DK147857B - METHOD FOR PREPARING 9- (2-HYDROXYEPHOXYMETHYL) GUANINE OR 9- (2-HYDROXYETHOXYMETHYL) ADENIN - Google Patents
METHOD FOR PREPARING 9- (2-HYDROXYEPHOXYMETHYL) GUANINE OR 9- (2-HYDROXYETHOXYMETHYL) ADENIN Download PDFInfo
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Description
147857147857
Opfindelsen angår en fremgangsmåde til fremstilling af 9-(2-hydroxyethoxymethyl)guanin eller 9-(2-hydroxyethoxymethyl)-adenin med formlenThe invention relates to a process for the preparation of 9- (2-hydroxyethoxymethyl) guanine or 9- (2-hydroxyethoxymethyl) -adenine of the formula
RR
Λ «ν aX>Λ «ν aX>
2 I2 I
CH2.O.CH2.CH2.OHCH2.O.CH2.CH2.OH
hvori R betegner amino eller hydroxy.wherein R represents amino or hydroxy.
Disse to forbindelser har antiviral virkning overfor forskellige grupper af DNA og RNA virus både ved in vivo og in vitro 147857 2 forsøg. Særligt er disse forbindelser virksomme som antivirale midler overfor adenovirus som f.eks. adenovirus 5 og rhinovirus.These two compounds have antiviral activity against different groups of DNA and RNA virus both in in vivo and in vitro experiments. In particular, these compounds act as antiviral agents for adenoviruses such as e.g. adenovirus 5 and rhinovirus.
De er særlig virksomme som antivirale midler overfor vaccinia, og herpes virus, herunder simplex, zoster og varicella hos pattedyr. Disse virus forårsager sådanne sygdomme, som keratitis herpetica hos kaniner og encephalitisk herpetica hos mus.They are particularly effective as antiviral agents for vaccinia, and herpes viruses, including simplex, zoster and varicella in mammals. These viruses cause such diseases as keratitis herpetica in rabbits and encephalitic herpetica in mice.
Der kendes en række fremgangsmåder til at fremstille 9—(2— hydroxyethoxymethyl)derivater af puriner. Por eksempel kan de fremstilles ved at fjerne en beskyttende gruppe fra 2-stillingen på sidekæden. Alternativt kan de dannes ved omdannelse af 2-og/eller 6-substituenten på purinringen til den anden substituent (se dansk patentansøgning nr. 3926/75).A number of methods are known for preparing 9- (2-hydroxyethoxymethyl) derivatives of purines. For example, they can be prepared by removing a protective group from the 2-position of the side chain. Alternatively, they may be formed by converting the 2 and / or 6 substituent on the purine ring to the other substituent (see Danish Patent Application No. 3926/75).
I tysk offentliggørelsesskrift 2.539.963 beskrives forskellige fremgangsmåder til fremstilling af de nævnte forbindelser.German Publication No. 2,539,963 discloses various methods for preparing said compounds.
Disse fremgangsmåder omhandler sådanne, hvori forbindelser beskyttet ved endestillingen af kæden i 9-stillingen déblokeres ved basisk hydrolyse, samt sådanne, hvori forbindelser beskyttet ved 2- og/eller 6-stillingerne déblokeres ved solvolyse med vandig eller alkoholisk ammoniak eller ved alkoholyse.These methods deal with those in which compounds protected at the end position of the chain at the 9-position are unblocked by basic hydrolysis, and those in which compounds protected at the 2- and / or 6-positions are unblocked by solvolysis with aqueous or alcoholic ammonia or by alcoholysis.
I det tyske fremlæggelsesskrift drages der et klart skel mellem på den ene side mulige blokeringsgrupper i 2- og/eller 6-stillingerne og de til fjernelse af sådanne grupper nødvendige betingelser, og på den anden side mulige blokeringsgrupper ved terminalstillingen i sidekæden i 9-stillingen og de til fjernelse af sådanne grupper i denne stilling nødvendige betingelser, og det har ikke været nærliggende at foretage en samtidig fjernelse af blokerende grupper i 2-, 6- og 9-stillingerne.In the German disclosure, a clear distinction is drawn between, on the one hand, possible blocking groups in the 2 and / or 6 positions and the conditions necessary for removing such groups, and on the other hand possible blocking groups at the terminal position in the side chain in the 9 position. and the conditions necessary for removing such groups in this position, and it has not been obvious to carry out simultaneous removal of blocking groups in the 2-, 6- and 9 positions.
