DK148594B - Analogifremgangsmaade til fremstilling af bis-(2-methyl-3-hydroxy-5-vinyl-4-pyridylmethyl)disulfid eller farmaceutisk acceptable salte oghydrater deraf - Google Patents

Analogifremgangsmaade til fremstilling af bis-(2-methyl-3-hydroxy-5-vinyl-4-pyridylmethyl)disulfid eller farmaceutisk acceptable salte oghydrater deraf Download PDF

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DK148594B
DK148594B DK290274AA DK290274A DK148594B DK 148594 B DK148594 B DK 148594B DK 290274A A DK290274A A DK 290274AA DK 290274 A DK290274 A DK 290274A DK 148594 B DK148594 B DK 148594B
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methyl
hydroxy
compound
formula
bis
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DK148594C (da
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Tsung-Ying Shen
Howard Jones
Conrad Peter Dorn
George Gustave Hazen
Thomas Bing Kin Lee
David Gregory Melillo
Meyer Sletzinger
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Merck & Co Inc
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Description

148594
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af det hidtil ukendte terapeutisk aktive bis-(2-methyl-3-hydroxy-5-vinyl-4-pyridylrnethyl)disulfid og farmaceutisk acceptable salte og hydrater deraf, som er velegnede til behandling af rheumatisk arthritis og beslægtede inflammatoriske sygdomme.
De ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser har den i krav l's indledning angivne almene formel I.
Fremgangsmåden ifølge opfindelsen er ejendommelig ved det i krav l's kendetegnende del anførte.
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De farmaceutisk acceptable salte er fremstillet af mineralsyrer eller organiske syrer af i og for sig kendt art, såsom saltsyre, hydrogenbromidsyre, svovlsyre, salpetersyre, maleinsyre, fumar-syre, vinsyre og ravsyre.
Til trods for den omfattende forskning i forbindelse med anti-inflammatoriske midler inden for de sidste 20 år er der stadig et klart behov for et effektivt og uskadeligt middel til behandling af rheumatisk arthritis. Konventionelle ikke-steroide antiinflammatoriske, analgesiske og antipyretiske midler, såsom aspirin og mange forsøgslægemidler under klinisk afprøvning, virker hovedsageligt kun til afhjælpning af symptomer på det akutte syndrom. Som følge deraf har den anti-rheumatiske virkning af to gamle lægemidler, nemlig guld og D-penicillinamin, til trods for deres kraftige bivirkninger, fundet fornyet inseresse inden for de sidste få år. Den kliniske effektivitet af begge lægemidler blev bekræftet ved godt kontrollerede undersøgelser på flere klinikker. Flere gigtforskere har givet udtryk for den opfattelse, at en forbedret D-penicillamin-lignen-de forbindelse vil være et værdifuldt bidrag til medicinen inden for dette vigtige område. Det er derfor en betydningsfuld opdagelse, at de hidtil ukendte forbindelser fremstillet ved fremgangsmåden ifølge opfindelsen har en betydelig grad af anti-rheumatisk arthritis-aktivitet.
Fra Arzneimittelforschung bind 11 (1961) kendes mercaptopyri-doxinderivater med analgetisk virkning. De ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser har imidlertid ikke blot smertestillende virkning, men er midler til bekæmpelse af rheumatisk arthritis og dermed beslægtede inflammatoriske sygdomme. Man bekæmper således selve sygdommen og ikke blot dens symptomer.
De omhandlede forbindelser kan gives oralt, topisk, parenteralt, ved spray-inhalering eller rektalt i enhedsdoser indeholdende konventionelle ikke-giftige farmaceutisk acceptable bærermedier, fortyndingsmidler og fyldstoffer. Ved udtrykket parenteral forstås subcutan injektion, intravenøs, intramuskulær, intra- 3 148594 steranal eller intraarticulær injektion eller infusion. Ud over behandling af varmblodede dyr, såsom mus, rotter, heste, hunde eller katte, er forbindelserne effektive til behandling af mennesker.
