NO132353B - - Google Patents
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- NO132353B NO132353B NO2081/72A NO208172A NO132353B NO 132353 B NO132353 B NO 132353B NO 2081/72 A NO2081/72 A NO 2081/72A NO 208172 A NO208172 A NO 208172A NO 132353 B NO132353 B NO 132353B
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- salt
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- tris
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- hydroxymethyl
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- 239000013078 crystal Substances 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 18
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims abstract description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 33
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 22
- 229960002986 dinoprostone Drugs 0.000 claims description 21
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 claims description 21
- 150000001875 compounds Chemical class 0.000 claims description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 239000007788 liquid Substances 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 claims description 6
- 150000002894 organic compounds Chemical class 0.000 claims description 5
- AVQQQNCBBIEMEU-UHFFFAOYSA-N 1,1,3,3-tetramethylurea Chemical compound CN(C)C(=O)N(C)C AVQQQNCBBIEMEU-UHFFFAOYSA-N 0.000 claims description 3
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 206010000210 abortion Diseases 0.000 description 2
- 231100000176 abortion Toxicity 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000003637 basic solution Substances 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 229960004132 diethyl ether Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 239000000644 isotonic solution Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000002175 menstrual effect Effects 0.000 description 2
- 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- 229910004373 HOAc Inorganic materials 0.000 description 1
- SUAKHGWARZSWIH-UHFFFAOYSA-N N,N‐diethylformamide Chemical compound CCN(CC)C=O SUAKHGWARZSWIH-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 238000011085 pressure filtration Methods 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
Abstract
Fremgangsmåte ved fremstilling av frittstrømmende krystaller av tris-(hydroxymethyl)-aminomethan-saltet av PGEProcess for the preparation of free-flowing crystals of the tris- (hydroxymethyl) -aminomethane salt of PGE
Description
Foreliggende oppfinnelse angår en fremgangsmåte ved fremstilling av frittstrommende krystaller av tris-(hydroxymethyl)-aminomethansaltet av prostaglandin E2 (PGE2)av formel: The present invention relates to a method for the production of free-flowing crystals of the tris-(hydroxymethyl)-aminomethane salt of prostaglandin E2 (PGE2) of the formula:
Prostaglandin E (PGE2) er kjent for å være nyttig for Prostaglandin E (PGE2) is known to be useful for
et flertall farmakologiske og medisinske formål, f.eks. ved fremkalling av veer og abort hos gravide dyr, innbefattende mennesker, og til menstruasjonsregulering hos både gravide og ikke-gravide dyr, innbefattet mennesker. For disse formål er intravenos injeksjon eller infusjon den vanlige administreringsform, selv om oral administrering også benyttes ved ve-fremkalling og vaginal og intrauterin-administrering også benyttes ved abort og menstruasjonsregulering; a plurality of pharmacological and medicinal purposes, e.g. by inducing labor and abortion in pregnant animals, including humans, and for menstrual regulation in both pregnant and non-pregnant animals, including humans. For these purposes, intravenous injection or infusion is the usual form of administration, although oral administration is also used for labor induction and vaginal and intrauterine administration is also used for abortion and menstrual regulation;
Det er vanskelig å formulere disse carboxylsyrer av formel I i sammensetninger som er egnet for farmakologisk og medisinsk bruk. Eksempelvis er de ikke lett opploselige i vann eller i de isotoniske opplosninger som er nodvendige for intravenos injeksjon eller infusjon. Preliminær behandling av prostaglandinene med et vann-blandbart organisk opplosningsmiddel og/eller en vandig opp-løsning av en base, f.eks. natriumhydroxyd eller natriumcarbonat, It is difficult to formulate these carboxylic acids of formula I in compositions suitable for pharmacological and medicinal use. For example, they are not easily soluble in water or in the isotonic solutions required for intravenous injection or infusion. Preliminary treatment of the prostaglandins with a water-miscible organic solvent and/or an aqueous solution of a base, e.g. sodium hydroxide or sodium carbonate,
er vanligvis nodvendig for en isotonisk vandig opplosning av den passende konsentrasjon kan dannes. Selv om PGE2 er et krystallinsk, fast materiale, er det også voksaktig og opploses sakte i vandige, basiske opplosninger. is usually necessary for an isotonic aqueous solution of the appropriate concentration to be formed. Although PGE2 is a crystalline, solid material, it is also waxy and dissolves slowly in aqueous, basic solutions.