Det har nu overraskende vist sig, at blokerende acylgrupper i 2-, 6- og 9-stillingerne kan fjernes i et enkelt trin ved basisk hydrolyse og under opnåelse af mere tilfredsstillende udbytter end hvad der fås ved de kendte fremgangsmåder, hvorfor fremgangsmåden ifølge opfindelsen er ejendommelig ved, at man i nærværelse af en base hydrolyserer en forbindelse med formlen II (se krav 1), 1 2 112 hvori R betegner hydroxy eller -NR .CX , og X og X , der er ens 0 eller forskellige, hver betegner en alkyl- eller phenylgruppe, 2 1 og R betegner hydrogen eller -CX , under den forudsætning, at når 0 1 2 12 R betegner hydroxy, betegner R hydrogen. Dersom X og X er alkyl- 3 147857 grupper, har de fortrinsvis 1-4 carbonatomer og mest foretrukken er de ens og betegner hver en methylgruppe.Surprisingly, it has now been found that blocking acyl groups at the 2-, 6- and 9-positions can be removed in a single step by basic hydrolysis and obtaining more satisfactory yields than are obtained by the known processes, so the method of the invention is peculiar in that, in the presence of a base, a compound of formula II (see claim 1) is hydrolyzed, wherein R is hydroxy or -NR .CX, and X and X, which are the same 0 or different, each denote a alkyl or phenyl group, 2 1 and R represents hydrogen or -CX, provided that when 0 1 2 12 R represents hydroxy, R represents hydrogen. If X and X are alkyl, they preferably have 1-4 carbon atoms and most preferably they are the same and each represents a methyl group.
At fremgangsmåden ikke har været nærliggende fremgår endvidere af Bowles et al: "J. Med. Chem.}september 1963, side 471-480", hvor der beskrives en deacyleringsproces, hvor en 9-acetyl-gruppe fjernes fra et purinderivat, hvorved den beskyttende ace-tylgruppe i 2-stillingen forbliver intakt og fjernes i et påfølgende trin. På denne baggrund er det overraskende, at en fremgangsmåde, hvor beskyttelsesgrupper i to eller tre forskellige stillinger fjernes, kan udføres med godt udbytte under anvendelse af ensartede betingelser.Further, the process has not been apparent from Bowles et al: "J. Med. Chem.} September 1963, pages 471-480", which describes a deacylation process wherein a 9-acetyl group is removed from a purine derivative, thereby protective acetyl group at the 2-position remains intact and is removed in a subsequent step. Against this background, it is surprising that a method whereby protecting groups in two or three different positions are removed can be carried out in good yield using uniform conditions.
Den anvendte base til hydrolysen kan være en vandig eller alkoholisk primær, sekundær eller tertiær alifatisk amin, et alkoxid i alkohol, eller et vandigt eller alkoholisk hydroxid, f.éks. natriumalkoxid eller -hydroxid. Den foretrukne base er en vandig primær alifatisk amin f.eks. vandig rnethylamin. Afhængig af den anvendte base kan hydrolysen udføres ved en temperatur fra stuetemperatur til temperaturen af et dampbad. Sædvanligvis giver lavere reaktionstemperatur længere reaktionstid, men færre sidereaktioner.The base used for the hydrolysis may be an aqueous or alcoholic primary, secondary or tertiary aliphatic amine, an alcohol alkoxide, or an aqueous or alcoholic hydroxide, e.g. sodium alkoxide or hydroxide. The preferred base is an aqueous primary aliphatic amine e.g. aqueous methylamine. Depending on the base used, the hydrolysis can be carried out at a temperature from room temperature to the temperature of a steam bath. Usually, lower reaction temperature gives longer reaction time, but fewer side reactions.
1 2 11 2 1
Et mellemprodukt af formlen II, hvori R betegner -NR CX ,An intermediate of formula II wherein R is -NR CX,
OISLAND
2 1 og R betegner -CX , kan fuldstændig hydrolyseres i et trin ved f.eks.2 and R represents -CX, can be completely hydrolyzed in one step by e.g.
2) at anvende vandig rnethylamin. Alternativtog mere foretrukkeitkan mellemproduktet af formlen II deacyleres i to trin. I det første trin fjernes en enkelt -C-X^-gruppe fra 2- og 6-stillingen på2) to use aqueous methylamine. Alternatively, more preferably, the intermediate of formula II can be deacylated in two steps. In the first step, a single -C-X 2 group is removed from the 2- and 6-positions
OISLAND
ringen ved mild hydrolyse ved stuetemperatur, idet man f.eks. anvender butylamin i en lavere alkohol.the ring by mild hydrolysis at room temperature, e.g. uses butylamine in a lower alcohol.