• Data for adjuvant arthritis-hæmning for den ved fremgangsmåden ifølge opfindelsen fremstillede forbindelse er som følger:
Adjuvant arthritis - metode I
Metode: Grupper på 6 Sprague-Dawley hanrotter med en legemsvagt på 170 til 190 g blev injiceret subcutant i den yderste tredjedel af halen med en suspension af 0,5 mg M. butyricum i 0,1 ml let mineralolie på dag 0. Målinger af fodvolumen blev foretaget på dag 0 og dag 14, legemsvagt blev målt dagligt, inflammationsenheder i plasma og sankning på dag 14.
Forsøgsforbindelsen blev indgivet oralt én gang om dagen begyndende på dag -1, idet forbindelsen var suspenderet eller opløst i 0,5% "Methocel1 . Adjuvanskontrollerne fik kun "Methocel"®.
Adjuvant arthritis - metode II
Metode: Lægemiddeldoser blev indgivet oralt på dag -1, 0 og +1 med adjuvansinjektion i halen (0,5 mg M. butyricum i 0,1 ml mineralolie) på dag 0, i grupper på 6 Sprague-Dawley hanrotter pr. behandling med legemsvægt på 170 til 190 g. Målinger af potevolumen blev foretaget på dag 0 og dag 14. Der var 12 kontrolrotter.
TABEL 1
Dosis Inhibering af (mg/kg legemsvægt) inflammation, %
Metode I 50 51 25 34
Metode II 50 42 25 38
Som prøveforbindelse blev anvendt bis-(2-methyl-3-hydroxy-5-vinyl-4-pyridylmethyl)disulfid, 2^0, smp. 197 - 198 °C (dekom-ponering). Prøveresultaterne viser en rimelig god inhibering af inflammation. Procedurerne er standardmetoder til afprøvning af anti-inflammatorisk aktivitet.
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Doser af en størrelse på 0,5 til 140 mg pr. kg legemsvægt pr. dag egner sig til behandling af de ovennævnte lidelser (25 mg til 7 g pr. patient pr. dag). Por eksempel kan inflammationer behandles effektivt og den antipyretiske og analgetiske aktivitet viser sig ved indgift af 0,1 til 50 mg af forbindelsen pr. kg legemsvægt pr. dag (5 mg til 3,5 g pr. patient pr. dag).
Til opnåelse af særligt effektive resultater benyttes 1 - 15 mg pr. kg legemsvægt pr. dag (50 mg til 1 g pr. patient pr. dag).
Mængden af aktiv bestanddel, der kan kombineres med bærermateriale til at producere en enkelt dosisform, varierer i afhængighed af den, der behandles, og indgivelsesmetoden. For eksempel kan et præparat til oral indgift på mennesker indeholde fra 5 mg til 5 g aktiv bestanddel blandet med en passende mængde bærermedium, som kan udgøre 5 - 95 % af præparatet.'
En enhedsdosis vil sædvanligvis indeholde mellem 25 mg og 500 mg aktiv bestanddel.
Dosisstørrelsen skal afpasses efter forholdene, såsom patientens alder, legemsvægt, sundhedstilstand, køn, diæt, indgivelsestidspunktet, indgivelsesvejen, udskillelseshastigheden, lægemiddelkombination og sygdommens styrke.
De omhandlede forbindelser fremstilles sædvanligvis ud fra kendte pyridinderivater. Særlig foretrukkent er sulfatmonohydrat-saltet af forbindelsen I, da denne forbindelse er særlig stabil.