PGE2 er carboxylsyre, og saltdannelse er innbefattet når PGE2 opploses i vandige, basiske opplosninger som et preliminært trinn i de kjente formuleringsprosedyrer. Se britisk patentskrift nr. 1.040.544 hvor farmakologisk og medisinsk bruk av PGE2 i form av farmakologisk akseptable salter er foreslått. Blant de foreslåtte farmakologisk akseptable kationer er slike som avledes fra alkali-og jordalkaliaretalier, ammoniakk, og forskjellige aminer. PGE2 is a carboxylic acid, and salt formation is involved when PGE2 is dissolved in aqueous basic solutions as a preliminary step in the known formulation procedures. See British patent document no. 1,040,544 where the pharmacological and medical use of PGE2 in the form of pharmacologically acceptable salts is proposed. Among the proposed pharmacologically acceptable cations are those derived from alkali and alkaline earth metals, ammonia, and various amines.
Det ville være en vesentlig fordel å ha tilgjengelig PGE2 i form av et stabilt, krystallinsk, hoytsmeltende salt som hurtig It would be a significant advantage to have available PGE2 in the form of a stable, crystalline, high-melting salt that quickly
opploses i vann eller i de isotoniske opplosninger som er nodvendige for intravenos administrering. Disse salter ville også være nyttige i formuleringer beregnet på andre administreringsformer, f.eks. oral, buccal, intravaginal og intra-uterin administrering. Det ville også være en vesentlig fordel å kunne være istand til å omkrystallisere disse samme salter for å fremstille preparater av onsket renhetsgrad. dissolve in water or in the isotonic solutions necessary for intravenous administration. These salts would also be useful in formulations intended for other forms of administration, e.g. oral, buccal, intravaginal and intra-uterine administration. It would also be a significant advantage to be able to recrystallize these same salts to produce preparations of the desired degree of purity.
Det er ganske overraskende og uventet at frittstrommende krystaller av tris-(hydroxymethyl)-aminomethansaltet av PGE2 frem-stilles ved en fremgangsmåte som er kjennetegnet ved at 1) en konsentrert opplosning av ekvivalente mengder PGE2 og tris-(hydroxymethyl)-aminomethan i en vannblandbar, polar, normalt flytende organisk forbindelse valgt blant dimethylsulfoxyd, dimethylformamid, methanol, tetramethylurea og teti^drohdofen-l,lddcksyd med en temperatur under 40°C, blandes med tilstrekkelig av en mindre polar, normalt flytende organisk forbindelse valgt blant acetonitril, methylpropylketon, diethylether, kloroform, diklormethan og butyronitril, og som er blandbar med nevnte polare forbindelse for å bevirke at minst en del av nevnte salt bunnfelles ved en temperatur mellom -20 Og 40°C, og 2) den resulterende blanding holdes i nevnte temperaturområde til der er dannet krystaller, hvorefter 3) nevnte krystaller isoleres. It is rather surprising and unexpected that free-flowing crystals of the tris-(hydroxymethyl)-aminomethane salt of PGE2 are produced by a method which is characterized by 1) a concentrated solution of equivalent amounts of PGE2 and tris-(hydroxymethyl)-aminomethane in a water-miscible , polar, normally liquid organic compound selected from dimethylsulfoxyd, dimethylformamide, methanol, tetramethylurea and teti^drohdofen-l,lddcksyd with a temperature below 40°C, is mixed with sufficient of a less polar, normally liquid organic compound selected from acetonitrile, methylpropyl ketone, diethyl ether, chloroform, dichloromethane and butyronitrile, and which is miscible with said polar compound to cause at least part of said salt to precipitate at a temperature between -20 and 40°C, and 2) the resulting mixture is kept in said temperature range until crystals are formed, after which 3) said crystals are isolated.
I den foretrukne fremgangsmåte menes med uttrykket "normalt flytende'<»> en forbindelse som er flytende ved 40°C og ved et atmosfærisk trykk (760 mm kvikksolv). Nitriler er foretrukne mind-repolare forbindelser ved fremgangsmåten, spesielt acetonitril. In the preferred method, the term "normally liquid" means a compound which is liquid at 40°C and at atmospheric pressure (760 mm of mercury). Nitriles are preferred mind-repolar compounds in the method, especially acetonitrile.
En spesielt foretrukken kombinasjon av polare og mindre polare forbindelser er dimethylsulfoxyd og acetonitril. A particularly preferred combination of polar and less polar compounds is dimethyl sulfoxide and acetonitrile.