Hydrolysens andet trin til fjernelse af de tiloversblevne -jj-X1-grupper udføres, idet man anvender en stærkere base, som OThe second step of the hydrolysis to remove the remaining -jj-X1 groups is carried out using a stronger base such as O
f.eks. vandig rnethylamin.eg. aqueous methylamine.
Udgangsmaterialerne med formlen II er hidtil ukendte. Disse forbindelser kan fremstilles ved at omsætte guanin eller 2-amino-adenin, hvori 2-og 9-, eller 2-, 6-og 9-stillingerne er acylerede, med en diester eller 2-oxa-l,4-butandiol i nærværelse af en katalytisk mængde af en stærk syre som f.eks. svovlsyre, sulfonsyrer som para-toluensulfon-, methansulfon- eller 4 147857 trifluormethansulfonsyre, sulfaminsyre, bis-(p-nitrophenyl)phosphat eller polyphosphorsyre.The starting materials of formula II are novel. These compounds can be prepared by reacting guanine or 2-amino-adenine wherein the 2 and 9, or 2-, 6 and 9 positions are acylated with a diester or 2-oxa-1,4-butanediol in the presence of a catalytic amount of a strong acid such as sulfuric acid, sulfonic acids such as para-toluenesulfonic, methanesulfonic or trifluoromethanesulfonic acid, sulfamic acid, bis (p-nitrophenyl) phosphate or polyphosphoric acid.
Den acylerede purin for sit vedkommende kan fremstilles ved at omsætte den passende purin med et syreanhydrid som f.eks. eddike-syreanhydrid eller et andet acylerende middel, f.eks. et syre-halogenid. For at fremstille diesteren af 2-oxa-l,4-butandiol, omsættes dioxolan med et syreanhydrid i nærværelse af en katalytisk mængde af en stærk syre som f.eks. en af de ovenfor nævnte syrer.The acylated purine, for its part, can be prepared by reacting the appropriate purine with an acid anhydride such as e.g. acetic anhydride or other acylating agent, e.g. an acid halide. To prepare the diester of 2-oxa-1,4-butanediol, dioxolane is reacted with an acid anhydride in the presence of a catalytic amount of a strong acid such as e.g. one of the acids mentioned above.
Opfindelsen belyses nærmere i de følgende eksempler.The invention is further illustrated in the following examples.
Eksempel 1 9-(2-Hydroxyethoxymethyl)guanin.Example 1 9- (2-Hydroxyethoxymethyl) guanine.
Til en blanding af eddikesyreanhydrid (102 g), eddikesyre (15 g ) og p-toluensulfonsyre (5,0 g) afkølet til 10°C sattes dioxolan (70 g) under omrøring og afkøling med en sådan temperatur, at reaktionsblandingens temperatur aldrig oversteg 40°C. Herefter afkøledes blandingen til stuetemperatur, og toluen (300 ml) og diacetylguanin (50 g) tilsattes. Herefter opvarmedes reaktionsblandingen med tilbagesvaling under omrøring i 16 timer. Derefter afkølede man til stuetemperatur, og chloroform (50 ml) tilsattes.To a mixture of acetic anhydride (102 g), acetic acid (15 g) and p-toluenesulfonic acid (5.0 g) cooled to 10 ° C was added dioxolane (70 g) with stirring and cooling at such a temperature that the temperature of the reaction mixture never exceeded. 40 ° C. The mixture was then cooled to room temperature and toluene (300 ml) and diacetylguanine (50 g) were added. Then, the reaction mixture was heated at reflux with stirring for 16 hours. Then, it was cooled to room temperature and chloroform (50 ml) was added.
Det faste produkt fjernedes ved filtrering. Filterkagen vaskedes grundigt med chloroform og tørredes. Den tørrede filterkage sattes til 40% vandig methylamin (350 ml), og blandingen opvarmedes med tilbagesvaling under omrøring i 40 minutter, hvorefter den afkøledes og-filtreredes. Filtratet inddampedes under reduceret tryk til en tyk opslæmning. Opslæmningen afkøledes og filtreredes, og filterkagen vaskedes med ethanol og tørredes,hvorved man opnåede 9—(2— hydroxyethoxymethyl)guanin (27 g, mere end 90% rent), smp. 255-257°C. Udbytte =56%.The solid product was removed by filtration. The filter cake was thoroughly washed with chloroform and dried. The dried filter cake was added to 40% aqueous methylamine (350 ml) and the mixture was heated at reflux with stirring for 40 minutes, then cooled and filtered. The filtrate was evaporated under reduced pressure to a thick slurry. The slurry was cooled and filtered, and the filter cake was washed with ethanol and dried to give 9- (2-hydroxyethoxymethyl) guanine (27 g, more than 90% pure), m.p. 255-257 ° C. Yield = 56%.