Når udgangsmaterialet har en fri <A-mercaptoalkylgruppe i 4-stillin-gen, som er ved siden af en hydroxylsubstituent som i 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridin, dannes det let ved at opløse den tilsvarende of-hydroxyalkylforbindelse i en lavere al-kanol, fortrinsvis ethanol, indeholdende et alkalimetalhydroxid, såsom natriumhydroxid eller kaliumhydroxid, behandle opløsningen med carbondisulfid og opvarme i 2 - 8 timer ved en temperatur på
5 U859A
fra 50 °C til tilbagesvalingstemperaturen, efterfulgt af syrning af den afkølede blanding. Isoleringen udføres ved standardmetoder som inddampning til tørhed og ekstraktion med et opløsningsmiddel.
Mercaptomethylforbindelsen (II) fås også fra thiosulfatsaltet (III) ved reduktion med lithiumaluminiumhydrid eller natrium-borhydrid ved -10 - 10 °C i et inert opløsningsmiddel, såsom tetrahydrofuran eller blandinger af tetrahydrofuran og ether.
Endvidere kan mercaptomethylforbindelsen (II) fås ved en fremgangsmåde illustreret i efterfølgende skema:
[ (J CH2SH
CH > HO J. CH=CH2 A ΓΪ <*3 lp
B
Fremgangsmåden omfatter en behandling af enten forbindelsen A eller forbindelsen B med en stærk base, såsom et alkalimetal-amid, f.eks. natriumamid eller kaliumamid, i flydende ammoniak ved -5 til -35 °C i 15 minutter til 2 timer, efterfulgt af afdampning af ammoniakken, opløsning af den faste remanens i vand og indstilling til neutral reaktion.
Andre stærke baser, som kan anvendes, er alkalimetalhydroxider, alkalimetalalkoxider og alkalimetalalkyler, alkalimetalaryler, alkalimetalhydrider, Grignard-reagenser, alkalimetalalkylami-der (f.eks. lithiumdiisopropylamid).
Disulfiderne (I) kan ifølge alternativ (b) fås ud fra thiosulfatsaltet (III) ved, ved 20 - 100 °C at blande omtrent molære ækvivalenter af thiosulfatsaltet og 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridin med et vandigt alkalimetalhy-droxid, såsom natrium- eller kaliumhydroxid.
6 148594
Ifølge alternativ (c) overføres thiosulfatsaltet af 2-methyl- 3-hydroxy-4-mercaptomethyl-5-vinylpyridin, i det symmetriske disulfid, bis-(2-methyl-3-hydroxy-5-vinyl-4-pyridylmethyl)-disulfid ved forskellige fremgangsmåder: ved at behandle det med vandig alkali eller fortyndet mineralsyre ved 20 - 100 SC, ved at behandle med Na£S2 i en vandig alkanol ved 20 - 100 °C i 3 - 24 timer, ved at behandle det med Na2S i en vandig alkanol ved 20 - 100 °C i fra nogle minutter til 4 timer eller ved at behandle det med iod ved stuetemperatur i en vandig alkanol i 8 - 24 timer.
En anden fremgangsmåde (e) til fremstilling af bis-(2-methyl-3-hydroxy-5-vinyl-4-pyridylmethyl)disulfid er at behandle 2-methyl-3-hydroxy-4-hydroxymethylpyridin med phosphorpenta-sulfid i et opløsningsmiddel, såsom pyridin, ved 50 °C til tilbagesvalingstemperaturen i 2 - 10 timer efterfulgt af syrning og yderligere opvarmning i 1 - 4 timer.
En anden fremgangsmåde (f) til at fremstille bis-(2-methyl-3-hydroxy-5-vinyl-4-pyridylmethyl)disulfid er at behandle 2-methyl-3-hydroxy-5-vinyl-4-pyridylmethyl-isothiouroniumsalt ved 10 °C til stuetemperatur med fortyndet vandig alkali, såsom 50 - 150 g/liter natriumhydroxid, og vandig hydrogen-peroxid i fra nogle få minutter til 2 timer.
På lignende måde kan et isothiouroniumsalt overføres i et disulfid ved at anvende natriumtetrathionat i ovenstående reaktion efterfulgt af syrning til pH 5 - 7.