I denne fremgangsmåte foregår saltdannelsen når PGE2 og tris-(hydroxymethyl)-aminomethanet blandes sammen og danner en opplosning i den vannblandbare, polare, normalt flytende organiske forbindelse. Saltet bevirkes derefter til å utfelle i form av de onskede f rittstrommende krystaller ved tilsetning av tilstrekkelig av den mindre polare forbindelse til nevnte opplosning og ved å opp-rettholde den resulterende blanding i det ovenfor angitte temperaturområde fra -20 til 40°C. Det er onskelig at minimumsmengden av den polare forbindelse benyttes for å danne og opplose PGE2 og tris-(hydromethyl)-aminomethan og det resulterende salt. Siden mengden av polar forbindelse er relativt liten i enkelte tilfeller, er det fordelaktig i visse tilfelle også å ha tilstede en mindre mengde av den tilsiktede mindre polare forbindelse ved det oyeblikk PGE2 og tris-(hydromethyl)-aminomethan forst blandes. Derefter tilsettes tilstrekkelig ikke polar forbindelse for å bevirke den onskede utfelling. In this method, salt formation takes place when PGE2 and tris-(hydroxymethyl)-aminomethane are mixed together and form a solution in the water-miscible, polar, normally liquid organic compound. The salt is then caused to precipitate in the form of the desired free-flowing crystals by adding sufficient of the less polar compound to said solution and by maintaining the resulting mixture in the above temperature range of -20 to 40°C. It is desirable that the minimum amount of the polar compound be used to form and dissolve PGE 2 and tris-(hydromethyl)aminomethane and the resulting salt. Since the amount of polar compound is relatively small in some cases, it is advantageous in certain cases to also have a smaller amount of the intended less polar compound present when PGE2 and tris-(hydromethyl)-aminomethane are first mixed. Sufficient non-polar compound is then added to effect the desired precipitation.
Ved denne fremgangsmåte er det en fordel å utfore fremgangsmåten for forste gang i et glasskår, hvor de indre vegger skra-pes kraftig med en glasstav mens trinn 2 utfores. Dette fremskynder krystalldannelsen. Ved senere utforelser kan noen få krystaller fra denne forste krystallisasjon tilsettes som krystallisasjonskorn ved det samme punkt i prosessen for å fremskynde krystalldannelsen, og det er da heller ikke nodvendig å benytte glasskår. With this method, it is an advantage to carry out the method for the first time in a piece of glass, where the inner walls are scraped vigorously with a glass rod while step 2 is carried out. This accelerates crystal formation. In later embodiments, a few crystals from this first crystallization can be added as crystallization grains at the same point in the process to speed up crystal formation, and it is then not necessary to use shards of glass either.
Mengden av den mindre polare forbindelse som er nodvendig for å fremkalle bunnfellingen av det frittstrommende krystallinske salt vil variere noe som folge av kombinasjonen av den bestemte polare forbindelse og den mindre polare forbindelse som benyttes. Til-synekomst av grumsethet under tilsetningen av den mindre polare forbindelse er en. nyttig indikasjon på at minimumsmengden av den mindre polare forbindelse er tilsatt. Ytterligere mindre polar forbindelse ut over denne mengde er vanligvis nodvendig, og den eksakte totale mengde som må benyttes kan derefter bestemmes. Bruk av en over-skuddsmengde av mindre polar forbindelse vil resultere i et oljeak-tig salt heller enn et krystallinsk salt. The amount of the less polar compound required to cause the precipitation of the free-flowing crystalline salt will vary somewhat as a result of the combination of the particular polar compound and the less polar compound used. Appearance of turbidity during the addition of the less polar compound is a. useful indication that the minimum amount of the less polar compound has been added. Additional less polar compound beyond this amount is usually required and the exact total amount to be used can then be determined. Using an excess amount of less polar compound will result in an oily salt rather than a crystalline salt.
Selv om vanligvis tilfredsstillende resultater erholdes ved å utfore denne fremgangsmåte i et temperaturområde fra 20 til 30°C, er det ofte en fordel å kjole under annet trinn av fremgangsmåten til under 20°C, helst ned til C°C, eller til og med så lavt som -20°C, og derefter tillate den avkjolte blanding å oppvarmes sakte til en temperaturområde fra 20°C til 30°C. Ved å utfore dette minst én, og i enkelte tilfelle to eller flere ganger, vil kry-stallisasjonen påskyndes. Når krystalldannelsen er fullfort, opp-samles saltet som vaskes og torkes som ovenfor beskrevet for den forste fremgangsmåte. Although generally satisfactory results are obtained by carrying out this process in a temperature range of 20 to 30°C, it is often advantageous to cool during the second step of the process to below 20°C, preferably down to 100°C, or even as low as -20°C, and then allowing the cooled mixture to warm slowly to a temperature range of 20°C to 30°C. By doing this at least once, and in some cases two or more times, the crystallization will be accelerated. When the crystal formation is complete, the salt is collected which is washed and dried as described above for the first method.