Eksempel 2 9- (2-Hydroxyethoxymethyl)guanin.Example 2 9- (2-Hydroxyethoxymethyl) guanine.
En blanding af diacetylguanin (50 g), 2-oxa-l,4-butandiol-diacetat (59,8 g) og p-toluensulfonsyre (1,2 g) i toluen (350 ml) opvarmedes under omrøring med tilbagesvaling i 16 timer. Herefter afkøledes blandingen til stuetemperatur og filtreredes. Filterkagen vaskedes grundigt med toluen. Filterkagen tørredes, og den sattes til 40% vandig methylamin (350 ml). Blandingen opvarmedes under omrøring med tilbagesvaling i 40 minutter, hvorefter den .afkøledes til stuetemperatur og filtreredes. Filtratet inddampedes under re- 5 147857 duceret tryk, hvorved man opnåede en tyk opslæmning. Ethanol (200 ml) sattes til opslæmningen, som herefter afkøledes og filtreredes.A mixture of diacetylguanine (50 g), 2-oxa-1,4-butanediol diacetate (59.8 g) and p-toluenesulfonic acid (1.2 g) in toluene (350 ml) was heated under reflux for 16 hours. . Then the mixture was cooled to room temperature and filtered. The filter cake was thoroughly washed with toluene. The filter cake was dried and added to 40% aqueous methylamine (350 ml). The mixture was heated under reflux for 40 minutes, then cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure to give a thick slurry. Ethanol (200 ml) was added to the slurry, which was then cooled and filtered.
Den vaskedes med ethanol og tørredes, hvorved man fik 9-(2-hydroxy-ethoxymethyl)guanin (36 g, mere end 90% rent). Udbytte = 75%.It was washed with ethanol and dried to give 9- (2-hydroxyethoxymethyl) guanine (36 g, more than 90% pure). Yield = 75%.
Eksempel 3 2-Acetamidcr9- (2-acetyloxyethoxymethyl) hypoxanthin.Example 3 2-Acetamide Cr9- (2-Acetyloxyethoxymethyl) hypoxanthine.
En blanding af diacetylguanin (1,0 g), 2-oxo-l,4-butandiol-diacetat (0,82 g) og p-toluensulfonsyre (23 mg) i mineralsk olie (4 g) opvarmedes under omrøring ved 115°C ved reduceret tryk natten over. Den mineralske olie dekanteredes fra. Resten tritureredes med chloroform, hvorefter den ekstraheredes med kogende methanol. Methanolekstrakten koncentreredes til 50 ml, afkøledes med is og filtreredes. Filtratet inddampedes til tørhed, hvorved man fik en fast rest (0,43 g). Den faste rest rensede ved søjlechromatografi (silicagel, 10 g, i chloroform; eluering med 1:1 chlorofor:acetone), hvorefter man omkrystalliserede med ethanol til opnåelse af 2-acet-amido-9-(2-acetyloxyethoxymethyl)hypoxanthin (0,14 g), smp. 202,5-204,5°C.A mixture of diacetylguanine (1.0 g), 2-oxo-1,4-butanediol diacetate (0.82 g) and p-toluenesulfonic acid (23 mg) in mineral oil (4 g) was heated with stirring at 115 ° C. at reduced pressure overnight. The mineral oil was decanted off. The residue was triturated with chloroform and then extracted with boiling methanol. The methanol extract was concentrated to 50 ml, cooled with ice and filtered. The filtrate was evaporated to dryness to give a solid residue (0.43 g). The solid residue was purified by column chromatography (silica gel, 10 g, in chloroform; elution with 1: 1 chlorophore: acetone), then recrystallized with ethanol to give 2-acetamido-9- (2-acetyloxyethoxymethyl) hypoxanthine ( 14 g), m.p. 202.5 to 204.5 ° C.
Eksempel 4 2-Amino-9-(2-hydroxyethoxymethyl)adenin.Example 4 2-Amino-9- (2-hydroxyethoxymethyl) adenine.