En yderligere fremgangsmåde (d) til fremstilling af de symmetriske disulfider ifølge opfindelsen består i at behandle en forbindelse med formlen
CH,Q
HO jL CH-CH- ]| (VII)
1485 9A
Λ> 7 eller et salt deraf, hvor Q er en let fraspaltelig gruppe, såsom chlor, brom, iod, methansulfonyloxy, benzensulfonyloxy, toluen-sulfonyloxy eller 2,4-dinitrobenzoyloxy, med natriumdisulfid (^282). Reaktionen udføres i vandig alkanol ved omtrent stuetemperatur, skønt temperaturen ikke er kritisk, i 2 - 24 timer.
4
Ifølge alternativ (a) kan monomeren (II) oxideres med en persyre, såsom m-chlorperbenzoesyre, pereddikesyre, perphthalsyre, natrium-hypochlorit, iod eller hydrogenperoxid, i vandig opløsning ved 0-15 °c.
De ved fremgangsmåden ifølge opfindelsren fremstillede hidtil ukendte forbindelser har en alkenylsubstituent. Alkenylsubstituen-ten fremstilles i almindelighed ud fra den tilsvarende formylpyri-din ved hjælp af et sædvanligt Wittig-reagens, f.eks. triphenyl-methylphosphoniumbromid, i nærværelse af en stærk base, såsom natriumhydrid, i et opløsningsmiddel, såsom dimethylsulfoxid. Reaktionen udføres bedst koldt, under 25 °C, efterfulgt af henstand ved stuetemperatur i længere tid, såsom 1-3 dage, eller ved at opvarme ved temperaturer på 40 - 90 °C i 1 - 7 timer.
Alternativt kan alkenylgruppen fremstilles ud fra en formylpyri-din ved at underkaste den en Grignard-reaktion under standardbetingelser til fremstilling af en a.-hydroxyalkylpyridin efterfulgt af termisk dehydratisering af c^-hydroxyforbindelsen ved kogning under tilbagesvaling i et højtkogende opløsningsmiddel, såsom diethylenglycoldimethylether (diglym).
Opfindelsen skal i det efterfølgende illustreres nærmere ved hjalp af nogle udførelseseksempler.
Eksempel 1 31s-f 2-methyl-3-hydroxy-5-vinyl-4-pyridylinethylldisiilf id 2-Methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridin-hydrochlorid (9 g) opløses i 50 ml vand og behandles med 2 N ammoniumhydroxid til pH = 9. Luft bobles gennem opløsningen i 24 timer. Det 8 U8594 udfældede bis-[2-methyl-3-hydroxy-5-vinyl-4-pyridylmethyl]-
disulfid opsamles på et filter og tørres, smp.: 178 - 180 C
(dek.).
Eksempel 2
Bis-[2-methyl-3-hydroxy-5-vinyl-4-pyridylmethyl'|disulfid 2-Methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridin-hydrochlorid (4,36 g) opløstes i 40 ml vand ved 2 - 7° C under en nitrogen-atmosfære. Til denne opløsning sattes 2,0 ml af en 30 fS hydrogenperoxidopløsning i løbet af 2 minutter, medens tempera ^turen opretholdtes ved 2 - 7° G. Efter 30 minutters omrøring ved denne temperatur filtreredes blandingen under nitrogen, og filtratet omrørtes med overskud af mættet natrium-bicarbonatopløsning ved 2° C i 10 minutter. Blandingen filtreredes hurtigt, og filterkagen blev vasket med 2 x 40 ml acetonitril. Det faste stof blev tørret over phosphorpentoxid til dannelse af 1,5 g bis-[2-methyl-3-hydroxy-5-viayl-4·-pyridylmethyl]-disulfid, smp.: > 300° G. Monohydratet har et smp.: 178 - 180° C. Dihydratet har et smp.: 197 - 198° C (dek.).
