel I, og overføres til deres farmakologisk akseptable salter eller spaltes i optiske isomerer.
4. Legemiddel, karakterisert vedat det inneholder, ved siden av vanlige bære- eller hjelpestoffer, en forbindelse ifølge krav 1 eller 2.
5. Anvendelse av forbindelser ifølge krav 1 eller 2,karakterisert vedat forbindelsene anvendes ved behandling av hjerte- eller kretsløpssykdommer.
NO89890803A 1988-02-27 1989-02-24 Fremgangsmaate for fremstilling av trisubstituerte aminer. NO890803L (no)

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US4921713A (en) * 1987-06-05 1990-05-01 Fowler Daniel L Versatile controlled flavor straw assembly
DE3928247A1 (de) * 1989-08-26 1991-02-28 Boehringer Mannheim Gmbh Neue optisch aktive basische ether, verfahren zu ihrer herstellung sowie arzneimittel, die diese verbindungen enthalten
IE903614A1 (en) * 1989-10-10 1991-04-24 Glaxo Group Ltd Phenethanolamine Compound
US5610183A (en) * 1991-07-10 1997-03-11 Merck, Sharp & Dohme Ltd. Phenylglycine derivatives pharmaceutical compositions containing them and their use in therapy
GB9211193D0 (en) * 1992-05-27 1992-07-08 Merck Sharp & Dohme Therapeutic agents
AU4718093A (en) * 1992-07-31 1994-03-03 Merck Sharp & Dohme Limited Substituted amines as tachykinin receptor antagonists
US5747523A (en) * 1996-01-24 1998-05-05 Guilford Pharmaceuticals Inc. Substituted ethyl α,α-diarylmethyl ether derivatives

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GB1237352A (en) * 1969-01-03 1971-06-30 Ct Europ De Rech S Mauvernay Substituted propylamines
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EP0330940A3 (de) 1990-10-31
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ZA891435B (en) 1989-11-29
HUT50800A (en) 1990-03-28
AU3010589A (en) 1989-08-31
JPH023633A (ja) 1990-01-09
DK90189A (da) 1989-08-28
FI890903A (fi) 1989-08-28
DE3806321A1 (de) 1989-09-07
KR890012990A (ko) 1989-09-19
NZ228046A (en) 1991-04-26
CS274445B2 (en) 1991-04-11
EP0330940A2 (de) 1989-09-06
DD283616A5 (de) 1990-10-17
US4999361A (en) 1991-03-12
CS108389A2 (en) 1990-08-14
FI890903A0 (fi) 1989-02-24
IL89395A0 (en) 1989-09-10
PT89824A (pt) 1989-10-04
DK90189D0 (da) 1989-02-24
CN1035506A (zh) 1989-09-13

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