(a) 2-Formamidoadenin (89,0 g) anbragtes i en 5-liter kolbe udstyret med en luftomrører og tilbagesvalingskondensator (CaC^ i tørrerøret). Hertil sattes eddikesyreanhydrid (4 liter). Blandingen blev bragt til kogning med tilbagesvaling, og blev holdt her i 60 timer. Efter denne tid fjernedes overskud af anhydrid ved destillation ved atmosfærisk tryk, indtil ca. 3,5 liter déstillat opnåedes. Destillationen fortsattes under reduceret tryk for at fjerne det meste af det tilbageblevne anhydrid. Den mørkebrune reaktionsblanding blev en viskos gummiagtig masse efter afkøling til stuetemperatur. Herefter opløstes den i dichlormethan, filtreredes for at fjerne eventuelle opslæmmede faste stoffer, og opløsningsmidlet fjernedes i vakuum, hvormed man opnåede 211,0 g (> 100%) 2,6-bis-(diacetyl-amino)-9-acetylpurin. Forsøgsudbyttet var 96,7%, baseret på NMR, når man gik ud fra eddikesyreanhydrid.(a) 2-Formamidoadenine (89.0 g) was placed in a 5-liter flask equipped with an air stirrer and reflux condenser (CaCl 2 in the drying tube). To this was added acetic anhydride (4 liters). The mixture was refluxed and kept here for 60 hours. After this time, excess anhydride was removed by distillation at atmospheric pressure until approx. 3.5 liters of distillate were obtained. The distillation was continued under reduced pressure to remove most of the remaining anhydride. The dark brown reaction mixture became a viscous rubbery mass after cooling to room temperature. Then it was dissolved in dichloromethane, filtered to remove any suspended solids and the solvent removed in vacuo to give 211.0 g (> 100%) of 2,6-bis- (diacetylamino) -9-acetylpurine. The experimental yield was 96.7%, based on NMR when starting from acetic anhydride.
(b) penta-acetylpurin (174 g ) anbragtes sammen med 1,4-diacetoxy-2-oxobutan (126,8 g) i en kolbe, der var udstyret med en luftomrører og tørrerør. Herefter anbragtes denne blanding i et oliebad ved 6 147857 130°C og omrørtes i nogle få minutter for at homogenisere blandingen. Dernæst sattes syrekatalysatoren p-toluensulfonsyre (2,74 g) til på én gang, og man fortsatte opvarmningen i 4 timer, efter hvilket tidsrum man fandt en næste kvantitativ omdannelse til produkter. Herefter afkøledes blandingen til stuetemperatur og oplagredes under-tør nitrogen.(b) penta-acetylpurine (174 g) was placed together with 1,4-diacetoxy-2-oxobutane (126.8 g) in a flask equipped with an air stirrer and dryer tube. Then this mixture was placed in an oil bath at 130 ° C and stirred for a few minutes to homogenize the mixture. Next, the acid catalyst p-toluenesulfonic acid (2.74 g) was added at once, and heating was continued for 4 hours, after which time a next quantitative conversion to products was found. The mixture was then cooled to room temperature and stored under nitrogen.