Eksempel 3
Bis-£2-methyl-3-hydroxy-5-vinyl-4-pyridylmethyl3 disulfid 0,1 mol 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinyl-4-pyridyl-methyl-thiosulfat kogtes under tilbagesvaling i 18 timer med 1 N svovlsyre. Dette inddampedes til tørhed, remanensen blev optaget i isopropanol, filtreret og atter inddampet til en olie. Olien blev behandlet med vandig natriumbicarbonatopløs-ning. Det dannede faste stof, bis-[2-methyl-3-hydroxy-5-vinyl- 4-pyridylmethyl]-disulfid, opnåedes i et udbytte på 43% med smp. 150-155 °C.
9
1485 9A
Eksempel 4
Bie-Γ 2-methyl-5-h-Vdro3cy-5-vinylp.yrldin-4-methyl1 disulfid
Til en Blanding af 0,035 mol natriumsulfid-nonahydrat og 0,034 mol S i 50 ml vand sættes under omrøring 0,02 mol 4-brommethyl- 3-hydroxy-2-methyl-5-vinylpyridin-liydrobromid i 50 ml E^O. Reaktionsblandingen omrøres i 18 timer og filtreres til isolering af det urene produkt og svovl. Bundfaldet ekstraheres med 8 % vandig saltsyre, filtreres, og filtratet neutraliseres derefter med natriumbicarbonat. Det dannede bundfald filtreres til dannelse af bis- £2-methyl-3-hydroxy-5-vinylpyridin-4-methy 11 disulfid, smp. 280 °C; udbytte: 68%.
Eksempel 5
Bis-[2-methyl-3-hydroxy-5-vinylpyridyl-4-methylJ disulfid
Thiosulfatsaltet af 2-methyl-3-hydroxy-4-iAercaptcwaethyl~5-vinylpyri-din (2,6 g) opløses i en opløsning af 1,9 g 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridin i 16 ml 10^ (vægt/vol.) natriumhydrox-idopløsning. Opløsningens pH-værdi indstilles på 6,5 med fortyndet saltsyre. Bundfaldet opsamles, vaskes med vand, acetone og ether og tørres, hvorved fås bis-C2-methyl-3-hydroxy-5-vinylpyri-dyl-4-methylldisulfid, smp. 160 °C; udbytte: 92%.
Eksempel '6
Bis-f2-methyl-3-hydroxy-5-vinylpyridyl-4-methylJ disulfid
En opløsning af 3»3 g sf thiosulfatsaltet af 2-methvl-3-hydroxy-4-mercaptometiiyl-5-vinylpyridin i 50 ml 60 f (vol,,/vol.) vandig methanol behandles med 0,85 g natriumdisulfid (Na2S2) i 5 ml vand under omrøring i 3 timer. Opløsningen opbevares ved stuetemperatur i i 10 148594 16 timer. Bundfaldet opsamles, vaskes med vand, acetone og ether og tørres, hvorved fås bis-C2-methyl-3-hydroxy-5-vinylpy-ridyl-4-methylJdisulfid. Udbytte: 30%; smp. 195 °C.
Ved i stedet for 0,85 g NagSg i ovennævnte eksempel at anvende 1,2 g Na2S.9H20, fås samme resultat.
Eksempel 7
Bis-Cz-methyl-S-hydroxy-S-vinylpyridyl^-methyl] disulf id
En opløsning af 12,2 g af thiosulfatsaltet af 2-methyl-3-hydroxy-4-mercaptometliyl-5-vinylpyridin i 200 ml 50# (vol./vol.) vandig methanol behandles med 6,4 g iod, og blandingen omrøres ved stuetemperatur i 16 timer. Bundfaldet opsamles, vaskes med vand, acetone og ether og tørres, hvorved fåe bis- C2-methyl-3-hydroxy-5-vinylpyridyl-4-methyl]disulfid. Udbytte 87%. Identisk med autentisk prøve i-følge chromatografi og massespektroskopi.