Når det er onskelig å omkrystallisere tris-(hydroxymethyl)-aminomeihansaltet av PGE2, er en foretrukken utforelsesform å opplose saltet i en minimumsmengde av en av dé ovenfor angitte polare væsker, med fordel dimethylsulfoxyd, og derefter tilsette tilstrekkelig av en av de ovenfor angitte mindre polare væsker, med fordel acetonitril, for å bevirke utfelling av det frittstrommende krystallinske salt i et temperaturområde fra -20 til 40°C. Krystallene oppsamies, vaskes og torkes som ovenfor angitt. When it is desired to recrystallize the tris-(hydroxymethyl)-amino meihan salt of PGE2, a preferred embodiment is to dissolve the salt in a minimum amount of one of the above stated polar liquids, preferably dimethylsulfoxide, and then add sufficient of one of the above stated smaller polar liquids, preferably acetonitrile, to effect precipitation of the free-flowing crystalline salt in a temperature range from -20 to 40°C. The crystals are collected, washed and dried as indicated above.
Det er fordelaktig, selv om det ikke er nodvendig, å utfore alle de ovenfor angitte fremgangsmåtetrinn under minimal kontakt med oxygen ved å erstatte luften med en inert gass, f.eks. nitrogen eller argon. It is advantageous, although not necessary, to carry out all the above process steps under minimal contact with oxygen by replacing the air with an inert gas, e.g. nitrogen or argon.
Når det er onskelig å gjenvinne PGE2 fra dets tris-(hydr-oxymethyl)-aminomethansalt, utfores dette ved å opplose saltet i vann (10 ml pr. gram salt), justere opplbsningens pH til et område fra 6 til 7, og ekstrahere opplosningen gjentatte ganger med ethylacetat. Ethylacetatekstraktene blandes, vaskes henholdsvis med vann og mettet vandig natriumkloridopplosning, torkes og fordampes, hvorved erholdes PGE2. When it is desired to recover PGE2 from its tris-(hydroxymethyl)aminomethane salt, this is accomplished by dissolving the salt in water (10 ml per gram of salt), adjusting the pH of the solution to a range of 6 to 7, and extracting the solution repeatedly with ethyl acetate. The ethyl acetate extracts are mixed, washed respectively with water and saturated aqueous sodium chloride solution, dried and evaporated, whereby PGE2 is obtained.
Oppfinnelsen skal nu nærmere illustreres ved folgende ek-sempler: Eksempel 1 Frittstrdmmende krystaller av tris-(hydroxymethyl)- aminomethansaltet av PGE2The invention will now be further illustrated by the following examples: Example 1 Free-flowing crystals of tris-(hydroxymethyl)- the aminomethane salt of PGE2
En opplbsning av 36,5 mg tris-(hydroxymethyl)-aminomethan A solution of 36.5 mg of tris-(hydroxymethyl)-aminomethane
i 0,4 ml dimethylsulfoxyd ble tilsatt til en oppldsning av 116 mg PGE2 i 1 ml acetonitril ved 25°C. 3 ml acetonitril ble tilsatt gradvis til denne blanding under omroring. Ved dette punkt var blandingen svakt grumset. Derefter ble ytterligere 15 ml acetonitril tilsatt under omroring, og blandingen kjolet ti 1 0°C og derefter tillatt å oppvarmes sakte til 25°C. De flokkede, frittstrommende krystaller som ble dannet, ble separert fra blandingen ved trykkfiltrering (nitrogen), vasket på filteret med acetonitril og derefter tbrket ved å fore nitrogen gjennom filterkaken ved 25°C i 15 minutter. Tdrkingen ble fullfort under redusert trykk ved 30°C i 24 timer, hvorved man fikk 80 mg tris-(hydroxymethyl)-aminomethansaltet av PGE2 i form av frittstrommende krystaller. Rf 0,3 - TLC - EtOAc + 3 % HOAc. in 0.4 ml of dimethylsulfoxide was added to a solution of 116 mg of PGE2 in 1 ml of acetonitrile at 25°C. 3 mL of acetonitrile was added gradually to this mixture while stirring. At this point the mixture was slightly cloudy. Then a further 15 ml of acetonitrile was added with stirring and the mixture cooled to 10°C and then allowed to warm slowly to 25°C. The flocked, free-flowing crystals that formed were separated from the mixture by pressure filtration (nitrogen), washed on the filter with acetonitrile and then dried by passing nitrogen through the filter cake at 25°C for 15 minutes. The drying was completed under reduced pressure at 30°C for 24 hours, whereby 80 mg of the tris-(hydroxymethyl)-aminomethane salt of PGE2 was obtained in the form of free-flowing crystals. Rf 0.3 - TLC - EtOAc + 3% HOAc.