(c) Fusionsproduktet (208,5 g) opløstes i ethanol (5 ml/g) ved stuetemperatur og overførtes til en kolbe udstyret med en dryppetragt, luftomrører og termometer, n-butylamin (140,4 g) tilsattes dernæst dråbevis i løbet af 2 timer, og den exotherme reaktion kontrolleredes under anvendelse af et vandbad. Maksimumtemperaturen, som reaktionen måtte nå op på, var kun 30°C. Produktet begynde at udskille fra reaktionsblandingen i løbet af tilsætningen. Efter at tilsætningen var afsluttet, omrørtes blandingen ved stuetemperatur i 3 timer, hvorefter den anbragtes natten over på et koldt sted. Herefter fjernedes reaktionsproduktet ved filtrering, hvorved man opnåede en pastaagtig masse, der opslæmmedes med acetone (1 x 500 ml) og atter filtreredes. Man tørrede i vakuum ved 65°C i 3 timer, hvorefter blandingen henstod natten over ved stuetemperatur. Herved opnåedes 154,2 g (91,7%) af et lysebrunt hårdt fast stof. Produktet rensedes ved opløsning i varm dimethylformamid (10 ml/g) ved 100-110°C, hvorved man opnåede en uigennemsigtig brun opløsning. Efter afkøling natten over ved 5°C, fjernedes produktet ved filtrering, vaskedes med acetone (1 x 250 ml) og lufttørredes til opnåelse af 121,7 g (78,8%) 2,6-diacetamido-9-(2-acetoxyethoxymethyl)purin.(c) The fusion product (208.5 g) was dissolved in ethanol (5 ml / g) at room temperature and transferred to a flask equipped with a drip funnel, air stirrer and thermometer, n-butylamine (140.4 g) was then added dropwise over time. 2 hours and the exothermic reaction was monitored using a water bath. The maximum temperature to reach the reaction was only 30 ° C. The product begins to separate from the reaction mixture during the addition. After the addition was complete, the mixture was stirred at room temperature for 3 hours and then placed overnight in a cold place. Then, the reaction product was removed by filtration to obtain a paste-like mass which was slurried with acetone (1 x 500 ml) and again filtered. The mixture was dried in vacuo at 65 ° C for 3 hours, after which the mixture was allowed to stand overnight at room temperature. There was obtained 154.2 g (91.7%) of a light brown hard solid. The product was purified by dissolving in hot dimethylformamide (10 ml / g) at 100-110 ° C to give an opaque brown solution. After cooling overnight at 5 ° C, the product was removed by filtration, washed with acetone (1 x 250 mL) and air dried to give 121.7 g (78.8%) of 2,6-diacetamido-9- (2-acetoxyethoxymethyl) ) purine.
(d) 2,6-Diacetamido-9-(2-acetoxyethoxymethyl)purin (121,7 g) sattes til en omrørt opløsning af vandig methaylamin (608,5 ml af en 40% opløsning) i løbet af 5 minutter. Tilsætningen fulgtes af en mild exotherm proces, der hævede blandingens temperatur til 35°C(d) 2,6-Diacetamido-9- (2-acetoxyethoxymethyl) purine (121.7 g) was added to a stirred solution of aqueous methaylamine (608.5 ml of a 40% solution) over 5 minutes. The addition was followed by a gentle exothermic process which raised the temperature of the mixture to 35 ° C
og alt fast materiale opløstes i løbet af få minutter. Efter omrøring i 2 1/2 time angav tyndtlagschromatografi af blandingen, at reaktionen var løbet til ende. Herefter koncentreredes blandingen i vakuum på vandbad ved 45 til 50°C, hvorved man opnåede en tyk masse af brune krystaller. Disse opslæmmedes med acetone (545 ml, 7 ml/g) i 15 minutter for at fjerne N-methylacetamid og vakuumfiltreredes. Kagen rensedes med acetone (1 x 200 ml) og lufttørrede, hvorved man opnåede 74,7 g (96,0%) af rå hydratiseret 2-amino-9-(2-hydroxy-ethoxymethyl))adenin i form af lysebrune krystaller. Disse tørredes i vakuum ved 80°C i 18 timer, hvorved man opnåede 69,3 g (89,0%). af tørt produkt.and all solid matter dissolved in minutes. After stirring for 2 1/2 hours, thin layer chromatography of the mixture indicated that the reaction was complete. Then the mixture was concentrated in vacuo on a water bath at 45 to 50 ° C to give a thick mass of brown crystals. These were slurried with acetone (545 ml, 7 ml / g) for 15 minutes to remove N-methylacetamide and vacuum filtered. The cake was purified with acetone (1 x 200 ml) and air dried to give 74.7 g (96.0%) of crude hydrated 2-amino-9- (2-hydroxy-ethoxymethyl) adenine as light brown crystals. These were dried in vacuo at 80 ° C for 18 hours to give 69.3 g (89.0%). of dry product.
7 1478577 147857
Eksempel 5 2-Acetamido-9-(2-acetyloxyethoxymethyl)hypoxan-thin (6,19 g) blev suspenderet i 1N natriumhydroxid (40 ml)og opvarmet til tilbagesvaling i 1 time. Blandingen blev afkølet, neutraliseret med 6N saltsyre og produktet filtreret fra. Det faste stof blev vasket med isvand (10 ml) og med acetone (15 ml) og tørret under vakuum natten over. Der blev opnået 4,13 g (91,8%) 9-(2-hydroxyethoxy-methyl)guanin, smp. 255-257°C.Example 5 2-Acetamido-9- (2-acetyloxyethoxymethyl) hypoxane thin (6.19 g) was suspended in 1N sodium hydroxide (40 ml) and heated to reflux for 1 hour. The mixture was cooled, neutralized with 6N hydrochloric acid and the product filtered off. The solid was washed with ice water (10 ml) and with acetone (15 ml) and dried under vacuum overnight. 4.13 g (91.8%) of 9- (2-hydroxyethoxy-methyl) guanine, m.p. 255-257 ° C.