Eksempel 3
Bis- C2-methyl-3-hydroxy-5-vinylpyridyl-4-methyl3 disulfid
En opløsning af 4»9 g 2-methyl-3-hydroxy-4-hydroxymethyl-5-vinyl-pyridin i 250 ml pyridin behandles med 2,5 g frisk fremstillet PgSjj-pulver, og blandingen koges under tilbagesvaling i 4 timer. Opløsningsmidlet afdampes under reduceret tryk. Til remanensen sættes 200 ml 2,5 N saltsyre, og blandingen koges under tilbagesvaling i 2 timer. Efter afkøling hældes blandingen i mættet natriumbicarbonatopløsning. Bundfaldet opsamles, vaskes med vand, acetone og ether og tørres, hvorved fås bis-C2-methyl-3-hydroxy- 5-vinylpyri dy1-4-me thy1]di sulfid.
1485 9A
Eksempel 9 11
Bis- C2-methyl-3-hydroxy-5-yinylpyridyl-4-methylldisulfid
En opløsning af 10 g 2-methyl-3-hydroxy-5-vinylpyridyl-4-methyl-isothiuroniumbromid i 35 ml methanol og 15 ml vand "behandles med 50 ml 10# (vægt/vol.)vandig natnumhydroxidopløsning. 8,0 g af en 10# vandig hydrogenperoxidopløsning tilsættes ved 20° C, og blandingen omrores i 5 minutter og neutraliseres derefter med 10# saltsyreopløsning. Bundfaldet opsamles, vaskes med vand, acetone og ether og tørres, hvorved fås bis-C2-methyl-3-hydroxy-5~vinyl-pyridyl-4-methyl]disulfid. udbytte: 46%; smp. 185 °c.
Eksempel 10
Bis-C2-methyl-5-1ινάΓθχν-5-ν1ην1ρν:ι:ίάν1-4-ιιιβ'ί1ινΐ2άΪ5η1£ id
En blanding af 77,8 g 2-methyl-3-h.ydroxy-5-vinylpyridy1-4-methy1-isothiuroniumbromid i 250 ml vand, 27 g natriumt etra thi onat i 500 ml vand og 350 ml 4 N natriumhydroxidopløsriinq omrores ved stuetemperatur i 30 minutter. Saltsyre (4 n) tilsættes ti-l en _pH-vsrdi på 6. Bundfaldet opsamles, vaskes med vand, acetone og ether og tørres, hvorved bis-C2-methyl-5-hydroxy-5-vinylpv-ridyl-4-methyl]disulfid.
, Eksempel 11
Bis-C2-methyl-3-hydroxy-5-vinylpyridyl-4-methylJ disulfid
Trin A: Præparation af 2-methyl-3-hydroxy-4-methansulfonyl- oxymethyl-5-vinylpyridin_
En blanding af 0,1 mol 2-methyl-3-hydroxy-4-hydroxymethyl-5-vinylpyridin og 0,1 mol methansulfonylchlorid i 100 ml tør pyri-din opretholdes i 1 time ved stuetemperatur og inddampes derefter i vakuum til ca. 10 ml. Denne remanens fordeles mellem 100 ml chloroform og 100 ml mættet vandig natriumbicarbonatopløsning.
Den organiske fase fraskilles, vaskes med vand, tørres, filtreres 12 14859Λ og inddampes til tørhed, hvorved fås 2-methyl-3-hydroxy-4-methan-sulfonyloxyme thyl-5-vinylpyri din.
Trin B: Præparation af bis-C2-methyl-3-hydroxy-5-vinylpyridyl-4- methyl]disulfid_
Remanensen fra trin A optages i 100 ml 60# (efter rumfang) vandigt methanol og behandles med 0,1 mol NagSg i 10 ml vand. Efter omrøring i 16 timer ved stuetemperatur opsamles bundfaldet, der vaskes med vand, acetone og ether og tørres til dannelse af bis - C2-methyl-3-hydroxy-5-vinylpyridyl-4-methyl3 disulfid.