Ved å folge den i eksempel 3 angitte fremgangsmåte, men å benytte separat ditnethylformamid, methanol og tetramethylurea i stedet for dimethylsulfoxyd,' ble det samme frittstrommende krystallinske salt erholdt. By following the procedure indicated in example 3, but using diethylformamide, methanol and tetramethylurea separately instead of dimethylsulfoxide, the same free-flowing crystalline salt was obtained.
Ved også å folge den i eksempel 3 angitte fremgangsmåte, By also following the procedure specified in example 3,
men å benytte separat methylpropylketon, diethylether, kloroform, diklormethan og butyronitril i stedet for acetonitril, ble det samme frittstrommende krystallinske salt erholdt. but using separately methylpropylketone, diethylether, chloroform, dichloromethane and butyronitrile instead of acetonitrile, the same free-flowing crystalline salt was obtained.
Eksempel 2 Frittstrbmmende krystaller av tris-(hydroxymethyl)-aminomethansaltet av PGE2Example 2 Free-flowing crystals of the tris-(hydroxymethyl)-aminomethane salt of PGE2
48,4 mg tris-(hydroxymethyl)-aminomethan ble tilsatt under omroring til en opplbsning av 140,8 mg PGE2 i 0,8 ml dimethylformamid. 150 ml acetonitril ble tilsatt gradvis til den resulterende opplbsning under omroring ved 25°C. Blandingen ble derefter opprett-holdt ved 25°C i 24 timer under nitrogenatmosfære.. De dannede krystaller ble separert, vasket og tbrket som beskrevet i eksempel 3, hvorved man fikk 50 mg av tris-(hydroxymethyl)-aminomethansaltet av PGE2 i form av frittstrbmmende krystaller. Smeltepunkt: 94,2-95°C. 48.4 mg of tris-(hydroxymethyl)-aminomethane was added with stirring to a solution of 140.8 mg of PGE2 in 0.8 ml of dimethylformamide. 150 ml of acetonitrile was added gradually to the resulting solution with stirring at 25°C. The mixture was then maintained at 25°C for 24 hours under a nitrogen atmosphere. The formed crystals were separated, washed and dried as described in example 3, whereby 50 mg of the tris-(hydroxymethyl)-aminomethane salt of PGE2 was obtained in the form of free-flowing crystals. Melting point: 94.2-95°C.
Ved å folge den i eksempel 2 angitte fremgangsmåte, men å benytte tetrahydrothiofen-1,1-dioksyd i stedet for dimethylformamid, By following the procedure indicated in example 2, but using tetrahydrothiophene-1,1-dioxide instead of dimethylformamide,
ble det samme frittstrbmmende krystallinske salt erholdt. the same free-flowing crystalline salt was obtained.
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Application Number | Priority Date | Filing Date | Title |
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NO208172A NO132353C (en) | 1970-06-01 | 1972-06-13 |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US4245870A | 1970-06-01 | 1970-06-01 | |
NO2017/71A NO132194C (en) | 1970-06-01 | 1971-05-28 | |
NO208172A NO132353C (en) | 1970-06-01 | 1972-06-13 |
Publications (2)
Publication Number | Publication Date |
---|---|
NO132353B true NO132353B (en) | 1975-07-21 |
NO132353C NO132353C (en) | 1975-10-29 |
Family
ID=27352584
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO208172A NO132353C (en) | 1970-06-01 | 1972-06-13 |
Country Status (1)
Country | Link |
---|---|
NO (1) | NO132353C (en) |
-
1972
- 1972-06-13 NO NO208172A patent/NO132353C/no unknown
Also Published As
Publication number | Publication date |
---|---|
NO132353C (en) | 1975-10-29 |
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