Eksempel 6 2-Acetamido-9-(2-acetyloxyethoxymethyl)hypoxan-thin (6,19 g) blev opslæmmet i en opløsning af natrium-methylat (3,24 g) i methanol (40 ml). Blandingen blev opvarmet til tilbagesvaling i 1 time og henstillet til afkøling. Der blev tilsat iseddike (3,96 g), og blandingen blev udhældt i vand (40 ml). Efter afkøling til 0 C blev det resulterende bundfald filtreret fra, vasket med koldt vand (15 ml) og med acetone (15 ml) og tørret under vakuum til opnåelse af 4,03 g (89,6%) 9-(2-hydroxy-ethoxymethyl)guanin, smp. 255-257°C.Example 6 2-Acetamido-9- (2-acetyloxyethoxymethyl) hypoxane thin (6.19 g) was slurried in a solution of sodium methylate (3.24 g) in methanol (40 ml). The mixture was heated to reflux for 1 hour and allowed to cool. Glacial acetic acid (3.96 g) was added and the mixture was poured into water (40 ml). After cooling to 0 ° C, the resulting precipitate was filtered off, washed with cold water (15 ml) and with acetone (15 ml) and dried in vacuo to give 4.03 g (89.6%) of 9- (2-hydroxy) (ethoxymethyl) guanine, m.p. 255-257 ° C.
Eksempel 7 2-Acetamido-9-(2-acetyloxyethoxymethyl)hypoxan-thin (6,19 g) blev sat til en opløsning af kaliumhydroxid (3,96 g) i ethanol (40 ml) og opvarmet under tilbagesvaling i 1 time. Blandingen blev henstillet til afkøling, og der blev tilsat iseddikesyre (3,96 g). Blandingen blev udhældt i vand (40 ml) og 50 ml vand blev tilsat. pH blev indstillet til 7,0 med vandig natriumhydroxid og blandingen afkølet med isvand og filtreret. Det faste stof blev vasket med koldt vand (20 ml) og med acetone (20 ml) og tørret under vakuum til opnåelse af 4,0 g (88,9%) 9-(2-hydroxyethoxymethyl)guanin, smp. 225-257°C.Example 7 2-Acetamido-9- (2-acetyloxyethoxymethyl) hypoxane-thin (6.19 g) was added to a solution of potassium hydroxide (3.96 g) in ethanol (40 ml) and heated under reflux for 1 hour. The mixture was allowed to cool and glacial acetic acid (3.96 g) was added. The mixture was poured into water (40 ml) and 50 ml of water was added. The pH was adjusted to 7.0 with aqueous sodium hydroxide and the mixture cooled with ice water and filtered. The solid was washed with cold water (20 ml) and with acetone (20 ml) and dried in vacuo to give 4.0 g (88.9%) of 9- (2-hydroxyethoxymethyl) guanine, m.p. 225-257 ° C.