Eksempel 12
Bis- C2-methyl-3-hydroxy-5-vinylpyridin-4-inethyl3disulf jd
Trin A: Præparation af 4-mercaptopyridoxal-diethylacetal
Pyridoxal-diethylacetal (0,01 mol) opløses i 125 ml ethanol indeholdende 3 g kaliumhydroxid. Efter omrøring i 10 minutter tilsættes 5 ml carbondisulfid, og blandingen koges under tilbagesvaling i 4 timer. Den afkølede blanding neutraliseres med fortyndet saltsyre. Blandingen inddampes til et lille rumfang 3 vakuum, og remanensen fordeles mellem vand og ethylacetat. Ethylacetatet fraskilles, tørres over vandfrit natriumsulfat og inddampes til tørhed.
Trin B: Præparation af bis-C2-methyl-3-hydroxy-5-formylpyridin- 4-methyijdisulf id
Remanensen fra trin A optages i 100 ml ethanol og behandles med 25 ml koncentreret ammoniakvand. Der bobles luft gennem blandingen i 24 timer ved stuetemperatur. Overskud af ammoniak og hovedparten af ethanolen afdampes under reduceret tryk, og blandingen neutraliseres med 2,5 N saltsyre og opvarmes på dampbad i 30 minutter. Opløsningen inddampes til tørhed, og remanensen omkrystalliseres af ethylacetat, hvorved fås bis-C2-methyl-3-hydroxy- 5-formylpyridin-4-methylldisulfid- · 13 148534
Trin C: Præparation af bis-£2-methyl-3-hydroxy-5-vinylpyridin- 4-methyl3disulfid __
En blanding af 50 ml dimethylsulfoxid og 5 g natriumhydridemul-sion (50 ¢) (0,1 mol) opvarmes til 70 - 85° C på dampbad under nitrogen. Efter ophør af hydrogenudviklingen tildryppes en opløsning af 37 g triphenylethylphosphoniumbromid i varm dimethyl-sulfoxid, medens temperaturen opretholdes ved 10 - 20° C. 30 minutter efter at tilsætningen er afsluttet, tilsættes en opløsning af 18,2 g bis-C2-methyl-3-hydroxy-5-formylpyridin-4-methyl3~ disulfid i varm dimethylsulfoxid, og blandingen omrøres i 16 timer ved stuetemperatur. Den hældes i vand, og bundfaldet opsamles på filter og vaskes med acetonitril. Det faste stof tørres over phosphorpentoxid, hvorved fås bis-C2-methyl-3-hydroxy-5-vinylpyridin-4-methyl3disulfid, smp.: > 300 °C. Dihydratet smelter ved 197 - 198° C (dek.).
Eksempel 13
Bis-C2-methyl-3-hydroxy-5-vinyl-4-pyridylmethylJdisulfid-sulfat-monohydrat_
Til en opløsning af 6,1 g 95,6%'s svovlsyre i 100 ml vand ved 35°C blev der under omrøring sat 10,0 g bis-C2-methyl-3-hydroxy- 5-vinyl-4-pyridylmethylldisulfid. Opløsningen blev opvarmet, indtil man ved 90°C fik en skarp gul, klar opløsning.
Opløsningen blev afkølet langsomt til 0 - 5°C og henstod i 1 time. Bundfaldet blev opsamlet på et filter, vasket med 2x3 ml isvand og tørret ved stuetemperatur under vakuum, hvorved man opnåede 11,05 g (84%) bis-["2-methyl-3-hydroxy-5-vinyl-4-pyri-dylmethyl3disulfid-sulfat,monohydrat med smp.:159 - 162 °C.

Claims (2)

148594
1. Analogifremgangsmåde til fremstilling af en terapeutisk aktiv forbindelse med formlen: ch2-S-- »•γίγ»«. _ _2 eller farmaceutisk acceptable salte og hydrater deraf, kendetegnet ved, at (a) en forbindelse med formlen CHjSH H°nJL^CH-CH2 jf jT 11 ch3 eller et salt deraf behandles med et oxydationsmiddel, fortrinsvis hydrogenperoxid, (b) en forbindelse med formlen CH2SS03 © ho^1^ch=ch2 XT 111 3 Θ omsættes med en forbindelse med formlen CH-SH ho^A>Ch=ch2 XT CH^IT eller et salt deraf og med et alkalimetalhydroxid, 148594 (c) en forbindelse med formlen CH2SS03 © H°\A^CH=CH2 Λ J 111 3 Θ behandles med (i) syre (ii) alkali, (iii) Na2S2, (iv) Na2S, eller (v) iod, -i (d) en forbindelse med formlen ch2q H0V^L/CH“CH2 XJ CH3 eller et salt deraf, hvor Q er chlor, brom, iod, methansulfonyl-oxy, bensensulfonyloxy, toluensulfonyloxy eller 2,4-dinitrobenzoyl-oxy, behandles med Na2S2, (e) en forbindelse med formlen CH-OH HO CH-CH2 viii åJ C»3 eller et salt deraf behandles med P2S^, (f) en forbindelse med formlen /NH CH,-S-C HO 1 iTH2 N(TyHecH2 κ CH3 148594 eller et salt deraf behandles med et alkalimetalhydroxid og et oxidationsmiddel, eller (g) en forbindelse med formlen ch2-S-- ΗΟχ1/·ΟΗΟ _3 _)2 eller et salt deraf behandles med et carbonylolefineringsreagens, og at en under punkt (a) - (g) opnået forbindelse eventuelt overføres i et salt eller hydrat deraf.
2. Fremgangsmåde ifølge krav 1 til fremstilling af sulfat,monohydratsaltet af forbindelsen med formlen I, kendetegnet ved, at man anvender et sulfatsalt af udgangsmaterialet eller omsætter den dannede frie base med svovlsyre. Fremdragne publikationer: Arzneimittel-Forschung, bind 11 (1961), side 922-929.
DK290274A 1973-06-15 1974-05-29 Analogifremgangsmaade til fremstilling af bis-(2-methyl-3-hydroxy-5-vinyl-4-pyridylmethyl)disulfid eller farmaceutisk acceptable salte oghydrater deraf DK148594C (da)

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US3591584A (en) * 1968-08-27 1971-07-06 Pfizer Benzothiazine dioxides
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CH605764A5 (da) 1978-10-13
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AU6976574A (en) 1975-12-04
LU70318A1 (da) 1975-03-06
SE411208B (sv) 1979-12-10
NL7407212A (da) 1974-12-17
DE2428470A1 (de) 1975-01-23
IL44958A0 (en) 1974-09-10
SE7406972L (da) 1974-12-16
EG11578A (en) 1978-03-29
IE39896L (en) 1974-12-15
FR2233055B1 (da) 1977-11-04
NL187395C (nl) 1991-09-16
JPS59511B2 (ja) 1984-01-07
NO144569C (no) 1981-09-23
DK290274A (da) 1975-02-10
ZM9274A1 (en) 1976-02-23
CA1021342A (en) 1977-11-22
SE7711211L (sv) 1977-10-06
FI167474A (da) 1974-12-16
GB1473591A (en) 1977-05-18
DE2428470C2 (da) 1988-10-13
NO741962L (da) 1975-01-13
NL187395B (nl) 1991-04-16
ES427187A1 (es) 1977-01-01
IL44958A (en) 1978-09-29
SE426170B (sv) 1982-12-13
FR2233055A1 (da) 1975-01-10
DK148594C (da) 1986-01-27

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