Claims (2)
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US71810576A | 1976-08-27 | 1976-08-27 | |
US71810576 | 1976-08-27 | ||
US77313577 | 1977-02-28 | ||
US05/773,135 US4146715A (en) | 1975-08-27 | 1977-02-28 | 2-amido-9-(2-acyloxyethoxymethyl)hypoxanthines |
Publications (3)
Publication Number | Publication Date |
---|---|
DK380377A DK380377A (en) | 1978-02-28 |
DK147857B true DK147857B (en) | 1984-12-24 |
DK147857C DK147857C (en) | 1985-06-10 |
Family
ID=27109837
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DK380377A DK147857C (en) | 1976-08-27 | 1977-08-26 | METHOD FOR PREPARING 9- (2-HYDROXYEPHOXYMETHYL) GUANINE OR 9- (2-HYDROXYETHOXYMETHYL) ADENIN |
Country Status (12)
Country | Link |
---|---|
AT (1) | AT357566B (en) |
CA (2) | CA1096863A (en) |
CH (1) | CH634843A5 (en) |
CS (1) | CS196384B2 (en) |
DD (1) | DD131856A6 (en) |
DK (1) | DK147857C (en) |
FI (1) | FI64160C (en) |
GB (1) | GB1567671A (en) |
NL (1) | NL7709458A (en) |
NO (2) | NO147186C (en) |
SE (2) | SE432764B (en) |
YU (1) | YU41079B (en) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4880820A (en) * | 1983-06-24 | 1989-11-14 | Merck & Co., Inc. | Guanine derivatives |
US4918219A (en) * | 1983-10-31 | 1990-04-17 | Warner-Lambert Company | Glycerine derivatives |
IE842642L (en) * | 1983-10-31 | 1985-04-30 | Harvard College | Purine Derivatives |
YU45690B (en) * | 1984-12-22 | 1992-07-20 | Krka Tovarna Zdraviln.Sol.O. | PROCEDURE FOR PREPARING 9- (2-HYDROXYETHOXYMETHYL) -GUANINE |
DE3889248T2 (en) * | 1987-05-04 | 1994-11-17 | Kemijski Inst | Process for the preparation of purine compounds. |
EP0717744B1 (en) * | 1993-09-10 | 1997-05-07 | RECORDATI S.A. CHEMICAL and PHARMACEUTICAL COMPANY | A process for the preparation of 9-(2-hydroxy)-ethoxymethyl-guanine |
DE19536164A1 (en) * | 1995-09-28 | 1997-04-03 | Boehringer Ingelheim Kg | Improved Process for the Production of 9 - [(2-Hydroxyethoxy) methyl] guanine (Acyclovir) |
IT1276126B1 (en) * | 1995-11-14 | 1997-10-27 | Archimica Spa | PROCEDURE FOR THE PREPARATION OF 9 - ((2-HYDROXYETHOXY) METHYL) GUANINE |
WO1997024357A1 (en) * | 1995-12-28 | 1997-07-10 | Mallinckrodt Chemical, Inc. | Process for synthesis and purification of a compound useful in the preparation of acyclovir |
-
1977
- 1977-08-24 YU YU2022/77A patent/YU41079B/en unknown
- 1977-08-26 GB GB35914/77A patent/GB1567671A/en not_active Expired
- 1977-08-26 CH CH1046677A patent/CH634843A5/en not_active IP Right Cessation
- 1977-08-26 DK DK380377A patent/DK147857C/en not_active IP Right Cessation
- 1977-08-26 SE SE7709606A patent/SE432764B/en not_active IP Right Cessation
- 1977-08-26 DD DD7700200760A patent/DD131856A6/en not_active IP Right Cessation
- 1977-08-26 NO NO772959A patent/NO147186C/en unknown
- 1977-08-26 NL NL7709458A patent/NL7709458A/en active Search and Examination
- 1977-08-26 FI FI772548A patent/FI64160C/en not_active IP Right Cessation
- 1977-08-26 CS CS775615A patent/CS196384B2/en unknown
- 1977-08-26 AT AT620177A patent/AT357566B/en not_active IP Right Cessation
- 1977-08-26 CA CA285,592A patent/CA1096863A/en not_active Expired
-
1980
- 1980-06-20 CA CA354,538A patent/CA1096864A/en not_active Expired
-
1982
- 1982-07-20 NO NO822502A patent/NO150119C/en unknown
-
1983
- 1983-08-23 SE SE8304549A patent/SE447113B/en not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
CA1096864A (en) | 1981-03-03 |
SE447113B (en) | 1986-10-27 |
SE7709606L (en) | 1978-02-28 |
DK380377A (en) | 1978-02-28 |
FI772548A (en) | 1978-02-28 |
NO147186C (en) | 1983-02-16 |
NO150119C (en) | 1984-08-22 |
FI64160B (en) | 1983-06-30 |
CS196384B2 (en) | 1980-03-31 |
ATA620177A (en) | 1979-12-15 |
YU202277A (en) | 1983-02-28 |
CA1096863A (en) | 1981-03-03 |
NL7709458A (en) | 1978-03-01 |
SE8304549L (en) | 1983-08-23 |
YU41079B (en) | 1986-12-31 |
NO150119B (en) | 1984-05-14 |
CH634843A5 (en) | 1983-02-28 |
SE432764B (en) | 1984-04-16 |
FI64160C (en) | 1983-10-10 |
DK147857C (en) | 1985-06-10 |
NO772959L (en) | 1978-02-28 |
DD131856A6 (en) | 1978-07-26 |
SE8304549D0 (en) | 1983-08-23 |
NO822502L (en) | 1978-02-28 |
NO147186B (en) | 1982-11-08 |
GB1567671A (en) | 1980-05-21 |
AT357566B (en) | 1980-07-25 |
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